BioMed Research International: Nephrology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. CYLD Deubiquitinase Negatively Regulates High Glucose-Induced NF-κB Inflammatory Signaling in Mesangial Cells Sun, 12 Nov 2017 07:43:33 +0000 Nuclear factor-kappa B (NF-κB) is the key part of multiple signal transduction of inflammation in the pathogenesis of diabetic nephropathy (DN). The ubiquitin-proteasome system is extensively involved in the regulation of the NF-κB pathway. Cylindromatosis (CYLD) has deubiquitinase activity and acts as a negative regulator of the NF-κB signaling pathway. However, the association between CYLD and NF-κB inflammatory signaling in DN is unclear. In the present study, mouse glomerular mesangial cells (GMCs) and rat GMCs were stimulated by elevated concentrations of glucose (10, 20, and 30 mmol/L high glucose) or mannitol as the osmotic pressure control. CYLD was overexpressed or suppressed by transfection with a CYLD expressing vector or CYLD-specific siRNA, respectively. Our data showed that high glucose significantly inhibited the protein and mRNA expression of CYLD in a dose- and time-dependent manner (both ). siRNA-mediated knockdown CYLD facilitated the high glucose-induced activation of NF-κB signaling and triggered the release of MCP-1, IL-6, and IL-8 (all ). However, these high glucose-mediated effects were blunted by overexpression of CYLD (). The present results support the involvement of CYLD in the regulation of NF-κB inflammatory signaling induced by elevated glucose, implicating CYLD as a potential therapeutic target of DN. Yanhui Li, Wei Huang, Youhua Xu, Luping Zhou, Yaling Liang, Chenlin Gao, Yang Long, and Yong Xu Copyright © 2017 Yanhui Li et al. All rights reserved. Circulating Interferon-λ3, Responsiveness to HBV Vaccination, and HBV/HCV Infections in Haemodialysis Patients Tue, 31 Oct 2017 00:00:00 +0000 The IFN-λ3 gene (IFNL3) plays a role in HCV clearance. We investigated circulating IFN-λ3 and IFNL3 SNPs in haemodialysis patients who differed in their response to HBV vaccination and their HBV/HCV infection status. In 201 patients, plasma IFN-λ3 was determined using ELISA. IFNL3 SNPs (rs12979860, rs8099917) were genotyped using HRM analysis. Differences in IFN-λ3 levels were shown between responders and nonresponders to HBV vaccination and between HBsAg-positive patients and those who developed anti-HBs after infection and became HBsAg negative. HBV vaccine responders without HCV resolution revealed lower IFN-λ3 than noninfected responders. HBsAg/HCV RNA-positive subjects showed lower IFN-λ3 than patients positive only for HCV RNA or subjects who resolved both infections. Circulating IFN-λ3 correlated positively with anti-HBs and negatively with positive HCV RNA testing in the adjusted regression analyses. HBV vaccine nonresponders, HBsAg-positive patients, and subjects with replicating HCV composed a group with unfavourable outcomes. Responders to HBV vaccination, subjects who became HBsAg negative, and those who cleared HCV were analysed as having favourable outcomes. The latter showed higher IFN-λ3 but did not differ in distribution of IFNL3 SNPs compared with subjects with unfavourable outcomes. Higher IFN-λ3 concentrations are associated with response to HBV vaccination, self-limited HBV infection, and HCV resolution. Alicja E. Grzegorzewska, Monika K. Świderska, Adrianna Mostowska, and Paweł P. Jagodziński Copyright © 2017 Alicja E. Grzegorzewska et al. All rights reserved. miR-217 Is a Useful Diagnostic Biomarker and Regulates Human Podocyte Cells Apoptosis via Targeting TNFSF11 in Membranous Nephropathy Mon, 30 Oct 2017 00:00:00 +0000 Background. MicroRNAs have recently been verified as useful diagnostic biomarkers in various diseases. In this study, we investigated whether miR-217 is a useful diagnostic biomarker and the possible pathological mechanism of miR-217 in this disease. Methods. Patients with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and diabetic nephropathy (DN) and control patients were enrolled in this study. The miR-217 inhibitor and mimics were transfected into human podocyte cells to investigate the pathological mechanism of miR-217 in this disease. Relevant indicators were detected and tested. Results. Compared with control patients, miR-217 was significantly downregulated and TNFSF11 was significantly upregulated in MN. Then, miR-217 had obvious separation between patients with MN and control patients, with an AUC of 0.941, a cutoff value of <750.0 copies/ul, and sensitivity and specificity of 88.9% and 75.9%. In addition, the TNFSF11 was confirmed to be the target gene of miR-217. Finally, in in vitro experiments, the upregulation of miR-217 could decrease the expression of TNFSF11 and not induce human podocyte cells apoptosis; however, the downregulation of miR-217 could bring about an opposite change. Conclusions. miR-217 is a useful diagnostic biomarker and is involved in human podocyte cells apoptosis via targeting TNFSF11 in membranous nephropathy. Jing Li, Bin Liu, Hen Xue, Qiao Qiao Zhou, and Ling Peng Copyright © 2017 Jing Li et al. All rights reserved. Protective Effects of Pyridoxamine Supplementation in the Early Stages of Diet-Induced Kidney Dysfunction Sun, 29 Oct 2017 08:26:33 +0000 Pyridoxamine, a structural analog of vitamin B6 that exerts antiglycative effects, has been proposed as supplementary approach in patients with initial diabetic nephropathy. However, the molecular mechanism(s) underlying its protective role has been so far slightly examined. C57Bl/6J mice were fed with a standard diet (SD) or a diet enriched in fat and fructose (HD) for 12 weeks. After 3 weeks, two subgroups of SD and HD mice started pyridoxamine supplementation (150 mg/kg/day) in the drinking water. HD fed mice showed increased body weight and impaired glucose tolerance, whereas pyridoxamine administration significantly improved insulin sensitivity, but not body weight, and reduced diet-induced increase in serum creatinine and urine albumin. Kidney morphology of HD fed mice showed strong vacuolar degeneration and loss of tubule brush border, associated with a drastic increase in both advanced glycation end products (AGEs) and AGEs receptor (RAGE). These effects were significantly counteracted by pyridoxamine, with consequent reduction of the diet-induced overactivation of NF-kB and Rho/ROCK pathways. Overall, the present study demonstrates for the first time that the administration of the antiglycative compound pyridoxamine can reduce the early stages of diet-dependent kidney injury and dysfunction by interfering at many levels with the profibrotic signaling and inflammatory cascades. F. Chiazza, A. S. Cento, D. Collotta, D. Nigro, G. Rosa, F. Baratta, V. Bitonto, J. C. Cutrin, M. Aragno, R. Mastrocola, and M. Collino Copyright © 2017 F. Chiazza et al. All rights reserved. Gender Differences in the Progression of Experimental Chronic Kidney Disease Induced by Chronic Nitric Oxide Inhibition Wed, 18 Oct 2017 00:00:00 +0000 Chronic kidney disease (CKD) is considered a public health problem, assuming epidemic proportions worldwide. In this context, the preponderance of CKD prevalence in male over age-matched female patients is of note. In the present study, we investigated the impact of the gender on the development of experimental CKD induced by chronic nitric oxide (NO) inhibition in Wistar male and female rats through the administration of L-NAME. CKD model induced by L-NAME is characterized by systemic vasoconstriction, resulting in severe hypertension, albuminuria, renal ischemia, glomerulosclerosis, interstitial expansion, and macrophage infiltration. After 30 days of CKD induction, male NAME rats exhibited remarkable albuminuria, augmented cortical histological damage, interstitial inflammation, and fibrosis. Age-matched female NAME rats showed significantly lower albuminuria, diminished glomerular ischemia, and glomerulosclerosis, as well as a significant reduction in the expression of α-smooth muscle actin renal interstitial Ang II+ cells. Thus, the present study demonstrated that female rats submitted to the NAME model developed less severe CKD than males. Female renoprotection could be promoted by both the estrogen anti-inflammatory activity and/or by the lack of testosterone, related to renin-angiotensin-aldosterone system hyperactivation and fibrogenesis. However, the influence of sex hormones on the progression of CKD needs to be further investigated. Camilla Fanelli, Humberto Dellê, Rita Cassia Cavaglieri, Wagner Vasques Dominguez, and Irene L. Noronha Copyright © 2017 Camilla Fanelli et al. All rights reserved. Effects of Nitric Oxide on Renal Proximal Tubular Na+ Transport Tue, 17 Oct 2017 00:00:00 +0000 Nitric oxide (NO) has a wide variety of physiological functions in the kidney. Besides the regulatory effects in intrarenal haemodynamics and glomerular microcirculation, in vivo studies reported the diuretic and natriuretic effects of NO. However, opposite results showing the stimulatory effect of NO on Na+ reabsorption in the proximal tubule led to an intense debate on its physiological roles. Animal studies have showed the biphasic effect of angiotensin II (Ang II) and the overall inhibitory effect of NO on the activity of proximal tubular Na+ transporters, the apical Na+/H+ exchanger isoform 3, basolateral Na+/K+ ATPase, and the Na+/ cotransporter. However, whether these effects could be reproduced in humans remained unclear. Notably, our recent functional analysis of isolated proximal tubules demonstrated that Ang II dose-dependently stimulated human proximal tubular Na+ transport through the NO/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway, confirming the human-specific regulation of proximal tubular transport via NO and Ang II. Of particular importance for this newly identified pathway is its possibility of being a human-specific therapeutic target for hypertension. In this review, we focus on NO-mediated regulation of proximal tubular Na+ transport, with emphasis on the interaction with individual Na+ transporters and the crosstalk with Ang II signalling. Nobuhiko Satoh, Motonobu Nakamura, Atsushi Suzuki, Hiroyuki Tsukada, Shoko Horita, Masashi Suzuki, Kyoji Moriya, and George Seki Copyright © 2017 Nobuhiko Satoh et al. All rights reserved. Deterioration of Cerebral Oxygenation by Aortic Arch Calcification Progression in Patients Undergoing Hemodialysis: A Cross-Sectional Study Tue, 03 Oct 2017 06:36:35 +0000 Background. Near-infrared spectroscopy revealed that the regional saturation of oxygen (rSO2) in cerebral tissue is lower in hemodialysis (HD) patients than in healthy subjects. However, no study has examined the changes in cerebral oxygenation by aortic arch calcification (AAC) progression in HD patients. Methods. A total of 104 HD patients were divided into four groups by AAC grade determined using chest radiography: 23 patients at grade 0, 24 at grade 1, 30 at grade 2, and 27 at grade 3. Differences in clinical parameters, including cerebral rSO2, among AAC grades were investigated and atherosclerotic parameters affecting cerebral rSO2 values were identified. Results. Cerebral rSO2 significantly decreased as AAC progressed (AAC grade 3 versus grade 0, versus grade 1, ). Multivariate logistic regression analysis was performed using parameters with values < 0.20 in univariate analysis between cerebral rSO2 values less than the mean and atherosclerotic parameters. AAC grades 2 and 3, serum phosphate level, and history of smoking were factors associated with the cerebral rSO2 decrease. Conclusions. Cerebral rSO2 significantly decreased as AAC progressed and was independently associated with higher AAC grade, serum phosphate level, and history of smoking. Kiyonori Ito, Susumu Ookawara, Tomohisa Okochi, Yuichiro Ueda, Masaya Kofuji, Hideyuki Hayasaka, Takayuki Uchida, Haruhisa Miyazawa, Katsunori Yanai, Hiroki Ishii, Taisuke Kitano, Mitsutoshi Shindo, Keiji Hirai, Yoshio Kaku, Taro Hoshino, Osamu Tanaka, Kaoru Tabei, and Yoshiyuki Morishita Copyright © 2017 Kiyonori Ito et al. All rights reserved. Molecular Mechanisms and Treatment Strategies in Diabetic Nephropathy: New Avenues for Calcium Dobesilate—Free Radical Scavenger and Growth Factor Inhibition Tue, 26 Sep 2017 07:32:25 +0000 Diabetic nephropathy is one of the most important microvascular complications of diabetes mellitus and is responsible for 40–50% of all cases of end stage renal disease. The therapeutic strategies in diabetic nephropathy need to be targeted towards the pathophysiology of the disease. The earlier these therapeutic strategies can bring about positive effects on vascular changes and prevent the vasculature in patients with diabetes from deteriorating, the better the renal function can be preserved. Studies evaluating anti-inflammatory and antioxidative strategies in diabetic nephropathy demonstrate the need and value of these novel treatment avenues. CaD is an established vasoactive and angioprotective drug that has shown a unique, multitarget mode of action in several experimental studies and in different animal models of diabetic microvascular complications. On the molecular level, CaD reduces oxidative stress and inhibits growth factors such as fibroblast growth factor and vascular endothelial growth factors. Recent findings have demonstrated a strong rationale for its use in reducing urine albumin excretion rate and markers of inflammation as well as improving endothelial function. Its beneficial effects make it an attractive therapeutic compound especially in the early stages of the disease. These findings, although promising, need further confirmation in prospective clinical trials with CaD. Hermann Haller, Linong Ji, Klaus Stahl, Anna Bertram, and Jan Menne Copyright © 2017 Hermann Haller et al. All rights reserved. Vitamin B-6, Independent of Homocysteine, Is a Significant Factor in Relation to Inflammatory Responses for Chronic Kidney Disease and Hemodialysis Patients Tue, 26 Sep 2017 00:00:00 +0000 The purpose of this study was to investigate whether plasma pyridoxal 5′-phosphate (PLP) and homocysteine were dependent on or independent of each other in order to be associated with inflammatory markers in patients with chronic kidney disease (CKD) or those receiving hemodialysis treatment. This was a cross-sectional study. Sixty-eight stage 2–5 CKD patients and 68 hemodialysis patients had one time fasting blood drawn for measurements of plasma PLP, pyridoxal (PL), homocysteine, and several inflammatory markers. Early CKD stage (stages 2-3) patients showed significantly lower plasma PLP levels and homocysteine concentrations than patients in an advanced CKD stage (stages 4-5) and those undergoing hemodialysis. Plasma PLP significantly correlated with CRP levels (partial = −0.21, ) and plasma PL significantly correlated with IL-10 levels (partial = −0.24, ), while plasma PLP plus PL significantly correlated with both CRP levels (partial = −0.20, ) and interleukin-1β (partial = 0.22, ) levels after adjusting for plasma homocysteine and other potential confounders. Plasma homocysteine displayed no significant correlations with any inflammatory markers. Vitamin B-6 status, rather than homocysteine, appeared to be a significant factor in relation to inflammatory responses for CKD and hemodialysis patients. Cheng-Hsu Chen, En-Ling Yeh, Chih-Chung Chen, Shih-Chien Huang, and Yi-Chia Huang Copyright © 2017 Cheng-Hsu Chen et al. All rights reserved. Predictability of Urinary CD80 in the Relapse of Primary Nephrotic Syndrome Tue, 29 Aug 2017 00:00:00 +0000 Purpose. The current study is aimed at investigating whether urinary CD80 is reliable to predict the recurrence of pediatric PNS. Materials and Methods. A total of 128 children, 105 males and 23 females, were enrolled in this study. Urinary samples were collected from SSNS and SRNS patients and 25 healthy children as controls. Urinary CD80 was measured by ELISA and adjusted for urinary creatinine excretion. Results. Urinary CD80 in relapse stage of SSNS was significantly higher, and the urinary CD80 of paired relapse and remission stages of each SSNS patient were also significantly different. No significant difference was found between the urinary CD80 in SRNS relapse group, SRNS remission group, and the control group. Similarly, there was no significant difference between frequent SSNS and not frequent SSNS in remission group, as well as the relapse group. There is no correlation between urinary CD80 and 24-hour urinary protein. Conclusion. The increase of urinary CD80 was closely associated with the relapse of SSNS but was not related to the frequency of relapse. The urinary CD80 changes of concentration were reliable to predict the recurrence of SSNS. However, it cannot be used to predicate the frequent recurrence of PNS. Juan Liao, Xiao-Chuan Wu, Qia Cheng, Can-Lin Li, Zhu-Wen Yi, Yan Cao, and Lan-Jun Shuai Copyright © 2017 Juan Liao et al. All rights reserved. Exercise Affects Cardiopulmonary Function in Patients with Chronic Kidney Disease: A Meta-Analysis Mon, 28 Aug 2017 09:15:53 +0000 This study aimed to comprehensively assess the effects of exercise on cardiopulmonary function indices in patients with chronic kidney disease (CKD). A literature review was performed by searching literatures in PubMed and Embase before June 2016. Studies were selected based on predefined inclusion and exclusion criteria, followed by data extraction and a quality assessment of the included studies using the Cochrane Collaboration’s tool. Correlations between exercise and cardiopulmonary function indices [pulse wave velocity, respiratory exchange ratio, and peak oxygen uptake (VO2 peak)] were then evaluated using mean differences and 95% confidence intervals. All meta-analyses were conducted using R 3.12 software. Finally, five eligible studies involving 179 CKD patients were included. After intervention, a heterogeneity test showed that the VO2 peak values of the treatment group were greater than those of the control group, whereas no significant differences were found for the other indices. However, a sensitivity analysis showed inconsistent results both before and after intervention. Thus, we concluded that exercise might play an important role in improving the VO2 peak values in CKD patients. Additional studies are needed to verify this conclusion. Hongchang Yang, Xueping Wu, and Min Wang Copyright © 2017 Hongchang Yang et al. All rights reserved. Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy Thu, 17 Aug 2017 07:55:27 +0000 Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50–100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in primary MN. Several other rare antigens have been described, including antibodies against neutral endopeptidase as a cause of antenatal MN and circulating cationic bovine serum albumin as an antigen with implications in childhood MN. This review focuses on the progress with a special focus on diagnostic accuracy, predictive value, and treatment implications of the established and proposed antigens. Andreas Kronbichler, Jun Oh, Björn Meijers, Gert Mayer, and Jae Il Shin Copyright © 2017 Andreas Kronbichler et al. All rights reserved. Multiple Targets for Novel Therapy of FSGS Associated with Circulating Permeability Factor Thu, 10 Aug 2017 07:17:56 +0000 A plasma component is responsible for altered glomerular permeability in patients with focal segmental glomerulosclerosis. Evidence includes recurrence after renal transplantation, remission after plasmapheresis, proteinuria in infants of affected mothers, transfer of proteinuria to experimental animals, and impaired glomerular permeability after exposure to patient plasma. Therapy may include decreasing synthesis of the injurious agent, removing or blocking its interaction with cells, or blocking signaling or enhancing cell defenses to restore the permeability barrier and prevent progression. Agents that may prevent the synthesis of the permeability factor include cytotoxic agents or aggressive chemotherapy. Extracorporeal therapies include plasmapheresis, immunoadsorption with protein A or anti-immunoglobulin, or lipopheresis. Oral or intravenous galactose also decreases activity. Studies of glomeruli have shown that several strategies prevent the action of FSGS sera. These include blocking receptor-ligand interactions, modulating cell reactions using indomethacin or eicosanoids 20-HETE or 8,9-EET, and enhancing cytoskeleton and protein interactions using calcineurin inhibitors, glucocorticoids, or rituximab. We have identified cardiotrophin-like cytokine factor 1 (CLCF-1) as a candidate for the permeability factor. Therapies specific to CLCF-1 include potential use of cytokine receptor-like factor (CRLF-1) and inhibition of Janus kinase 2. Combined therapy using multiple modalities offers therapy to reverse proteinuria and prevent scarring. Virginia J. Savin, Mukut Sharma, Jianping Zhou, David Genochi, Ram Sharma, Tarak Srivastava, Amna Ilahe, Pooja Budhiraja, Aditi Gupta, and Ellen T. McCarthy Copyright © 2017 Virginia J. Savin et al. All rights reserved. Urinary Neutrophil Gelatinase-Associated Lipocalin Is Complementary to Albuminuria in Diagnosis of Early-Stage Diabetic Kidney Disease in Type 2 Diabetes Sun, 06 Aug 2017 00:00:00 +0000 Background. Two clinical phenotypes of diabetic kidney disease (DKD) have been reported, that is, with or without increased albuminuria. The aim of study was to assess the usefulness of urinary neutrophil gelatinase-associated lipocalin (uNGAL) for the early diagnosis of DKD in the type 2 diabetes mellitus (T2DM). Methods. The study group consisted of 123 patients with T2DM (mean age 62 ± 14 years), with urine albumin/creatinine ratio (uACR) < 300 mg/g and eGFR ≥ 60 ml/min/1.73 m2. The control group included 22 nondiabetic patients with comparable age, sex, and comorbidities. uNGAL, albumin, and creatinine were measured in the first morning urine samples. uACR and uNGAL/creatinine ratios (uNCR) were calculated. Results. In the control group, maximum uNCR was 39.64 µg/g. In T2DM group, 24 patients (20%) had higher results, with the maximum value of 378.6 µg/g. Among patients with uNCR > 39.64 µg/g, 13 (54%) did not have markedly increased albuminuria. Women with T2DM had higher uNCR than men (), without difference in uACR (). uNCR in T2DM patients correlated significantly with HbA1c. Sex, total cholesterol, and uACR were independent predictors of uNCR above 39.64 µg/g. Conclusions. Increased uNGAL and uNCR may indicate early tubular damage, associated with dyslipidemia and worse diabetes control, especially in females with T2DM. Agnieszka Gala-Błądzińska, Paulina Dumnicka, Beata Kuśnierz-Cabala, Katarzyna Rybak, Ryszard Drożdż, Agnieszka Żyłka, and Marek Kuźniewski Copyright © 2017 Agnieszka Gala-Błądzińska et al. All rights reserved. Antiangiogenic Therapy for Diabetic Nephropathy Tue, 01 Aug 2017 10:15:42 +0000 Angiogenesis has been shown to be a potential therapeutic target for early stages of diabetic nephropathy in a number of animal experiments. Vascular endothelial growth factor (VEGF) is the main mediator for abnormal angiogenesis in diabetic glomeruli. Although beneficial effects of anti-VEGF antibodies have previously been demonstrated in diabetic animal experiments, recent basic and clinical evidence has revealed that the blockade of VEGF signaling resulted in proteinuria and renal thrombotic microangiopathy, suggesting the importance of maintaining normal levels of VEGF in the kidneys. Therefore, antiangiogenic therapy for diabetic nephropathy should eliminate excessive glomerular angiogenic response without accelerating endothelial injury. Some endogenous antiangiogenic factors such as endostatin and tumstatin inhibit overactivation of endothelial cells but do not specifically block VEGF signaling. In addition, the novel endothelium-derived antiangiogenic factor vasohibin-1 enhances stress tolerance and survival of the endothelial cells, while inhibiting excess angiogenesis. These factors have been demonstrated to suppress albuminuria and glomerular alterations in a diabetic mouse model. Thus, antiangiogenic therapy with promising candidates will possibly improve renal prognosis in patients with early stages of diabetic nephropathy. Katsuyuki Tanabe, Yohei Maeshima, Yasufumi Sato, and Jun Wada Copyright © 2017 Katsuyuki Tanabe et al. All rights reserved. NPHS2 Mutations: A Closer Look to Latin American Countries Wed, 12 Jul 2017 09:06:44 +0000 Nephrotic syndrome is one of the most common kidney pathologies in childhood, being characterized by proteinuria, edema, and hypoalbuminemia. In clinical practice, it is divided into two categories based on the response to steroid therapy: steroid-sensitive and steroid resistant. Inherited impairments of proteins located in the glomerular filtration barrier have been identified as important causes of nephrotic syndrome, with one of these being podocin, coded by NPHS2 gene. NPHS2 mutations are the most frequent genetic cause of steroid resistant nephrotic syndrome. The aim of this review is to update the list of NPHS2 mutations reported between June 2013 and February 2017, with a closer look to mutations occurring in Latin American countries. Mara Sanches Guaragna, Anna Cristina G. B. Lutaif, Andréa T. Maciel-Guerra, Vera M. S. Belangero, Gil Guerra-Júnior, and Maricilda P. De Mello Copyright © 2017 Mara Sanches Guaragna et al. All rights reserved. Are There Modifiable Risk Factors to Improve AKI? Tue, 04 Jul 2017 00:00:00 +0000 Acute kidney injury (AKI) is a common critical syndrome, with high morbidity and mortality. Patients with AKI typically have an adverse prognosis, from incident chronic kidney disease (CKD), progression to end-stage renal disease (ESRD), subsequent cardiovascular disease, and ultimately death. However, there is currently no effective therapy for AKI. Early detection of risk factors for AKI may offer a good approach to prevention or early intervention. Traditional risk factors include extreme age, many common comorbid diseases, such as preexisting CKD, some specific exposures, such as sepsis, and exposure to some nephrotoxic agents. Recently, several novel risk factors for AKI, such as hyperuricemia, hypoalbuminemia, obesity, anemia, and hyperglycemia, have been identified. The underlying mechanisms between these nontraditional risk factors and AKI and whether their correction can reduce AKI occurrence remain to be clarified. This review describes the current epidemiology of AKI, summarizes its outcome, outlines the traditional risk profile, and finally highlights some recently identified novel risk factors. Sasa Nie, Li Tang, Weiguang Zhang, Zhe Feng, and Xiangmei Chen Copyright © 2017 Sasa Nie et al. All rights reserved. Chronic Kidney Disease-Mineral and Bone Disorder Mon, 19 Jun 2017 00:00:00 +0000 Wen-Chin Lee, Xiong-Zhong Ruan, You-Ying Chau, and Jin-Bor Chen Copyright © 2017 Wen-Chin Lee et al. All rights reserved. Impact of Different Levels of iPTH on All-Cause Mortality in Dialysis Patients with Secondary Hyperparathyroidism after Parathyroidectomy Mon, 05 Jun 2017 00:00:00 +0000 Background. Secondary hyperparathyroidism (SHPT) usually required parathyroidectomy (PTX) when drugs treatment is invalid. Analysis was done on the impact of different intact parathyroid hormone (iPTH) after the PTX on all-cause mortality. Methods. An open, retrospective, multicenter cohort design was conducted. The sample included 525 dialysis patients with SHPT who had undergone PTX. Results. 404 patients conformed to the standard, with 36 (8.91%) deaths during the 11 years of follow-up. One week postoperatively, different levels of serum iPTH were divided into four groups: A: ≤20 pg/mL; B: 21–150 pg/mL; C: 151–600 pg/mL; and D: >600 pg/mL. All-cause mortality in groups with different iPTH levels appeared as follows: A (8.29%), B (3.54%), C (10.91%), and D (29.03%). The all-cause mortality of B was the lowest, with D the highest. We used group A as reference (hazard ratio (HR) = 1) compared with the other groups, and HRs on groups B, C, and D appeared as 0.57, 1.43, and 3.45, respectively. Conclusion. The all-cause mortality was associated with different levels of iPTH after the PTX. We found that iPTH > 600 pg/mL appeared as a factor which increased the risk of all-cause mortality. When iPTH levels were positively and effectively reducing, the risk of all-cause mortality also decreased. The most appropriate level of postoperative iPTH seemed to be 21–150 pg/mL. Qiu Ping Xi, Xi Sheng Xie, Ling Zhang, Rui Zhang, Yue Fei Xiao, Cheng Gang Jin, Yan Bo Li, Lin Wang, Xiao Xuan Zhang, and Shu Tong Du Copyright © 2017 Qiu Ping Xi et al. All rights reserved. Aortic Arch Calcification as a Predictor of Repeated Arteriovenous Fistula Failure within 1-Year in Hemodialysis Patients Wed, 31 May 2017 08:55:05 +0000 Objectives. The aim of the study was to identify the factors associated with repeated arteriovenous fistula (AVF) failure within 1-year, especially the impact of aortic arch calcification (AAC) on patency of AVF. Materials and Methods. We retrospectively assessed chest radiography in hemodialysis patients who had undergone initial AVF. The extent of AAC was categorized into four grades (0–3). The association between AAC grade, other clinical variables, and repeated failure of AVF was then analyzed by binary logistic regression analysis. Results. This study included 284 patients (158 males, mean age years). Patients with higher AAC grade were older, had more frequently diabetes mellitus and cardiovascular disease, had lower diastolic blood pressure, and had higher corrected calcium and lower intact parathyroid hormone levels. In multivariate analysis, the presence of higher AAC grade (odds ratio (95% confidence interval): 2.98 (1.43–6.23); ), lower mean corrected calcium (), and mean serum albumin level () were associated with repeated failure of AVF. Conclusions. The presence of higher AAC grade, lower mean corrected calcium and mean serum albumin level were independently associated with repeated AVF failure within 1 year in hemodialysis patients. Yit-Sheung Yap, Kai-Ting Ting, Wen-Che Chi, Cheng-Hao Lin, Yi-Chun Liu, Po-Lin Kuo, and Wan-Long Chuang Copyright © 2017 Yit-Sheung Yap et al. All rights reserved. Pulsed Vincristine Therapy in Steroid-Resistant Nephrotic Syndrome Mon, 29 May 2017 10:18:58 +0000 Steroid-resistant nephrotic syndrome (SRNS) poses a therapeutic challenge for the paediatric nephrologist. As relentless progression to renal failure occurs with continued proteinuria, such patients will be treated with different cytotoxic medications with variable success rates and side-effects. We present here our findings on administering the anticancer drug vincristine for SRNS patients at a single centre in Sri Lanka. Methods. Between 2002 and 2007, fifty-four children presenting with steroid and cyclophosphamide resistance were treated with vincristine at 1.5 mg/m2 in weekly intravenous pulses for 8 weeks along with a tapering steroid regimen of 6 months. All patients were closely followed up for 5 years. Results. Of the 54 patients 39 were males and 15 were females (age range 3.5–11.6 years, median 6.1 years). At the end of the treatment course, 21 patients achieved complete remission while 7 had partial remission and no response was seen in 26 patients. Sustained remission at 6, 12, 24, and 60 months were 15 (27.78%), 11 (20.37%), 9 (16.67%), and 7 (12.96%), respectively. Most side-effects observed were reversible and no serious side-effects were noted during vincristine therapy. Conclusion. Although its therapeutic mechanisms in nephrotic syndrome are still not elucidated, vincristine appears to be a potent alternative that could be considered for treating SRNS. Shenal Thalgahagoda, Shamali Abeyagunawardena, Heshan Jayaweera, Umeshi Ishanthika Karunadasa, and Asiri Samantha Abeyagunawardena Copyright © 2017 Shenal Thalgahagoda et al. All rights reserved. Insights into Living with Kidney Disease Tue, 16 May 2017 00:00:00 +0000 Veronica Swallow, Houry Puzantian, Leah Krischock, and Ulf Gunnar Bronas Copyright © 2017 Veronica Swallow et al. All rights reserved. Rituximab for Treatment of Membranoproliferative Glomerulonephritis and C3 Glomerulopathies Tue, 09 May 2017 07:25:52 +0000 Membranoproliferative glomerulonephritis (MPGN) is a histological pattern of injury resulting from predominantly subendothelial and mesangial deposition of immunoglobulins or complement factors with subsequent inflammation and proliferation particularly of the glomerular basement membrane. Recent classification of MPGN is based on pathogenesis dividing MPGN into immunoglobulin-associated MPGN and complement-mediated C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Current guidelines suggest treatment with steroids, cytotoxic agents with or without plasmapheresis only for subjects with progressive disease, that is, nephrotic range proteinuria and decline of renal function. Rituximab, a chimeric B-cell depleting anti-CD20 antibody, has emerged in the last decade as a treatment option for patients with primary glomerular diseases such as minimal change disease, focal-segmental glomerulosclerosis, or idiopathic membranous nephropathy. However, data on the use of rituximab in MPGN, C3GN, and DDD are limited to case reports and retrospective case series. Patients with immunoglobulin-associated and idiopathic MPGN who were treated with rituximab showed partial and complete responses in the majorities of cases. However, rituximab was not effective in few cases of C3GN and DDD. Despite promising results in immunoglobulin-associated and idiopathic MPGN, current evidence on this treatment remains weak, and controlled and prospective data are urgently needed. Michael Rudnicki Copyright © 2017 Michael Rudnicki. All rights reserved. Recent Treatment Advances and New Trials in Adult Nephrotic Syndrome Wed, 03 May 2017 00:00:00 +0000 The etiology of nephrotic syndrome is complex and ranges from primary glomerulonephritis to secondary forms. Patients with nephrotic syndrome often need immunosuppressive treatment with its side effects and may progress to end stage renal disease. This review focuses on recent advances in the treatment of primary causes of nephrotic syndrome (idiopathic membranous nephropathy (iMN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS)) since the publication of the KDIGO guidelines in 2012. Current treatment recommendations are mostly based on randomized controlled trials (RCTs) in children, small RCTs, or case series in adults. Recently, only a few new RCTs have been published, such as the Gemritux trial evaluating rituximab treatment versus supportive antiproteinuric and antihypertensive therapy in iMN. Many RCTs are ongoing for iMN, MCD, and FSGS that will provide further information on the effectiveness of different treatment options for the causative disease. In addition to reviewing recent clinical studies, we provide insight into potential new targets for the treatment of nephrotic syndrome from recent basic science publications. Eva Königshausen and Lorenz Sellin Copyright © 2017 Eva Königshausen and Lorenz Sellin. All rights reserved. Relaxin Attenuates Contrast-Induced Human Proximal Tubular Epithelial Cell Apoptosis by Activation of the PI3K/Akt Signaling Pathway In Vitro Sun, 30 Apr 2017 11:50:56 +0000 Background. Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of iatrogenic acute kidney injury (AKI); however, therapeutic strategies for AKI remain limited. This study aims to explore the effect of relaxin (RLX) on contrast-induced HK-2 apoptosis and its underlying mechanisms. Methods. Renal tubular epithelial cells (HK-2) were incubated either with or without ioversol, human H2 relaxin, and LY294002 (the inhibitor of the PI3K/Akt signal pathway). Cell viability was evaluated with a CCK-8 assay. Apoptotic morphologic alterations were observed using the Hoechst 33342 staining method. Apoptosis was detected with Annexin V staining. Western blot analysis was employed to measure the expression of pAkt (S473), Akt, cleaved caspase-3, Bcl-2, Bax, and actin proteins. Results. Ioversol reduced the viability of HK-2 cells. Western blotting results revealed decreased expression of phosphorylated Akt in cells treated with ioversol. The activities of caspase-3 and Bax protein increased, while the expression of Bcl-2 protein decreased. As a result, the Bax/Bcl-2 ratio increased after treatment with ioversol. These effects were reversed when HK-2 cells were cotreated with RLX. However, with preadministration of PI3K/Akt pathway inhibitor LY294002, the effect of RLX was blocked. Conclusion. Our study demonstrates that relaxin attenuates ioversol induced cell apoptosis via activation of the PI3K/Akt signaling pathway, suggesting that RLX might play a protective role in the treatment of CI-AKI. Xiang-Cheng Xie, Yizhi Cao, Xiu Yang, Qun-Hong Xu, Wei Wei, and Ming Wang Copyright © 2017 Xiang-Cheng Xie et al. All rights reserved. Cognitive Impairment in Chronic Kidney Disease: Vascular Milieu and the Potential Therapeutic Role of Exercise Wed, 19 Apr 2017 07:05:16 +0000 Chronic kidney disease (CKD) is considered a model of accelerated aging. More specifically, CKD leads to reduced physical functioning and increased frailty, increased vascular dysfunction, vascular calcification and arterial stiffness, high levels of systemic inflammation, and oxidative stress, as well as increased cognitive impairment. Increasing evidence suggests that the cognitive impairment associated with CKD may be related to cerebral small vessel disease and overall impairment in white matter integrity. The triad of poor physical function, vascular dysfunction, and cognitive impairment places patients living with CKD at an increased risk for loss of independence, poor health-related quality of life, morbidity, and mortality. The purpose of this review is to discuss the available evidence of cerebrovascular-renal axis and its interconnection with early and accelerated cognitive impairment in patients with CKD and the plausible role of exercise as a therapeutic modality. Understanding the cerebrovascular-renal axis pathophysiological link and its interconnection with physical function is important for clinicians in order to minimize the risk of loss of independence and improve quality of life in patients with CKD. Ulf G. Bronas, Houry Puzantian, and Mary Hannan Copyright © 2017 Ulf G. Bronas et al. All rights reserved. Modulation of Myostatin/Hepatocyte Growth Factor Balance by Different Hemodialysis Modalities Tue, 28 Mar 2017 00:00:00 +0000 Background. In this study we investigated the relevance of myostatin and Hepatocyte Growth Factor (HGF) in patients undergoing hemodialysis HD and the influence of different HD modalities on their levels. Methods. We performed a prospective crossover study in which HD patients were randomized to undergo 3-month treatment periods with bicarbonate hemodialysis (BHD) followed by online hemodiafiltration (HDF). Clinical data, laboratory parameters, and myostatin and HGF serum levels were collected and compared. Results. Ten patients and six controls (C) were evaluated. In any experimental condition myostatin and HGF levels were higher in HD than in C. At enrollment and after BHD there were not significant correlations, whereas at the end of the HDF treatment period myostatin and HGF were inversely correlated (, ), myostatin serum levels inversely correlated with transferrin (, ), and HGF levels that resulted positively correlated with BMI ( 0.67, ). Moving from BHD to HDF, clinical and laboratory parameters were unchanged, as well as serum HGF, whereas myostatin levels significantly decreased (6.3 ± 4.1 versus 4.3 ± 3.1 ng/ml, ). Conclusions. Modulation of myostatin levels and myostatin/HGF balance by the use of different HD modalities might represent a novel approach to the prevention and treatment of HD-related muscle wasting syndrome. Pasquale Esposito, Edoardo La Porta, Marta Calatroni, Maria Antonietta Grignano, Samantha Milanesi, Daniela Verzola, Yuri Battaglia, Marilena Gregorini, Carmelo Libetta, Giacomo Garibotto, and Teresa Rampino Copyright © 2017 Pasquale Esposito et al. All rights reserved. Molecular Abnormalities Underlying Bone Fragility in Chronic Kidney Disease Wed, 22 Mar 2017 00:00:00 +0000 Prevention of bone fractures is one goal of therapy for patients with chronic kidney disease-mineral and bone disorder (CKD-MBD), as indicated by the Kidney Disease: Improving Global Outcomes guidelines. CKD patients, including those on hemodialysis, are at higher risk for fractures and fracture-related death compared to people with normal kidney function. However, few clinicians focus on this issue as it is very difficult to estimate bone fragility. Additionally, uremia-related bone fragility has a more complicated pathological process compared to osteoporosis. There are many uremia-associated factors that contribute to bone fragility, including severe secondary hyperparathyroidism, skeletal resistance to parathyroid hormone, and bone mineralization disorders. Uremia also aggravates bone volume loss, disarranges microarchitecture, and increases the deterioration of material properties of bone through abnormal bone cells or excess oxidative stress. In this review, we outline the prevalence of fractures, the interaction of CKD-MBD with osteoporosis in CKD patients, and discuss possible factors that exacerbate the mechanical properties of bone. Yoshiko Iwasaki, Junichiro James Kazama, and Masafumi Fukagawa Copyright © 2017 Yoshiko Iwasaki et al. All rights reserved. Posttransplant Anemia as a Prognostic Factor of Mortality in Kidney-Transplant Recipients Sun, 19 Mar 2017 08:34:21 +0000 Background. Findings on the association between posttransplant anemia (PTA) and mortality in posttransplant patients are scarce. This study explored whether PTA shortly after kidney transplantation (KT) predicts mortality at up to 10 years’ follow-up, stratified for chronic kidney disease (CKD) stages. Methods. PTA was divided into 3 categories according to the hemoglobin (Hb) value: severe (Hb < 10 g/dl), mild (10.0 g/dl ≤ Hb < 11.9 g/dl), or no PTA (Hb ≥ 12 g/dl). CKD stages were estimated using the CKD-EPI formula and divided into 2 groups: CKD1-2 and CKD3–5. Cox regression, stratified according to CKD, was performed to identify whether different categories of PTA predicted mortality in KT recipients. Results. Age, being female, and both mild and severe PTA contributed significantly to the Cox regression model on mortality in CKD1-2. In the Cox regression model for mortality in CKD3–5, age and severe PTA contributed significantly to this model. Conclusion. PTA shortly after KT increased the risk of mortality at up to 10 years’ follow-up. Even mild PTA is associated with a 6-fold higher risk of mortality and severe PTA with a 10-fold higher risk of mortality in CKD1-2. Clinical evaluation and treatment of anemia might reduce the higher risk of mortality in patients with PTA in early stages of CKD after KT. Maria Majernikova, Jaroslav Rosenberger, Lucia Prihodova, Miriam Jarcuskova, Robert Roland, Johan W. Groothoff, and Jitse P. van Dijk Copyright © 2017 Maria Majernikova et al. All rights reserved. Corrigendum to “Dual Inhibiting Senescence and Epithelial-to-Mesenchymal Transition by Erythropoietin Preserve Tubular Epithelial Cell Regeneration and Ameliorate Renal Fibrosis in Unilateral Ureteral Obstruction” Sun, 19 Mar 2017 00:00:00 +0000 Adis Tasanarong, Supranee Kongkham, and Sookkasem Khositseth Copyright © 2017 Adis Tasanarong et al. All rights reserved. Association between Parathyroid Hormone, 25 (OH) Vitamin D, and Chronic Kidney Disease: A Population-Based Study Tue, 07 Mar 2017 00:00:00 +0000 Identification of the accurate risk factor for CKD remains mandatory to combat the high prevalence of diseases. Growing evidence suggests the association of serum vitamin D with diverse health conditions. However, the relationship between vitamin D, intact parathyroid hormone (PTH), and calcium-phosphate metabolism and development of CKD remains controversial. We conduct this cross-sectional observational study to investigate the association between serum 25 (OH) vitamin D, intact PTH, and calcium and phosphate levels with eGFR and albuminuria, as a surrogate marker of CKD, in a community population. A total of 4080 participants were recruited. The mean age was 58.4 ± 13.3 years and 1480 (36.3%) were men. The mean eGFR was 94.1 ± 26.3 mL/min/1.73 m2. The prevalence of CKD was 19.8%. Serum 25 (OH) vitamin D and log intact PTH levels were inversely correlated with eGFR but positively correlated with log albuminuria. Logistic regression analysis identified the log intact PTH as an independent factor associated with eGFR ≤ 60 mL/min/1.73 m2 and proteinuria. This association was consistent when serum intact PTH was analyzed as continuous as well as categorical variables (as hyperparathyroidism). The relationship remains significant using resampling subset analysis with comparable baseline characteristics and adjustment for 25 (OH) vitamin D, calcium, and phosphate levels. This finding warranted further research to clarify the causal relationship of PTH/25 (OH) vitamin D with the risk of CKD in the general population. Wei-Hao Wang, Li-Wei Chen, Chin-Chan Lee, Chiao-Yin Sun, Yu-Chiau Shyu, Heng-Rong Hsu, Rong-Nang Chien, and I-Wen Wu Copyright © 2017 Wei-Hao Wang et al. All rights reserved. Imaging of Myocardial Fibrosis in Patients with End-Stage Renal Disease: Current Limitations and Future Possibilities Thu, 02 Mar 2017 10:04:57 +0000 Cardiovascular disease in patients with end-stage renal disease (ESRD) is driven by a different set of processes than in the general population. These processes lead to pathological changes in cardiac structure and function that include the development of left ventricular hypertrophy and left ventricular dilatation and the development of myocardial fibrosis. Reduction in left ventricular hypertrophy has been the established goal of many interventional trials in patients with chronic kidney disease, but a recent systematic review has questioned whether reduction of left ventricular hypertrophy improves cardiovascular mortality as previously thought. The development of novel imaging biomarkers that link to cardiovascular outcomes and that are specific to the disease processes in ESRD is therefore required. Postmortem studies of patients with ESRD on hemodialysis have shown that the extent of myocardial fibrosis is strongly linked to cardiovascular death and accurate imaging of myocardial fibrosis would be an attractive target as an imaging biomarker. In this article we will discuss the current imaging methods available to measure myocardial fibrosis in patients with ESRD, the reliability of the techniques, specific challenges and important limitations in patients with ESRD, and how to further develop the techniques we have so they are sufficiently robust for use in future clinical trials. M. P. M. Graham-Brown, A. S. Patel, D. J. Stensel, D. S. March, A.-M. Marsh, J. McAdam, G. P. McCann, and J. O. Burton Copyright © 2017 M. P. M. Graham-Brown et al. All rights reserved. The Effects of Long-Term Chaetomellic Acid A Administration on Renal Function and Oxidative Stress in a Rat Model of Renal Mass Reduction Thu, 23 Feb 2017 11:16:16 +0000 Purpose. This study aimed to evaluate the effect of chronic treatment with chaetomellic acid A (CAA) on oxidative stress and renal function in a model of renal mass reduction. Methods. Male Wistar rats were subjected to 5/6 nephrectomy (RMR) or sham-operated (SO). One week after surgery, rats have been divided into four experimental groups: RMR: RMR rats without treatment ; RMR + CAA: RMR rats treated with CAA ; SO: SO rats without treatment ; and SO + CAA: SO rats treated with CAA . CAA was intraperitoneally administered in a dose of 0.23 µg/Kg three times a week for six months. Results. RMR was accompanied by a significant reduction in catalase and glutathione reductase (GR) activity and a decrease in reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio. CAA administration significantly increased catalase and GR activity and increased GSH/GSSG ratio, but no significant difference between the treated and nontreated groups was found in this ratio. No significant differences were found between the RMR groups in any of the parameters of renal function. However, CAA administration slightly improves some parameters of renal function. Conclusions. These data suggest that CAA could attenuate 5/6 RMR-induced oxidative stress. António Nogueira, Francisco Peixoto, Maria Manuel Oliveira, Carlos André Pires, Bruno Colaço, Paula Alexandra Oliveira, and Maria João Pires Copyright © 2017 António Nogueira et al. All rights reserved. Ameliorating Effect of Gemigliptin on Renal Injury in Murine Adriamycin-Induced Nephropathy Thu, 23 Feb 2017 00:00:00 +0000 Background. Previous studies have shown the antiapoptotic and anti-inflammatory potential of DPP-IV inhibitor in experimental models of renal injury. We tested whether DPP-IV inhibitor (gemigliptin) ameliorates renal injury by suppressing apoptosis, inflammation, and oxidative stress in mice with adriamycin nephropathy. Methods. Mice were treated with normal saline (control), gemigliptin (GM), adriamycin (ADR), or adriamycin combined with gemigliptin (ADR+GM). Apoptosis, inflammation, and oxidative stress were analyzed via western blotting, real-time PCR, light microscopy, and immunofluorescence. Results. In the ADR+GM group, urine albumin creatinine ratio decreased significantly compared with that in the ADR group on day 15. Glomerulosclerosis index and tubulointerstitial injury index in mice with adriamycin-induced nephropathy decreased after gemigliptin treatment. ADR group showed higher levels of apoptosis, inflammation, and oxidative stress-related molecules compared with the control group. The upregulation of these molecules was significantly reduced by gemigliptin. In the ADR group, the staining intensities of WT-1 and nephrin reduced, but these changes were ameliorated in the ADR+GM group. Conclusion. We demonstrated that gemigliptin ameliorates nephropathy by suppressing apoptosis, inflammation, and oxidative stress in mice administered adriamycin. Our data demonstrate that gemigliptin has renoprotective effects on adriamycin-induced nephropathy. Da Rae Kim, Shin Yeong Lee, Jin Sug Kim, Yang Gyun Kim, Ju-Young Moon, Sang Ho Lee, Tae Won Lee, Chun Gyoo Ihm, and Kyung Hwan Jeong Copyright © 2017 Da Rae Kim et al. All rights reserved. Hyperphosphatemia and hs-CRP Initiate the Coronary Artery Calcification in Peritoneal Dialysis Patients Wed, 22 Feb 2017 10:02:10 +0000 Background. Coronary artery calcification (CAC) contributes to high risk of cardiocerebrovascular diseases in dialysis patients. However, the risk factors for CAC initiation in peritoneal dialysis (PD) patients are not known clearly. Methods. Adult patients with baseline CaCS = 0 and who were followed up for at least 3 years or until the conversion from absent to any measurable CAC detected were included in this observational cohort study. Binary logistic regression was performed to identify the risk factors for CAC initiation in PD patients. Results. 70 patients recruited to our study were split into a noninitiation group () and an initiation group () according to the conversion of any measurable CAC during their follow-up or not. In univariate analysis, systolic blood pressure, serum phosphorus, fibrinogen, hs-CRP, serum creatinine, and triglycerides were positively associated with the initiation of CAC, while the high density lipoprotein and nPCR did the opposite function. Multivariate analysis revealed that hyperphosphatemia and hs-CRP were the independent risk factors for CAC initiation after adjustments. Conclusions. Hyperphosphatemia and hs-CRP were the independent risk factors for CAC initiation in PD patients. These results suggested potential clinical strategies to prevent the initiation of CAC in PD patients. Da Shang, Qionghong Xie, Bin Shang, Min Zhang, Li You, Chuan-Ming Hao, and Tongying Zhu Copyright © 2017 Da Shang et al. All rights reserved. Etiology of End-Stage Renal Disease and Arterial Stiffness among Hemodialysis Patients Sun, 19 Feb 2017 00:00:00 +0000 Background. Prior studies have demonstrated that conventional and emerging CV risk factors are associated with worsening arterial stiffness among end-stage renal disease (ESRD) patients on hemodialysis. The present cross-sectional study evaluates the association between the etiology of ESRD and arterial stiffness among a cohort of hemodialysis patients. Methods. Etiology of ESRD was identified from patients’ medical records and classified as either vascular renal disease, diabetic nephropathy, nondiabetic glomerulopathy, tubular interstitial nephropathy, hereditary nephropathy, or ESRD of unconfirmed etiology. Results. A total of 82 subjects were enrolled. cfPWV was independently associated with the composite of either diabetic nephropathy or vascular renal disease (), pulse pressure (), and a history of CV events (), but not history of hypertension or diabetes mellitus alone. The median cfPWVs in diabetic nephropathy and vascular renal disease were comparable and significantly higher than median cfPWVs in other etiologies of ESRD. Conclusion. The study suggests that the etiology of ESRD is independently associated with arterial stiffness among hemodialysis patients. Furthermore, arterial stiffness was higher among patients who developed renal sequelae of either diabetes mellitus or hypertension as compared with those who have a history of either diabetes mellitus or hypertension alone. Balsam El Ghoul, Yazan Daaboul, Serge Korjian, Andrew El Alam, Anthony Mansour, Essa Hariri, Salam Samad, Pascale Salameh, Georges Dahdah, Jacques Blacher, Michel E. Safar, and Sola Aoun Bahous Copyright © 2017 Balsam El Ghoul et al. All rights reserved. Clinical Epidemiology of Mineral Bone Disorder Markers in Prevalent Hemodialysis Patients in the Xinjiang Uyghur Autonomous Region in China Sun, 19 Feb 2017 00:00:00 +0000 We investigated the clinical epidemiology of mineral bone disorder markers in prevalent hemodialysis (HD) patients in Xinjiang, the largest province in China. Data were obtained from 59 hospitals. A total of 3725 patients tracked from January 1 to December 31, 2014, were enrolled. Serum calcium (Ca) levels, phosphorus (P) levels, and intact parathyroid hormone (iPTH) levels were analyzed. Serum Ca levels were lower compared to the International Dialysis Outcomes and Practice Patterns Study (DOPPS4) and the Chinese DOPPS. The hypercalcemia rate was similar to DOPPS4 and lower than in the Chinese DOPPS. Serum P levels were higher than in DOPPS4 and lower than those in the Chinese DOPPS. Hyperphosphatemia rates were higher than DOPPS4 and lower than Chinese DOPPS. Serum iPTH levels were higher than in DOPPS4 and the Chinese DOPPS. We demonstrated higher serum P and iPTH levels in Xinjiang HD patients than in the DOPPS4 and Chinese DOPPS. In contrast, serum Ca levels were lower than the other two studies. High hypocalcemia and hyperphosphatemia rates may suggest that HD services in Xinjiang are inadequate. A multidiscipline chronic kidney disease (CKD) care program needs to be established to improve chronic kidney disease-mineral and bone disorder (CKD-MBD) target achievement in Xinjiang. Ying-Ping Sun, Wen-Jun Yang, Su-Hua Li, Yuan-yuan Han, and Jian Liu Copyright © 2017 Ying-Ping Sun et al. All rights reserved. Cytoplasmic Localization of WT1 and Decrease of miRNA-16-1 in Nephrotic Syndrome Sun, 19 Feb 2017 00:00:00 +0000 Nephrotic syndrome (NS) is a glomerular disease that is defined by the leakage of protein into the urine and is associated with hypoalbuminemia, hyperlipidemia, and edema. Steroid-resistant NS (SRNS) patients do not respond to treatment with corticosteroids and show decreased Wilms tumor 1 (WT1) expression in podocytes. Downregulation of WT1 has been shown to be affected by certain microRNAs (miRNAs). Twenty-one patients with idiopathic NS (68.75% were SSNS and 31.25% SRNS) and 10 healthy controls were enrolled in the study. Podocyte number and WT1 location were determined by immunofluorescence, and the serum levels of miR-15a, miR-16-1, and miR-193a were quantified by RT-qPCR. Low expression and delocalization of WT1 protein from the nucleus to the cytoplasm were found in kidney biopsies of patients with SRNS and both nuclear and cytoplasmic localization were found in steroid-sensitive NS (SSNS) patients. In sera from NS patients, low expression levels of miR-15a and miR-16-1 were found compared with healthy controls, but only the miR-16-1 expression levels showed statistically significant decrease (). The miR-193a expression levels only slightly increased in NS patients. We concluded that low expression and delocalization from the WT1 protein in NS patients contribute to loss of podocytes while modulation from WT1 protein is not associated with the miRNAs analyzed in sera from the patients. Pablo Zapata-Benavides, Mariela Arellano-Rodríguez, Juan José Bollain-y-Goytia, Moisés Armides Franco-Molina, Gloria Azucena Rangel-Ochoa, Esperanza Avalos-Díaz, Rafael Herrera-Esparza, and Cristina Rodríguez-Padilla Copyright © 2017 Pablo Zapata-Benavides et al. All rights reserved. The Strategy to Prevent and Regress the Vascular Calcification in Dialysis Patients Tue, 14 Feb 2017 00:00:00 +0000 The high prevalence of arterial calcification in end-stage renal disease (ESRD) is far beyond the explanation by common cardiovascular risk factors such as aging, diabetes, hypertension, and dyslipidemia. The finding relies on the fact that vascular and valvular calcifications are predictors of cardiovascular diseases and mortality in persons with chronic renal failure. In addition to traditional cardiovascular risk factors such as diabetes mellitus and blood pressure control, other ESRD-related risks such as phosphate retention, excess calcium, and prolonged dialysis time also contribute to the development of vascular calcification. The strategies are to reverse “calcium paradox” and lower vascular calcification by decreasing procalcific factors including minimization of inflammation (through adequate dialysis and by avoiding malnutrition, intravenous labile iron, and positive calcium and phosphate balance), correction of high and low bone turnover, and restoration of anticalcification factor balance such as correction of vitamin D and K deficiency; parathyroid intervention is reserved for severe hyperparathyroidism. The role of bone antiresorption therapy such as bisphosphonates and denosumab in vascular calcification in high-bone-turnover disease remains unclear. The limited data on sodium thiosulfate are promising. However, if calcification is to be targeted, ensure that bone health is not compromised by the treatments. Nai-Ching Chen, Chih-Yang Hsu, and Chien-Liang Chen Copyright © 2017 Nai-Ching Chen et al. All rights reserved. Role of Vitamin D in Uremic Vascular Calcification Sun, 12 Feb 2017 00:00:00 +0000 The risk of cardiovascular death is 10 times higher in patients with CKD (chronic kidney disease) than in those without CKD. Vascular calcification, common in patients with CKD, is a predictor of cardiovascular mortality. Vitamin D deficiency, another complication of CKD, is associated with vascular calcification in patients with CKD. GFR decline, proteinuria, tubulointerstitial injury, and the therapeutic dose of active form vitamin D aggravate vitamin D deficiency and reduce its pleiotropic effect on the cardiovascular system. Vitamin D supplement for CKD patients provides a protective role in vascular calcification on the endothelium by (1) renin-angiotensin-aldosterone system inactivation, (2) alleviating insulin resistance, (3) reduction of cholesterol and inhibition of foam cell and cholesterol efflux in macrophages, and (4) modulating vascular regeneration. For the arterial calcification, vitamin D supplement provides adjunctive role in regressing proteinuria, reverse renal osteodystrophy, and restoring calcification inhibitors. Recently, adventitial progenitor cell has been linked to be involved in the vascular calcification. Vitamin D may provide a role in modulating adventitial progenitor cells. In summary, vitamin D supplement may provide an ancillary role for ameliorating uremic vascular calcification. Yi-Chou Hou, Wen-Chih Liu, Cai-Mei Zheng, Jing-Quan Zheng, Tzung-Hai Yen, and Kuo-Cheng Lu Copyright © 2017 Yi-Chou Hou et al. All rights reserved. Urinary Exosomal miR-193a Can Be a Potential Biomarker for the Diagnosis of Primary Focal Segmental Glomerulosclerosis in Children Sun, 29 Jan 2017 00:00:00 +0000 Background. Glomerular upregulation of miR-193a has been detected in primary focal segmental glomerulosclerosis (FSGS) but not in other glomerular diseases. We aimed to isolate exosomes from urine of children with primary FSGS and to assess the diagnostic potential of urinary exosomal miR-193a for primary FSGS. Methods. The first morning urine samples were collected from children with primary FSGS () and minimal change disease (MCD, ). Isolated urinary exosomes were confirmed by electron microscopy and Western blotting. Urinary exosomal microRNA was extracted, and the expression levels of exosomal miR-193a were quantified by real-time PCR. The diagnosis value of urinary exosomal miR-193a levels for primary FSGS was evaluated by ROC analysis. Results. The isolated vesicles were qualitatively compatible with exosomes. The levels of urinary exosomal miR-193a were significantly higher in children with primary FSGS than those in children with MCD. Moreover, the area under the ROC for the diagnosis of primary FSGS using urinary exosomal miR-193a was 0.85. Conclusions. A significant increase in the levels of urinary exosomal miR-193a in primary FSGS patients compared to those in MCD ones was observed. This study suggests that urinary exosomal miR-193a may be a new noninvasive biomarker for the diagnosis of primary FSGS. Zhibin Huang, Yong Zhang, Jianhua Zhou, and Yu Zhang Copyright © 2017 Zhibin Huang et al. All rights reserved. Curcumin Ameliorates Diabetic Nephropathy by Suppressing NLRP3 Inflammasome Signaling Tue, 17 Jan 2017 09:17:14 +0000 Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, partly because of the lack of effective treatments for DN. Curcumin has been shown to exert strong antifibrotic effects in DN, but the underlying mechanisms are not well characterized. In this study, we sought to determine the effects of curcumin on diabetic renal disease in db/db mice and characterize the underlying mechanism of action. We administered curcumin to db/db mice for 16 weeks. In comparison to mock-treated db/db mice, curcumin-treated mice showed diminished renal hypertrophy, reduced mesangial matrix expansion, and a lower level of albuminuria. Furthermore, the upregulated protein and mRNA expressions of collagen IV and fibronectin in the renal cortices of the db/db mice were inhibited by curcumin treatment. Additionally, curcumin treatment was associated with significant reductions in mature interleukin-1β, cleaved caspase-1, and NLRP3 protein levels in the renal cortices of db/db mice as well as in HK-2 cells exposed to high glucose concentration. In summary, curcumin, a potent antifibrotic agent, is a promising treatment for DN, and its renoprotective effects appear to be mediated by the inhibition of NLRP3 inflammasome activity. Miaomiao Lu, Nanchang Yin, Wei Liu, Xiangfei Cui, Shuo Chen, and Ermin Wang Copyright © 2017 Miaomiao Lu et al. All rights reserved. Intestinal Barrier Disturbances in Haemodialysis Patients: Mechanisms, Consequences, and Therapeutic Options Tue, 17 Jan 2017 00:00:00 +0000 There is accumulating evidence that the intestinal barrier and the microbiota may play a role in the systemic inflammation present in HD patients. HD patients are subject to a number of unique factors, some related to the HD process and others simply to the uraemic milieu but with common characteristic that they can both alter the intestinal barrier and the microbiota. This review is intended to provide an overview of the current methods for measuring such changes in HD patients, the mechanisms behind these changes, and potential strategies that may mitigate these modifications. Lastly, intradialytic exercise is an increasingly employed intervention in HD patients; however the potential implications that this may have for the intestinal barrier are not known; therefore future research directions are also covered. D. S. March, M. P. M. Graham-Brown, C. M. Stover, N. C. Bishop, and J. O. Burton Copyright © 2017 D. S. March et al. All rights reserved. Renal Expression and Urinary Excretion of Na-K-2Cl Cotransporter in Obstructive Nephropathy Tue, 10 Jan 2017 09:43:14 +0000 Renal damage due to urinary tract obstruction accounts for up to 30% of acute kidney injury in paediatrics and adults. Bilateral ureteral obstruction (BUO) is associated with polyuria and reduced urinary concentrating capacity. We investigated the renal handling of water and electrolytes together with the renal expression and the urinary excretion of the Na-K-Cl cotransporter (NKCC2) after 1 (BUO-1), 2 (BUO-2), and 7 (BUO-7) days of release of BUO. Immunoblotting and immunohistochemical studies showed that NKCC2 expression was upregulated in apical membranes both from BUO-2 and from BUO-7 rats. The apical membrane expression, where NKCC2 is functional, may be sufficient to normalize water, potassium, sodium, and osmolytes tubular handling. NKCC2 abundance in homogenates and mRNA levels of NKCC2 was significantly decreased in almost all groups suggesting a decrease in the synthesis of the transporter. Urinary excretion of NKCC2 was increased in BUO-7 groups. These data suggest that the upregulation in the expression of NKCC2 in apical membranes during the postobstructive phase of BUO could contribute to improving the excretion of sodium and consequently also the excretion of potassium, osmolytes, and water. Moreover, the increase in urinary excretion of NKCC2 in BUO-7 group could be a potential additional biomarker of renal function recovery. Anabel Brandoni and Adriana M. Torres Copyright © 2017 Anabel Brandoni and Adriana M. Torres. All rights reserved. 7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells Tue, 27 Dec 2016 13:56:35 +0000 Acute kidney injury (AKI) is a common syndrome which is strongly linked to high morbidity and mortality. Hypoxia is the leading cause of AKI and the proximal renal tubular cells are the most damaged part in the kidney during this period. It has been observed that 7,8-dihydroxyflavone (7,8-DHF) plays a protective role by acting on antiapoptosis and antioxidative stress. In this study we explored functions of 7,8-DHF in protecting human proximal tubular cell line HK-2 from hypoxia insults. We observed that treatment of 7,8-DHF could improve the viability of ischemic cell. Mechanistically, we found that 7,8-DHF could elevate the expression of cysteine-rich protein 61 (Cyr61), a protective immediate early gene in AKI. In addition, treatment of 7,8-DHF decreased CCAAT/enhancer-binding protein homologous protein (CHOP) expression, which is a marker protein during endoplasmic reticulum (ER) stress activation. Intriguingly, overexpression of Cyr61 significantly reduced CHOP expression. Taken together, our results provide novel insights into the possible protective role of 7,8-DHF by activating Cyr61 signaling and suppressing ER stress in hypoxic HK-2 cells which have potential clinical implications for the treatment of AKI. Rui Ma, Jisheng Zhang, Xiaoyu Liu, Shaoheng Yue, Qing Zhao, and Yan Xu Copyright © 2016 Rui Ma et al. All rights reserved. Association between the Achievement of Target Range CKD-MBD Markers and Mortality in Prevalent Hemodialysis Patients in Taiwan by Using the Kidney Disease: Improving Global Outcomes Clinical Guidelines Sun, 27 Nov 2016 11:41:18 +0000 Background. This study evaluated the association between achieving target chronic kidney disease-mineral and bone disorder (CKD-MBD) marker levels and mortality in Taiwanese hemodialysis (HD) patients. Target levels were based on the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Methods. We performed a retrospective medical record review of 1126 HD patients between 2009 and 2013. A logistic regression model was used to evaluate the relationship between achieving target marker levels and the risk for all-cause and cardiovascular (CV) mortality. Reference target ranges were 7.9 ≤ calcium (Ca) ≤ 9.9 mg/dL, 2.4 ≤ phosphate (P) ≤ 4.7 mg/dL, and 144 ≤ intact parathyroid hormone (iPTH) ≤ 648 pg/mL. Results. Achievement of target P levels was associated with a lower risk for all-cause mortality compared to achievement of either target Ca or iPTH levels. Achieving target P + iPTH levels (OR 1.32) was associated with a lower odds ratio for all-cause mortality compared to achieving target Ca + P (OR 1.66) and Ca + iPTH (OR 1.43) levels. Similar trends were observed for CV mortality risk. Conclusions. The present study demonstrated that achieving serum P levels within the KDIGO target range is the most important factor for lowering mortality in HD patients. Ying Liu, Wen-Chin Lee, Ben-Chung Cheng, Lung-Chih Li, Chih-Hsiung Lee, Wen-Xiu Chang, and Jin-Bor Chen Copyright © 2016 Ying Liu et al. All rights reserved. Changes in Serum Concentrations of Fibroblast Growth Factor 23 and Soluble Klotho in Hemodialysis Patients after Total Parathyroidectomy Thu, 24 Nov 2016 09:12:57 +0000 Background. We examined the changes in circulating fibroblast growth factor 23 (FGF23) and Klotho concentrations in hemodialysis patients after parathyroidectomy (PTX). Methods. We enrolled a cohort of hemodialysis patients who received PTX. Postoperatively, patients received calcium supplements and/or vitamin D analogue (calcitriol) to maintain serum calcium within 7.0–8.0 mg/dL. Information on clinical parameters including bone-mineral metabolic variables was collected pre-PTX and on days 5 and 90 after PTX. Concomitantly, serum full-length FGF23 and α-Klotho levels were measured. The relationship between FGF23 and clinical parameters was analyzed by single linear regression. Results. Forty-six participants (33 women; 13 men) were enrolled in the study. Their mean age was 56.49 years. Serum FGF23 and α-Klotho concentrations were elevated on days 5 and 90 after PTX compared to baseline (). Serum FGF23 concentrations negatively correlated with serum calcium concentrations pre-PTX (Beta ; 0.0949; ), day 5 post-PTX (Beta ; 0.0982; ), and day 90 post-PTX (Beta ; 0.1528; ). Conclusions. There was no change in circulating FGF23 and Klotho concentrations after PTX in hemodialysis patients given postoperative calcium supplements and/or vitamin D analogue. Serum FGF23 concentrations pre-PTX and at days 5 and 90 after PTX were inversely related to serum calcium concentrations. Shang-Chih Liao, Sin-Hua Moi, Fong-Fu Chou, Cheng-Hong Yang, and Jin-Bor Chen Copyright © 2016 Shang-Chih Liao et al. All rights reserved. How Should Disaster Base Hospitals Prepare for Dialysis Therapy after Earthquakes? Introduction of Double Water Piping Circuits Provided by Well Water System Wed, 23 Nov 2016 14:00:14 +0000 After earthquakes, continuing dialysis for patients with ESRD and patients suffering from crush syndrome is the serious problem. In this paper, we analyzed the failure of the provision of dialysis services observed in recent disasters and discussed how to prepare for disasters to continue dialysis therapy. Japan has frequently experienced devastating earthquakes. A lot of dialysis centers could not continue dialysis treatment owing to damage caused by these earthquakes. The survey by Japanese Society for Dialysis Treatment (JSDT) after the Great East Japan Earthquake in 2011 showed that failure of lifelines such as electric power and water supply was the leading cause of the malfunction of dialysis treatment. Our hospital is located in Shizuoka Prefecture, where one of the biggest earthquakes is predicted to occur in the near future. In addition to reconstructing earthquake-resistant buildings and facilities, we therefore have adopted double electric and water lifelines by introducing emergency generators and well water supply systems. It is very important to inform politicians, bureaucrats, and local water departments that dialysis treatment, a life sustaining therapy for patients with end stage renal diseases, requires a large amount of water. We cannot prevent an earthquake but can curb the extent of a disaster by preparing for earthquakes. Naoki Ikegaya, George Seki, and Nobutaka Ohta Copyright © 2016 Naoki Ikegaya et al. All rights reserved. The Experience of Older People in the Shared Decision-Making Process in Advanced Kidney Care Sun, 20 Nov 2016 14:14:05 +0000 Introduction. This qualitative descriptive study was designed to understand the experiences of older people (>70 years) when making a decision about renal replacement therapy. This was a coproduced study, whereby patients and carers were involved in all aspects of the research process. Methods. A Patient and Carer Group undertook volunteer and research training. The group developed the interview questions and interviewed 29 people who had commenced dialysis or made a decision not to have dialysis. Interview data were transcribed and analysed, and common themes were identified. Results. 