Journal of Transplantation

Inflammatory Signalling Associated with Brain Dead Organ Donation: From Brain Injury to Brain Stem Death and Posttransplant Ischaemia Reperfusion Injury

Ryan P. Watts, Ogilvie Thom, and John F. Fraser — Mon, 15 Apr 2013 12:29:29 +0000

Brain death is associated with dramatic and serious pathophysiologic changes that adversely affect both the quantity and quality of organs available for transplant. To fully optimise the donor pool necessitates a more complete understanding of the underlying pathophysiology of organ dysfunction associated with transplantation. These injurious processes are initially triggered by catastrophic brain injury and are further enhanced during both brain death and graft transplantation. The activated inflammatory systems then contribute to graft dysfunction in the recipient. Inflammatory mediators drive this process in concert with the innate and adaptive immune systems. Activation of deleterious immunological pathways in organ grafts occurs, priming them for further inflammation after engraftment. Finally, posttransplantation ischaemia reperfusion injury leads to further generation of inflammatory mediators and consequent activation of the recipient’s immune system. Ongoing research has identified key mediators that contribute to the inflammatory milieu inherent in brain dead organ donation. This has seen the development of novel therapies that directly target the inflammatory cascade.

Preoperative Comorbidity Correlates Inversely with Survival after Intestinal and Multivisceral Transplantation in Adults

Mon, 15 Apr 2013 09:48:39 +0000

We investigated the relationship between preoperative comorbidity and postoperative survival after intestinal transplantation. Each patient received a score for preoperative comorbidity. Each comorbidity was given a score based on the degree it impaired function (score range 0–3). A total score was derived from the summation of individual comorbidity scores. Patients (72 adults (M : F, 33 : 39)) received an isolated intestinal graft (27) or a cluster graft (45). Mean (standard deviation) survival was 1501 (1444) days. The Kaplan-Meier analysis revealed a significant inverse association between survival and comorbidity score (logrank test for trend, ). Patients grouped into comorbidity scores of 0 and 1, 2 and 3, 4 and 5, 6, and above had hazard ratios (95% confidence intervals) for death (compared to group 0 + 1), which increased with comorbidity scores: 1.945 (0.7622–5.816), 5.075 (3.314–36.17), and 13.77 (463.3–120100), respectively, (). Receiver-operator curves at 1, 3, 5, and 10 years postoperative had “C” statistics of 0.88, 0.85, 0.88, and 0.92, respectively. When evaluating patients for transplantation, the degree of comorbidity should be considered as a major factor influencing postoperative survival.

Outcome and Challenges of Kidney Transplant in Patients with Sickle Cell Disease

U. H. Okafor and E. Aneke — Thu, 11 Apr 2013 15:56:27 +0000

Sickle cell nephropathy is a common presentation in patients with sickle cell disease. End-stage kidney disease is the most severe presentation of sickle cell nephropathy in terms of morbidity and mortality. Sickle cell disease patients with end-stage kidney disease are amenable to renal replacement therapy including kidney transplant. Kidney transplant in these patients has been associated with variable outcome with recent studies reporting short- and long-term outcomes comparable to that of patients with HbAA. Sickle cell disease patients are predisposed to various haematological, cardiorespiratory, and immunological challenges. These challenges have the potential to limit, delay, or prevent kidney transplant in patients with sickle cell disease. There are few reports on the outcome and challenges of kidney transplant in this group of patients. The aim of this review is to highlight the outcome and challenges of kidney transplant in patients with sickle cell disease.

High-Urgency Renal Transplantation: Indications and Long-Term Outcomes

Thu, 07 Feb 2013 16:20:41 +0000

The concept of high-urgency (HU) renal transplantation was introduced in order to offer to patients, who are not able to undergo long-term dialysis treatment, a suitable renal graft in a short period of time, overcoming by this way the obstacle of the prolonged time spent on the waiting list. The goal of this study was to evaluate the patient and graft survivals after HU renal transplantation and compare them to the long-term outcomes of the non-high-urgency renal transplant recipients. The clinical course of 33 HU renal transplant recipients operated on at our center between 1995 and 2010 was retrospectively analyzed. The major indication for the HU renal transplantation was the imminent lack of access for either hemodialysis or peritoneal dialysis (67%). The patient survival of the study population was 67%, 56%, and 56%, whereas the graft survival was 47%, 35% and 35%, at 5, 10, and 15 years, respectively. In the comparison between our study population and the non-HU renal transplant recipients, our study population presented statistically significant lower patient survival rates. The HU renal transplant recipients also presented lower graft survival rates, but statistical significance was reached only in the 5-year graft survival rate.

Heart Transplantation in Congenital Heart Disease: In Whom to Consider and When?