22 men and 7 women (mean age 77.4 yrs) from two hospitals were interviewed. 18 had chosen haemodialysis, 6 peritoneal dialysis, and 5 supportive care. The majority of patients were involved in the dialysis decision. Most were satisfied with the amount of information that they received, although some identified that the quality of the information could be improved, especially how daily living can be affected by dialysis. Conclusion. Our findings show that overall older patients were involved in the dialysis decision along with their families. Our approach is innovative because it is the first time that patients and carers have been involved in a coproduced study about shared decision-making. Nicola Thomas, Karen Jenkins, Breeda McManus, and Brian Gracey Copyright © 2016 Nicola Thomas et al. All rights reserved. Upregulation of Oxidative Stress Related Genes in a Chronic Kidney Disease Attributed to Specific Geographical Locations of Sri Lanka Wed, 16 Nov 2016 12:32:03 +0000 Objective. To infer the influence of internal and external oxidative stress in chronic kidney disease patients of unknown etiology (CKDu) in Sri Lanka, by analyzing expression of genes related directly or indirectly to oxidative stress: glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase mu 1 (GSTM1), glucose-6-phosphate dehydrogenase (G6PD), fibroblast growth factor-23 (FGF23), and NLR family pyrin domain containing 3 (NLRP3). Methods. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was carried out for the selected populations: CKDu patients (), chronic kidney disease patients (CKD; ), healthy individuals from a CKDu endemic area (GHI; ), and nonendemic area (KHI; ). Fold changes were quantified relative to KHI. Results. GCLC had greater than threefold upregulation in all three study groups, with a maximum of 7.27-fold upregulation in GHI (). GSTM1 was not expressed in 25.6% of CKDu and 42.9% of CKD patients, but CKDu patients expressing GSTM1 showed upregulation of 2.60-fold (). Upregulation of FGF23 and NLRP3 genes in CKD and CKDu was observed (), with greater fold changes in CKD. Conclusion. Results suggest higher influence of external sources of oxidative stress in CKDu, possibly owing to environmental conditions. Saravanabavan Sayanthooran, Dhammika N. Magana-Arachchi, Lishanthe Gunerathne, Tilak D. J. Abeysekera, and Suneth S. Sooriyapathirana Copyright © 2016 Saravanabavan Sayanthooran et al. All rights reserved. Histopathological Evaluation of Contrast-Induced Acute Kidney Injury Rodent Models Wed, 16 Nov 2016 07:33:04 +0000 Contrast-induced acute kidney injury (CI-AKI) can occur in 3–25% of patients receiving radiocontrast material (RCM) despite appropriate preventive measures. Often patients with an atherosclerotic vasculature have to receive large doses of RCM. Thus, animal studies to uncover the exact pathomechanism of CI-AKI are needed. Sensitive and specific histologic end-points are lacking; thus in the present review we summarize the histologic appearance of different rodent models of CI-AKI. Single injection of RCM causes overt renal damage only in rabbits. Rats and mice need an additional insult to the kidney to establish a clinically manifest CI-AKI. In this review we demonstrate that the concentrating ability of the kidney may be responsible for species differences in sensitivity to CI-AKI. The most commonly held theory about the pathomechanism of CI-AKI is tubular cell injury due to medullary hypoxia. Thus, the most common additional insult in rats and mice is some kind of ischemia. The histologic appearance is tubular epithelial cell (TEC) damage; however severe TEC damage is only seen if RCM is combined by additional ischemia. TEC vacuolization is the first sign of CI-AKI, as it is a consequence of RCM pinocytosis and lysosomal fusion; however it is not sensitive as it does not correlate with renal function and is not specific as other forms of TEC damage also cause vacuolization. In conclusion, histopathology alone is insufficient and functional parameters and molecular biomarkers are needed to closely monitor CI-AKI in rodent experiments. Norbert Kiss and Péter Hamar Copyright © 2016 Norbert Kiss and Péter Hamar. All rights reserved. Piloting Psychology Annual Reviews as a Method of Measuring Psychological Distress and Quality of Life in Paediatric Renal Transplant Patients Mon, 14 Nov 2016 06:50:37 +0000 Psychosocial distress and poorer quality of life after renal transplantation are common in children and young people. This has implications for medication adherence and survival. Posttransplant psychology annual reviews were introduced in one Paediatric Renal Service in the UK as a means of measuring psychological distress and quality of life, as well as facilitating identification of patients and parents/carers who would benefit from psychological intervention. The process of completing posttransplant psychology annual reviews is discussed within this paper. The posttransplant psychology annual review appointments identified patients experiencing depression and/or anxiety and problems in quality of life. These assessments have led to appropriate referrals to, and engagement with, the renal psychology service as well as with community tier 3 child and adolescent mental health services. The posttransplant psychology annual review will continue to be completed at this UK site and discussions will be undertaken with other paediatric renal transplant services to consider whether these could be introduced at a national level to facilitate collection of longitudinal data regarding long-term psychosocial impact of paediatric renal transplantation and its effect on quality of life. Jade Bamford and Lucy Wirz Copyright © 2016 Jade Bamford and Lucy Wirz. All rights reserved. Danggui Buxue Tang Attenuates Tubulointerstitial Fibrosis via Suppressing NLRP3 Inflammasome in a Rat Model of Unilateral Ureteral Obstruction Mon, 31 Oct 2016 08:18:00 +0000 Inflammation significantly contributes to the progression of chronic kidney disease (CKD). This study aimed to characterize Danggui Buxue Tang (DBT) renoprotection and relationship with NOD-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome expression in rats with unilateral ureteral obstruction (UUO). Sprague-Dawley rats were subjected to UUO and randomly assigned to untreated UUO, enalapril-treated (10 mg/kg/day), and DBT-treated (9 g/kg/day) groups. Sham-operated rats served as controls, with 8 rats in each group. All rats were sacrificed for blood and renal specimen collection at 14 days after UUO. Untreated UUO rats exhibited azotemia, intense tubulointerstitial collagen deposition, upregulations of tubulointerstitial injury index, augmentation levels of collagen I (Col I), α-smooth muscle actin (α-SMA), NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase-1, caspase-1, IL-1β, and pro-IL-1β. DBT treatment significantly attenuated interstitial collagen deposition and tubulointerstitial injury, lowering Col I and α-SMA levels. Synchronous expressions of NLRP3, ASC, pro-caspase-1, caspase-1, pro-IL-1β, and IL-1β decreased in renal tissue. In comparison to enalapril, DBT significantly reduced tubulointerstitial injury, interstitial collagen deposition, and expressions of Col I and IL-1β. Thus, DBT offers renoprotection in UUO rats, which was associated with suppressing NLRP3 inflammasome expression and following reduction of the secretion of cytokine IL-1β. The mechanisms of multitargets of traditional Chinese medicine can be better used for antifibrotic treatment. Linna Wang, Jiwei Ma, Cunxia Guo, Changyong Chen, Zhong Yin, Xueguang Zhang, and Xiangmei Chen Copyright © 2016 Linna Wang et al. All rights reserved. Relationship between Interdialytic Weight Gain and Blood Pressure in Pediatric Patients on Chronic Hemodialysis Mon, 24 Oct 2016 13:34:11 +0000 Overhydration is reported to be the main cause of hypertension (HTN) as well as to have no association with HTN in hemodialysis (HD) population. This is the first report of the relationship between interdialytic weight gain (IDWG) and pre-HD blood pressure (BP) in pediatric patients in relation to residual urine output (RUO). We studied 170 HD sessions and interdialytic periods performed during a 12-week period in 5 patients [age 4–17 years, weight 20.8–66 kg, 3 anuric (102 HD sessions), and 2 nonanuric (68 HD sessions)]. BP is presented as systolic BP index (SBPI) and diastolic BP index (DBPI), calculated as systolic or diastolic BP/95th percentile for age, height, and gender. IDWG did not differ () between anuric and nonanuric pts. There was a positive but not significant correlation between IDWG and both pre-HD SBPI (, ) and pre-HD DBPI (, ). Pre-HD SBPI ( versus ) and DBPI ( versus ) were higher in nonanuric patents ( and , resp.). Pre-HD HTN may not be solely related to IDWG and therapies beyond fluid removal may be needed. Individualized approach to HTN management is necessary in pediatric dialysis population. Olivera Marsenic, Michael Anderson, and Kevin G. Couloures Copyright © 2016 Olivera Marsenic et al. All rights reserved. Comprehensive Comparison of the Performance of Autogenous Brachial-Basilic Transposition Arteriovenous Fistula and Prosthetic Forearm Loop Arteriovenous Graft in a Multiethnic Asian Hemodialysis Population Thu, 20 Oct 2016 05:58:46 +0000 Aim. For patients who have exhausted cephalic vein arteriovenous fistula (AVF) options, controversy exists on whether brachial-basilic AVF with transposition (BBTAVF) or a forearm arteriovenous graft (AVG) should be the next vascular access of choice. This study compared the outcomes of these two modalities. Methods. A retrospective study of 122 Asian multiethnic patients who underwent either a BBTAVF (81) or an AVG (41). Maturation time and intervention rates were analyzed. Functional primary, secondary, and overall patency rates were evaluated. Results. The maturation time for BBTAVFs was significantly longer than AVGs. There was also a longer deliberation time before surgeons abandon a failing BBTAVF compared to an AVG. Both functional primary and secondary patency rates were significantly higher in the BBTAVF group at 1-year follow-up: 73.2% versus 34.1% () and 71.8% versus 54.3% (), respectively. AVGs also required more interventions to maintain patency. When maturation rates were considered, the overall patency of AVGs was initially superior in the first 25 weeks after creation and then became inferior afterwards. Conclusion. BBTAVFs had superior primary and functional patency and required less salvage interventions. The forearm AVG might have a role in patients who require early vascular access due to complications from central venous catheters or with limited life expectancy. Koy Min Chue, Kyi Zin Thant, Hai Dong Luo, Yu Hang Rodney Soh, and Pei Ho Copyright © 2016 Koy Min Chue et al. All rights reserved. Management of Patient Care in Hemodialysis While Focusing on Cardiovascular Disease Events and the Atypical Role of Hyper- and/or Hypotension: A Systematic Review Wed, 19 Oct 2016 12:34:23 +0000 Background. Hemodialysis related hemodynamic instability is a major but an underestimated issue. Moreover, cardiovascular events are the leading cause of morbidity and mortality associated with blood pressure in hemodialysis patients. However, there have been many controversies regarding the role and management of hyper- and/or hypotension during hemodialysis that needs to be addressed. Objective. To critically review the available published data on the atypical role of hyper- and/or hypotension in cardiovascular associated morbidity and mortality in patients on hemodialysis and to understand the discrepancies in this context. Methods. A comprehensive search of literature employing electronic as well as manual sources and screening 2783 papers published between Jan 1980 and Oct 2015 was conducted to collect, identify, and analyze relevant information through peer-reviewed research articles, systematic reviews, and other published works. The cardiovascular events, including accelerated atherosclerotic cardiovascular disease (ASCVD), stroke, heart failure, myocardial infarction, myocardial ischemia, and stress induced myocardial dysfunction, leading to death were considered relevant. Results. A total of 23 published articles met the inclusion criteria and were included for in-depth review and analysis to finalize a comprehensive systematic review article. All the studies showed a significant association between the blood pressure and cardiovascular disease events in hemodialysis patients. Conclusions. Both intradialytic hypertension/hypotension episodes are major risk factors for cardiovascular mortality with a high percentage of probable causality; however, clinicians are faced with a dilemma on how to evaluate blood pressure and treat this condition. Amjad Khan, Amer Hayat Khan, Azreen Syazril Adnan, Syed Azhar Syed Sulaiman, Siew Hua Gan, and Irfanullah Khan Copyright © 2016 Amjad Khan et al. All rights reserved. Corrigendum to “β-Catenin-Dependent Signaling Pathway Contributes to Renal Fibrosis in Hypertensive Rats” Mon, 10 Oct 2016 14:34:15 +0000 Catherina A. Cuevas, Cheril Tapia-Rojas, Carlos Cespedes, Nibaldo C. Inestrosa, and Carlos P. Vio Copyright © 2016 Catherina A. Cuevas et al. All rights reserved. Role of Cilostazol Therapy in Hemodialysis Patients with Asymptomatic Peripheral Arterial Disease: A Retrospective Cohort Study Thu, 22 Sep 2016 09:01:29 +0000 Background. Peripheral arterial disease (PAD) and its relevant complications are more common in hemodialysis (HD) patients, while the evidence regarding antiplatelet therapy in CKD patients is scarce. We retrospectively analyzed the efficacy of cilostazol on outcomes in HD patients with asymptomatic PAD (aPAD). Methods. This cohort study enrolled 217 HD patients (median follow-up time: 5.75 years). Associations between cilostazol use and the outcomes were evaluated by time-dependent Cox regression analysis. Results. During follow-up, 39.5% (47/119) patients used cilostazol for aPAD and 31.8% (69/217) patients died. Cilostazol users had significantly lower CVD and all-cause mortalities (adjusted HR [95% CI]: 0.11 [0.03, 0.51] and 0.2 [0.08, 0.52]) than nonusers. Both death risks were nonsignificantly higher in cilostazol users than in HD patients without aPAD. The unadjusted and adjusted HR [95% CI] of CVD death risk were 0.4 [0.07, 2.12] and 0.14 [0.02, 0.8] for patients with aPAD during follow-up and were 0.74 [0.16, 3.36] and 0.19 [0.04, 0.93] for those with aPAD at initial. Conclusions. In HD patients with aPAD, lower CVD and all-cause mortality rates were observed in low-dose cilostazol user. Further evidences from large-scale prospective study and randomization trial are desired to confirm the effect of cilostazol. Paik Seong Lim, Yachung Jeng, Ming Ying Wu, Mei-Ann Pai, Tsai-Kun Wu, and Chang Hsu Chen Copyright © 2016 Paik Seong Lim et al. All rights reserved. Matrix Metalloproteinase-9 −1562C/T Gene Polymorphism Is Associated with Diabetic Nephropathy Thu, 18 Aug 2016 15:59:30 +0000 To investigate the association between the metalloproteinase-9 (MMP9) −1562C/T polymorphism and diabetic nephropathy (DN) in Han Chinese, the patients with type 2 diabetes were collected and divided into the non-DN (NDN) and DN groups; controls were recruited. Genotype and allele frequencies were assessed using polymerase chain reaction and restriction fragment length polymorphism. Results showed that SBP, DBP, HbA1c, UAER, Cr, BUN, TG, and TC were higher in the DN group compared with the control and NDN groups. SBP, HbA1c, and TC in DN patients with the TT and CT genotypes were lower than in those with CC. Compared with controls, the frequency of the T allele in the DN group was significantly lower. The MMP9 −1562C allele, SBP, Cr, BUN, TG, and TC were independent risk factors for DN. All of the above suggested that the MMP9 −1562C/T polymorphism was associated with DN in Han Chinese. Shufen Feng, Gang Ye, Shi Bai, Hongcheng Wei, Xueling Liao, and Lu Li Copyright © 2016 Shufen Feng et al. All rights reserved. Establishment of Simple and Routine Methods in Early Diagnosis of Gentamicin-Induced Kidney Injury Based on a Rat Model Thu, 18 Aug 2016 07:31:25 +0000 The changes in biomarkers of gentamycin- (GM-) induced kidney injury have been studied by using simple and routine methods and also assessed the efficacy and utility of these routine biomarkers in early diagnosis. Eighty Sprague-Dawley (SD) rats were randomly divided into 4 groups: three experimental groups treated with different GM dosages (4, 20, and 100 mg·kg−1) and a control group. The experimental groups were given intramuscular GM injections once daily for 14 days, and the control group was given intramuscular sterile water. Blood and urine samples were collected on treatment days 1, 3, 7, and 14 to test for total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (CRE), uric acid (UA), pH, specific gravity (SG), proteins (PRO), and cells in urinary sediment. Histopathology and kidney coefficient were performed on excised kidney specimens. The result indicated that serum CRE, BUN, and TP, urine PRO, and urinary hyaline casts and low-transitional epithelium showed an immediate and highly sensitive response to kidney injury, and the combined diagnosis with the above methods could be used in early diagnosis. Particularly, the process of the test was simple and quick, no special equipment, so it is more suit for primary medical institution. Cuiyan Liu, Youxi Kang, Huiqin Zhang, Long Zhu, Hai Yu, and Chunyang Han Copyright © 2016 Cuiyan Liu et al. All rights reserved. Novel Developments in Acute Kidney Injury Wed, 10 Aug 2016 06:55:31 +0000 Jeremiah R. Brown, Peter A. McCullough, and Michael E. Matheny Copyright © 2016 Jeremiah R. Brown et al. All rights reserved. Focal Segmental Glomerulosclerosis: Genetics, Mechanism, and Therapies Sun, 26 Jun 2016 07:54:06 +0000 Andreas Kronbichler, Jun Oh, Björn Meijers, and Jae Il Shin Copyright © 2016 Andreas Kronbichler et al. All rights reserved. Prediction and Prevention of Acute Kidney Injury after Cardiac Surgery Thu, 23 Jun 2016 12:56:43 +0000 The incidence of acute kidney injury after cardiac surgery (CS-AKI) ranges from 33% to 94% and is associated with a high incidence of morbidity and mortality. The etiology is suggested to be multifactorial and related to almost all aspects of perioperative management. Numerous studies have reported the risk factors and risk scores and novel biomarkers of AKI have been investigated to facilitate the subclinical diagnosis of AKI. Based on the known independent risk factors, many preventive interventions to reduce the risk of CS-AKI have been tested. However, any single preventive intervention did not show a definite and persistent benefit to reduce the incidence of CS-AKI. Goal-directed therapy has been considered to be a preventive strategy with a substantial level of efficacy. Many pharmacologic agents were tested for any benefit to treat or prevent CS-AKI but the results were conflicting and evidences are still lacking. The present review will summarize the current updated evidences about the risk factors and preventive strategies for CS-AKI. Su Rin Shin, Won Ho Kim, Dong Joon Kim, Il-Woo Shin, and Ju-Tae Sohn Copyright © 2016 Su Rin Shin et al. All rights reserved. Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease Tue, 21 Jun 2016 15:06:23 +0000 Chronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The “omics” techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other “omics” methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients. Simona Granata, Alessandra Dalla Gassa, Gloria Bellin, Antonio Lupo, and Gianluigi Zaza Copyright © 2016 Simona Granata et al. All rights reserved. Hospital Mortality in the United States following Acute Kidney Injury Wed, 08 Jun 2016 09:30:13 +0000 Acute kidney injury (AKI) is a common reason for hospital admission and complication of many inpatient procedures. The temporal incidence of AKI and the association of AKI admissions with in-hospital mortality are a growing problem in the world today. In this review, we discuss the epidemiology of AKI and its association with in-hospital mortality in the United States. AKI has been growing at a rate of 14% per year since 2001. However, the in-hospital mortality associated with AKI has been on the decline starting with 21.9% in 2001 to 9.1 in 2011, even though the number of AKI-related in-hospital deaths increased almost twofold from 147,943 to 285,768 deaths. We discuss the importance of the 71% reduction in AKI-related mortality among hospitalized patients in the United States and draw on the discussion of whether or not this is a phenomenon of hospital billing (coding) or improvements to the management of AKI. Jeremiah R. Brown, Michael E. Rezaee, Emily J. Marshall, and Michael E. Matheny Copyright © 2016 Jeremiah R. Brown et al. All rights reserved. FSGS: Diagnosis and Diagnostic Work-Up Tue, 24 May 2016 09:57:26 +0000 Focal segmental glomerulosclerosis is a histologic lesion, rather than a clinical disease. FSGS is common cause of nephrotic syndrome in both adults and children worldwide. In the United States it is the most common primary glomerular disease resulting in end-stage renal disease and recent reports have suggested that its incidence might be on the rise. Currently the incidence is estimated to be 7 per million. The podocyte is the cellular target cell in FSGS and in recent years substantial insight in the pathogenesis and genetics of FSGS have accumulated. Furthermore the discovery of potential novel biomarkers to diagnose FSGS and monitor disease activity has renewed interest in this disease. In this review article we will focus on the clinical presentation and diagnosis of FSGS. Ben Sprangers, Björn Meijers, and Gerald Appel Copyright © 2016 Ben Sprangers et al. All rights reserved. Infection-Related Focal Segmental Glomerulosclerosis in Children Tue, 17 May 2016 13:42:46 +0000 Focal segmental glomerulosclerosis (FSGS) is the most common cause of steroid resistant nephrotic syndrome in children. It describes a unique histological picture of glomerular damage resulting from several causes. In the majority of patients the causing agent is still unknown, but in some cases viral association is evident. In adults, the most established FSGS causing virus is the human immune-deficiency virus, which is related to a collapsing variant of FSGS. Nevertheless, other viruses are also suspected for causing a collapsing or noncollapsing variant, for example, hepatitis B virus, parvovirus B19, and Cytomegalovirus. Although the systemic infection mechanism is different for these viruses, there are similarities in the pathomechanism for the induction of FSGS. As the podocyte is the key structure in the pathogenesis of FSGS, a direct infection of these cells or immediate damage through the virus or viral components has to be considered. Although viral infections are a very rare cause for FSGS in children, the treating pediatric nephrologist has to be aware of a possible underlying infection, as this has a relevant impact on therapy and prognosis. Anne Katrin Dettmar and Jun Oh Copyright © 2016 Anne Katrin Dettmar and Jun Oh. All rights reserved. Practical Application of Columbia Classification for Focal Segmental Glomerulosclerosis Mon, 09 May 2016 11:28:12 +0000 Focal segmental glomerulosclerosis (FSGS) is a heterogeneous clinicopathological entity. Two frameworks for the classification of FSGS have been described: etiologic and morphologic. The etiologic classification is distinguished among genetic, adaptive, virus-associated, drug-induced, and idiopathic types. Morphologic classification is commonly referred to as the Columbia classification published in 2004, which distinguishes five variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS). This classification is based on light microscopic patterns with rigorously defined specific criteria, which can be applied to primary and secondary forms of FSGS, and has been widely used over the past 10 years both as a diagnostic and as a prognostic clinical tool. This paper defines common histopathological features of FSGS, distinguished characters among five variants, and points out the confusion about terminology of variants, because most were proposed in the past with different definitions. Despite good interobserver reproducibility of this classification system, difficulty in its application may arise in the interpretation of lesions with mixed features of more than one variant in the same tissue specimen and with late lesions, because other variants may evolve into the NOS variant over time. Man-Hoon Han and Yong-Jin Kim Copyright © 2016 Man-Hoon Han and Yong-Jin Kim. All rights reserved. Histone Lysine Methylation in TGF-β1 Mediated p21 Gene Expression in Rat Mesangial Cells Mon, 09 May 2016 09:50:19 +0000 Transforming growth factor beta1- (TGF-β1-) induced p21-dependent mesangial cell (MC) hypertrophy plays a key role in the pathogenesis of chronic renal diseases including diabetic nephropathy (DN). Increasing evidence demonstrated the role of posttranscriptional modifications (PTMs) in the event; however, the precise regulatory mechanism of histone lysine methylation remains largely unknown. Here, we examined the roles of both histone H3 lysine 4 and lysine 9 methylations (H3K4me/H3K9me) in TGF-β1 induced p21 gene expression in rat mesangial cells (RMCs). Our results indicated that TGF-β1 upregulated the expression of p21 gene in RMCs, which was positively correlated with the increased chromatin marks associated with active genes (H3K4me1/H3K4me2/H3K4me3) and negatively correlated with the decreased levels of repressive marks (H3K9me2/H3K9me3) at p21 gene promoter. TGF-β1 also elevated the recruitment of the H3K4 methyltransferase (HMT) SET7/9 to the p21 gene promoter. SET7/9 gene silencing with small interfering RNAs (siRNAs) significantly abolished the TGF-β1 induced p21 gene expression. Taken together, these results reveal the key role of histone H3Kme in TGF-β1 mediated p21 gene expression in RMC, partly through HMT SET7/9 occupancy, suggesting H3Kme and SET7/9 may be potential renoprotective agents in managing chronic renal diseases. Qiaoyan Guo, Xiaoxia Li, Hongbo Han, Chaoyuan Li, Shujun Liu, Wenhui Gao, and Guangdong Sun Copyright © 2016 Qiaoyan Guo et al. All rights reserved. Selective Insulin Resistance in the Kidney Mon, 09 May 2016 09:40:33 +0000 Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. Shoko Horita, Motonobu Nakamura, Masashi Suzuki, Nobuhiko Satoh, Atsushi Suzuki, and George Seki Copyright © 2016 Shoko Horita et al. All rights reserved. MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy Wed, 27 Apr 2016 14:08:32 +0000 Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. Katerina Popovska-Jankovic, Predrag Noveski, Ljubinka Jankovic-Velickovic, Slavica Stojnev, Rade Cukuranovic, Vladisav Stefanovic, Draga Toncheva, Rada Staneva, Momir Polenakovic, and Dijana Plaseska-Karanfilska Copyright © 2016 Katerina Popovska-Jankovic et al. All rights reserved. Recurrence and Treatment after Renal Transplantation in Children with FSGS Sun, 24 Apr 2016 13:55:08 +0000 Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease and a common pathologic diagnosis of idiopathic nephrotic syndrome (NS), especially in steroid-resistant cases. FSGS is known to recur after kidney transplantation, frequently followed by graft loss. However, not all patients with FSGS suffer from recurrence after kidney transplantation, and genetic and secondary FSGS have a negligible risk of recurrence. Furthermore, many cases of recurrence achieve remission with the current management of recurrence (intensive plasmapheresis/immunosuppression, including rituximab), and other promising agents are being evaluated. Therefore, a pathologic diagnosis of FSGS itself should not cause postponement of allograft kidney transplantation. For patients with a high risk of recurrence who presented with classical symptoms of NS, that is, severe edema, proteinuria, and hypoalbuminemia, close monitoring of proteinuria is necessary, followed by immediate, intensive treatment for recurrence. Hee Gyung Kang, Il-Soo Ha, and Hae Il Cheong Copyright © 2016 Hee Gyung Kang et al. All rights reserved. Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates Thu, 21 Apr 2016 07:48:21 +0000 Primary focal segmental glomerulosclerosis (FSGS) is a major cause of the nephrotic syndrome and often leads to end-stage renal disease. This review focuses on circulating permeability factors in primary FSGS that have been implicated in the pathogenesis for a long time, partly due to the potential recurrence in renal allografts within hours after transplantation. Recently, three molecules have been proposed as a potential permeability factor by different groups: the soluble urokinase plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF-1), and CD40 antibodies. Both CLCF-1 and CD40 antibodies have not been validated by independent research groups yet. Since the identification of suPAR, different studies have questioned the validity of suPAR as a biomarker to distinguish primary FSGS from other proteinuric kidney diseases as well as suPAR’s pathogenic role in podocyte damage. Researchers have suggested that cleaved molecules of suPAR have a pathogenic role in FSGS but further studies are needed to determine this role. In future studies, proposed standards for the research of the permeability factor should be carefully followed. The identification of the permeability factor in primary FSGS would be of great clinical relevance as it could influence potential individual treatment regimen. Eva Königshausen and Lorenz Sellin Copyright © 2016 Eva Königshausen and Lorenz Sellin. All rights reserved. Valproic Acid Prevents Renal Dysfunction and Inflammation in the Ischemia-Reperfusion Injury Model Mon, 18 Apr 2016 14:18:24 +0000 Ischemia-reperfusion injury (IRI) is a major contributor to acute kidney injury (AKI). At present, there are no effective therapies to prevent AKI. The aim of this study was to analyse whether valproic acid (VPA), a histone deacetylase inhibitor with anti-inflammatory properties, prevents renal IRI. Male Wistar rats were divided into three groups: SHAM rats were subjected to a SHAM surgery, IRI rats underwent bilateral renal ischemia for 45 min, and IRI + VPA rats were treated with VPA at 300 mg/kg twice daily 2 days before bilateral IRI. Animals were euthanized at 48 hours after IRI. VPA attenuated renal dysfunction after ischemia, which was characterized by a decrease in BUN (mg/dL), serum creatinine (mg/dL), and FENa (%) in the IRI + VPA group (, , and , resp.) compared with the IRI group (, , and , resp.; ). Additionally, significantly lower acute tubular necrosis grade and number of apoptotic cells were found in the IRI + VPA group compared to the IRI group (). Furthermore, VPA treatment reduced inflammatory cellular infiltration and expression of proinflammatory cytokines. These data suggest that VPA prevents the renal dysfunction and inflammation that is associated with renal IRI. Elerson C. Costalonga, Filipe M. O. Silva, and Irene L. Noronha Copyright © 2016 Elerson C. Costalonga et al. All rights reserved. Recent Advances in Treatments of Primary Focal Segmental Glomerulosclerosis in Children Mon, 18 Apr 2016 10:57:56 +0000 Focal segmental glomerulosclerosis (FSGS) is a nephrotic syndrome. Up to around 80% of cases of primary FSGS are resistant to steroid treatment. A large proportion of patients with steroid-resistant FSGS progress to end-stage renal disease. The purpose of treatment is to obtain a complete remission of proteinuria, a necessary step that precedes improved renal survival and reduces the risk of progression to chronic kidney disease. When this is not possible, the secondary goal is a partial remission of proteinuria. Reduction or remission of proteinuria is the most important factor predictive of renal survival. We will review the current updated strategies for treatment of primary FSGS in children, including traditional therapies consisting of corticosteroids and calcineurin inhibitors and novel therapies such as rituximab, abatacept, adalimumab, and fresolimumab. Kyoung Hee Han and Seong Heon Kim Copyright © 2016 Kyoung Hee Han and Seong Heon Kim. All rights reserved. FSGS Recurrence in Adults after Renal Transplantation Sun, 10 Apr 2016 07:32:35 +0000 Recurrence of focal segmental glomerulosclerosis (FSGS) in the allograft occurs in 30–50% of patients, and it is associated with poor renal allograft survival. Major risk factors for recurrence are younger age at diagnosis, rapid progression to end-stage renal disease, white race, and the loss of previous allografts due to recurrence. Recent data support the hypothesis that circulating permeability factors play a crucial role in podocyte injury and progression of FSGS. Due to lack of controlled trials, the management of recurrent FSGS is inconsistent and highly empirical. Prophylactic and perioperative treatment with plasmapheresis and high-dose (intravenous) cyclosporine represent the main cornerstones of immunosuppressive therapy. In recent years, therapy with rituximab has shown promising results. Despite evidence of activation of the renin-angiotensin system (RAS) in recurrent FSGS and its association with progression, only limited data exist on the renoprotective role of RAS blockade in this setting. Further well designed studies are needed on pathogenesis risk factors and therapeutical options in FSGS and its recurrence after transplantation. Michael Rudnicki Copyright © 2016 Michael Rudnicki. All rights reserved. Treatment Strategies of Adult Primary Focal Segmental Glomerulosclerosis: A Systematic Review Focusing on the Last Two Decades Thu, 07 Apr 2016 06:29:53 +0000 Adult primary focal segmental glomerulosclerosis (FSGS) remains a therapeutic challenge for the treating physician. With the advent of novel immunosuppressive measures, our arsenal of therapeutic options increased considerably. The aim of this review was to summarize reports published over the last two decades which reported on treatment outcome. Most reports included patients with a steroid-resistant (SR) disease course, yet the cohort with the highest unmet need, since persistent nephrotic range proteinuria is associated with a poor renal prognosis and portends a high risk of developing end-stage renal disease. While in first-line treatment, steroid treatment remains the recommended standard with an overall remission rate of 50% and higher, optimal treatment strategies for steroid-dependent/multirelapsing (SD/MR) and SR patients have to be defined. In both entities, calcineurin inhibitors showed good efficacy, while mycophenolate mofetil was less effective in SR cases compared to those with SD/MR. The same was true for rituximab, a monoclonal antibody targeting B-cells. In resistant cases, addition of extracorporeal treatment options or treatment with alkylating agents may be considered. To shape the future for treatment of FSGS, international collaborations to conduct larger clinical trials are needed to identify potential novel efficacious immunosuppressive or immunomodulatory therapies. Arno Beer, Gert Mayer, and Andreas Kronbichler Copyright © 2016 Arno Beer et al. All rights reserved. Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1α Tue, 05 Apr 2016 09:26:19 +0000 In this study, rat models of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1α). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1α. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1α during hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1α can regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1α. Dan Wen, Yan-Fang Zou, Yao-Hui Gao, Qian Zhao, Yin-Yin Xie, Ping-Yan Shen, Yao-Wen Xu, Jing Xu, Yong-Xi Chen, Xiao-Bei Feng, Hao Shi, and Wen Zhang Copyright © 2016 Dan Wen et al. All rights reserved. Secondary Focal Segmental Glomerulosclerosis: From Podocyte Injury to Glomerulosclerosis Mon, 21 Mar 2016 07:25:39 +0000 Focal segmental glomerulosclerosis (FSGS) is a common cause of proteinuria and nephrotic syndrome leading to end stage renal disease (ESRD). There are two types of FSGS, primary (idiopathic) and secondary forms. Secondary FSGS shows less severe clinical features compared to those of the primary one. However, secondary FSGS has an important clinical significance because a variety of renal diseases progress to ESRD thorough the form of secondary FSGS. The defining feature of FSGS is proteinuria. The key event of FSGS is podocyte injury which is caused by multiple factors. Unanswered questions about how these factors act on podocytes to cause secondary FSGS are various and ill-defined. In this review, we provide brief overview and new insights into FSGS, podocyte injury, and their potential linkage suggesting clues to answer for treatment of the disease. Jae Seok Kim, Byoung Geun Han, Seung Ok Choi, and Seung-Kuy Cha Copyright © 2016 Jae Seok Kim et al. All rights reserved. Rapid Identification of Potential Drugs for Diabetic Nephropathy Using Whole-Genome Expression Profiles of Glomeruli Wed, 16 Mar 2016 12:48:53 +0000 Objective. To investigate potential drugs for diabetic nephropathy (DN) using whole-genome expression profiles and the Connectivity Map (CMAP). Methodology. Eighteen Chinese Han DN patients and six normal controls were included in this study. Whole-genome expression profiles of microdissected glomeruli were measured using the Affymetrix human U133 plus 2.0 chip. Differentially expressed genes (DEGs) between late stage and early stage DN samples and the CMAP database were used to identify potential drugs for DN using bioinformatics methods. Results. (1) A total of 1065 DEGs (FDR < 0.05 and fold change > 1.5) were found in late stage DN patients compared with early stage DN patients. (2) Piperlongumine, 15d-PGJ2 (15-delta prostaglandin J2), vorinostat, and trichostatin A were predicted to be the most promising potential drugs for DN, acting as NF-κB inhibitors, histone deacetylase inhibitors (HDACIs), PI3K pathway inhibitors, or PPARγ agonists, respectively. Conclusion. Using whole-genome expression profiles and the CMAP database, we rapidly predicted potential DN drugs, and therapeutic potential was confirmed by previously published studies. Animal experiments and clinical trials are needed to confirm both the safety and efficacy of these drugs in the treatment of DN. Jingsong Shi, Song Jiang, Dandan Qiu, Weibo Le, Xiao Wang, Yinhui Lu, and Zhihong Liu Copyright © 2016 Jingsong Shi et al. All rights reserved. Plasma Neutrophil Gelatinase-Associated Lipocalin as a Predictor of Cardiovascular Events in Patients with Chronic Kidney Disease Mon, 14 Mar 2016 13:14:51 +0000 Background. Our aim was to assess plasma neutrophil gelatinase-associated lipocalin (NGAL) as a predictor of cardiovascular (CV) events in patients with chronic kidney disease (CKD) and no history of CV events. Methods. This was a prospective observational cohort study of 252 patients with predialysis CKD. CV events were defined as CV death, acute coronary syndrome, and hospitalization for worsening heart failure, stroke, and aortic dissection. Results. During a median follow-up period of 63 months, 36 CV events occurred. On Cox stepwise multivariate analysis, plasma NGAL and B-type natriuretic peptide (BNP) were significant predictors of CV events. Kaplan-Meier incidence rates of CV event-free survival at 5 years were 96.6%, 92.9%, 85.9%, and 61.3%, respectively, among quartiles of plasma NGAL (). The C-index for the receiver-operating characteristic curves for CV events was greater when plasma NGAL was added to an established risk model (0.801, 95% CI 0.717–0.885), compared to the model without plasma NGAL (0.746, 95% CI 0.653–0.840, ). Conclusion. Elevated plasma NGAL could predict future CV events in CKD patients with no history of CV events and add incremental value to the established risk model. Midori Hasegawa, Junichi Ishii, Fumihiko Kitagawa, Hiroshi Takahashi, Kazuhiro Sugiyama, Masashi Tada, Kyoko Kanayama, Kazuo Takahashi, Hiroki Hayashi, Shigehisa Koide, Shigeru Nakai, Yukio Ozaki, and Yukio Yuzawa Copyright © 2016 Midori Hasegawa et al. All rights reserved. Factors Associated with the Choice of Peritoneal Dialysis in Patients with End-Stage Renal Disease Sun, 06 Mar 2016 13:07:01 +0000 Background. The purpose of this study was to analyze the factors associated with receiving peritoneal dialysis (PD) in patients with incident end-stage renal disease (ESRD) in a hospital in Southern Taiwan. Methods. The study included all consecutive patients with incident ESRD who participated in a multidisciplinary predialysis education (MPE) program and started their first dialysis therapy between January 1, 2008, and June 30, 2013, in the study hospital. We provided small group teaching sessions to advanced CKD patients and their family to enhance understanding of various dialysis modalities. Multivariate logistic regression models were used to analyze the association of patient characteristics with the chosen dialysis modality. Results. Of the 656 patients, 524 (80%) chose hemodialysis and 132 chose PD. Our data showed that young age, high education level, and high scores of activities of daily living (ADLs) were positively associated with PD treatment. Patients who received small group teaching sessions had higher percentages of PD treatment (30.5% versus 19.5%; ) and preparedness for dialysis (61.1% versus 46.6%; ). Conclusion. Young age, high education level, and high ADL score were positively associated with choosing PD. Early creation of vascular access may be a barrier for PD. Pei-Chun Chiang, Jia-Jeng Hou, Ing-Ching Jong, Peir-Haur Hung, Chih-Yen Hsiao, Tsung-Liang Ma, and Yueh-Han Hsu Copyright © 2016 Pei-Chun Chiang et al. All rights reserved. Clinical Characteristics and 30-Day Outcomes of Intermittent Hemodialysis for Acute Kidney Injury in an African Intensive Care Unit Thu, 03 Mar 2016 15:12:13 +0000 Introduction. Acute kidney injury (AKI) is a common occurrence in the intensive care unit (ICU). Studies have looked at outcomes of renal replacement therapy using intermittent haemodialysis (IHD) in ICUs with varying results. Little is known about the outcomes of using IHD in resource-limited settings where continuous renal replacement therapy (CRRT) is limited. We sought to determine outcomes of IHD among critically ill patients admitted to a low-income country ICU. Methods. A retrospective review of patient records was conducted. Patients admitted to the ICU who underwent IHD for AKI were included in the study. Patients’ demographic and clinical characteristics, cause of AKI, laboratory parameters, haemodialysis characteristics, and survival were interpreted and analyzed. Primary outcome was mortality. Results. Of 62 patients, 40 had complete records. Median age of patients was 38.5 years. Etiologic diagnoses associated with AKI included sepsis, malaria, and ARDS. Mortality was 52.5%. APACHE II (OR 4.550; 95% CI 1.2–17.5, ), mechanical ventilation (OR 13.063; 95% CI 2.3–72, ), and need for vasopressors (OR 16.8; 95% CI 3.4–82.6, ) had statistically significant association with mortality. Conclusion. IHD may be a feasible alternative for RRT in critically ill haemodynamically stable patients in low resource settings where CRRT may not be available. Arthur Kwizera, Janat Tumukunde, Lameck Ssemogerere, Emmanuel Ayebale, Peter Agaba, Jamali Yakubu, Aggrey Lubikire, Mary Nabukenya, and Robert Kalyesubula Copyright © 2016 Arthur Kwizera et al. All rights reserved. Impact of Iodinated Contrast on Renal Function and Hemodynamics in Rats with Chronic Hyperglycemia and Chronic Kidney Disease Mon, 29 Feb 2016 18:49:23 +0000 Iodinated contrast (IC) is clinically used in diagnostic and interventional procedures, but its use can result in contrast-induced acute kidney injury (CI-AKI). Chronic kidney disease (CKD) and chronic hyperglycemia (CH) are important predisposing factors to CI-AKI. The aim of this study was to investigate the impact of iodinated contrast on the renal function and hemodynamics in rats with chronic hyperglycemia and chronic kidney disease. A total of 30 rats were divided into six groups; Sham: control of chronic renal disease; Citrate: control of chronic hyperglycemia (CH); Nx5/6: rats with 5/6 nephrectomy; Chronic Hyperglycemia: rats receiving Streptozotocin 65 mg/kg; Nx5/6 + IC: rats Nx5/6 received 6 mL/kg of IC; CH + IC: Chronic hyperglycemia rats receiving 6 mL/kg of IC. Renal function (inulin clearance; urinary neutrophil gelatinase-associated lipocalin, NGAL) and hemodynamics (arterial blood pressure; renal blood flow; renal vascular resistance) were evaluated. Iodinated contrast significantly increased urinary NGAL and reduced inulin clearance, while the hemodynamics parameters showed changes in arterial blood pressure, renal blood flow, and renal vascular resistance in both CKD and CH groups. The results suggest that the iodinated contrast in risk factors models has important impact on renal function and hemodynamics. NGAL was confirmed to play a role of highlight in diagnosis of CI-AKI. Sheila Marques Fernandes, Daniel Malisani Martins, Cassiane Dezoti da Fonseca, Mirian Watanabe, and Maria de Fátima Fernandes Vattimo Copyright © 2016 Sheila Marques Fernandes et al. All rights reserved. Rhabdomyolysis following Cardiac Surgery: A Prospective, Descriptive, Single-Center Study Mon, 29 Feb 2016 09:31:50 +0000 Purpose. Rhabdomyolysis (RML) following cardiac surgery and its relationship with acute kidney injury (AKI) require investigation. Patients and Methods. All patients undergoing cardiac surgery in our hospital were enrolled in this prospective study during a 1-year period. To investigate the occurrence of RML and its association with AKI, all patients in the study underwent serial assessment of serum creatine kinase (CK) and myoglobin levels. Serial renal function, prior statin treatment, and outcome variables were recorded. Results. In total, 201 patients were included in the study: 185 men and 16 women with a mean age of 52.0±12.4 years. According to the presence of RML (CK of ≥2,500 U/L), the patients were divided into Group I (RML present in 17 patients) and Group II (RML absent in 184 patients). Seven patients in Group I had AKI (41%) where 34 patients in group II had AKI (18.4%), P=0.025. We observed a significantly longer duration of ventilation, length of stay in the ICU, and hospitalization in Group I (P<0.001 for all observations). Conclusions. An early elevation of serum CK above 2500 U/L postoperatively in high-risk cardiac surgery could be used to diagnose RML that may predict the concomitance of early AKI. Amr S. Omar, Hesham Ewila, Sameh Aboulnaga, Alejandro Kohn Tuli, and Rajvir Singh Copyright © 2016 Amr S. Omar et al. All rights reserved. Immunologic Changes Implicated in the Pathogenesis of Focal Segmental Glomerulosclerosis Wed, 17 Feb 2016 14:04:22 +0000 Focal segmental glomerulosclerosis is a histological pattern on renal biopsy caused by diverse mechanisms. In its primary form, a circulatory factor is implicated in disease onset and recurrence. The natural history of primary FSGS is unpredictable, since some patients are unresponsive towards immunosuppressive measures. Immunologic changes, leading to a proinflammatory or profibrotic milieu, have been implicated in disease progression, namely, glomerular scarring, eventually leading to end-stage renal disease. Among these, interleukin-1ß, tumor-necrosis factor-α (TNF-α), and transforming growth factor-ß1 (TGF-ß1) have emerged as important factors. Translating these findings into clinical practice dampened the enthusiasm, since both TNF-α and TGF-ß1 blockade failed to achieve significant control of the disease. More recently, a role of the complement system has been demonstrated which in fact may be another attractive target in clinical practice. Rituximab, blocking CD20-bearing cells, demonstrated conflicting data regarding efficacy in FSGS. Finally, the T-cell costimulating molecule B7-1 (CD80) is implicated in development of proteinuria in general. Blockade of this target demonstrated significant benefits in a small cohort of resistant patients. Taken together, this review focuses on immunology of FSGS, attributable to either the disease or progression, and discusses novel therapeutic approaches aiming at targeting immunologic factors. Andreas Kronbichler, Johannes Leierer, Jun Oh, Björn Meijers, and Jae Il Shin Copyright © 2016 Andreas Kronbichler et al. All rights reserved. Recombinant Brain Natriuretic Peptide for the Prevention of Contrast-Induced Nephropathy in Patients with Chronic Kidney Disease Undergoing Nonemergent Percutaneous Coronary Intervention or Coronary Angiography: A Randomized Controlled Trial Tue, 02 Feb 2016 12:40:01 +0000 The role of brain natriuretic peptide (BNP) in the prevention of contrast-induced nephropathy (CIN) is unknown. This study aimed to investigate BNP’s effect on CIN in chronic kidney disease (CKD) patients undergoing elective percutaneous coronary intervention (PCI) or coronary angiography (CAG). The patients were randomized to BNP (0.005 μg/kg/min before contrast media (CM) exposure and saline hydration, ) or saline hydration alone (). Cystatin C, serum creatinine (SCr) levels, and estimated glomerular filtration rates (eGFR) were assessed at several time points. The primary endpoint was CIN incidence; secondary endpoint included changes in cystatin C, SCr, and eGFR. CIN incidence was significantly lower in the BNP group compared to controls (6.6% versus 16.5%, ). In addition, a more significant deterioration of eGFR, cystatin C, and SCr from 48 h to 1 week () was observed in controls compared to the BNP group. Although eGFR gradually deteriorated in both groups, a faster recovery was achieved in the BNP group. Multivariate logistic regression revealed that using >100 mL of CM (odds ratio: 4.36, ) and BNP administration (odds ratio: 0.21, ) were independently associated with CIN. Combined with hydration, exogenous BNP administration before CM effectively decreases CIN incidence in CKD patients. Jinming Liu, Yanan Xie, Fang He, Zihan Gao, Yuming Hao, Xiuguang Zu, Liang Chang, and Yongjun Li Copyright © 2016 Jinming Liu et al. All rights reserved. Renal Ischemia/Reperfusion Injury in Diabetic Rats: The Role of Local Ischemic Preconditioning Tue, 26 Jan 2016 16:37:17 +0000 Background. The aim of this study was to evaluate the effects of local ischemic preconditioning using biochemical markers and histopathologically in the diabetic rat renal IR injury model. Methods. DM was induced using streptozotocin. Rats were divided into four groups: Group I, nondiabetic sham group (), Group II, diabetic sham group (), Group III, diabetic IR group (diabetic IR group, ), and Group IV, diabetic IR + local ischemic preconditioning group (diabetic IR + LIPC group, ). Ischemic renal injury was induced by clamping the bilateral renal artery for 45 min. 4 h following ischemia, clearance protocols were applied to assess biochemical markers and histopathologically in rat kidneys. Results. The histomorphologic total cell injury scores of the nondiabetic sham group were significantly lower than diabetic sham, diabetic IR, and diabetic IR + LIPC groups. Diabetic IR group scores were not significantly different than the diabetic sham group. But diabetic IR + LIPC group scores were significantly higher than the diabetic sham and diabetic IR groups. Conclusion. Local ischemic preconditioning does not reduce the risk of renal injury induced by ischemia/reperfusion in diabetic rat model. Sule Ozbilgin, Sevda Ozkardesler, Mert Akan, Nilay Boztas, Mucahit Ozbilgin, Bekir Ugur Ergur, Serhan Derici, Mehmet Ensari Guneli, and Reci Meseri Copyright © 2016 Sule Ozbilgin et al. All rights reserved. Functional Magnetic Resonance Imaging in Acute Kidney Injury: Present Status Tue, 26 Jan 2016 12:14:05 +0000 Acute kidney injury (AKI) is a common complication of hospitalization that is characterized by a sudden loss of renal excretory function and associated with the subsequent development of chronic kidney disease, poor prognosis, and increased mortality. Although the pathophysiology of renal functional impairment in the setting of AKI remains poorly understood, previous studies have identified changes in renal hemodynamics, perfusion, and oxygenation as key factors in the development and progression of AKI. The early assessment of these changes remains a challenge. Many established approaches are not applicable to humans because of their invasiveness. Functional renal magnetic resonance (MR) imaging offers an alternative assessment tool that could be used to evaluate renal morphology and function noninvasively and simultaneously. Thus, the purpose of this review is to illustrate the principle, application, and role of the techniques of functional renal MR imaging, including blood oxygen level-dependent imaging, arterial spin labeling, and diffusion-weighted MR imaging, in the management of AKI. The use of gadolinium in MR imaging may exacerbate renal impairment and cause nephrogenic systemic fibrosis. Therefore, dynamic contrast-enhanced MR imaging will not be discussed in this paper. Hai Ying Zhou, Tian Wu Chen, and Xiao Ming Zhang Copyright © 2016 Hai Ying Zhou et al. All rights reserved. New Therapeutic Concept of NAD Redox Balance for Cisplatin Nephrotoxicity Tue, 05 Jan 2016 09:42:20 +0000 Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects such as ototoxicity, nephrotoxicity, and peripheral neuropathy. Various mechanisms such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses are closely associated with cisplatin-induced nephrotoxicity; however, the precise mechanism remains unclear. The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of cellular energy metabolism and homeostasis. Recent studies have demonstrated associations between disturbance in intracellular NAD+ levels and clinical progression of various diseases through the production of reactive oxygen species and inflammation. Furthermore, we demonstrated that reduction of the intracellular NAD+/NADH ratio is critically involved in cisplatin-induced kidney damage through inflammation and oxidative stress and that increase of the cellular NAD+/NADH ratio suppresses cisplatin-induced kidney damage by modulation of potential damage mediators such as oxidative stress and inflammatory responses. In this review, we describe the role of NAD+ metabolism in cisplatin-induced nephrotoxicity and discuss a potential strategy for the prevention or treatment of cisplatin-induced adverse effects with a particular focus on NAD+-dependent cellular pathways. Gi-Su Oh, Hyung-Jin Kim, AiHua Shen, Su-Bin Lee, Sei-Hoon Yang, Hyeok Shim, Eun-Young Cho, Kang-Beom Kwon, Tae Hwan Kwak, and Hong-Seob So Copyright © 2016 Gi-Su Oh et al. All rights reserved. Addressing Peritoneal Dialysis: In Vitro PD Models, In Vivo Rodent PD Model, Clinical Biobanks, and Underutilization of PD Sun, 03 Jan 2016 13:20:06 +0000 Robert H. J. Beelen, Donald J. Fraser, Peter Rutherford, and Janusz Witowski Copyright © 2016 Robert H. J. Beelen et al. All rights reserved. Tanshinone IIA Attenuates Renal Fibrosis after Acute Kidney Injury in a Mouse Model through Inhibition of Fibrocytes Recruitment Tue, 29 Dec 2015 08:25:02 +0000 Acute kidney injury (AKI) is associated with an increased risk of developing advanced chronic kidney disease (CKD). Yet, effective interventions to prevent this conversion are unavailable for clinical practice. In this study, we examined the beneficial effects of Tanshinone IIA on renal fibrosis in a mouse model of folic acid induced AKI. We found that Tanshinone IIA treatment significantly attenuated the folic acid elicited kidney dysfunction on days 3, 14, and 28. This effect was concomitant with a much lessened accumulation of fibronectin and collagen in tubulointerstitium 28 days after folic acid injury, denoting an ameliorated renal fibrosis. The kidney protective and antifibrotic effect of Tanshinone IIA was likely attributable to an early inhibition of renal recruitment of fibrocytes positive for both CD45 and collagen I. Mechanistically, Tanshinone IIA treatment not only markedly diminished renal expression of chemoattractants for fibrocytes such as TGF1 and MCP-1, but also significantly reduced circulating fibrocytes at the acute phase of kidney injury. These data suggested that Tanshinone IIA might be a novel therapy for preventing progression of CKD after AKI. Chunming Jiang, Qiuyuan Shao, Bo Jin, Rujun Gong, Miao Zhang, and Biao Xu Copyright © 2015 Chunming Jiang et al. All rights reserved. Effects of Low-Protein Diets Supplemented with Ketoacid on Expression of TGF-β and Its Receptors in Diabetic Rats Tue, 15 Dec 2015 13:30:00 +0000 TGF-β1 has been recognized as a key mediator in DN. This study aimed to observe the effects of low-protein diets supplemented with ketoacid on mRNA and protein expression of TGF-β and TβRI and t TβRII receptors in the renal tissue of diabetic rats. A diabetes model was established in 72 male SD rats. They were then equally randomized to three groups: NPD group, LPD group, and LPD + KA group. Additional 24 male SD rats receiving normal protein diets were used as the control. Eight rats from each group were sacrificed at weeks 4, 8, and 12 after treatment, from which SCr, BUN, serum albumin, and 24 h urinary protein excretion were collected. The expressions of TGF-β1, TβRI, and TβRII in LPD and LPD + KA groups were significantly lower than those in NPD group and lower in LPD + KA group than those in LPD group. Low-protein diets supplemented with ketoacid have been demonstrated to provide a protective effect on the renal function as represented by reduced SCr, BUN, and urinary protein excretion, probably through downregulating the gene expression of TGF-β1 and its receptors in LPD + KA group. Xiu Yang, Ming Yang, Ming Cheng, Li-Bin Ma, Xiang-Cheng Xie, Shuai Han, Bo Zhang, Xiao Fei, Ming Wang, and Chang-Lin Mei Copyright © 2015 Xiu Yang et al. All rights reserved. Effluent Tenascin-C Levels Reflect Peritoneal Deterioration in Peritoneal Dialysis: MAJOR IN PD Study Sun, 06 Dec 2015 14:03:29 +0000 Peritoneal deterioration causing structural changes and functional decline is a major complication of peritoneal dialysis (PD). The aim of this study was to explore effluent biomarkers reflecting peritoneal deterioration. In an animal study, rats were intraperitoneally administered with PD fluids adding 20 mM methylglyoxal (MGO) or 20 mM formaldehyde (FA) every day for 21 days. In the MGO-treated rats, tenascin-C (TN-C) levels in the peritoneal effluents were remarkably high and a cluster of TN-C-positive mesothelial cells with epithelial-to-mesenchymal transition- (EMT-) like change excessively proliferated at the peritoneal surface, but not in the FA-treated rats. Effluent matrix metalloproteinase-2 (MMP-2) levels increased in both the MGO- and FA-treated rats. In a clinical study at 18 centers between 2006 and 2013, effluent TN-C and MMP-2 levels were quantified in 182 PD patients with end-stage renal disease. Peritoneal function was estimated using the peritoneal equilibration test (PET). From the PET results, the D/P Cr ratio was correlated with effluent levels of TN-C (ρ = 0.57, ) and MMP-2 (ρ = 0.73, ). We suggest that TN-C in the effluents may be a diagnostic marker for peritoneal deterioration with EMT-like change in mesothelial cells in PD. Ichiro Hirahara, Eiji Kusano, Toshimi Imai, Yoshiyuki Morishita, Makoto Inoue, Tetsu Akimoto, Osamu Saito, Shigeaki Muto, and Daisuke Nagata Copyright © 2015 Ichiro Hirahara et al. All rights reserved. Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT Wed, 25 Nov 2015 12:12:32 +0000 Preservation of peritoneal membrane (PM) is essential for long-term survival in peritoneal dialysis (PD). Continuous presence of PD fluids (PDF) in the peritoneal cavity generates chronic inflammation and promotes changes of the PM, such as fibrosis, angiogenesis, and lymphangiogenesis. Mesothelial-to-mesenchymal transition (MMT) and endothelial-to-mesenchymal transition (Endo-MT) seem to play a central role in this pathogenesis. We speculated that Rapamycin, a potent immunosuppressor, could be beneficial by regulating blood and lymphatic vessels proliferation. We demonstrate that mice undergoing a combined PD and Rapamycin treatment (PDF + Rapa group) presented a reduced PM thickness and lower number of submesothelial blood and lymphatic vessels, as well as decreased MMT and Endo-MT, comparing with their counterparts exposed to PD alone (PDF group). Peritoneal water transport in the PDF + Rapa group remained at control level, whereas PD effluent levels of VEGF, TGF-β, and TNF-α were lower than in the PDF group. Moreover, the treatment of mesothelial cells with Rapamycin in vitro significantly decreased VEGF synthesis and selectively inhibited the VEGF-C and VEGF-D release when compared with control cells. Thus, Rapamycin has a protective effect on PM in PD through an antifibrotic and antiproliferative effect on blood and lymphatic vessels. Moreover, it inhibits Endo-MT and, at least partially, MMT. Guadalupe Tirma González-Mateo, Anna Rita Aguirre, Jesús Loureiro, Hugo Abensur, Pilar Sandoval, José Antonio Sánchez-Tomero, Gloria del Peso, José Antonio Jiménez-Heffernan, Vicente Ruiz-Carpio, Rafael Selgas, Manuel López-Cabrera, Abelardo Aguilera, and Georgios Liappas Copyright © 2015 Guadalupe Tirma González-Mateo et al. All rights reserved. Pauci-Immune Crescentic Glomerulonephritis: An ANCA-Associated Vasculitis Wed, 25 Nov 2015 07:35:34 +0000 Rapidly progressive glomerulonephritis (RPGN) is a syndrome signified by a precipitous loss of renal function, with features of glomerulonephritis including dysmorphic erythrocyturia and glomerular proteinuria. RPGN is associated with extensive crescent formation, and, thus, the clinical term RPGN is often used interchangeably with the pathologic term crescentic glomerulonephritis (CGN). From an immunopathologic standpoint, primary RPGN is divided into pauci-immune GN (PICG), anti-GBM GN, and immune complex GN. PICG, the most common etiology of primary RPGN, refers to a necrotizing glomerulonephritis with few or no immune deposits by immunofluorescence (IF) or electron microscopy (EM). In most patients, pauci-immune CGN is a component of a systemic small vessel vasculitis such as granulomatosis with polyangiitis (GPA). Approximately 90% of patients with PICG have circulating ANCA antibodies, leading to the nomenclature ANCA-associated vasculitis (AAV). Recent research has identified several other antibodies associated with PICG, which is now understood to be a complex spectrum of disease with considerable overlap in terms of clinical phenotype and outcomes. In addition, several genetic and environmental factors have recently been implicated in the pathogenesis of this disorder. With new prognostic classifications, enhanced understanding of immunopathologic mechanisms, and novel treatment paradigms, clinical and experimental interest in PICG remains high. Rafeel Syed, Amina Rehman, Gautam Valecha, and Suzanne El-Sayegh Copyright © 2015 Rafeel Syed et al. All rights reserved. Overcoming the Underutilisation of Peritoneal Dialysis Wed, 11 Nov 2015 11:28:41 +0000 Peritoneal dialysis is troubled with declining utilisation as a form of renal replacement therapy in developed countries. We review key aspects of therapy evidenced to have a potential to increase its utilisation. The best evidence to repopulate PD programmes is provided for the positive impact of timely referral and systematic and motivational predialysis education: average odds ratio for instituting peritoneal dialysis versus haemodialysis was 2.6 across several retrospective studies on the impact of predialysis education. Utilisation of PD for unplanned acute dialysis starts facilitated by implantation of peritoneal catheters by interventional nephrologists may diminish the vast predominance of haemodialysis done by central venous catheters for unplanned dialysis start. Assisted peritoneal dialysis can improve accessibility of home based dialysis to elderly, frail, and dependant patients, whose quality of life on replacement therapy may benefit most from dialysis performed at home. Peritoneal dialysis providers should perform close monitoring, preventing measures, and timely prophylactic therapy in patients judged to be prone to EPS development. Each peritoneal dialysis programme should regularly monitor, report, and act on key quality indicators to manifest its ability of constant quality improvement and elevate the confidence of interested patients and financing bodies in the programme. Jernej Pajek Copyright © 2015 Jernej Pajek. All rights reserved. Senescence-Associated Changes in Proteome and O-GlcNAcylation Pattern in Human Peritoneal Mesothelial Cells Tue, 10 Nov 2015 06:03:31 +0000 Introduction. Senescence of peritoneal mesothelial cells represents a biological program defined by arrested cell growth and altered cell secretory phenotype with potential impact in peritoneal dialysis. This study aims to characterize cellular senescence at the level of global protein expression profiles and modification of proteins with O-linked N-acetylglucosamine (O-GlcNAcylation). Methods. A comparative proteomics analysis between young and senescent human peritoneal mesothelial cells (HPMC) was performed using two-dimensional gel electrophoresis. O-GlcNAc status was assessed by Western blot under normal conditions and after modulation with 6-diazo-5-oxo-L-norleucine (DON) to decrease O-GlcNAcylation or O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenyl carbamate (PUGNAc) to increase O-GlcNAcylation. Results. Comparison of protein pattern of senescent and young HPMC revealed 29 differentially abundant protein spots, 11 of which were identified to be actin (cytoplasmic 1 and 2), cytokeratin-7, cofilin-2, transgelin-2, Hsp60, Hsc70, proteasome β-subunits (type-2 and type-3), nucleoside diphosphate kinase A, and cytosolic 5′(3′)-deoxyribonucleotidase. Although the global level of O-GlcNAcylation was comparable, senescent cells were not sensitive to modulation by PUGNAc. Discussion. This study identified changes of the proteome and altered dynamics of O-GlcNAc regulation in senescent mesothelial cells. Whereas changes in cytoskeleton-associated proteins likely reflect altered cell morphology, changes in chaperoning and housekeeping proteins may have functional impact on cellular stress response in peritoneal dialysis. Rebecca Herzog, Silvia Tarantino, András Rudolf, Christoph Aufricht, Klaus Kratochwill, and Janusz Witowski Copyright © 2015 Rebecca Herzog et al. All rights reserved. The Role and Mechanism of α-Klotho in the Calcification of Rat Aortic Vascular Smooth Muscle Cells Mon, 02 Nov 2015 12:57:12 +0000 Objective. To investigate the role and possible mechanism of α-Klotho in the calcification and the osteogenic transition of cultured VSMCs. Methods. VSMCs were cultured in vitro and divided into 5 groups, each using a different medium: (1) control; (2) β-GP; (3) β-GP + Klotho; (4) β-GP + LiCl; (5) β-GP + Klotho + LiCl. Calcium deposits were visualized using Alizarin Red S staining. The calcium concentrations were determined by the o-cresolphthalein complexone method. BMP2, Runx2 and β-catenin levels were estimated by western blotting, and the level of α-SMA was determined by using immunofluorescence at day 12. Results. β-GP induced an increase in the expression of BMP2, Runx2, and β-catenin. The calcium content increased, and the expression of α-SMA decreased. Alizarin Red S staining was positive under the high phosphorus conditions. BMP2, Runx2, and β-catenin levels and the calcium content decreased when the cells were cultured with rmKlotho; however, the levels of each were upregulated after treatment with the LiCl. Conclusions. Klotho can ameliorate the calcification and osteogenic transition of VSMCs induced by β-GP. The mechanism of Klotho in preventing calcification in VSMCs may be partially mediated by the inhibition of the Wnt/β-catenin signaling pathway. Tianlei Chen, Huijuan Mao, Cheng Chen, Lin Wu, Ningning Wang, Xiufen Zhao, Jun Qian, and Changying Xing Copyright © 2015 Tianlei Chen et al. All rights reserved. Protective Effects of Paricalcitol on Peritoneal Remodeling during Peritoneal Dialysis Thu, 29 Oct 2015 06:20:08 +0000 Peritoneal dialysis (PD) is associated with structural and functional alterations of the peritoneal membrane, consisting of fibrosis, angiogenesis, and loss of ultrafiltration capacity. Vitamin D receptor activation (VDRA) plays an important role in mineral metabolism and inflammation, but also antiangiogenic and antifibrotic properties have been reported. Therefore, the effects of active vitamin D treatment on peritoneal function and remodeling were investigated. Rats were either kept naïve to PDF exposure or daily exposed to 10 mL PDF and were treated for five or seven weeks with oral paricalcitol or vehicle control. Non-PDF-exposed rats showed no peritoneal changes upon paricalcitol treatment. Paricalcitol reduced endogenous calcitriol but did not affect mineral homeostasis. However, upon PDF exposure, loss of ultrafiltration capacity ensued which was fully rescued by paricalcitol treatment. Furthermore, PD-induced ECM thickening was significantly reduced and omental PD-induced angiogenesis was less pronounced upon paricalcitol treatment. No effect of paricalcitol treatment on total amount of peritoneal cells, peritoneal leukocyte composition, and epithelial to mesenchymal transition (EMT) was observed. Our data indicates that oral VDRA reduces tissue remodeling during chronic experimental PD and prevents loss of ultrafiltration capacity. Therefore, VDRA is potentially relevant in the prevention of treatment technique failure in PD patients. Andrea W. D. Stavenuiter, Karima Farhat, Marc Vila Cuenca, Margot N. Schilte, Eelco D. Keuning, Nanne J. Paauw, Pieter M. ter Wee, Robert H. J. Beelen, and Marc G. Vervloet Copyright © 2015 Andrea W. D. Stavenuiter et al. All rights reserved. Geographic Variation of Chronic Kidney Disease Prevalence: Correlation with the Incidence of Renal Cell Carcinoma or Urothelial Carcinoma? Wed, 28 Oct 2015 12:23:23 +0000 Background. The aim of this study is to evaluate whether geographic variations in the prevalence of late-stage chronic kidney disease (CKD) exist and are associated with incidence rates of renal cell carcinoma (RCC), upper tract urothelial carcinoma (UTUC), or lower tract urothelial carcinoma (LTUC). Methods. Prevalence rates of late-stage CKD for 366 townships () in Taiwan were calculated for 1,518,241 and 1,645,151 subjects aged 40 years or older in years 2010 and 2009, respectively. Late-stage CKD prevalence in year 2010 was used as a training set and its age-adjusted standardized morbidity rates (ASMR) were divided into three groups as defined <1.76%, 1.76% ≤ ASMR < 2.64%, and ≥2.64%, respectively. Year 2009, defined as the validation set, was used to validate the results. Results. The ASMR of late-stage CKD in years 2010 and 2009 were 1.76%, and 2.09%, respectively. Geographic variations were observed, with notably higher rates of disease in areas of the central, southwestern mountainside, and southeastern seaboard. There were no significant differences among different combined risk groups of RCC, UTUC, and LTUC incidence. Conclusion. The substantial geographic variations in the prevalence of late-stage CKD exist, but are not correlated with RCC, UTUC, or LTUC incidence. Yit-Sheung Yap, Kai-Wen Chuang, Chun-Ju Chiang, Hung-Yi Chuang, and Sheng-Nan Lu Copyright © 2015 Yit-Sheung Yap et al. All rights reserved. A Novel Mouse Model of Peritoneal Dialysis: Combination of Uraemia and Long-Term Exposure to PD Fluid Mon, 26 Oct 2015 13:37:23 +0000 Different animal models for peritoneal dialysis (PD) have been used in the past decades to develop PD fluids compatible with patient life and to identify markers of peritoneal fibrosis and inflammation. Only few of those studies have taken into account the importance of uraemia-induced alterations at both systemic and peritoneal levels. Moreover, some animal studies which have reported about PD in a uremic setting did not always entirely succeed in terms of uraemia establishment and animal survival. In the present study we induced uraemia in the recently established mouse PD exposure model in order to obtain a more clinically relevant mouse model for kidney patients. This new designed model reflected both the slight thickening of peritoneal membrane induced by uraemia and the significant extracellular matrix deposition due to daily PD fluid instillation. In addition the model offers the opportunity to perform long-term exposure to PD fluids, as it is observed in the clinical setting, and gives the advantage to knock out candidate markers for driving peritoneal inflammatory mechanisms. E. Ferrantelli, G. Liappas, E. D. Keuning, M. Vila Cuenca, G. González-Mateo, M. Verkaik, M. López-Cabrera, and R. H. J. Beelen Copyright © 2015 E. Ferrantelli et al. All rights reserved. Antiphospholipase A2 Receptor Autoantibodies: A Step Forward in the Management of Primary Membranous Nephropathy Tue, 20 Oct 2015 09:46:11 +0000 Since the identification of PLA2R (M-type phospholipase A2 receptor) as the first human antigenic target in primary membranous nephropathy (MN), perpetual progress has been made in understanding the pathogenesis of this disease. Accumulating clinical data support a pathogenic role for the anti-PLA2R antibodies (PLA2R ABs), but confirmation in an animal model is still lacking. However, PLA2R ABs were related to disease activity and outcome, as well as to response therapy. Accordingly, PLA2R ABs assay seems to be promising tool not only to diagnose MN but also to predict the course of the disease and could open the way to personalize therapy. Nevertheless, validation of a universal assay with high precision and definition of cut-off levels, followed by larger studies with a prolonged follow-up period, are needed to confirm these prospects. Bogdan Obrisca, Gener Ismail, Roxana Jurubita, Catalin Baston, Andreea Andronesi, and Gabriel Mircescu Copyright © 2015 Bogdan Obrisca et al. All rights reserved. Regulation of Synthesis and Roles of Hyaluronan in Peritoneal Dialysis Tue, 13 Oct 2015 08:06:16 +0000 Hyaluronan (HA) is a ubiquitous extracellular matrix glycosaminoglycan composed of repeated disaccharide units of alternating D-glucuronic acid and D-N-acetylglucosamine residues linked via alternating β-1,4 and β-1,3 glycosidic bonds. HA is synthesized in humans by HA synthase (HAS) enzymes 1, 2, and 3, which are encoded by the corresponding HAS genes. Previous in vitro studies have shown characteristic changes in HAS expression and increased HA synthesis in response to wounding and proinflammatory cytokines in human peritoneal mesothelial cells. In addition, in vivo models and human peritoneal biopsy samples have provided evidence of changes in HA metabolism in the fibrosis that at present accompanies peritoneal dialysis treatment. This review discusses these published observations and how they might contribute to improvement in peritoneal dialysis. Timothy Bowen, Soma Meran, Aled P. Williams, Lucy J. Newbury, Matthias Sauter, and Thomas Sitter Copyright © 2015 Timothy Bowen et al. All rights reserved. Cross-Omics Comparison of Stress Responses in Mesothelial Cells Exposed to Heat- versus Filter-Sterilized Peritoneal Dialysis Fluids Thu, 01 Oct 2015 07:38:16 +0000 Recent research suggests that cytoprotective responses, such as expression of heat-shock proteins, might be inadequately induced in mesothelial cells by heat-sterilized peritoneal dialysis (PD) fluids. This study compares transcriptome data and multiple protein expression profiles for providing new insight into regulatory mechanisms. Two-dimensional difference gel electrophoresis (2D-DIGE) based proteomics and topic defined gene expression microarray-based transcriptomics techniques were used to evaluate stress responses in human omental peritoneal mesothelial cells in response to heat- or filter-sterilized PD fluids. Data from selected heat-shock proteins were validated by 2D western-blot analysis. Comparison of proteomics and transcriptomics data discriminated differentially regulated protein abundance into groups depending on correlating or noncorrelating transcripts. Inadequate abundance of several heat-shock proteins following exposure to heat-sterilized PD fluids is not reflected on the mRNA level indicating interference beyond transcriptional regulation. For the first time, this study describes evidence for posttranscriptional inadequacy of heat-shock protein expression by heat-sterilized PD fluids as a novel cytotoxic property. Cross-omics technologies introduce a novel way of understanding PDF bioincompatibility and searching for new interventions to reestablish adequate cytoprotective responses. Klaus Kratochwill, Thorsten O. Bender, Anton M. Lichtenauer, Rebecca Herzog, Silvia Tarantino, Katarzyna Bialas, Achim Jörres, and Christoph Aufricht Copyright © 2015 Klaus Kratochwill et al. All rights reserved. Vitamin D Can Ameliorate Chlorhexidine Gluconate-Induced Peritoneal Fibrosis and Functional Deterioration through the Inhibition of Epithelial-to-Mesenchymal Transition of Mesothelial Cells Thu, 01 Oct 2015 07:36:11 +0000 Background. Peritoneal dialysis (PD) can induce fibrosis and functional alterations in PD patients’ peritoneal membranes, due to long-term unphysiological dialysate exposure, partially occurring via triggering of epithelial-to-mesenchymal transition (EMT) in peritoneal mesothelial cells (MCs). Vitamin D can ameliorate these negative effects; however, the mechanism remains unexplored. Therefore, we investigated its possible links to MCs EMT inhibition. Methods. Peritoneal fibrosis was established in Sprague-Dawley rats by chlorhexidine gluconate (CG) intraperitoneal injection for 21 days, with and without 1α,25(OH)2D3 treatment. Morphological and functional evaluation and western blot analysis of EMT marker were performed upon peritoneum tissue. In vitro study was also performed in a primary human peritoneal MC culture system; MCs were incubated with transforming growth factor-β1 (TGF-β1) in the absence or presence of 1α,25(OH)2D3. EMT marker expression, migration activities, and cytoskeleton redistribution of MCs were determined. Results. 1α,25(OH)2D3 ameliorated CG-induced morphological and functional deterioration in animal model, along with CG-induced upregulation of α-SMA and downregulation of E-cadherin expression. Meanwhile, 1α,25(OH)2D3 also ameliorated TGF-β1-induced decrease in E-cadherin expression, increase in Snai1 and α-SMA expression, intracellular F-actin redistribution, and migration activity in vitro. Conclusion. 1α,25(OH)2D3 can ameliorate CG-induced peritoneal fibrosis and attenuate functional deterioration through inhibiting MC EMT. Yi-Che Lee, Shih-Yuan Hung, Hung-Hsiang Liou, Tsun-Mei Lin, Chu-Hung Tsai, Sheng-Hsiang Lin, Yau-Sheng Tsai, Min-Yu Chang, Hsi-Hao Wang, Li-Chun Ho, Yi-Ting Chen, Ching-Fang Wu, Ho-Ching Chen, Hsin-Pao Chen, Kuang-Wen Liu, Chih-I. Chen, Kuan Min She, Hao-Kuang Wang, Chi-Wei Lin, and Yuan-Yow Chiou Copyright © 2015 Yi-Che Lee et al. All rights reserved. microRNA Regulation of Peritoneal Cavity Homeostasis in Peritoneal Dialysis Thu, 01 Oct 2015 07:19:48 +0000 Preservation of peritoneal cavity homeostasis and peritoneal membrane function is critical for long-term peritoneal dialysis (PD) treatment. Several microRNAs (miRNAs) have been implicated in the regulation of key molecular pathways driving peritoneal membrane alterations leading to PD failure. miRNAs regulate the expression of the majority of protein coding genes in the human genome, thereby affecting most biochemical pathways implicated in cellular homeostasis. In this review, we report published findings on miRNAs and PD therapy, with emphasis on evidence for changes in peritoneal miRNA expression during long-term PD treatment. Recent work indicates that PD effluent- (PDE-) derived cells change their miRNA expression throughout the course of PD therapy, contributing to the loss of peritoneal cavity homeostasis and peritoneal membrane function. Changes in miRNA expression profiles will alter regulation of key molecular pathways, with the potential to cause profound effects on peritoneal cavity homeostasis during PD treatment. However, research to date has mainly adopted a literature-based miRNA-candidate methodology drawing conclusions from modest numbers of patient-derived samples. Therefore, the study of miRNA expression during PD therapy remains a promising field of research to understand the mechanisms involved in basic peritoneal cell homeostasis and PD failure. Melisa Lopez-Anton, Timothy Bowen, and Robert H. Jenkins Copyright © 2015 Melisa Lopez-Anton et al. All rights reserved. New Developments in Peritoneal Fibroblast Biology: Implications for Inflammation and Fibrosis in Peritoneal Dialysis Thu, 01 Oct 2015 07:05:24 +0000 Uraemia and long-term peritoneal dialysis (PD) can lead to fibrotic thickening of the peritoneal membrane, which may limit its dialytic function. Peritoneal fibrosis is associated with the appearance of myofibroblasts and expansion of extracellular matrix. The extent of contribution of resident peritoneal fibroblasts to these changes is a matter of debate. Recent studies point to a significant heterogeneity and complexity of the peritoneal fibroblast population. Here, we review recent developments in peritoneal fibroblast biology and summarize the current knowledge on the involvement of peritoneal fibroblasts in peritoneal inflammation and fibrosis. Janusz Witowski, Edyta Kawka, Andras Rudolf, and Achim Jörres Copyright © 2015 Janusz Witowski et al. All rights reserved. The Potential Role of NFAT5 and Osmolarity in Peritoneal Injury Thu, 01 Oct 2015 06:30:52 +0000 A rise in osmotic concentration (osmolarity) activates the transcription factor Nuclear Factor of Activated T Cells 5 (NFAT5, also known as Tonicity-responsive Enhancer Binding Protein, TonEBP). This is part of a regulatory mechanism of cells adjusting to environments of high osmolarity. Under physiological conditions these are particularly important in the kidney. Activation of NFAT5 results in the modulation of various genes including some which promote inflammation. The osmolarity increases in patients with renal failure. Additionally, in peritoneal dialysis the cells of the peritoneal cavity are repeatedly exposed to a rise and fall in osmotic concentrations. Here we review the current information about NFAT5 activation in uremic patients and patients on peritoneal dialysis. We suggest that high osmolarity promotes injury in the “uremic” milieu, which results in inflammation locally in the peritoneal membrane, but most likely also in the systemic circulation. Harald Seeger, Daniel Kitterer, Joerg Latus, Mark Dominik Alscher, Niko Braun, and Stephan Segerer Copyright © 2015 Harald Seeger et al. All rights reserved. Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport Mon, 28 Sep 2015 11:36:03 +0000 A serine/threonine kinase Akt is a key mediator in various signaling pathways including regulation of renal tubular transport. In proximal tubules, Akt mediates insulin signaling via insulin receptor substrate 2 (IRS2) and stimulates sodium-bicarbonate cotransporter (NBCe1), resulting in increased sodium reabsorption. In insulin resistance, the IRS2 in kidney cortex is exceptionally preserved and may mediate the stimulatory effect of insulin on NBCe1 to cause hypertension in diabetes via sodium retention. Likewise, in distal convoluted tubules and cortical collecting ducts, insulin-induced Akt phosphorylation mediates several hormonal signals to enhance sodium-chloride cotransporter (NCC) and epithelial sodium channel (ENaC) activities, resulting in increased sodium reabsorption. Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates aldosterone signaling. Insulin can stimulate SGK1 to exert various effects on renal transporters. In renal cortical collecting ducts, SGK1 regulates the expression level of ENaC through inhibition of its degradation. In addition, SGK1 and Akt cooperatively regulate potassium secretion by renal outer medullary potassium channel (ROMK). Moreover, sodium-proton exchanger 3 (NHE3) in proximal tubules is possibly activated by SGK1. This review focuses on recent advances in understanding of the roles of Akt and SGK1 in the regulation of renal tubular transport. Nobuhiko Satoh, Motonobu Nakamura, Masashi Suzuki, Atsushi Suzuki, George Seki, and Shoko Horita Copyright © 2015 Nobuhiko Satoh et al. All rights reserved. Significance of Neutrophil Gelatinase-Associated Lipocalin Level-to-Serum Creatinine Ratio for Assessing Severity of Inflammation in Patients with Renal Dysfunction Mon, 28 Sep 2015 07:01:29 +0000 The aim of this study was to assess the significance of the neutrophil gelatinase-associated lipocalin/serum creatinine ratio (NGAL/sCr ratio) in patients with renal dysfunction. The percent difference between plasma NGAL level and the NGAL/sCr ratio was 36.7% (95% CI, 18.4–83.7%) in patients with sCr level ≥ 1.2 mg/dL. In a multivariate analysis, high sensitivity C-reactive protein (hsCRP) was significantly associated with the NGAL/sCr ratio and plasma NGAL level ( and , resp., ). In a receiver operating characteristics curve, the diagnostic ability of the NGAL/sCr ratio to identify hsCRP > 4.0 mg/dL was superior to that of NGAL [0.783 (95% CI, 0.674–0.892) versus 0.733 (95% CI, 0.615–0.852), ]. The area under the curve of the NGAL/sCr ratio was larger than that of hsCRP to detect corrected erythrocyte sedimentation rate > 25 mm/h and the neutrophil-to-lymphocyte ratio >4.5 in renal dysfunction. In short, the NGAL/sCr ratio may offer useful information when screening patients with both systemic inflammation and renal dysfunction. Jong Weon Choi, Tatsuyoshi Fujii, and Noriyoshi Fujii Copyright © 2015 Jong Weon Choi et al. All rights reserved. Risk Factors for Development of Septic Shock in Patients with Urinary Tract Infection Tue, 25 Aug 2015 12:35:28 +0000 Introduction. Severe sepsis and septic shock are associated with substantial mortality. However, few studies have assessed the risk of septic shock among patients who suffered from urinary tract infection (UTI). Materials and Methods. This retrospective study recruited UTI cases from an acute care hospital between January 2006 and October 2012 with prospective data collection. Results. Of the 710 participants admitted for UTI, 80 patients (11.3%) had septic shock. The rate of bacteremia is 27.9%; acute kidney injury is 12.7%, and the mortality rate is 0.28%. Multivariable logistic regression analyses indicated that coronary artery disease (CAD) (OR: 2.521, 95% CI: 1.129–5.628, ), congestive heart failure (CHF) (OR: 4.638, 95% CI: 1.908–11.273, ), and acute kidney injury (AKI) (OR: 2.992, 95% CI: 1.610–5.561, ) were independently associated with septic shock in patients admitted with UTI. In addition, congestive heart failure (female, OR: 4.076, 95% CI: 1.355–12.262, ; male, OR: 5.676, 95% CI: 1.103–29.220, , resp.) and AKI (female, OR: 2.995, 95% CI: 1.355–6.621, ; male, OR: 3.359, 95% CI: 1.158–9.747, , resp.) were significantly associated with risk of septic shock in both gender groups. Conclusion. This study showed that patients with a medical history of CAD or CHF have a higher risk of shock when admitted for UTI treatment. AKI, a complication of UTI, was also associated with septic shock. Therefore, prompt and aggressive management is recommended for those with higher risks to prevent subsequent treatment failure in UTI patients. Chih-Yen Hsiao, Huang-Yu Yang, Chih-Hsiang Chang, Hsing-Lin Lin, Chao-Yi Wu, Meng-Chang Hsiao, Peir-Haur Hung, Su-Hsun Liu, Cheng-Hao Weng, Cheng-Chia Lee, Tzung-Hai Yen, Yung-Chang Chen, and Tzu-Chin Wu Copyright © 2015 Chih-Yen Hsiao et al. All rights reserved. Sepsis and AKI in Clinical Emergency Room Patients: The Role of Urinary NGAL Tue, 14 Jul 2015 06:01:20 +0000 Background. Few studies have investigated the predictive properties of urinary (u) NGAL as an AKI marker in septic population. Objectives. This study evaluated the efficacy of uNGAL as predictor of AKI and death in septic patients admitted to the clinical emergency room (ER). Methodology. We prospectively studied patients with sepsis admitted to the ER. Urine was analyzed for NGAL within the first 24 hours after admission (classified as NGAL1), between 24 and 48 h (NGAL2), and at moment of AKI diagnosis (NGAL3). Results. Among 168 septic patients admitted to ER, 72% developed AKI. The uNGAL and its relationship with creatinine (Cr) were high in septic patients but statistically higher in those with sepsis and AKI. The uNGAL1 and uNGAL2, as well as uNGAL1/uCr1 and uNGAL2/uCr2, were good predictors for AKI (AUC-ROC 0.73, 0.70, 0.77, and 0.84, resp.). The uNGAL1 and uNGAL1/uCr1 were poor predictors for death (AUC-ROC 0.66 and 0.68, resp.), whereas uNGAL2 and uNGAL2/uCr2 were better predictors (AUC-ROC 0.70 and 0.81, resp.). Conclusion. The uNGAL is highly sensitive but nonspecific predictor of AKI and death in septic patients admitted into ER. Hong Si Nga, Pamela Medeiros, Precil Menezes, Ramaiane Bridi, André Balbi, and Daniela Ponce Copyright © 2015 Hong Si Nga et al. All rights reserved. Type of Renal Replacement Therapy (Hemodialysis versus Peritoneal Dialysis) Does Not Affect Cytokine Gene Expression or Clinical Parameters of Renal Transplant Candidates Wed, 08 Jul 2015 08:27:19 +0000 Patients with renal failure suffer from immune disturbances, caused by uremic toxins and influenced by dialysis treatment. The aim of the present study was to reveal whether type of dialysis modality (hemodialysis, HD, versus peritoneal dialysis, PD) differentially affects the immunocompetence, particularly the expression of genes involved in the immune response. Material. 87 renal transplant candidates (66 HD, 21 PD) were included in the study. Methods. The peripheral blood RNA samples were obtained with the PAXgene Blood system just before transplantation. The gene expression of CASP3, FAS, TP53, FOXP3, IFNG, IL2, IL6, IL8, IL10, IL17, IL18, LCN2, TGFB1, and TNF was assessed with real-time PCR on custom-designed low density arrays (TaqMan). Gene expression data were analyzed in relation to pretransplant clinical parameters. Results. The mean expression of examined genes showed no significant differences between PD and HD with the exception of FAS, expression of which was 30% higher in PD patients compared to the HD group. There was nonsignificantly higher expression of proinflammatory cytokines in the PD group. The clinical inflammatory parameters (CRP, albumin, cholesterol, and hemoglobin levels) did not differ between the groups. Conclusion. Type of renal replacement therapy exerts no differential effect on cytokine gene expression or inflammatory clinical parameters. Dorota Kamińska, Katarzyna Kościelska-Kasprzak, Paweł Chudoba, Oktawia Mazanowska, Mirosław Banasik, Marcelina Żabinska, Maria Boratyńska, Agnieszka Lepiesza, Krzysztof Korta, Agnieszka Gomółkiewicz, Piotr Dzięgiel, and Marian Klinger Copyright © 2015 Dorota Kamińska et al. All rights reserved. Prevalence and Diagnostic Approach to Sleep Apnea in Hemodialysis Patients: A Population Study Wed, 01 Jul 2015 10:02:36 +0000 Background. Previous observations found a high prevalence of obstructive sleep apnea (OSA) in the hemodialysis population, but the best diagnostic approach remains undefined. We assessed OSA prevalence and performance of available screening tools to propose a specific diagnostic algorithm. Methods. 104 patients from 6 Swiss hemodialysis centers underwent polygraphy and completed 3 OSA screening scores: STOP-BANG, Berlin’s Questionnaire, and Adjusted Neck Circumference. The OSA predictors were identified on a derivation population and used to develop the diagnostic algorithm, which was validated on an independent population. Results. We found 56% OSA prevalence (AHI ≥ 15/h), which was largely underdiagnosed. Screening scores showed poor performance for OSA screening (ROC areas 0.538 [SE 0.093] to 0.655 [SE 0.083]). Age, neck circumference, and time on renal replacement therapy were the best predictors of OSA and were used to develop a screening algorithm, with higher discriminatory performance than classical screening tools (ROC area 0.831 [0.066]). Conclusions. Our study confirms the high OSA prevalence and highlights the low diagnosis rate of this treatable cardiovascular risk factor in the hemodialysis population. Considering the poor performance of OSA screening tools, we propose and validate a specific algorithm to identify hemodialysis patients at risk for OSA for whom further sleep investigations should be considered. Valentina Forni Ogna, Adam Ogna, Menno Pruijm, Isabelle Bassi, Emilie Zuercher, Georges Halabi, Olivier Phan, Roberto Bullani, Daniel Teta, Thierry Gauthier, Anne Cherpillod, Claudine Mathieu, Alexandra Mihalache, Francoise Cornette, José Haba-Rubio, Michel Burnier, and Raphaël Heinzer Copyright © 2015 Valentina Forni Ogna et al. All rights reserved. Effects of Sucroferric Oxyhydroxide Compared to Lanthanum Carbonate and Sevelamer Carbonate on Phosphate Homeostasis and Vascular Calcifications in a Rat Model of Chronic Kidney Failure Mon, 29 Jun 2015 11:52:38 +0000 Elevated serum phosphorus, calcium, and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease in chronic renal disease. This study evaluated the effects of sucroferric oxyhydroxide (PA21), a new iron-based phosphate binder, versus lanthanum carbonate (La) and sevelamer carbonate (Se), on serum FGF23, phosphorus, calcium, and intact parathyroid hormone (iPTH) concentrations, and the development of vascular calcification in adenine-induced chronic renal failure (CRF) rats. After induction of CRF, renal function was significantly impaired in all groups: uremic rats developed severe hyperphosphatemia, and serum iPTH increased significantly. All uremic rats (except controls) then received phosphate binders for 4 weeks. Hyperphosphatemia and increased serum iPTH were controlled to a similar extent in all phosphate binder-treatment groups. Only sucroferric oxyhydroxide was associated with significantly decreased FGF23. Vascular calcifications of the thoracic aorta were decreased by all three phosphate binders. Calcifications were better prevented at the superior part of the thoracic and abdominal aorta in the PA21 treated rats. In adenine-induced CRF rats, sucroferric oxyhydroxide was as effective as La and Se in controlling hyperphosphatemia, secondary hyperparathyroidism, and vascular calcifications. The role of FGF23 in calcification remains to be confirmed. Olivier Phan, Marc Maillard, Hartmut H. Malluche, Jean-Christophe Stehle, Felix Funk, and Michel Burnier Copyright © 2015 Olivier Phan et al. All rights reserved. Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus Mon, 08 Jun 2015 09:50:24 +0000 The aim of our work was to evaluate, in an animal model of severe diabetes mellitus, the effect of mesenchymal stem cells (MSCs) administration on diabetic nephropathy (DN) progression. After diabetes induction, one group of mice received the vehicle (DM) and other group received a single dose of MSCs (DM + MSCs). DM + MSCs mice showed a significant improvement in functional parameters of the kidney compared with untreated mice. While DM mice presented marked histopathological changes characteristics of advanced stages of DN (fibrosis, glomerulosclerosis, glomerular basement membrane thickening, capillary occlusion, decreased podocyte density, and effacement of foot processes), DM + MSCs mice showed only slight tubular dilatation. The renoprotection was not associated with an improvement in diabetic condition and very low number of donor cells was found in the kidney of DM + MSCs mice, suggesting that renoprotection could be mediated by paracrine effects. Indeed, DM + MSC mice presented increased renal proliferation index, decreased renal apoptotic index and the restoration of proregenerative factors, and anti-inflammatory cytokines levels. Moreover, macrophage infiltration and oxidative stress damage were also reduced in DM + MSCs mice. Our data demonstrate that MSC administration triggers a proregenerative microenvironment in DN kidney, which allows the preservation of the renal function even if diabetes was uncorrected. Fernando Ezquer, Maximiliano Giraud-Billoud, Daniel Carpio, Fabián Cabezas, Paulette Conget, and Marcelo Ezquer Copyright © 2015 Fernando Ezquer et al. All rights reserved. Mean Expected Error in Prediction of Total Body Water: A True Accuracy Comparison between Bioimpedance Spectroscopy and Single Frequency Regression Equations Tue, 02 Jun 2015 13:38:46 +0000 For several decades electrical bioimpedance (EBI) has been used to assess body fluid distribution and body composition. Despite the development of several different approaches for assessing total body water (TBW), it remains uncertain whether bioimpedance spectroscopic (BIS) approaches are more accurate than single frequency regression equations. The main objective of this study was to answer this question by calculating the expected accuracy of a single measurement for different EBI methods. The results of this study showed that all methods produced similarly high correlation and concordance coefficients, indicating good accuracy as a method. Even the limits of agreement produced from the Bland-Altman analysis indicated that the performance of single frequency, Sun’s prediction equations, at population level was close to the performance of both BIS methods; however, when comparing the Mean Absolute Percentage Error value between the single frequency prediction equations and the BIS methods, a significant difference was obtained, indicating slightly better accuracy for the BIS methods. Despite the higher accuracy of BIS methods over 50 kHz prediction equations at both population and individual level, the magnitude of the improvement was small. Such slight improvement in accuracy of BIS methods is suggested insufficient to warrant their clinical use where the most accurate predictions of TBW are required, for example, when assessing over-fluidic status on dialysis. To reach expected errors below 4-5%, novel and individualized approaches must be developed to improve the accuracy of bioimpedance-based methods for the advent of innovative personalized health monitoring applications. Fernando Seoane, Shirin Abtahi, Farhad Abtahi, Lars Ellegård, Gudmundur Johannsson, Ingvar Bosaeus, and Leigh C. Ward Copyright © 2015 Fernando Seoane et al. All rights reserved. High Intensity Interval Training Favourably Affects Angiotensinogen mRNA Expression and Markers of Cardiorenal Health in a Rat Model of Early-Stage Chronic Kidney Disease Sun, 24 May 2015 06:24:42 +0000 The majority of CKD-related complications stem from cardiovascular pathologies such as hypertension. To help reduce cardiovascular complications, aerobic exercise is often prescribed. Emerging evidence suggests high intensity interval training (HIIT) may be more beneficial than traditional aerobic exercise. However, appraisals of varying forms of aerobic exercise, along with descriptions of mechanisms responsible for health-related improvements, are lacking. This study examined the effects of 8 weeks of HIIT (85% VO2max), versus low intensity aerobic exercise (LIT; 45–50% VO2max) and sedentary behaviour (SED), in an animal model of early-stage CKD. Tissue-specific mRNA expression of RAAS-related genes and CKD-related clinical markers were examined. Compared to SED, HIIT resulted in increased plasma albumin (), reduced remnant kidney weight (), and reduced kidney weight-body weight ratios (). Compared to LIT, HIIT resulted in reduced Agt mRNA expression (), reduced plasma LDL (), triglycerides (), and total cholesterol (), increased plasma albumin (), reduced remnant kidney weight (), and reduced kidney weight-body weight ratios (). These results suggest HIIT is a more potent regulator of several markers that describe and influence health in CKD. Patrick S. Tucker, Aaron T. Scanlan, and Vincent J. Dalbo Copyright © 2015 Patrick S. Tucker et al. All rights reserved. Physical Activity in Hemodialysis Patients Measured by Triaxial Accelerometer Sun, 24 May 2015 06:16:45 +0000 Different factors can contribute to a sedentary lifestyle among hemodialysis (HD) patients, including the period they spend on dialysis. The aim of this study was to evaluate characteristics of physical activities in daily life in this population by using an accurate triaxial accelerometer and to correlate these characteristics with physiological variables. Nineteen HD patients were evaluated using the DynaPort accelerometer and compared to nineteen control individuals, regarding the time spent in different activities and positions of daily life and the number of steps taken. HD patients were more sedentary than control individuals, spending less time walking or standing and spending more time lying down. The sedentary behavior was more pronounced on dialysis days. According to the number of steps taken per day, 47.4% of hemodialysis patients were classified as sedentary against 10.5% in control group. Hemoglobin level, lower extremity muscle strength, and physical functioning of SF-36 questionnaire correlated significantly with the walking time and active time. Looking accurately at the patterns of activity in daily life, HDs patients are more sedentary, especially on dialysis days. These patients should be motivated to enhance the physical activity. Edimar Pedrosa Gomes, Maycon Moura Reboredo, Erich Vidal Carvalho, Daniel Rodrigues Teixeira, Laís Fernanda Caldi d’Ornellas Carvalho, Gilberto Francisco Ferreira Filho, Julio César Abreu de Oliveira, Helady Sanders-Pinheiro, Júlio Maria Fonseca Chebli, Rogério Baumgratz de Paula, and Bruno do Valle Pinheiro Copyright © 2015 Edimar Pedrosa Gomes et al. All rights reserved. Extraskeletal Functions of Vitamin D Mon, 11 May 2015 07:28:10 +0000 Domenico Santoro, Katarina Sebekova, Daniel Teta, and Luca De Nicola Copyright © 2015 Domenico Santoro et al. All rights reserved. Paricalcitol Inhibits Aldosterone-Induced Proinflammatory Factors by Modulating Epidermal Growth Factor Receptor Pathway in Cultured Tubular Epithelial Cells Wed, 06 May 2015 06:57:10 +0000 Chronic kidney disease is characterized by Vitamin D deficiency and activation of the renin-angiotensin-aldosterone system. Increasing data show that vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti-inflammatory properties, but the underlying mechanism remains unknown. Emerging evidence suggests that “a disintegrin and metalloproteinase” (ADAM)/epidermal growth factor receptor (EGFR) signalling axis contributes to renal damage. Aldosterone induces EGFR transactivation regulating several processes including cell proliferation and fibrosis. However, data on tubular epithelial cells is scarce. We have found that, in cultured tubular epithelial cells, aldosterone induced EGFR transactivation via TGF-α/ADAM17. Blockade of the TGF-α/ADAM17/EGFR pathway inhibited aldosterone-induced proinflammatory gene upregulation. Moreover, among the potential downstream mechanisms, we found that TGF-α/ADAM17/EGFR inhibition blocked ERK and STAT-1 activation in response to aldosterone. Next, we investigated the involvement of TGF-α/ADAM17/EGFR axis in VDRA anti-inflammatory effects. Preincubation with the VDRA paricalcitol inhibited aldosterone-induced EGFR transactivation, TGF-α/ADAM-17 gene upregulation, and downstream mechanisms, including proinflammatory factors overexpression. In conclusion, our data suggest that the anti-inflammatory actions of paricalcitol in tubular cells could depend on the inhibition of TGF-α/ADAM17/EGFR pathway in response to aldosterone, showing an important mechanism of VDRAs action. Jose L. Morgado-Pascual, Sandra Rayego-Mateos, Jose M. Valdivielso, Alberto Ortiz, Jesus Egido, and Marta Ruiz-Ortega Copyright © 2015 Jose L. Morgado-Pascual et al. All rights reserved. Role of Vitamin D Deficiency in Extraskeletal Complications: Predictor of Health Outcome or Marker of Health Status? Tue, 05 May 2015 12:40:31 +0000 The relationship of vitamin D with extraskeletal complications, such as cardiovascular disease, cancer, and autoimmune disease, is of major interest considering its roles in key biological processes and the worldwide high prevalence of vitamin D deficiency. However, the causal relationships between vitamin D and most extraskeletal complications are weak. Currently, a heated debate over vitamin D is being conducted according to two hypotheses. In this review, we first present the different arguments that suggest a major role of vitamin D in a very broad type of extraskeletal complications (hypothesis #1). We then present results from recent meta-analyses of randomized controlled trials indicating a lack of association of vitamin D with major extraskeletal complications (hypothesis #2). We discuss different issues (e.g., causality, confounding, reverse causation, misclassification, and Mendelian randomization) that contribute to the favoring of one hypothesis over the other. While ultimately only one hypothesis is correct, we anticipate that the results from the ongoing randomized controlled trials will be unlikely to reconcile the divided experts. Idris Guessous Copyright © 2015 Idris Guessous. All rights reserved. The Impact of Vitamin D3 Supplementation on Mechanisms of Cell Calcium Signaling in Chronic Kidney Disease Mon, 04 May 2015 12:57:51 +0000 Intracellular calcium concentration in peripheral blood mononuclear cells (PBMCs) of patients with chronic kidney disease (CKD) is significantly increased, and the regulatory mechanisms maintaining cellular calcium homeostasis are impaired. The purpose of this study was to examine the effect of vitamin on predominant regulatory mechanisms of cell calcium homeostasis. The study involved 16 CKD stages 2-3 patients with vitamin D deficiency treated with cholecalciferol 7000–14000 IU/week for 6 months. The regulatory mechanisms of calcium signaling were studied in PBMCs and red blood cells. After vitamin supplementation, serum concentration of 25(OH) increased () and decreased (). The differences in were inversely related to differences in 25(OH) concentration (). Vitamin supplementation decreased the calcium entry through calcium release activated calcium (CRAC) channels and purinergic P2X7 channels. The function of P2X7 receptors was changed in comparison with their baseline status, and the expression of these receptors was reduced. There was no effect of vitamin on P2X7 pores and activity of plasma membrane Ca2+-ATPases. Vitamin supplementation had a beneficial effect on decreasing calcium entry via CRAC and P2X7 channels and reducing P2X7 receptors expression. Ingrid Lajdova, Viera Spustova, Adrian Oksa, Zuzana Kaderjakova, Dusan Chorvat Jr., Marcela Morvova Jr., Libusa Sikurova, and Alzbeta Marcek Chorvatova Copyright © 2015 Ingrid Lajdova et al. All rights reserved. Vitamin D Binding Protein Is Not Involved in Vitamin D Deficiency in Patients with Chronic Kidney Disease Mon, 04 May 2015 12:33:36 +0000 Objective. This study was designed to evaluate vitamin D status with separate determination of 25-OH D2 and 25-OH D3 and its relationship to vitamin D binding protein (VDBP) in patients with chronic kidney disease (CKD) and long-term haemodialysis patients (HD). Methods. 45 CKD patients, 103 HD patients, and 25 controls (C) were included. Plasma vitamin D concentrations were determined using chromatography and VDBP in serum and urine in CKD using enzyme immunoassay. Results. Plasma vitamin D levels were lower in CKD (30.16 ± 16.74 ng/mL) and HD (18.85 ± 15.85 ng/mL) versus C (48.72 ± 18.35 ng/mL), . 25-OH D3 was the dominant form of vitamin D. Serum VDBP was higher in CKD (273.2 ± 93.8 ug/mL) versus C (222 ± 87.6 ug/mL) and HD (213.8 ± 70.9 ug/mL), . Vitamin D/VDBP ratio was the highest in C and the lowest in HD; however, there was no correlation between vitamin D and VDBP. Urinary concentration of VDBP in CKD (0.25 ± 0.13 ug/mL) correlated with proteinuria , . Conclusions. Plasma levels of vitamin D are decreased in CKD patients and especially in HD patients. 25-OH D3 was the major form of vitamin D. Despite urinary losses of VDBP, CKD patients had higher serum VDBP concentrations, indicating compensatory enhanced production. Vitamin D binding protein is not involved in vitamin D deficiency. Marta Kalousova, Sylvie Dusilova-Sulkova, Oskar Zakiyanov, Milada Kostirova, Roman Safranek, Vladimir Tesar, and Tomas Zima Copyright © 2015 Marta Kalousova et al. All rights reserved. Parathyroidectomy Is Associated with Reduced Mortality in Hemodialysis Patients with Secondary Hyperparathyroidism Sun, 03 May 2015 12:07:43 +0000 Secondary hyperparathyroidism increases morbidity and mortality in hemodialysis patients. The Kidney Disease Outcomes Quality Initiative Guidelines recommend parathyroidectomy for patients with chronic kidney disease and parathyroid hormone concentrations exceeding 800 pg/mL; however, this concentration represents an arbitrary cut-off value. The present study was conducted to identify factors influencing mortality in hemodialysis patients with parathyroid hormone concentrations exceeding 800 pg/mL and to evaluate the effects of parathyroidectomy on outcome for these patients. Two hundred twenty-one hemodialysis patients with parathyroid hormone concentrations > 800 pg/mL from July 2004 to June 2010 were identified. 21.1% of patients (n = 60) received parathyroidectomy and 14.9% of patients (n = 33) died during a mean follow-up of 36 months. Patients with parathyroidectomy were found to have lower all-cause mortality (adjusted hazard ratio [aHR]: 0.34). Other independent predictors included age ≥ 65 years (aHR: 2.11) and diabetes mellitus (aHR: 3.80). For cardiovascular mortality, parathyroidectomy was associated with lower mortality (HR = 0.31) but with a marginal statistical significance (p = 0.061). In multivariate analysis, diabetes was the only significant predictor (aHR: 3.14). It is concluded that, for hemodialysis patients with parathyroid hormone concentrations greater than 800 pg/mL, parathyroidectomy is associated with reduced all-cause mortality. Tsung-Liang Ma, Peir-Haur Hung, Ing-Ching Jong, Chih-Yen Hiao, Yueh-Han Hsu, Pei-Chun Chiang, How-Ran Guo, and Kuan-Yu Hung Copyright © 2015 Tsung-Liang Ma et al. All rights reserved. Diagnostic Significance of Diffusion-Weighted MRI in Renal Cancer Thu, 30 Apr 2015 07:19:29 +0000 Background. This study aimed to investigate whether diffusion-weighted imaging (DWI) could contribute to the discrimination between benign and malignant renal cancer. Methods. We searched the PubMed electronic database for eligible studies. STATA 12.0 software was used for statistical analysis. The SMD and 95% CI were calculated. Results. Decreased ADC signal was seen in all renal cancer patients (cancer tissue versus normal tissue: SMD = 1.63 and 95% CI = 0.96~2.29, ; cancer tissue versus benign tissue: SMD = 2.22 and 95% CI = 1.53~2.90 and , resp.). MRI machine type-stratified analysis showed that decreased ADC signal was found by all included MRI machine types in cancer tissues compared with benign cancer tissues (all ). The ADC values of renal cancer patients were significantly lower than those of normal controls for all included values (all ), and there was a decreased ADC signal at -500, -600, -1000, -500, and 1000 gradients compared with benign cancer tissues (all ). Conclusion. Our study concluded that decreased ADC signal presented in DWI may be essential for the differential diagnosis of renal cancer. Yu Lei, Hong Wang, Hai-Feng Li, Yan-Wei Rao, Jing-Hong Liu, Shi-Feng Tian, Ye Ju, Ye Li, An-Liang Chen, Li-Hua Chen, Ai-Lian Liu, and Ming-Li Sun Copyright © 2015 Yu Lei et al. All rights reserved. Interplay of Vitamin D, Erythropoiesis, and the Renin-Angiotensin System Mon, 27 Apr 2015 13:28:25 +0000 For many years deficiency of vitamin D was merely identified and assimilated to the presence of bone rickets. It is now clear that suboptimal vitamin D status may be correlated with several disorders and that the expression of 1-α-hydroxylase in tissues other than the kidney is widespread and of clinical relevance. Recently, evidence has been collected to suggest that, beyond the traditional involvement in mineral metabolism, vitamin D may interact with other kidney hormones such as renin and erythropoietin. This interaction would be responsible for some of the systemic and renal effects evoked for the therapy with vitamin D. The administration of analogues of vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Moreover, vitamin D deficiency could contribute to an inappropriately activated or unsuppressed RAS, as a mechanism for progression of CKD and/or cardiovascular disease. Experimental data on the anti-RAS and anti-inflammatory effects treatment with active vitamin D analogues suggest a therapeutic option particularly in proteinuric CKD patients. This option should be considered for those subjects that are intolerant to anti-RAS agents or, as add-on therapy, in those already treated with anti-RAS but not reaching the safe threshold level of proteinuria. Domenico Santoro, Daniela Caccamo, Silvia Lucisano, Michele Buemi, Katerina Sebekova, Daniel Teta, and Luca De Nicola Copyright © 2015 Domenico Santoro et al. All rights reserved. Vitamin D Status in Women with Gestational Diabetes Mellitus during Pregnancy and Postpartum Mon, 27 Apr 2015 13:16:25 +0000 Of many vitamin D extraskeletal functions, its modulatory role in insulin secretion and action is especially relevant for gestational diabetes mellitus (GDM). The aims of the present study were to determine midgestational and early postpartum vitamin D status in pregnant women with and without GDM and to describe the relationship between midgestational and postpartum vitamin D status and parallel changes of glucose tolerance. A total of 76 pregnant women (47 GDM and 29 healthy controls) were included in the study. Plasma levels of 25(OH)D were measured using an enzyme immunoassay. Vitamin D was not significantly decreased in GDM compared to controls during pregnancy; however, both groups of pregnant women exhibited high prevalence of vitamin D deficiency. Prevalence of postpartum 25(OH)D deficiency in post-GDM women remained significantly higher and their postpartum 25(OH)D levels were significantly lower compared to non-GDM counterparts. Finally, based on the oGTT repeated early postpartum persistent glucose abnormality was ascertained in 15% of post-GDM women; however, neither midgestational nor postpartum 25(OH)D levels significantly differed between subjects with GDM history and persistent postpartum glucose intolerance and those with normal glucose tolerance after delivery. Anna Pleskačová, Vendula Bartáková, Lukáš Pácal, Katarína Kuricová, Jana Bělobrádková, Josef Tomandl, and Kateřina Kaňková Copyright © 2015 Anna Pleskačová et al. All rights reserved. The Pleiotropic Effects of Vitamin D in Gynaecological and Obstetric Diseases: An Overview on a Hot Topic Mon, 27 Apr 2015 12:57:18 +0000 The traditionally recognized role of vitamin D consists in the regulation of bone metabolism and calcium-phosphorus homeostasis but recently a lot of in vitro and in vivo studies recognized several “noncalcemic” effects of vitamin D metabolites. Accumulating evidence suggests that the metabolic pathways of this vitamin may play a key role in the developing of gynaecological/obstetric diseases. VDR-mediated signalling pathways and vitamin D levels seem to (deeply) affect the risk of several gynaecological diseases, such as polycystic ovary syndrome (PCOS), endometriosis, and ovarian and even breast cancer. On the other hand, since also the maternal-fetal unit is under the influence of vitamin D, a breakdown in its homeostasis may underlie infertility, preeclampsia, and gestational diabetes mellitus (GDM). According to our literature review, the relationship between vitamin D and gynaecological/obstetric diseases must be replicated in future studies which could clarify the molecular machineries behind their development. We suggest that further investigation should take into account the different serum levels of this vitamin, the several actions which arise from the binding between it and its receptor (taking into account its possible polymorphism), and finally the interplay between vitamin D metabolism and other hormonal and metabolic pathways. Francesca Colonese, Antonio Simone Laganà, Elisabetta Colonese, Vincenza Sofo, Francesca Maria Salmeri, Roberta Granese, and Onofrio Triolo Copyright © 2015 Francesca Colonese et al. All rights reserved. Vitamin D Deficiency in HIV Infection: Not Only a Bone Disorder Mon, 27 Apr 2015 11:34:47 +0000 Hypovitaminosis D is a worldwide disorder, with a high prevalence in the general population of both Western and developing countries. In HIV patients, several studies have linked vitamin D status with bone disease, neurocognitive impairment, depression, cardiovascular disease, high blood pressure, metabolic syndrome, type 2 diabetes mellitus, infections, autoimmune diseases like type 1 diabetes mellitus, and cancer. In this review, we focus on the most recent epidemiological and experimental data dealing with the relationship between vitamin D deficiency and HIV infection. We analysed the extent of the problem, pathogenic mechanisms, clinical implications, and potential benefits of vitamin D supplementation in HIV-infected subjects. Pasquale Mansueto, Aurelio Seidita, Giustina Vitale, Sebastiano Gangemi, Chiara Iaria, and Antonio Cascio Copyright © 2015 Pasquale Mansueto et al. All rights reserved. Links between Vitamin D Deficiency and Cardiovascular Diseases Mon, 27 Apr 2015 11:27:07 +0000 The aim of the present paper was to review the most important mechanisms explaining the possible association of vitamin D deficiency and cardiovascular diseases, focusing on recent experimental and clinical data. Low vitamin D levels favor atherosclerosis enabling vascular inflammation, endothelial dysfunction, formation of foam cells, and proliferation of smooth muscle cells. The antihypertensive properties of vitamin D include suppression of the renin-angiotensin-aldosterone system, renoprotective effects, direct effects on endothelial cells and calcium metabolism, inhibition of growth of vascular smooth muscle cells, prevention of secondary hyperparathyroidism, and beneficial effects on cardiovascular risk factors. Vitamin D is also involved in glycemic control, lipid metabolism, insulin secretion, and sensitivity, explaining the association between vitamin D deficiency and metabolic syndrome. Vitamin D deficit was associated in some studies with the number of affected coronary arteries, postinfarction complications, inflammatory cytokines and cardiac remodeling in patients with myocardial infarction, direct electromechanical effects and inflammation in atrial fibrillation, and neuroprotective effects in stroke. In peripheral arterial disease, vitamin D status was related to the decline of the functional performance, severity, atherosclerosis and inflammatory markers, arterial stiffness, vascular calcifications, and arterial aging. Vitamin D supplementation should further consider additional factors, such as phosphates, parathormone, renin, and fibroblast growth factor 23 levels. Ioana Mozos and Otilia Marginean Copyright © 2015 Ioana Mozos and Otilia Marginean. All rights reserved. Vitamin D: A Review on Its Effects on Muscle Strength, the Risk of Fall, and Frailty Mon, 27 Apr 2015 11:16:31 +0000 Vitamin D is the main hormone of bone metabolism. However, the ubiquitary nature of vitamin D receptor (VDR) suggests potential for widespread effects, which has led to new research exploring the effects of vitamin D on a variety of tissues, especially in the skeletal muscle. In vitro studies have shown that the active form of vitamin D, calcitriol, acts in myocytes through genomic effects involving VDR activation in the cell nucleus to drive cellular differentiation and proliferation. A putative transmembrane receptor may be responsible for nongenomic effects leading to rapid influx of calcium within muscle cells. Hypovitaminosis D is consistently associated with decrease in muscle function and performance and increase in disability. On the contrary, vitamin D supplementation has been shown to improve muscle strength and gait in different settings, especially in elderly patients. Despite some controversies in the interpretation of meta-analysis, a reduced risk of falls has been attributed to vitamin D supplementation due to direct effects on muscle cells. Finally, a low vitamin D status is consistently associated with the frail phenotype. This is why many authorities recommend vitamin D supplementation in the frail patient. Matthieu Halfon, Olivier Phan, and Daniel Teta Copyright © 2015 Matthieu Halfon et al. All rights reserved. Vitamin D and Inflammatory Bowel Disease Mon, 27 Apr 2015 10:41:07 +0000 Vitamin D deficiency has been recognized as an environmental risk factor for Crohn’s disease since the early 80s. Initially, this finding was correlated with metabolic bone disease. Low serum 25-hydroxyvitamin D levels have been repeatedly reported in inflammatory bowel diseases together with a relationship between vitamin D status and disease activity. Subsequently, low serum vitamin D levels have been reported in various immune-related diseases pointing to an immunoregulatory role. Indeed, vitamin D and its receptor (VDR) are known to interact with different players of the immune homeostasis by controlling cell proliferation, antigen receptor signalling, and intestinal barrier function. Moreover, 1,25-dihydroxyvitamin D is implicated in NOD2-mediated expression of defensin-β2, the latter known to play a crucial role in the pathogenesis of Crohn’s disease (IBD1 gene), and several genetic variants of the vitamin D receptor have been identified as Crohn’s disease candidate susceptibility genes. From animal models we have learned that deletion of the VDR gene was associated with a more severe disease. There is a growing body of evidence concerning the therapeutic role of vitamin D/synthetic vitamin D receptor agonists in clinical and experimental models of inflammatory bowel disease far beyond the role of calcium homeostasis and bone metabolism. Marco Ardesia, Guido Ferlazzo, and Walter Fries Copyright © 2015 Marco Ardesia et al. All rights reserved. Is Vitamin D Deficiency Related to Accumulation of Advanced Glycation End Products, Markers of Inflammation, and Oxidative Stress in Diabetic Subjects? Mon, 27 Apr 2015 10:36:32 +0000 Objectives. In diabetes accumulated advanced glycation end products (AGEs) are involved in the striking cardiovascular morbidity/mortality. We asked whether a hypovitaminosis D associates with an increased formation and toxicity of AGEs in diabetes. Methods. In 276 diabetics (160 M/116 F, age: ; 43 type 1,T1DM, and 233 type 2 patients, T2DM) and 121 nondiabetic controls (60 M/61 F; age: years) routine biochemistry, levels of 25-hydroxyvitamin D3 (25-(OH)D), skin autofluorescence (SAF), plasma AGE-associated fluorescence (AGE-FL), -(carboxymethyl)lysine (CML), soluble receptor for AGEs (sRAGE), soluble vascular adhesion protein-1 (sVAP-1), high sensitive C-reactive protein (hs-CRP), and renal function (eGFR) were determined. Results. In the diabetics SAF and AGE-Fl were higher than those of the controls and correlated with age, duration of diabetes, and degree of renal impairment. In T2DM patients but not in T1DM the age-dependent rise of SAF directly correlated with hs-CRP and sVAP-1. 25-(OH)D levels in diabetics and nondiabetics were lowered to a similar degree averaging 22.5 ng/mL. No relationship between 25-(OH)D and studied markers except for sVAP-1 was observed in the diabetics. Conclusion. In diabetics hypovitaminosis D does not augment accumulation of AGEs and studied markers of microinflammation and oxidative stress except for sVAP-1. K. Šebeková, M. Stürmer, G. Fazeli, U. Bahner, F. Stäb, and A. Heidland Copyright © 2015 K. Šebeková et al. All rights reserved. 1,25-Dihydroxyvitamin D3 Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPAR Signaling Pathway Sun, 19 Apr 2015 11:50:17 +0000 Macrophages, especially their activation state, are closely related to the progression of diabetic nephropathy. Classically activated macrophages (M1) are proinflammatory effectors, while alternatively activated macrophages (M2) exhibit anti-inflammatory properties. 1,25-Dihydroxyvitamin D3 has renoprotective roles that extend beyond the regulation of mineral metabolism, and PPARγ, a nuclear receptor, is essential for macrophage polarization. The present study investigates the effect of 1,25-dihydroxyvitamin D3 on macrophage activation state and its underlying mechanism in RAW264.7 cells. We find that, under high glucose conditions, RAW264.7 macrophages tend to switch to the M1 phenotype, expressing higher iNOS and proinflammatory cytokines, including TNFα and IL-12. While 1,25-dihydroxyvitamin D3 significantly inhibited M1 activation, it enhanced M2 macrophage activation; namely, it upregulated the expression of MR, Arg-1, and the anti-inflammatory cytokine IL-10 but downregulated the M1 markers. However, the above effects of 1,25-dihydroxyvitamin D3 were abolished when the expression of VDR and PPARγ was inhibited by VDR siRNA and a PPARγ antagonist. In addition, PPARγ was also decreased upon treatment with VDR siRNA. The above results demonstrate that active vitamin D promoted M1 phenotype switching to M2 via the VDR-PPARγ pathway. Xiaoliang Zhang, Min Zhou, Yinfeng Guo, Zhixia Song, and Bicheng Liu Copyright © 2015 Xiaoliang Zhang et al. All rights reserved. β-Catenin-Dependent Signaling Pathway Contributes to Renal Fibrosis in Hypertensive Rats Tue, 07 Apr 2015 12:54:43 +0000 The mechanism of hypertension-induced renal fibrosis is not well understood, although it is established that high levels of angiotensin II contribute to the effect. Since -catenin signal transduction participates in fibrotic processes, we evaluated the contribution of -catenin-dependent signaling pathway in hypertension-induced renal fibrosis. Two-kidney one-clip (2K1C) hypertensive rats were treated with lisinopril (10 mg/kg/day for four weeks) or with pyrvinium pamoate (Wnt signaling inhibitor, single dose of 60 ug/kg, every 3 days for 2 weeks). The treatment with lisinopril reduced the systolic blood pressure from 220 ± 4 in 2K1C rats to 112 ± 5 mmHg (), whereas the reduction in blood pressure with pyrvinium pamoate was not significant (212 ± 6 in 2K1C rats to 170 ± 3 mmHg, ). The levels of collagen types I and III, osteopontin, and fibronectin decreased in the unclipped kidney in both treatments compared with 2K1C rats. The expressions of -catenin, p-Ser9-GSK-3beta, and the -catenin target genes cyclin D1, c-myc, and bcl-2 significantly decreased in unclipped kidney in both treatments (). In this study we provided evidence that -catenin-dependent signaling pathway participates in the renal fibrosis induced in 2K1C rats. Catherina A. Cuevas, Cheril Tapia-Rojas, Carlos Cespedes, Nibaldo C. Inestrosa, and Carlos P. Vio Copyright © 2015 Catherina A. Cuevas et al. All rights reserved. Identification of Subgingival Periodontal Pathogens and Association with the Severity of Periodontitis in Patients with Chronic Kidney Diseases: A Cross-Sectional Study Thu, 02 Apr 2015 09:45:48 +0000 Background. The aim of our study was to assess the subgingival profile of 9 periodontal pathogens, by means of real-time PCR, in a group of predialysis chronic kidney disease patients with and without periodontal disease and to identify the risk factors associated with periodontal disease in these patients. Material and Methods. This is a single centre cross-sectional cohort study performed on 70 CKD patients. Patients received a full-mouth periodontal examination and the following parameters were assessed: periodontal pocket depth (PPD), clinical attachment level, bleeding on probing, and plaque index; subgingival biofilm samples were collected from the deepest periodontal pocket of each quadrant and were pooled in one transporting unit. Clinical data were drawn from the medical file of the patients. Results. T. denticola (), T. forsythia (), and P. micros () are significantly associated with periodontal disease in CKD subjects but in a multivariate model only age and T. forsythia remain independent risk factors for periodontal disease in patients with CKD. Conclusions. In our cohort, age and T. forsythia are independently associated with periodontitis in CKD patients. Within the limits of this study, CKD was not significantly associated with a particular subgingival periodontal pathogens profile in periodontitis patients. Fidan Bahtiar Ismail, Gener Ismail, Anca Silvia Dumitriu, Catalin Baston, Vlad Berbecar, Roxana Jurubita, Andreea Andronesi, Horia Traian Dumitriu, and Ioanel Sinescu Copyright © 2015 Fidan Bahtiar Ismail et al. All rights reserved. Oral Tori in Chronic Hemodialysis Patients Tue, 31 Mar 2015 13:15:12 +0000 Background. This study investigated the epidemiology of torus palatinus (TP) and torus mandibularis (TM) in hemodialysis patients and analyzed the influences of hyperparathyroidism on the formation of oral tori. Method. During 2013, 119 hemodialysis patients were recruited for dental examinations for this study. Results. The prevalence of oral tori in our sample group was high at 33.6% (40 of 119). The most common location of tori was TP (70.0%), followed by TM (20.0%), and then both TP and TM (10.0%). Of the 40 tori cases, most (67.5%) were <2 cm in size; moreover, the majority (52.5%) were flat in shape. In symmetry, most (70.0%) occurred in the midline, followed by bilateral sides (20.0%). Notably, the levels of intact parathyroid hormone did not differ in patients with or without tori (). Furthermore, patients with tori did not differ from patients without tori in inflammatory variables such as log high-sensitivity C-reactive protein () or nutritional variables such as albumin (). Finally, there were no differences between patients with and without tori in adequacy of dialysis (). Conclusions. Neither hyperparathyroidism nor inflammation malnutrition syndrome was found to contribute to the formation of oral tori in chronic hemodialysis patients. Further studies are warranted. Pei-Jung Chao, Huang-Yu Yang, Wen-Hung Huang, Cheng-Hao Weng, I-Kuan Wang, Aileen I. Tsai, and Tzung-Hai Yen Copyright © 2015 Pei-Jung Chao et al. All rights reserved. Long-Term Clinical Practice Experience with Cinacalcet for Treatment of Hypercalcemic Hyperparathyroidism after Kidney Transplantation Tue, 10 Mar 2015 11:03:41 +0000 Within this prospective, open-label, self-controlled study, we evaluated the long-term effects of the calcimimetic cinacalcet on calcium and phosphate homeostasis in 44 kidney transplant recipients (KTRs) with hypercalcemic hyperparathyroidism by comparing biochemical parameters of mineral metabolism between pre- and posttreatment periods. Results are described as mean differences (95% CIs) between pre- and posttreatment medians that summarize all repeated measurements of a parameter of interest between the date of initial hypercalcemia and cinacalcet initiation (median of 1.6 (IQR: 0.6–3.8) years) and up to four years after treatment start, respectively. Cinacalcet was initiated after 1.8 (0.8–4.7) years posttransplant and maintained for 6.2 (3.9–7.6) years. It significantly decreased total serum calcium (−0.30 (−0.34 to −0.26) mmol/L, ) and parathyroid hormone levels (−79 (−103 to −55) pg/mL, ). Serum levels of inorganic phosphate (Pi) and renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) increased simultaneously (Pi: 0.19 (0.15–0.23) mmol/L, , TmP/GFR: 0.20 (0.16–0.23) mmol/L, ). In summary, cinacalcet effectively controlled hypercalcemic hyperparathyroidism in KTRs in the long-term and increased low Pi levels without causing hyperphosphatemia, pointing towards a novel indication for the use of cinacalcet in KTRs. Ursula Thiem, Alois Gessl, and Kyra Borchhardt Copyright © 2015 Ursula Thiem et al. All rights reserved. Bone Marrow Pathology Predicts Mortality in Chronic Hemodialysis Patients Tue, 24 Feb 2015 12:44:06 +0000 Introduction. A bone marrow biopsy is a useful procedure for the diagnosis and staging of various hematologic and systemic diseases. The objective of this study was to investigate whether the findings of bone marrow studies can predict mortality in chronic hemodialysis patients. Methods. Seventy-eight end-stage renal disease patients on maintenance hemodialysis underwent bone marrow biopsies between 2000 and 2011, with the most common indication being unexplained anemia followed by unexplained leukocytosis and leukopenia. Results. The survivors had a higher incidence of abnormal megakaryocyte distribution , band and segmented cells , and lymphoid cells than the nonsurvivors. The overall mortality rate was 38.5% (30/78), and the most common cause of mortality was sepsis (83.3%) followed by respiratory failure (10%). In multivariate Cox regression analysis, both decreased (OR 3.714, 95% CI 1.671–8.253, ) and absent (OR 9.751, 95% CI 2.030–45.115, ) megakaryocyte distribution (normal megakaryocyte distribution as the reference group), as well as myeloid/erythroid ratio (OR 1.054, CI 1.012–1.098, ), were predictive of mortality. Conclusion. The results of a bone marrow biopsy can be used to assess the pathology, and, in addition, myeloid/erythroid ratio and abnormal megakaryocyte distribution can predict mortality in chronic hemodialysis patients. Cheng-Hao Weng, Kuan-Ying Lu, Ching-Chih Hu, Wen-Hung Huang, I-Kwan Wang, and Tzung-Hai Yen Copyright © 2015 Cheng-Hao Weng et al. All rights reserved. Aortic Arch Calcification Predicts the Renal Function Progression in Patients with Stage 3 to 5 Chronic Kidney Disease Wed, 28 Jan 2015 06:15:36 +0000 Introduction. The presence of aortic arch calcification (AoAC) and cardiomegaly on chest radiography has been demonstrated as important risk factors for cardiovascular mortality in patients with chronic kidney disease (CKD). However, the interrelationship among AoAC, cardiomegaly, and renal function progression remains unclear. The aim of this study is to assess whether AoAC and cardiomegaly are independently associated with the renal function progression in patients with stages 3–5 CKD. Methods. We retrospectively determined AoAC and cardiomegaly by chest X-ray in 237 patients, followed up for at least three years without entering dialysis and classified into 4 groups according to the presence or absence of AoAC and cardiomegaly. The change in renal function was measured by the slope of estimated glomerular filtration rate (eGFR). Results. Of the 237 patients, the rate of eGFR decline was significantly higher in the group with coexistence of AoAC and cardiomegaly than any other groups. Baseline AoAC and proteinuria were independently associated with eGFR decline. AoAC were independently determined by age, eGFR slope, and cardiomegaly. Conclusions. The coexistence of AoAC and cardiomegaly is associated with faster eGFR decline. AoAC is an independent determinant of renal outcomes in patients with CKD stages 3–5. Lung-Chih Li, Yueh-Ting Lee, Yi-Wei Lee, Chia-An Chou, and Chien-Te Lee Copyright © 2015 Lung-Chih Li et al. All rights reserved. Solid Phase-Based Cross-Matching as Solution for Kidney Allograft Recipients Pretreated with Therapeutic Antibodies Thu, 15 Jan 2015 06:33:36 +0000 In order to select recipients without donor-specific anti-HLA antibodies, the complement-dependent cytotoxicity crossmatch (CDC-CM) was established as the standard procedure about 40 years ago. However, the interpretability of this functional assay strongly depends on the vitality of isolated donors’ lymphocytes. Since the application of therapeutic antibodies for the immunosuppressive regimen falsifies the outcome of the CDC-crossmatch as a result of these antibodies’ complement-activating capacity in the recipients’ sera, we looked for an alternative methodical approach. We here present 27 examples of AB0 blood group-incompatible living kidney allograft recipients who, due to their treatment with the humanized chimeric monoclonal anti-CD20 antibody Rituximab, did not present valid outcomes of CDC-based pretransplant cross-matching. Additionally, four cases of posttransplant cross-matching after living kidney allografting and consequent treatment with the therapeutic anti-CD25 antibody Basiliximab (Simulect) due to acute biopsy-proven rejection episodes are presented and compared regarding CDC- and ELISA-based crossmatch outcomes. In all cases, it became evident that the classical CDC-based crossmatch was completely unfeasible for the detection of donor-specific anti-HLA antibodies, whereas ELISA-based cross-matching not requiring vital cells was not artificially affected. We conclude that ELISA-based cross-matching is a valuable tool to methodically circumvent false positive CDC-based crossmatch results in the presence of therapeutically applied antibodies. Gerald Schlaf, Susanne Apel, Anja Wahle, and Wolfgang W. Altermann Copyright © 2015 Gerald Schlaf et al. All rights reserved. Intradialytic Hypotension and Cardiac Remodeling: A Vicious Cycle Wed, 14 Jan 2015 14:32:21 +0000 Hemodynamic instability during hemodialysis is a common but often underestimated issue in the nephrologist practice. Intradialytic hypotension, namely, a decrease of systolic or mean blood pressure to a certain level, prohibits the safe and smooth achievement of ultrafiltration and solute removal goal in chronic dialysis patients. Studies have elucidated the potential mechanisms involved in the development of Intradialytic hypotension, including excessive ultrafiltration and loss of compensatory mechanisms for blood pressure maintenance. Cardiac remodeling could also be one important piece of the puzzle. In this review, we intend to discuss the role of cardiac remodeling, including left ventricular hypertrophy, in the development of Intradialytic hypotension. In addition, we will also provide evidence that a bidirectional relationship might exist between Intradialytic hypotension and left ventricular hypertrophy in chronic dialysis patients. A more complete understanding of the complex interactions in between could assist the readers in formulating potential solutions for the reduction of both phenomena. Chia-Ter Chao, Jenq-Wen Huang, and Chung-Jen Yen Copyright © 2015 Chia-Ter Chao et al. All rights reserved. Acute Kidney Injury Tue, 06 Jan 2015 08:06:41 +0000 Raúl Lombardi, Emmanuel A. Burdmann, Alejandro Ferreiro, and Fernando Liaño Copyright © 2015 Raúl Lombardi et al. All rights reserved. Midkine: A Novel and Early Biomarker of Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Interventions Mon, 05 Jan 2015 07:12:59 +0000 We tested the hypothesis whether midkine could represent an early biomarker of contrast-induced acute kidney injury (CIAKI) in 89 patients with normal serum creatinine undergoing PCI. Midkine, serum and urinary NGAL, and cystatin C were evaluated before and 2, 4, 8, 24, and 48 hours after PCI using commercially available kits. Serum creatinine was assessed before and 24 and 48 hours after PCI. We found a significant rise in serum midkine as early as after 2 hours () when compared to the baseline values. It was also significantly higher 4 hours after PCI and then returned to the baseline values after 24 hours and started to decrease after 48 hours. When contrast nephropathy was defined as an increase in serum creatinine by >25% of the baseline level 48 hours after PCI, the prevalence of CIN was 10%. Patients with CIN received significantly more contrast agent (), but durations of PCI were similar. Midkine was significantly higher 2, 4, and 8 hours after PCI in patients with CIN. Since the “window of opportunity” is narrow in CIAKI and time is limited to introduce proper treatment after initiating insult, particularly when patients are discharged within 24 hours after the procedure, midkine needs to be investigated as a potential early marker for renal ischemia and/or nephrotoxicity. Jolanta Malyszko, Hanna Bachorzewska-Gajewska, Ewa Koc-Zorawska, Jacek S. Malyszko, Grazyna Kobus, and Slawomir Dobrzycki Copyright © 2015 Jolanta Malyszko et al. All rights reserved. Chronic Kidney Disease Requiring Healthcare Services: A New Approach to Evaluate Epidemiology of Renal Disease Thu, 20 Nov 2014 07:11:32 +0000 Background. Screening-based CKD estimates may not provide a sufficient insight into the impact of CKD on the use of healthcare resources in clinical practice. The aim of this study was to evaluate the epidemiology of “medicalized” CKD, that is, CKD requiring healthcare services, in an outpatient setting. Design, Setting, Participants, and Measurements. This is a retrospective, longitudinal population-based study conducted in a large general practice setting in Southern Italy (Caserta) using a healthcare database. Over 2006–2011, all patients with a CKD diagnosis, either through CKD-related indications of use associated with drug prescriptions or through CKD-related hospital discharge diagnoses/procedures, were identified using this database. The prevalence of “medicalized” CKD in the general population of Caserta was estimated by age, gender, and calendar year. Results. Overall, 1,989 (1.3%) patients with a diagnosis of CKD were identified from 2006–2011 in the Caserta general population. The one year prevalence increased from 0.9% in 2006 to 1.6% in 2011, which is much lower compared to previous screening-based studies. The prevalence was slightly higher in males and increased significantly with advancing age (in 2011, 0.2% in ≤44 years old versus 9.2% in >80 years old). Conclusions. The findings of this study suggest that, in the general population, the prevalence of “medicalized” CKD is lower compared to the screening-based CKD prevalence. Gianluca Trifirò, Janet Sultana, Francesco Giorgianni, Ylenia Ingrasciotta, Michele Buemi, Marco Muscianisi, Daniele Ugo Tari, Margherita Perrotta, Valeria Canale, Vincenzo Arcoraci, and Domenico Santoro Copyright © 2014 Gianluca Trifirò et al. All rights reserved. Chronic Kidney Disease and Upper Tract Urothelial Carcinomas Thu, 11 Sep 2014 06:13:45 +0000 Li-Jen Wang, Joëlle L. Nortier, Bin Tean Teh, Cheng-Keng Chuang, and Shen-Yang Lee Copyright © 2014 Li-Jen Wang et al. All rights reserved. A Network Meta-Analysis on Randomized Trials Focusing on the Preventive Effect of Statins on Contrast-Induced Nephropathy Sun, 07 Sep 2014 09:25:22 +0000 Contrast-induced nephropathy is a common complication of iodinated contrast administration. Statins may reduce the risk of contrast-induced nephropathy, but data remain inconclusive. We summarized the evidence based on statins for the prevention of contrast-induced nephropathy with a network meta-analysis. Randomized trials focusing on statins were searched and pooled with random-effect odds ratios. A total of 14 trials (6,160 patients) were included, focusing on atorvastatin (high/low dose), rosuvastatin (high dose), simvastatin (high/low dose), and placebo or no statin therapy before contrast administration. The risk of contrast-induced nephropathy was reduced by atorvastatin high dose and rosuvastatin high dose, with no difference between these two agents. Results for atorvastatin low dose and simvastatin (high/low dose) in comparison to placebo were inconclusive. Atorvastatin and rosuvastatin administered at high doses and before iodinated contrast administration have a consistent and beneficial preventive effect on contrast-induced nephropathy and may actually halve its incidence. Mariangela Peruzzi, Leonardo De Luca, Henrik S. Thomsen, Enrico Romagnoli, Fabrizio D’Ascenzo, Massimo Mancone, Gennaro Sardella, Luigi Lucisano, Antonio Abbate, Giacomo Frati, and Giuseppe Biondi-Zoccai Copyright © 2014 Mariangela Peruzzi et al. All rights reserved. Emerging Biomarkers in Renal Damage Wed, 03 Sep 2014 08:36:38 +0000 Pasquale Ditonno, Cees van Kooten, Loreto Gesualdo, Giuseppe Grandaliano, and Giuseppe Lucarelli Copyright © 2014 Pasquale Ditonno et al. All rights reserved. Angiotensin II Removes Kidney Resistance Conferred by Ischemic Preconditioning Thu, 28 Aug 2014 05:10:26 +0000 Ischemic preconditioning (IPC) by ischemia/reperfusion (I/R) renders resistance to the kidney. Strong IPC triggers kidney fibrosis, which is involved in angiotensin II (AngII) and its type 1 receptor (AT1R) signaling. Here, we investigated the role of AngII/AT1R signal pathway in the resistance of IPC kidneys to subsequent I/R injury. IPC of kidneys was generated by 30 minutes of bilateral renal ischemia and 8 days of reperfusion. Sham-operation was performed to generate control (non-IPC) mice. To examine the roles of AngII and AT1R in IPC kidneys to subsequent I/R, IPC kidneys were subjected to either 30 minutes of bilateral kidney ischemia or sham-operation following treatment with AngII, losartan (AT1R blocker), or AngII plus losartan. IPC kidneys showed fibrotic changes, decreased AngII, and increased AT1R expression. I/R dramatically increased plasma creatinine concentrations in non-IPC mice, but not in IPC mice. AngII treatment in IPC mice resulted in enhanced morphological damage, oxidative stress, and inflammatory responses, with functional impairment, whereas losartan treatment reversed these effects. However, AngII treatment in non-IPC mice did not change I/R-induced injury. AngII abolished the resistance of IPC kidneys to subsequent I/R via the enhancement of oxidative stress and inflammatory responses, suggesting that the AngII/AT1R signaling pathway is associated with outcome in injury-experienced kidney. Hee-Seong Jang, Jee In Kim, Jinu Kim, Jeen-Woo Park, and Kwon Moo Park Copyright © 2014 Hee-Seong Jang et al. All rights reserved. Multiple Analytical Approaches Demonstrate a Complex Relationship of Genetic and Nongenetic Factors with Cisplatin- and Carboplatin-Induced Nephrotoxicity in Lung Cancer Patients Thu, 28 Aug 2014 00:00:00 +0000 Background. Cisplatin and carboplatin cause nephrotoxicity by forming platinum-DNA adducts and lead to cell death. Methods. One-hundred and sixteen Taiwanese lung cancer patients who received cisplatin or carboplatin more than twice were recruited, and their genotypes were determined. The risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease (RIFLE) criteria were used to evaluate the occurrence of nephrotoxicity. A logistic regression, multiple regression with a classification and regression tree (CART), and the Framingham study risk score were used to analyze interactions between genetic and nongenetic factors in producing platinum-induced nephrotoxicity. Results. ERCC1 118C and TP53 72Arg polymorphisms were associated with increased risks of platinum-induced nephrotoxicity. Other risk factors found included the platinum type, baseline serum creatinine (Scr), coadministration of vinorelbine, and the number of chemotherapy cycles. The overall prediction rate of the CART was 82.7%, with a sensitivity of 0.630 and specificity of 0.896. The Framingham study risk prediction model contained 7 factors. Its prediction rate was 84.5%, with a sensitivity of 0.643 and specificity of 0.909. Conclusions. Genetic polymorphisms of ERCC1 and TP53 are risk factors for nephrotoxicity. The CART analysis may provide a clinically applicable model to predict the risk of cisplatin- and carboplatin-induced nephrotoxicity. H. Eugene Liu, Kuan-Jen Bai, Yu-Chen Hsieh, Ming-Chih Yu, Chun-Nin Lee, Jer-Hua Chang, Han-Lin Hsu, Pei-Chih Lu, and Hsiang-Yin Chen Copyright © 2014 H. Eugene Liu et al. All rights reserved. A Higher Frequency of CD4+CXCR5+ T Follicular Helper Cells in Adult Patients with Minimal Change Disease Wed, 27 Aug 2014 10:34:07 +0000 Background. T follicular helper (TFH) cells are involved in the humoral immune responses. This study is aimed at examining the frequencies of different subsets of CD4+CXCR5+ TFH cells in adult patients with minimal change disease (MCD). Methods. A total of 27 patients and 14 healthy controls (HC) were characterized for the levels of sera cytokines, inducible T-cell costimulator (ICOS), and programmed death 1 (PD-1) of positive TFH cells by flow cytometry. The level of sera IL-21 was examined; 24 h urinary protein and eGFR were calculated. The potential correlation between the frequency of different subsets of TFH cells and the values of clinical measures in MCD patients were analyzed. Results. The frequency of circulating CD4+CXCR5+, CD4+CXCR5+ICOS+, and CD4+CXCR5+PD-1+ TFH cells and the levels of sera IL-17A, IFN-γ, IL-2, IL-10, IL-4, and IL-21 were significantly higher in MCD patients () than that in the HC group. Furthermore, the percentages of circulating CD4+CXCR5+ TFH cells were negatively correlated with the values of eGFR (, ) and the percentages of CD4+CXCR5+PD-1+ TFH cells were correlated positively with the levels of serum IL-21 (, ) and 24 h urinary protein (, ) in those patients. Also, the percentages of CD4+CXCR5+ICOS+ TFH cells were correlated positively with the levels of serum IL-21 (, ) and 24 h urinary protein (, ). Following standard therapies, the percentages of circulating CD4+CXCR5+, CD4+CXCR5+PD-1+, and CD4+CXCR5+ICOS+ TFH cells and the levels of serum IL-21 were significantly reduced, but the levels of serum IL-4 and IL-10 were increased (). Conclusions. A higher frequency of CD4+CXCR5+ TFH cells that existed in adult patients with MCD could be new target for intervention of MCD. Nan Zhang, Pingwei Zhao, Amrita Shrestha, Li Zhang, Zhihui Qu, Mingyuan Liu, Songling Zhang, and Yanfang Jiang Copyright © 2014 Nan Zhang et al. All rights reserved. Chinese Herbs Containing Aristolochic Acid Associated with Renal Failure and Urothelial Carcinoma: A Review from Epidemiologic Observations to Causal Inference Wed, 27 Aug 2014 05:59:04 +0000 Herbal remedies containing aristolochic acid (AA) have been designated to be a strong carcinogen. This review summarizes major epidemiologic evidence to argue for the causal association between AA exposure and urothelial carcinoma as well as nephropathy. The exposure scenarios include the following: Belgian women taking slimming pills containing single material Guang Fang Ji, consumptions of mixtures of Chinese herbal products in the general population and patients with chronic renal failure in Taiwan, occupational exposure in Chinese herbalists, and food contamination in farming villages in valleys of the Danube River. Such an association is corroborated by detecting specific DNA adducts in the tumor tissue removed from affected patients. Preventive actions of banning such use and education to the healthcare professionals and public are necessary for the safety of herbal remedies. Hsiao-Yu Yang, Pau-Chung Chen, and Jung-Der Wang Copyright © 2014 Hsiao-Yu Yang et al. All rights reserved. Acute Kidney Injury by Radiographic Contrast Media: Pathogenesis and Prevention Thu, 14 Aug 2014 13:23:35 +0000 It is well known that iodinated radiographic contrast media may cause kidney dysfunction, particularly in patients with preexisting renal impairment associated with diabetes. This dysfunction, when severe, will cause acute renal failure (ARF). We may define contrast-induced Acute Kidney Injury (AKI) as ARF occurring within 24–72 hrs after the intravascular injection of iodinated radiographic contrast media that cannot be attributed to other causes. The mechanisms underlying contrast media nephrotoxicity have not been fully elucidated and may be due to several factors, including renal ischaemia, particularly in the renal medulla, the formation of reactive oxygen species (ROS), reduction of nitric oxide (NO) production, and tubular epithelial and vascular endothelial injury. However, contrast-induced AKI can be prevented, but in order to do so, we need to know the risk factors. We have reviewed the risk factors for contrast-induced AKI and measures for its prevention, providing a long list of references enabling readers to deeply evaluate them both. Michele Andreucci, Teresa Faga, Antonio Pisani, Massimo Sabbatini, and Ashour Michael Copyright © 2014 Michele Andreucci et al. All rights reserved. Long-Term Outcomes after Dialysis-Requiring Acute Kidney Injury Tue, 12 Aug 2014 11:06:40 +0000 AKI-dialysis patients had a higher incidence of long-term ESRD and mortality than the patients without AKI. The patients who recovered from dialysis were associated with a lower incidence of long-term ESRD and mortality than in the patients who still required dialysis. Vin-Cent Wu, Chih-Chung Shiao, Chia-Hsuin Chang, Tao-Min Huang, Chun-Fu Lai, Meng-Chun Lin, Wen-Chih Chiang, Tzong-Shinn Chu, Kwan-Dun Wu, Wen-Je Ko, Cheng-Yi Wang, Shuo-Meng Wang, and Likwang Chen Copyright © 2014 Vin-Cent Wu et al. All rights reserved. Hypervolemia for Hypertension Pathophysiology: A Population-Based Study Mon, 11 Aug 2014 07:10:38 +0000 Objectives. Hypertension and hypervolemia relationship was proven among renal disease, although it is not known in normal population. Present study determines the fluid distribution defects in relation to blood pressure. Material and Methods. In a population-based survey in Turkey demographics, height, weight, blood pressure, urine analysis, and serum creatinine measurements were recorded. Bioimpedance measured with the Body Composition Monitor. Results. Total 2034 population of 71.6% male, mean age 47 ± 12.6 (18–89) years, systolic blood pressure (SBP) 134.7 ± 20, diastolic blood pressure 77.9 ± 11.6 mmHg. Body mass index (BMI) was 28.5 ± 4.5 (15.8–50.6) kg/m2; overhydration was 0.05 ± 1.05 L. There was a correlation between extracellular water (ECW)/height and SBP (r = 0.21, P < 0.001). Receiver operating characteristic (ROC) curve with the performance of 0.60 (P < 0.001) that showed cut-off value of ECW/height was 10.06 L/m, with the 69% sensitivity and 45% specificity for SBP: 140 mmHg values. Risk factors for high SBP were increase of ECW/Height, age, BMI and presence of diabetes. ECW/height, SBP, and fat tissue index (FTI) increased in BMI categories (low, normal, and obese) and in diabetics. SBP and FTI were lower in smokers. Conclusions. High blood pressure may be accompanied by increased extracellular volume indices. In the future volume status assessment could be of use in evaluating the effectiveness of pharmacological intervention in the treatment of hypertension. Ender Hür, Melih Özişik, Cihan Ural, Gürsel Yildiz, Kemal Mağden, Sennur Budak Köse, Füruzan Köktürk, Çağatay Büyükuysal, İbrahim Yildirim, Gültekin Süleymanlar, Kenan Ateş, and Soner Duman Copyright © 2014 Ender Hür et al. All rights reserved. Dialysis Complications in AKI Patients Treated with Extended Daily Dialysis: Is the Duration of Therapy Important? Mon, 11 Aug 2014 07:06:22 +0000 This trial aimed to compare the dialysis complications occurring during different durations of extended daily dialysis (EDD) sessions in critically ill AKI patients. We included patients older than 18 years with AKI associated with sepsis admitted to the intensive care unit and using noradrenaline dose ranging from 0.3 to 0.7 μg/kg/min. Patients were divided into two groups randomly: in G1, 6 h sessions were performed and, in G2, 10 h sessions were performed. Seventy-five patients were treated with 195 EDD sessions for 18 consecutive months. The prevalence of hypotension, filter clotting, hypokalaemia, and hypophosphataemia was 82.6, 25.3, 20, and 10.6%, respectively. G1 and G2 were similar in male predominance and SOFA. There was no significant difference between the two groups in hypotension, filter clotting, hypokalaemia, and hypophosphataemia. However, the group treated with sessions of 10 hours showed higher refractory to clinical measures for hypotension and dialysis sessions were interrupted more often. Metabolic control and fluid balance were similar between G1 and G2. In conclusion, intradialysis hypotension was common in AKI patients treated with EDD. There was no difference in the prevalence of dialysis complications in patients undergoing different durations of EDD. Bianca Ballarin Albino, André Luis Balbi, and Daniela Ponce Copyright © 2014 Bianca Ballarin Albino et al. All rights reserved. A Modified Single Mini-Incision Complete Urinary Tract Exenteration for Urothelial Carcinoma in Dialysis Patients Mon, 11 Aug 2014 00:00:00 +0000 Objective. To present our experience with single mini-incision complete urinary tract exenteration (CUTE) for female dialysis patients suffering from urothelial carcinoma (UC). Patients and Methods. Institutional review board approval was obtained. From 2005 through 2012, 14 female dialysis patients with UC underwent single mini-incision CUTE, in combination with radical hysterectomy and bilateral salpingo-oophorectomy. All were placed in the modified dorsal lithotomy position without repositioning. An infraumbilical midline mini-incision was made. Bilateral nephroureterectomy was first performed entirely extraperitoneally, followed by radical cystectomy with removal of the uterus and ovaries transperitoneally. Results. All procedures were done successfully without major complications. The median operative time was 242.5 minutes, and estimated blood loss was 500 mL. The median time to oral intake was 2 postoperative days; the median hospital stay was 11 days. Ten patients remained cancer-free at a median follow-up of 46.5 months; six patients were confirmed as having preoperatively undetectable UC or renal cell carcinoma, even after reviewing preoperative computed tomography. Conclusions. This modified technique provides a time-saving complete urinary tract extirpation to eliminate preoperatively undetectable malignancy, reduce metachronous recurrences, and avert perioperative complications associated with pneumoperitoneum and repositioning. Good cancer control and early convalescence can mutually be achieved in experienced hands. I-Hsuan Chen, Jen-Tai Lin, Jeng-Yu Tsai, Tony Wu, and Chia-Cheng Yu Copyright © 2014 I-Hsuan Chen et al. All rights reserved. Nomogram Predicting Renal Insufficiency after Nephroureterectomy for Upper Tract Urothelial Carcinoma in the Chinese Population: Exclusion of Ineligible Candidates for Adjuvant Chemotherapy Sun, 10 Aug 2014 08:15:01 +0000 Objectives. To report the decline of renal function after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC) patients and to develop a nomogram to predict ineligibility for cisplatin-based adjuvant chemotherapy (AC). Methods. We retrospectively analyzed 606 consecutive Chinese UTUC patients treated by RNU from 2000 to 2010. We chose an eGFR of 60 and 45 ml/min/1.73 m2 as cut-offs for full-dose and reduced-dose AC eligibility. Results. Median eGFR for all patients before and after surgery was 64 and 49 ml/min/1.73 m2 (). The proportion of patients ineligible to receive full-dose and reduced-dose AC changed from 42% to 74% and from 20% to 38.1%. Older age (OR = 1.007), preoperative eGFR (OR = 0.993), absence of hydronephrosis (OR = 0.801), smaller tumor size (OR = 0.962), and tumor without multifocality (OR = 0.876) were predictive for ineligibility for full-dose AC. Preoperative eGFR (OR = 0.991), absence of hydronephrosis (OR = 0.881), tumor located in renal pelvis (OR = 1.164), and smaller tumor size (OR = 0.969) could predict ineligibility for reduced-dose AC. The c-index of the two models was 0.757 and 0.836. Postoperative renal function was not associated with worse survival. Conclusions. Older age, lower preoperative eGFR, smaller tumor size, tumor located in renal pelvis, and absence of hydronephrosis or multifocality were predictors of postoperative renal insufficiency. Dong Fang, Qifu Zhang, Xuesong Li, Cheng Qian, Gengyan Xiong, Lei Zhang, Xiaopeng Chen, Xiaoyu Zhang, Wei Yu, Zhisong He, and Liqun Zhou Copyright © 2014 Dong Fang et al. All rights reserved. Upper Tract Urothelial Carcinomas in Patients with Chronic Kidney Disease: Relationship with Diagnostic Challenge Thu, 07 Aug 2014 09:38:03 +0000 Chronic kidney disease and upper tract urothelial carcinomas display a bidirectional relationship. Review of the literature indicates that early diagnosis and correct localization of upper tract urothelial carcinomas in dialysis patients and kidney transplant recipients are important but problematic. Urine cytology and cystoscopy have limited sensitivity for the diagnosis of upper tract urothelial carcinomas in dialysis patients. Enhanced computed tomography and magnetic resonance imaging could prove useful for the detection and staging of upper tract urothelial carcinomas in dialysis patients. Renal ultrasound can detect hydronephrosis caused by upper tract urothelial carcinomas in kidney transplant recipients but cannot visualize the carcinomas themselves. High detection rates for upper tract urothelial carcinomas in kidney transplant recipients have recently been demonstrated using computed tomography urography, which appears to be a promising tool. To detect carcinomas in dialysis patients and kidney transplant recipients as early as possible, regular screening in asymptomatic patients and diagnostic work-up in symptomatic patients should be performed using a combination of urological and imaging methods. Careful assessment of subsequent recurrence within the contralateral upper urinary tract and the urinary bladder is necessary for dialysis patients and kidney transplant recipients with upper tract urothelial carcinomas. Li-Jen Wang, Shen-Yang Lee, Bin Tean Teh, Cheng-Keng Chuang, and Joëlle Nortier Copyright © 2014 Li-Jen Wang et al. All rights reserved. Extended Renal Outcomes with Use of Iodixanol versus Iohexol after Coronary Angiography Thu, 07 Aug 2014 07:19:36 +0000 The impact of isoosmolar versus low-osmolar contrast media (CM) administration on contrast-induced acute kidney injury (CI-AKI) and extended renal dysfunction (ERD) is unclear. We retrospectively examined incidences of CI-AKI and ERD in patients who received iodixanol (isoosmolar) versus iohexol (low-osmolar) during angiography for cardiac indications. Of 713 patients, 560 (cohort A), 190 (cohort B), and 172 (cohort C) had serum creatinine monitored at 3 days, 30 days, and 6 months after angiography, respectively. 18% of cohort A developed CI-AKI, which was more common with iodixanol than iohexol (22% versus 13%, ). However, patients given iodixanol were older with lower baseline estimated glomerular filtration rates (eGFR). On multivariate analysis, independent associations with higher CI-AKI risk include age >65 years, female gender, cardiac failure, ST-elevation myocardial infarction, intra-aortic balloon pump, and critical illness, but not CM type, higher CM load, or  mL/min/1.73 m2. 32% of cohort B and 34% of cohort C had ERD at 30 days and 6 months, while 44% and 41% of subcohorts had ERD at 90 days and 1 year, respectively. CI-AKI, but not CM type, was associated with medium- and longer-term ERD, with 3-fold higher risk. Advanced age, emergent cardiac conditions, and critical illness are stronger predictors of CI-AKI, compared with CM-related factors. CI-AKI predicts longer-term ERD. Horng-Ruey Chua, Mark Horrigan, Elizabeth Mcintosh, and Rinaldo Bellomo Copyright © 2014 Horng-Ruey Chua et al. All rights reserved. Pathophysiology of Cisplatin-Induced Acute Kidney Injury Wed, 06 Aug 2014 09:31:22 +0000 Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality. Abdullah Ozkok and Charles L. Edelstein Copyright © 2014 Abdullah Ozkok and Charles L. Edelstein. All rights reserved. Anticancer Drug 2-Methoxyestradiol Protects against Renal Ischemia/Reperfusion Injury by Reducing Inflammatory Cytokines Expression Wed, 06 Aug 2014 06:47:42 +0000 Background. Ischemia/reperfusion (I/R) injury is a major cause of acute renal failure and allograft dysfunction in kidney transplantation. ROS/inflammatory cytokines are involved in I/R injury. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, inhibits inflammatory cytokine expression and is an antiangiogenic and antitumor agent. We investigated the inhibitory effect of 2ME2 on renal I/R injury and possible molecular actions. Methods. BALB/c mice were intraperitoneally injected with 2ME2 (10 or 20 mg/kg) or vehicle 12 h before and immediately after renal I/R experiments. The kidney weight, renal function, tubular damages, and apoptotic response were examined 24 h after I/R injury. The expression of mRNA of interleukin-1β, tumor necrosis factor- (TNF) α, caspase-3, hypoxia inducible factor- (HIF) 1α, and proapoptotic Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) in kidney tissue was determined using RT-PCR, while the expression of nuclear factor κB (NF-κB), BCL-2, and BCL-xL, activated caspase-9, and HIF-1α was determined using immunoblotting. In vitro, we determined the effect of 2ME2 on reactive oxygen species (ROS) production and cell viability in antimycin-A-treated renal mesangial (RMC) and tubular (NRK52E) cells. Results. Serum creatinine and blood urea nitrogen were significantly higher in mice with renal I/R injury than in sham control and in I/R+2ME2-treated mice. Survival in I/R+2ME2-treated mice was higher than in I/R mice. Histological examination showed that 2ME2 attenuated tubular damage in I/R mice, which was associated with lower expression TNF-α, IL-1β, caspase-9, HIF-1α, and BNIP3 mRNA in kidney tissue. Western blotting showed that 2ME2 treatment substantially decreased the expression of activated caspase-9, NF-κB, and HIF-1α but increased the antiapoptotic proteins BCL-2 and BCL-xL in kidney of I/R injury. In vitro, 2MR2 decreased ROS production and increased cell viability in antimycin-A-treated RMC and NRK52E cells. Conclusions. 2ME2 reduces renal I/R injury in mice because it inhibits the expression of ROS and proinflammatory cytokines and induces antiapoptotic proteins. Ying-Yin Chen, Ching-Hua Yeh, Edmund Cheung So, Ding-Ping Sun, Li-Yun Wang, and Chung-Hsi Hsing Copyright © 2014 Ying-Yin Chen et al. All rights reserved. Metabolic Acidosis and Strong Ion Gap in Critically Ill Patients with Acute Kidney Injury Tue, 05 Aug 2014 12:15:45 +0000 Purpose. To determine the influence of physicochemical parameters on survival in metabolic acidosis (MA) and acute kidney injury (AKI) patients. Materials and Methods. Seventy-eight MA patients were collected and assigned to AKI or non-AKI group. We analyzed the physiochemical parameters on survival at 24 h, 72 h, 1 week, 1 month, and 3 months after AKI. Results. Mortality rate was higher in the AKI group. AKI group had higher anion gap (AG), strong ion gap (SIG), and apparent strong ion difference (SIDa) values than non-AKI group. SIG value was higher in the AKI survivors than nonsurvivors and this value was correlated serum creatinine, phosphate, albumin, and chloride levels. SIG and serum albumin are negatively correlated with Acute Physiology and Chronic Health Evaluation IV scores. AG was associated with mortality at 1 and 3 months post-AKI, whereas SIG value was associated with mortality at 24 h, 72 h, 1 week, 1 month, and 3 months post-AKI. Conclusions. Whether high or low SIG values correlate with mortality in MA patients with AKI depends on its correlation with serum creatinine, chloride, albumin, and phosphate (P) levels. AG predicts short-term mortality and SIG value predicts both short- and long-term mortality among MA patients with AKI. Cai-Mei Zheng, Wen-Chih Liu, Jing-Quan Zheng, Min-Tser Liao, Wen-Ya Ma, Kuo-Chin Hung, Chien-Lin Lu, Chia-Chao Wu, and Kuo-Cheng Lu Copyright © 2014 Cai-Mei Zheng et al. All rights reserved. Citrate Anticoagulation for CRRT in Children: Comparison with Heparin Sun, 03 Aug 2014 07:18:25 +0000 Regional anticoagulation with citrate is an alternative to heparin in continuous renal replacement therapies, which may prolong circuit lifetime and decrease hemorrhagic complications. A retrospective comparative cohort study based on a prospective observational registry was conducted including critically ill children undergoing CRRT. Efficacy, measured as circuit survival, and secondary effects of heparin and citrate were compared. 12 patients on CRRT with citrate anticoagulation and 24 patients with heparin anticoagulation were analyzed. Median citrate dose was 2.6 mmol/L. Median calcium dose was 0.16 mEq/kg/h. Median heparin dose was 15 UI/kg/h. Median circuit survival was 48 hours with citrate and 31 hours with heparin (). 66.6% of patients treated with citrate developed mild metabolic alkalosis, which was directly related to citrate dose. There were no cases of citrate intoxication: median total calcium/ionic calcium index (CaT/I) of 2.16 and a maximum CaT/I of 2.33, without metabolic acidosis. In the citrate group, 45.5% of patients developed hypochloremia and 27.3% hypomagnesemia. In the heparin group, 27.8% developed hypophosphatemia. Three patients were moved from heparin to citrate to control postoperatory bleeding. In conclusion citrate is a safe and effective anticoagulation method for CRRT in children and it achieves longer circuit survival than heparin. Sara Nicole Fernández, Maria José Santiago, Jesús López-Herce, Miriam García, Jimena Del Castillo, Andrés José Alcaraz, and Jose María Bellón Copyright © 2014 Sara Nicole Fernández et al. All rights reserved. Randomized Controlled Trial of Strain-Specific Probiotic Formulation (Renadyl) in Dialysis Patients Thu, 24 Jul 2014 00:00:00 +0000 Background. Primary goal of this randomized, double-blind, placebo-controlled crossover study of Renadyl in end-stage renal disease patients was to assess the safety and efficacy of Renadyl measured through improvement in quality of life or reduction in levels of known uremic toxins. Secondary goal was to investigate the effects on several biomarkers of inflammation and oxidative stress. Methods. Two 2-month treatment periods separated by 2-month washout and crossover, with physical examinations, venous blood testing, and quality of life questionnaires completed at each visit. Data were analyzed with SAS V9.2. Results. 22 subjects (79%) completed the study. Observed trends were as follows (none reaching statistical significance): decline in WBC count , and reductions in levels of C-reactive protein , and total indoxyl glucuronide , . No statistically significant changes were observed in other uremic toxin levels or measures of QOL. Conclusions. Renadyl appeared to be safe to administer to ESRD patients on hemodialysis. Stability in QOL assessment is an encouraging result for a patient cohort in such advanced stage of kidney disease. Efficacy could not be confirmed definitively, primarily due to small sample size and low statistical power—further studies are warranted. Ranganathan Natarajan, Bohdan Pechenyak, Usha Vyas, Pari Ranganathan, Alan Weinberg, Peter Liang, Mary C. Mallappallil, Allen J. Norin, Eli A. Friedman, and Subodh J. Saggi Copyright © 2014 Ranganathan Natarajan et al. All rights reserved. Frequency of TGF-β and IFN-γ Genotype as Risk Factors for Acute Kidney Injury and Death in Intensive Care Unit Patients Wed, 23 Jul 2014 10:57:21 +0000 Genetic variations in TGF-β and IFN-γ may interfere with proinflammatory cytokine production and, consequently, may be involved with inflammatory diseases, as acute kidney injury (AKI). We considered that genetic polymorphisms of these cytokines may have a crucial role in the outcome of critically ill patients. To investigate whether the genetic polymorphisms of rs1800470 (codon 10 T/C), rs1800471 (codon 25 C/G) from the TGF-β, and rs2430561 (+874 T/A) from IFN-γ may be a risk factor for ICU patients to the development of AKI and/or death. In a prospective nested case-control study, were included 139 ICU patients who developed AKI, 164 ICU patients without AKI, and 244 healthy individuals. We observed a higher frequency to T/A genotype for IFN-γ (intermediate producer phenotype) and higher frequency of TT GG and TC GG genotype (high producer) for TGF-β polymorphism in overall population. However, these polymorphisms have not been shown as a predictor of risk for AKI and death. We found an increased prevalence of high and intermediate producer phenotypes from TGF-β and IFN-γ, respectively, in patients in ICU setting. However, the studied genetic polymorphism of the TGF-β and IFN-γ was not associated as a risk factor for AKI or death in our population. Caren Cristina Grabulosa, Marcelo Costa Batista, Miguel Cendoroglo, Beata Marie Redublo Quinto, Roberto Narciso, Julio Cesar Monte, Marcelino Durão, Luiz Vicente Rizzo, Oscar Fernando Pavão Santos, and Maria Aparecida Dalboni Copyright © 2014 Caren Cristina Grabulosa et al. All rights reserved. Upregulation of Transglutaminase and ε (γ-Glutamyl)-Lysine in the Fisher-Lewis Rat Model of Chronic Allograft Nephropathy Mon, 21 Jul 2014 11:51:30 +0000 Background. Tissue transglutaminase (TG2), a cross-linking enzyme, modulates deposition of extracellular matrix protein in renal fibrosis. This study aimed to examine TG2 and its cross-link product ε(γ-glutamyl)-lysine in the Fisher-Lewis rat renal transplantation (RTx) model of chronic allograft nephropathy (CAN). Materials and Methods. Left renal grafts from male Fisher and Lewis were transplanted into Lewis rats, generating allografts and isografts, respectively. Blood pressure, renal function, and proteinuria were monitored for up to 52 weeks. At termination, CAN was assessed in the renal tissue by light and electron microscopy, TG2 and ε(γ-glutamyl)-lysine by immunofluorescence, and the urinary ε(γ-glutamyl)-lysine by high performance liquid chromatography. Results. Compared to the isograft, the allografts were hypertensive, proteinuric, and uraemic and developed CAN. Extracellular TG2 (glomerulus: versus , ; interstitium: versus , ), ε(γ-glutamyl)-lysine (glomerulus: versus , ; interstitium: versus , ), TG2 enzyme activity ( versus  nmol/h/mg protein, ), TG2 mRNA (20-fold rise), and urinary ε(γ-glutamyl)-lysine ( nmol/24 h versus  nmol/24 h, ) levels were significantly elevated in the allografts and showed a positive linear correlation with tubulointerstitial fibrosis. Conclusion. CAN was associated with upregulation of renal TG2 pathway, which has a potential for pharmacological intervention. The elevated urinary ε(γ-glutamyl)-lysine, measured for the first time in RTx, is a potential biomarker of CAN. Badri Shrestha, Imran Butt, Michelle Da Silva, Armando Sanchez-Lara, Bart Wagner, Andrew Raftery, Timothy Johnson, and John Haylor Copyright © 2014 Badri Shrestha et al. All rights reserved. Hypoxia-Pretreated Human MSCs Attenuate Acute Kidney Injury through Enhanced Angiogenic and Antioxidative Capacities Wed, 16 Jul 2014 00:00:00 +0000 Hypoxia preconditioning has been confirmed as an effective strategy to enhance the therapeutic potentials of mesenchymal stem cells (MSCs), such as for myocardial ischemia. However, whether hypoxia preconditioning would produce beneficial effects on MSC-based renal repair has not been demonstrated. In the study, we aimed to determine the feasibility and efficacy of hypoxia preconditioning to enhance MSC-based therapy of acute kidney injury (AKI). MSCs were isolated from human adipose tissues. The paracrine effects of MSCs under normoxia and hypoxia were determined in vitro. Rats of AKI were induced by kidney I/R surgery and randomly divided into three groups: I/R control receiving PBS injection; MSC group receiving normal MSC injection; hypoMSC group receiving hypoxia-preconditioned MSC injection. It was demonstrated in vitro that paracrine effects of MSCs were significantly enhanced, especially angiogenic factors. Dihydroethidium (DHE) staining showed that antioxidative activities of MSCs were significantly enhanced by hypoxia stimulation. Vascularization, apoptosis, and histological injury were all significantly improved in hypoMSC injected group compared with that in control and MSC injected groups. Finally, the renal function was also significantly improved in hypoMSC injected group compared with that in the other two groups as assessed by the serum creatinine and BUN levels. Wenbo Zhang, Lirui Liu, Yanhong Huo, Yonghong Yang, and Yaping Wang Copyright © 2014 Wenbo Zhang et al. All rights reserved. Could Pyelonephritic Scarring Be Prevented by Anti-Inflammatory Treatment? An Experimental Model of Acute Pyelonephritis Thu, 03 Jul 2014 07:05:14 +0000 Objectives. This study aimed to demonstrate if the addition of anti-inflammatory treatment to antibiotic therapy shows any superiority to the treatment with antibiotic only. Methods. Forty-nine Wistar rats were divided into 7 groups. Pyelonephritis was performed by E. coli injection to upper pole of kidneys except control group. Group 2 was not treated. Ceftriaxone, ketoprofen, “ceftriaxone + ketoprofen,” methylprednisolone, and “ceftriaxone + methylprednisolone” were given in the groups. The technetium-99m-dimercaptosuccinic acid scintigraphies were performed in 3rd day to detect pyelonephritis and 10th week to detect renal scarring. All kidneys were also histopathologically evaluated. Results. When 3rd day and 10th week scintigraphies were compared, initial 2.00 ± 0.30 point pyelonephritis score resulted in 0.71 ± 0.36 renal scar score in “ceftriaxone + ketoprofen” group (). Initial 2.00 ± 0.43 point pyelonephritis score resulted in 0.86 ± 0.26 renal scar score in “ceftriaxone + methylprednisolone” group (). Renal scar score was declined in “ceftriaxone + ketoprofen” group and “ceftriaxone + methylprednisolone” group compared with no-treatment group on 10th week of the study (, ). On histopathological evaluation, it was seen that renal scar prevalence and expansion declined significantly in “ceftriaxone + ketoprofen and ceftriaxone + methylprednisolone” (, ). Conclusion. It was evidenced that ceftriaxone treatment in combination with ketoprofen or methylprednisolone declined scar formation in scintigraphic and histopathologic examinations of the kidneys. Elif Bahat Özdoğan, Tuğba Özdemir, Seçil Arslansoyu Çamlar, Mustafa İmamoğlu, Ümit Çobanoğlu, Bircan Sönmez, İlknur Tosun, and İsmail Doğan Copyright © 2014 Elif Bahat Özdoğan et al. All rights reserved. Emerging Urinary Markers of Renal Injury in Obstructive Nephropathy Wed, 02 Jul 2014 12:17:44 +0000 The effects of obstruction on renal function are the consequence of many factors that profoundly alter all components of glomerular function. Besides the acute effects on glomerular filtration rate and tubule function, a chronic obstruction induces tubular and interstitial injury that results from the activation of different pathways. The progression of tubulointerstitial injury leads to chronic renal damage characterized by tubular atrophy, inflammatory cell infiltration, and interstitial fibrosis. Obstructive nephropathy is an evolving disease in which the renal damage continues even after relief of the obstruction. In particular, it has been demonstrated that the time of relief is the most important factor in predicting long-term renal function deterioration. In this setting, the EGF/MCP-1 ratio, urinary NGAL, and urinary KIM-1 are useful early biomarkers of progressive renal damage and could have a potential role in predicting the long-term renal outcome. This minireview summarizes the role of these emerging urinary biomarkers of obstructive nephropathy based on the current understanding of the pathophysiology of renal injury. Giuseppe Lucarelli, Vito Mancini, Vanessa Galleggiante, Monica Rutigliano, Antonio Vavallo, Michele Battaglia, and Pasquale Ditonno Copyright © 2014 Giuseppe Lucarelli et al. All rights reserved. Impact of Gentamicin Coadministration along with High Fructose Feeding on Progression of Renal Failure and Metabolic Syndrome in Sprague-Dawley Rats Mon, 23 Jun 2014 05:46:01 +0000 The current study evaluates the impact of high fructose feeding in rat model of gentamicin induced nephrotoxicity. Sprague-Dawley rats weighing 180–200 g were randomized into four groups; (C) received standard rodents chow with free access to ad libitum drinking water for 8 weeks and was considered as control, (F) received standard rodents chow with free access to drinking water supplemented with 20% (W/V) fructose for the same abovementioned period, (FG) was fed as group F and was given 80 mg/kg (body weight)/day gentamicin sulphate intraperitoneally during the last 20 days of the feeding period, and (G) was given gentamicin as above and fed as group C. Renal function was assessed at the end of the treatment period through measuring serum creatinine, uric acid and albumin, creatinine clearance, absolute and fractional excretion of both sodium and potassium, twenty-four-hour urinary excretion of albumin, and renal histology. For metabolic syndrome assessment, fasting plasma glucose and insulin were measured and oral glucose tolerance test was performed throughout the treatment period. Results showed that gentamicin enhances progression of fructose induced metabolic syndrome. On the other hand, fructose pretreatment before gentamicin injection produced a comparable degree of renal dysfunction to those which were given fructose-free water but the picture of nephrotoxicity was somewhat altered as it was characterized by higher extent of glomerular congestion and protein urea. Overall, more vigilance is required when nephrotoxic drugs are prescribed for patients with fructose induced metabolic syndrome. Zaid O. Ibraheem, Rusliza Basir, Ahmad Kh. Aljobory, Omar E. Ibrahim, Ajwad Alsumaidaee, and Mun Fee Yam Copyright © 2014 Zaid O. Ibraheem et al. All rights reserved. Acute Superoxide Radical Scavenging Reduces Blood Pressure but Does Not Influence Kidney Function in Hypertensive Rats with Postischemic Kidney Injury Sun, 22 Jun 2014 07:19:45 +0000 Acute kidney injury (AKI) is associated with significant morbidity and mortality in hypertensive surroundings. We investigated superoxide radical molecules influence on systemic haemodynamic and kidney function in spontaneously hypertensive rats (SHR) with induced postischemic AKI. Experiment was performed in anesthetized adult male SHR. The right kidney was removed, and left renal artery was subjected to ischemia by clamping for 40 minutes. The treated group received synthetic superoxide dismutase mimetic TEMPOL in the femoral vein 5 minutes before, during, and 175 minutes after the period of reperfusion, while the control AKI group received the vehicle via the same route. All parameters were measured 24 h after renal reperfusion. TEMPOL treatment significantly decreased mean arterial pressure and total peripheral resistance compared to AKI control. It also increased cardiac output and catalase activity . Lipid peroxidation and renal vascular resistance were decreased in TEMPOL . Plasma creatinine and kidney morphological parameters were unchanged among TEMPOL treated and control groups. Our study shows that superoxide radicals participate in haemodynamic control, but acute superoxide scavenging is ineffective in glomerular and tubular improvement, probably due to hypertension-induced strong endothelial dysfunction which neutralizes beneficial effects of scavenging. Zoran Miloradović, Milan Ivanov, Nevena Mihailović-Stanojević, Jelica Grujić Milanović, Đurđica Jovović, Una-Jovana Vajić, and Jasmina Marković-Lipkovski Copyright © 2014 Zoran Miloradović et al. All rights reserved. Increased Upper and Lower Tract Urothelial Carcinoma in Patients with End-Stage Renal Disease: A Nationwide Cohort Study in Taiwan during 1997–2008 Mon, 16 Jun 2014 08:08:01 +0000 Background. Urothelial cancer (UC) is the leading cancer of patients with end-stage renal disease (ESRD) in Taiwan. The aims of this study were to explore the time trends of UC incidences and propose possible etiologic factors. Methods. Abstracting from the National Health Insurance Research Database (NHIRD), there were 90,477 newly diagnosed cases of ESRD between 1997 and 2008 covering the patients aged 40–85. Among them, 2,708 had developed UC after diagnosis of ESRD. The CIR40–85 (cumulative incidence rate) of upper tract UC (UTUC) and lower tract UC (LTUC) were calculated for ESRD patients and general population, as well as SIR40–85 (standardized incidence ratio) for comparison. Results. Female ESRD patients were found to have 9–18 times of elevated risks of UC, while those of males were increased up to 4–14 times. The time trends of CIR40–84 and SIR40–84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA associated herbal products after 1998. Conclusions. Patients with ESRD are at increased risks for both LTUC and UTUC in Taiwan. We hypothesize that the time trends associate with the consumption of aristolochic acid in Chinese herbal products (female predominant). Shuo-Meng Wang, Ming-Nan Lai, Pau-Chung Chen, Yeong-Shiau Pu, Ming-Kuen Lai, Jing-Shiang Hwang, and Jung-Der Wang Copyright © 2014 Shuo-Meng Wang et al. All rights reserved. Caffeic Acid Phenethyl Ester Protects against Amphotericin B Induced Nephrotoxicity in Rat Model Mon, 16 Jun 2014 07:37:15 +0000 The present study was conducted to investigate whether caffeic acid phenethyl ester (CAPE), an active component of propolis extract, has a protective effect on amphotericin B induced nephrotoxicity in rat models. Male Wistar-Albino rats were randomly divided into four groups: (I) control group (), (II) CAPE group () which received 10 μmol/kg CAPE intraperitoneally (i.p.), (III) amphotericin B group () which received one dose of 50 mg/kg amphotericin B, and (IV) amphotericin B plus CAPE group () which received 10 μmol/kg CAPE i.p. and one dose of 50 mg/kg amphotericin B. The left kidney was evaluated histopathologically for nephrotoxicity. Levels of malondialdehyde (MDA), nitric oxide (NO), enzyme activities including catalase (CAT), and superoxide dismutase (SOD) were measured in the right kidney. Histopathological damage was prominent in the amphotericin B group compared to controls, and the severity of damage was lowered by CAPE administration. The activity of SOD, MDA, and NO levels increased and catalase activity decreased in the amphotericin B group compared to the control group (, , , and , resp.). Amphotericin B plus CAPE treatment caused a significant decrease in MDA, NO levels, and SOD activity (, , and , resp.) and caused an increase in CAT activity compared with amphotericin B treatment alone (). CAPE treatment seems to be an effective adjuvant agent for the prevention of amphotericin B nephrotoxicity in rat models. Atila Altuntaş, H. Ramazan Yılmaz, Ayşegül Altuntaş, Efkan Uz, Murat Demir, Alparslan Gökçimen, Oğuzhan Aksu, Dilek Şenol Bayram, and Mehmet Tuğrul Sezer Copyright © 2014 Atila Altuntaş et al. All rights reserved. Atrial Natriuretic Peptide and Renal Dopaminergic System: A Positive Friendly Relationship? Thu, 12 Jun 2014 10:41:54 +0000 Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways. Marcelo Roberto Choi, Natalia Lucía Rukavina Mikusic, Nicolás Martín Kouyoumdzian, María Cecilia Kravetz, and Belisario Enrique Fernández Copyright © 2014 Marcelo Roberto Choi et al. All rights reserved. Emerging Biomarkers and Metabolomics for Assessing Toxic Nephropathy and Acute Kidney Injury (AKI) in Neonatology Wed, 11 Jun 2014 09:19:23 +0000 Identification of novel drug-induced toxic nephropathy and acute kidney injury (AKI) biomarkers has been designated as a top priority by the American Society of Nephrology. Increasing knowledge in the science of biology and medicine is leading to the discovery of still more new biomarkers and of their roles in molecular pathways triggered by physiological and pathological conditions. Concomitantly, the development of the so-called “omics” allows the progressive clinical utilization of a multitude of information, from those related to the human genome (genomics) and proteome (proteomics), including the emerging epigenomics, to those related to metabolites (metabolomics). In preterm newborns, one of the most important factors causing the pathogenesis and the progression of AKI is the interaction between the individual genetic code, the environment, the gestational age, and the disease. By analyzing a small urine sample, metabolomics allows to identify instantly any change in phenotype, including changes due to genetic modifications. The role of liquid chromatography-mass spectrometry (LC-MS), proton nuclear magnetic resonance (1H NMR), and other emerging technologies is strategic, contributing basically to the sudden development of new biochemical and molecular tests. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are closely correlated with the severity of kidney injury, representing noninvasive sensitive surrogate biomarkers for diagnosing, monitoring, and quantifying kidney damage. To become routine tests, uNGAL and KIM-1 should be carefully tested in multicenter clinical trials and should be measured in biological fluids by robust, standardized analytical methods. M. Mussap, A. Noto, V. Fanos, and J. N. Van Den Anker Copyright © 2014 M. Mussap et al. All rights reserved. Stem Cell-Based Cell Therapy for Glomerulonephritis Mon, 09 Jun 2014 07:29:30 +0000 Glomerulonephritis (GN), characterized by immune-mediated inflammatory changes in the glomerular, is a common cause of end stage renal disease. Therapeutic options for glomerulonephritis applicable to all cases mainly include symptomatic treatment and strategies to delay progression. In the attempt to yield innovative interventions fostering the limited capability of regeneration of renal tissue after injury and the uncontrolled pathological process by current treatments, stem cell-based therapy has emerged as novel therapy for its ability to inhibit inflammation and promote regeneration. Many basic and clinical studies have been performed that support the ability of various stem cell populations to ameliorate glomerular injury and improve renal function. However, there is a long way before putting stem cell-based therapy into clinical practice. In the present article, we aim to review works performed with respect to the use of stem cell of different origins in GN, and to discuss the potential mechanism of therapeutic effect and the challenges for clinical application of stem cells. Meiling Jin, Yuansheng Xie, Qinggang Li, and Xiangmei Chen Copyright © 2014 Meiling Jin et al. All rights reserved. Side Effects of Radiographic Contrast Media Mon, 02 Jun 2014 07:03:47 +0000 Michele Andreucci Copyright © 2014 Michele Andreucci. All rights reserved. Novel Biomarkers for Contrast-Induced Acute Kidney Injury Thu, 29 May 2014 16:12:32 +0000 Biomarkers of acute kidney injury (AKI) may be classified in 2 groups: (1) those representing changes in renal function (e.g., serum creatinine or cystatin C and urine flow rate) and (2) those reflecting kidney damage (e.g., kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18, etc.). According to these 2 fundamental criteria, 4 subgroups have been proposed: (1) no marker change; (2) damage alone; (3) functional change alone; and (4) combined damage and functional change. Therefore, a new category of patients with “subclinical AKI” (that is, an increase in damage markers alone without simultaneous loss of kidney function) has been identified. This condition has been associated with higher risk of adverse outcomes (including renal replacement therapy and mortality) at followup. The ability to measure these physiological variables may lead to identification of patients at risk for AKI and early diagnosis of AKI and may lead to variables, which may inform therapeutic decisions. Carlo Briguori, Cristina Quintavalle, Elvira Donnarumma, and Gerolama Condorelli Copyright © 2014 Carlo Briguori et al. All rights reserved. Olmesartan Attenuates Tacrolimus-Induced Biochemical and Ultrastructural Changes in Rat Kidney Tissue Wed, 28 May 2014 10:46:23 +0000 Tacrolimus, a calcineurin inhibitor, is clinically used as an immunosuppressive agent in organ transplantation, but its use is limited due to its marked nephrotoxicity. The present study investigated the effect of olmesartan (angiotensin receptor blocker) on tacrolimus-induced nephrotoxicity in rats. A total of 24 rats were divided into four groups, which included control, tacrolimus, tacrolimus + olmesartan, and olmesartan groups. Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. Tacrolimus significantly increased BUN and creatinine level. Treatment with olmesartan reversed tacrolimus-induced changes in the biochemical markers (BUN and creatinine) of nephrotoxicity. Tacrolimus significantly decreased GSH level and catalase activity while increasing MDA level. Olmesartan also attenuated the effects of tacrolimus on MDA, GSH, and catalase. In tacrolimus group histological examination showed marked changes in renal tubule, mitochondria, and podocyte processes. Histopathological and ultrastructural studies showed that treatment with olmesartan prevented tacrolimus-induced renal damage. These results suggest that olmesartan has protective effects on tacrolimus-induced nephrotoxicity, implying that RAS might be playing role in tacrolimus-induced nephrotoxicity. Naif O. Al-Harbi, Faisal Imam, Mohammed M. Al-Harbi, Muzaffar Iqbal, Ahmed Nadeem, Mohammed M. Sayed-Ahmed, Ali D. Alabidy, and Ali F. Almukhallafi Copyright © 2014 Naif O. Al-Harbi et al. All rights reserved. Biological Pathways and Potential Targets for Prevention and Therapy of Chronic Allograft Nephropathy Tue, 27 May 2014 06:20:28 +0000 Renal transplantation (RT) is the best option for patients with end-stage renal disease, but the half-life is limited to a decade due to progressive deterioration of renal function and transplant failure from chronic allograft nephropathy (CAN), which is the leading cause of transplant loss. Extensive research has been done to understand the pathogenesis, the biological pathways of fibrogenesis, and potential therapeutic targets for the prevention and treatment of CAN. Despite the advancements in the immunosuppressive agents and patient care, CAN continues to remain an unresolved problem in renal transplantation. The aim of this paper is to undertake a comprehensive review of the literature on the pathogenesis, biological pathways of RT fibrogenesis, and potential therapeutic targets for the prevention and therapy of CAN. Badri Man Shrestha and John Haylor Copyright © 2014 Badri Man Shrestha and John Haylor. All rights reserved. Value of Plasmatic Membrane Attack Complex as a Marker of Severity in Acute Kidney Injury Sun, 25 May 2014 10:41:44 +0000 The aim of this study was to determine if complement pathway is activated in AKI; for this purpose, we measured, through ELISA sandwich, the terminal lytic fraction of the complement system, called membrane attack complex (C5b-C9), in AKI patients compared with patients with similar clinical conditions but normal renal function. Our data showed that complement system is activated in AKI. Plasmatic MAC concentrations were significantly higher in AKI patients than in those with normal renal function; this difference is maintained independently of the AKI etiology and is proportional to the severity of AKI, measured by ADQI classification. In addition, we found that plasmatic MAC concentrations were significantly higher in patients who did not recover renal function at time of hospitalization discharge, in patients who died during the acute process, and in patients who need renal replacement therapy during hospitalization, but in this last group, the differences did not reach statistical significance. In conclusion, plasmatic MAC concentration seems valuable as a marker of AKI severity. Eva Rodríguez, Marta Riera, Clara Barrios, and Julio Pascual Copyright © 2014 Eva Rodríguez et al. All rights reserved. Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers Mon, 19 May 2014 08:53:05 +0000 Protocols of conversion from cyclosporin A (CsA) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups () were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson’s trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κβ, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to SRL. José Sereno, Sara Nunes, Paulo Rodrigues-Santos, Helena Vala, Petronila Rocha-Pereira, João Fernandes, Alice Santos-Silva, Frederico Teixeira, and Flávio Reis Copyright © 2014 José Sereno et al. All rights reserved. Circulating Endothelial Cells and Chronic Kidney Disease Sun, 18 May 2014 07:05:06 +0000 Endothelial dysfunction may play a crucial role in initiation of the pathogenesis of vascular disease and atherosclerosis. The identification and quantification of circulating endothelial cells (CEC) have been developed as a novel marker of endothelial function. We describe, in great detail, mechanisms of endothelial dysfunction and CEC detachment. We also review the relationship between numbers of CEC and disease severity and response to treatment. In addition, we describe the possible clinical use of CEC in chronic kidney disease (CKD) and kidney transplantation. In summary, CEC have been developed as a novel approach to assess the endothelial damage. Measurement of the CEC level would provide an important diagnostic and prognostic value on the endothelium status and the long-term outcome of vascular dysfunction. Kunying Zhang, Fang Yin, and Lin Lin Copyright © 2014 Kunying Zhang et al. All rights reserved. NGS Nominated CELA1, HSPG2, and KCNK5 as Candidate Genes for Predisposition to Balkan Endemic Nephropathy Thu, 15 May 2014 15:15:18 +0000 Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients’ groups, we nominated 3 genes with possible deleterious/damaging variants—CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN. D. Toncheva, M. Mihailova-Hristova, R. Vazharova, R. Staneva, S. Karachanak, P. Dimitrov, V. Simeonov, S. Ivanov, L. Balabanski, D. Serbezov, M. Malinov, V. Stefanovic, R. Čukuranović, M. Polenakovic, L. Jankovic-Velickovic, V. Djordjevic, T. Jevtovic-Stoimenov, D. Plaseska-Karanfilska, A. Galabov, V. Djonov, and I. Dimova Copyright © 2014 D. Toncheva et al. All rights reserved. Heart Failure in Patients with Chronic Kidney Disease: A Systematic Integrative Review Thu, 15 May 2014 12:00:23 +0000 Introduction. Heart failure (HF) is highly prevalent in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and is strongly associated with mortality in these patients. However, the treatment of HF in this population is largely unclear. Study Design. We conducted a systematic integrative review of the literature to assess the current evidence of HF treatment in CKD patients, searching electronic databases in April 2014. Synthesis used narrative methods. Setting and Population. We focused on adults with a primary diagnosis of CKD and HF. Selection Criteria for Studies. We included studies of any design, quantitative or qualitative. Interventions. HF treatment was defined as any formal means taken to improve the symptoms of HF and/or the heart structure and function abnormalities. Outcomes. Measures of all kinds were considered of interest. Results. Of 1,439 results returned by database searches, 79 articles met inclusion criteria. A further 23 relevant articles were identified by hand searching. Conclusions. Control of fluid overload, the use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and optimization of dialysis appear to be the most important methods to treat HF in CKD and ESRD patients. Aldosterone antagonists and digitalis glycosides may additionally be considered; however, their use is associated with significant risks. The role of anemia correction, control of CKD-mineral and bone disorder, and cardiac resynchronization therapy are also discussed. Liviu Segall, Ionut Nistor, and Adrian Covic Copyright © 2014 Liviu Segall et al. All rights reserved. Side Effects of Radiographic Contrast Media: Pathogenesis, Risk Factors, and Prevention Sun, 11 May 2014 13:39:34 +0000 Radiocontrast media (RCM) are medical drugs used to improve the visibility of internal organs and structures in X-ray based imaging techniques. They may have side effects ranging from itching to a life-threatening emergency, known as contrast-induced nephropathy (CIN). We define CIN as acute renal failure occurring within 24–72 hrs of exposure to RCM that cannot be attributed to other causes. It usually occurs in patients with preexisting renal impairment and diabetes. The mechanisms underlying CIN include reduction in medullary blood flow leading to hypoxia and direct tubule cell damage and the formation of reactive oxygen species. Identification of patients at high risk for CIN is important. We have reviewed the risk factors and procedures for prevention, providing a long list of references enabling readers a deep evaluation of them both. The first rule to follow in patients at risk of CIN undergoing radiographic procedure is monitoring renal function by measuring serum creatinine and calculating the eGFR before and once daily for 5 days after the procedure. It is advised to discontinue potentially nephrotoxic medications, to choose radiocontrast media at lowest dosage, and to encourage oral or intravenous hydration. In high-risk patients N-acetylcysteine may also be given. Michele Andreucci, Richard Solomon, and Adis Tasanarong Copyright © 2014 Michele Andreucci et al. All rights reserved. Independent Value of Cardiac Troponin T and Left Ventricular Global Longitudinal Strain in Predicting All-Cause Mortality among Stable Hemodialysis Patients with Preserved Left Ventricular Ejection Fraction Wed, 07 May 2014 08:24:43 +0000 Using a speckle-tracking echocardiography (STE), we recently demonstrated that a left ventricular (LV) global longitudinal strain (GLS) ≥ −15% and the serum cardiac troponin T (cTnT) concentration are associated with mortality in stable hemodialysis patients with preserved LV ejection fraction (LVEF). In this study, we explored the relationship between cTnT and echocardiographic parameters and evaluated whether the prognostic value provided by cTnT is independent of a GLS ≥ −15% and vice versa. Eighty-eight stable hemodialysis patients with preserved LVEF were followed for 31 months. STE studies and measurements of cTnT were performed at baseline. CTnT concentration had a modest correlation with GLS (; ) but had a weak or nonsignificant correlation with other echocardiographic parameters. Adjusting for clinical parameters, hazard ratios for each increase of 0.01 ng/mL in cTnT, and a GLS ≥ −15% on mortality were 1.13 () and 3.09 () without significant interaction between cTnT and GLS ≥ −15%. In addition, an increased cTnT concentration, a GLS ≥ −15%, or their combination showed significant additional predictive value for mortality when included in models consisting of clinical parameters. Therefore, both cTnT and a GLS ≥ −15% are independent predictors of mortality and are useful for risk stratification. Junne-Ming Sung, Chi-Ting Su, Yu-Tzu Chang, Yu-Ru Su, Wei-Chuan Tsai, Saprina P. H. Wang, Chun-Shin Yang, Liang-Miin Tsai, Jyh-Hong Chen, and Yen-Wen Liu Copyright © 2014 Junne-Ming Sung et al. All rights reserved. Habitual Coffee Consumption Enhances Attention and Vigilance in Hemodialysis Patients Mon, 05 May 2014 14:10:14 +0000 Objective. Coffee drinking is the main source of caffeine intake among adult population in the western world. It has been reported that low to moderate caffeine intake has beneficial effect on alertness and cognitive functions in healthy subjects. The aim of this study is to evaluate the impact of habitual coffee consumption on cognitive function in hemodialysis patients. Methods. In a cross-sectional study, 86 patients from a single-dialysis centre underwent assessment by the Montreal Cognitive Assessment tool and evaluation for symptoms of fatigue, mood, and sleep disorders by well-validated questionnaires. The habitual coffee use and the average daily caffeine intake were estimated by participants’ response to a dietary questionnaire. Results. Sixty-seven subjects (78%) consumed black coffee daily, mostly in low to moderate dose. Cognitive impairment was found in three-quarters of tested patients. Normal mental performance was more often in habitual coffee users (25% versus 16%). Regular coffee drinkers achieved higher mean scores on all tested cognitive domains, but a significant positive correlation was found only for items that measure attention and concentration (). Conclusions. Moderate caffeine intake by habitual coffee consumption could have beneficial impact on cognitive function in hemodialysis patients due to selective enhancement of attention and vigilance. Petar M. Nikić, Branislav R. Andrić, Biljana B. Stojimirović, Jasna Trbojevic-Stanković, and Zoran Bukumirić Copyright © 2014 Petar M. Nikić et al. All rights reserved. Elastase and Cathepsin G from Primed Leukocytes Cleave Vascular Endothelial Cadherin in Hemodialysis Patients Sun, 04 May 2014 08:17:57 +0000 Aims. To test the hypothesis that primed PMNLs in blood of chronic kidney disease patients release the active form of elastase and cathepsin G causing degradation of vital proteins and promote tissue damage. Methods. RT-PCR, immunocytochemical staining, immunoblotting, and FACS analyses were used to study these enzymes in hemodialysis patients (HD) versus healthy normal controls (NC). Using PMNLs and endothelial cells cocultivation system we measure the effect of HD PMNLs on the endothelial VE-cadherin, an essential protein for maintaining endothelial integrity. Results. Levels of elastase and cathepsin G were reduced in PMNLs of HD patients, while mRNA enzymes levels were not different. Elevated levels of the active form of these enzymes were found in blood of HD patients compared to NC.HD plasma had higher levels of soluble VE-cadherin present in three molecular forms: whole 140 kDa molecule and two fragments of 100 and 40 kDa. Cocultivation studies showed that primed PMNLs cleave the endothelial cadherin, resulting in a 100 kDa fragment. Conclusions. Elastase and cathepsin G are elevated in the plasma of HD patients, originating from primed PMNLs. In these patients, chronic elevation of these enzymes contributes to cleavage of VE-cadherin and possible disruption of endothelial integrity. Meital Cohen-Mazor, Rafi Mazor, Batya Kristal, and Shifra Sela Copyright © 2014 Meital Cohen-Mazor et al. All rights reserved. Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media? Wed, 30 Apr 2014 00:00:00 +0000 The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function. Michele Mussap and Giampaolo Merlini Copyright © 2014 Michele Mussap and Giampaolo Merlini. All rights reserved. Posttransplant Allosensitization in Low Immunological Risk Kidney and Kidney-Pancreas Graft Recipients Tue, 15 Apr 2014 14:03:55 +0000 Introduction. Posttransplantation allosensitization prevalence and effect on kidney grafts outcomes remain unsettled. Methods. Between 2007 and 2012, 408 patients received a primary kidney graft (with 68 patients also receiving a pancreas graft) after a negative cytotoxic crossmatch. All patients had a pretransplant negative anti-HLA screening and 0% panel reactive antibodies. We analyzed retrospectively the results of anti-HLA antibodies screening by Luminex assay, performed between 6 and 24 months after transplant, and searched for the risk factors for antibody positivity and its impact on kidney graft outcomes. Results. Anti-HLA antibodies prevalence at 6 months was 17.4%. Previous steroid-insensitive acute rejection was the only risk factor for both anti-HLA classes detected antibodies. Antithymocyte globulin induction was also a risk factor for anti-HLA-I antibodies. Antibody positivity status was associated with reduced graft function at 12 months and graft survival at 5 years (91.5% versus 96.4%, ). In multivariable Cox analysis, delayed graft function (HR = 6.1, ), HLA mismatches 3 (HR = 10.2, ), and antibody positivity for anti-HLA class II (HR = 5.1, ) or class I/II (HR = 13.8, ) were independent predictors of graft loss. Conclusions. Allosensitization against HLA class after transplant was associated with adverse kidney graft outcomes. A screening protocol seems advisable within the first year in low immunological risk patients. Jorge Malheiro, Sandra Tafulo, Leonídio Dias, La Salete Martins, Isabel Fonseca, Manuela Almeida, Sofia Pedroso, Fátima Freitas, Idalina Beirão, António Castro Henriques, and António Cabrita Copyright © 2014 Jorge Malheiro et al. All rights reserved. Mechanisms of Contrast-Induced Nephropathy Reduction for Saline (NaCl) and Sodium Bicarbonate (NaHCO3) Tue, 15 Apr 2014 00:00:00 +0000 Nephropathy following contrast media (CM) exposure is reduced by administration before, during, and after the contrast procedure of either isotonic sodium chloride solution (Saline) or isotonic sodium bicarbonate solution (IsoBicarb). The reasons for this reduction are not well established for either sodium salt; probable mechanisms are discussed in this paper. For Saline, the mechanism for the decrease in CIN is likely related primarily to the increased tubular flow rates produced by volume expansion and therefore a decreased concentration of the filtered CM during transit through the kidney tubules. Furthermore, increased tubular flow rates produce a slight increase in tubular pH resulting from a fixed acid excretion in an increased tubular volume. The mechanism for the decreased CIN associated with sodium bicarbonate includes the same mechanisms listed for Saline in addition to a renal pH effect. Increased filtered bicarbonate anion raises both tubular pH and tubular bicarbonate anion levels toward blood physiologic levels, thus providing increased buffer for reactive oxygen species (ROS) formed in the tubules as a result of exposure to CM in renal tubular fluid. W. Patrick Burgess and Phillip J. Walker Copyright © 2014 W. Patrick Burgess and Phillip J. Walker. All rights reserved. Urokinase Gene 3′-UTR T/C Polymorphism Is Associated with Malignancy and ESRD in Idiopathic Membranous Nephropathy Mon, 14 Apr 2014 12:14:55 +0000 Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults, and 25% of MN patients proceed to ESRD. Urokinase plasminogen activator (uPA) may play an important role in reducing renal fibrosis. This study was conducted to clarify the relationship between uPA gene polymorphisms and clinical manifestations of MN. We recruited 91 biopsy-diagnosed MN patients and 105 healthy subjects. Genotyping of uPA gene 3′-UTR T/C polymorphism was performed by polymerase chain reaction methods. The genotype distribution had no effect on the development of MN. Thirteen patients (15.9%; ) acquired malignancies and seventeen (20.7%; ) patients progressed to ESRD with the C/C genotype, but no patients with the T/C genotype did. In conclusion, we demonstrated that the presence of the uPA gene 3′-UTR C/C genotype was associated with ESRD as well as acquired malignancies in MN patients. These findings should prompt specific considerations for the treatment of MN patients to maintain a balance between treating disease entities and protecting the immune system from cancers. Cheng-Hsu Chen, Shih-Yin Chen, Kuo-Hsiung Shu, Mei-Chin Wen, Chi-Hung Cheng, Ming-Ju Wu, Tung-Min Yu, Ya-Wen Chuang, and Fuu-Jen Tsai Copyright © 2014 Cheng-Hsu Chen et al. All rights reserved. Prophylaxis of Contrast-Induced Nephrotoxicity Thu, 10 Apr 2014 14:01:10 +0000 Contrast-induced nephrotoxicity (CIN) is a form of acute kidney injury that follows intravascular contrast media exposure. CIN may be preventable because its risk factors are well established and the timing of renal insult is commonly known in advance. However, contrast-induced nephrotoxicity is still the third leading cause of iatrogenic renal failure. This important complication accounts up to 10% of acute renal failure cases in hospitalized patients and it is associated with increased short- and long-term morbidity and mortality. Prolonged hospitalization follows and overall increases healthcare resource utilization. This paper will discuss the various prophylactic procedures tested in clinical trials. Ulla Ludwig and Frieder Keller Copyright © 2014 Ulla Ludwig and Frieder Keller. All rights reserved. Effects of Single Pill-Based Combination Therapy of Amlodipine and Atorvastatin on Within-Visit Blood Pressure Variability and Parameters of Renal and Vascular Function in Hypertensive Patients with Chronic Kidney Disease Tue, 08 Apr 2014 00:00:00 +0000 Both strict blood pressure (BP) control and improvements in BP profile such as BP variability are important for suppression of renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In the present study, we examined the beneficial effects of the single pill-based combination therapy of amlodipine and atorvastatin on achievement of the target BP and clinic BP profile, as well as markers of vascular and renal damages in twenty hypertensive CKD patients. The combination therapy with amlodipine and atorvastatin for 16 weeks significantly decreased clinic BP, and achievement of target BP control was attained in an average of 45% after the combination therapy in spite of the presence of no achievement at baseline. In addition, the combination therapy significantly decreased the within-visit BP variability. With respect to the effects on renal damage markers, combination therapy with amlodipine and atorvastatin for 16 weeks significantly decreased albuminuria (urine albumin-to-creatinine ratio, versus  mg/g-Cr, ) without decline in estimated glomerular filtration rate. Concerning parameters of vascular function, the combination therapy significantly improved both brachial-ankle pulse wave velocity (baPWV) and central systolic BP (cSBP) (baPWV, versus  cm/s, ; cSBP, versus  mmHg, ). Collectively, these results suggest that the combination therapy with amlodipine and atorvastatin may exert additional beneficial effects on renal and vascular damages as well as BP profile in addition to BP lowering in hypertension with CKD. Kengo Azushima, Kazushi Uneda, Kouichi Tamura, Hiromichi Wakui, Masato Ohsawa, Ryu Kobayashi, Toru Dejima, Tomohiko Kanaoka, Akinobu Maeda, Yoshiyuki Toya, and Satoshi Umemura Copyright © 2014 Kengo Azushima et al. All rights reserved. Is Contrast Medium Osmolality a Causal Factor for Contrast-Induced Nephropathy? Mon, 31 Mar 2014 14:33:47 +0000 The exact pathophysiology of contrast-induced nephropathy (CIN) is not fully clarified, yet the osmotic characteristics of contrast media (CM) have been a significant focus in many investigations of CIN. Osmotic effects of CM specific to the kidney include transient decreases in blood flow, filtration fraction, and glomerular filtration rate. Potentially significant secondary effects include an osmotically induced diuresis with a concomitant dehydrating effect. Clinical experiences that have compared the occurrence of CIN between the various classes of CM based on osmolality have suggested a much less than anticipated advantage, if any, with a lower osmolality. Recent animal experiments actually suggest that induction of a mild osmotic diuresis in association with iso-osmolar agents tends to offset potentially deleterious renal effects of high viscosity-mediated intratubular CM stagnation. Andreas M. Bucher, Carlo N. De Cecco, U. Joseph Schoepf, Felix G. Meinel, Aleksander W. Krazinski, James V. Spearman, Andrew D. McQuiston, Rui Wang, Judith Bucher, Thomas J. Vogl, and Richard W. Katzberg Copyright © 2014 Andreas M. Bucher et al. All rights reserved. Targeting Spleen Tyrosine Kinase-Bruton’s Tyrosine Kinase Axis for Immunologically Mediated Glomerulonephritis Sun, 30 Mar 2014 07:32:01 +0000 The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. The two nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) and Bruton’s tyrosine kinase (Btk), are primarily expressed by hematopoietic cells, and participate in B-cell-receptor- and Fc-receptor-mediated activation. Pharmacological inhibitors of Syk or Btk are undergoing preclinical development and clinical trials for several immune diseases; and Syk inhibitors have been shown to reduce disease activity in rheumatoid arthritis patients. However, the clinical therapeutic efficacies of these inhibitors in glomerulonephritis have not been evaluated. Herein, we review recent studies of Syk and Btk inhibitors in several experimental primary and secondary glomerulonephritis models. These inhibitors suppressed development of glomerular injury, and also ameliorated established kidney disease. Thus, targeting Syk and Btk signaling pathways is a potential therapeutic strategy for glomerulonephritis, and further evaluation is recommended. Jin-Shuen Chen, Li-Chien Chang, Shyh-Jer Huang, and Chao-Wen Cheng Copyright © 2014 Jin-Shuen Chen et al. All rights reserved.