Thu, 07 Feb 2013 08:00:02 +0000

Due to impressive improvements in surgical repair options, even patients with complex congenital heart disease (CHD) may survive into adulthood and have a high risk of end-stage heart failure. Thus, the number of patients with CHD needing heart transplantation (HTx) has been increasing in the last decades. This paper summarizes the changing etiology of causes of death in heart failure in CHD. The main reasons, contraindications, and risks of heart transplantation in CHD are discussed and underlined with three case vignettes. Compared to HTx in acquired heart disease, HTx in CHD has an increased risk of perioperative death and rejection. However, outcome of HTx for complex CHD has improved over the past 20 years. Additionally, mechanical support options might decrease the waiting list mortality in the future. The number of patients needing heart-lung transplantation (especially for Eisenmenger’s syndrome) has decreased in the last years. Lung transplantation with intracardiac repair of a cardiac defect is another possibility especially for patients with interatrial shunts. Overall, HTx will remain an important treatment option for CHD in the near future.

Transplant Coordinators' Perceived Impact of Availability of Multiple Generic Immunosuppression Therapies on Patients, Workload, and Posttransplant Maintenance Therapy

K. Parker, E. A. Zagadailov, A. S. Bruno, and A. M. Wiland — Tue, 08 Jan 2013 15:18:54 +0000

Background. No studies have evaluated the impact of multiple generic immunosuppression medications on transplant coordinators (TCs) and patients. Methods. A cross-sectional, multicenter online survey of TCs managing transplant recipients' outpatient immunosuppression was undertaken to assess TCs' perceptions of the impact of multiple generic immunosuppression therapies on patients and workload. Results. Forty-six of 106 transplant centers contacted (43%) completed the survey, with usable information from 34 TCs (53% in centers performing >100 solid organ transplants annually, 82% registered nurses, and 68% with >5-year experience working with transplant patients). TCs indicated that “change in strength,” “switching from branded to generics,” “heavy pill burden,” and “switching from one generic to another” were the four most frequent reasons for patient confusion regarding immunosuppression. TCs reported increased patient confusion over the previous year for patients on generic immunosuppression therapy: 44% answered ≥3 patient calls/day regarding confusion over immunosuppression therapy. Most TCs indicated increased workload since the introduction of generic immunosuppression therapy. TCs perceived “acute rejection rates,” “rate of graft loss,” and “poor patient adherence” as the three most likely consequences of multiple generic immunosuppression therapy. Conclusion. TCs associated availability of multiple generic immunosuppression therapy with increased patient confusion and time spent addressing patient concerns.

Urinary NGAL Ratio Is Not a Sensitive Biomarker for Monitoring Acute Tubular Injury in Kidney Transplant Patients: NGAL and ATI in Renal Transplant Patients

Thu, 27 Dec 2012 18:11:35 +0000

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is known to predict the prolonged delayed graft function after kidney transplantation. We examined the relation of uNGAL with histological findings of acute tubular injury (ATI). Analyses were made in biopsies taken at 6 weeks, 3 months, and 6 months after kidney transplantation. uNGAL was measured in the spot urines, normalized to urinary creatinine excretion, and correlated to biopsy findings and clinical, laboratory, and demographic variables. Controls included healthy individuals, individuals after kidney donation and ICU patients with acute kidney failure. Renal transplant recipients without ATI did not display elevated uNGAL levels compared to the healthy controls. Transplant patients with ATI had a higher uNGAL excretion at 6 weeks than patients without ATI (27,435 versus 13,605 ng/g; ). This increase in uNGAL was minor compared to ICU patients with acute renal failure ( ng/g). Patients with repeated findings of ATI or severe ATI did not have higher urinary NGAL levels compared to those with only one ATI finding or moderate ATI. Female recipient gender and urinary tract infection were identified as potential confounders. uNGAL has a relation with histological signs of acute tubular injury. The usability of this biomarker in renal allograft recipients is limited because of the low sensitivity.

Ischemia/Reperfusion Injury, Its Mechanisms, and Prevention

Wed, 26 Dec 2012 07:34:39 +0000

Increased Yield and Improved Transplantation Outcome of Mouse Islets with Bovine Serum Albumin

Suzanne Bertera, A. N. Balamurugan, Rita Bottino, Jing He, and Massimo Trucco — Sun, 09 Dec 2012 08:14:57 +0000

Isolation and transplantation of rodent islets are frequently used as a tool for predicting the behavior of new protocols for islet allotransplants in type 1 diabetes patients. Bovine serum albumin (BSA) is recognized as a protease inhibitor possibly protecting function and viability in islets. For this study, the addition of 0.2% BSA to the isolation protocol resulted in a 30% increase in islet yields while other parameters, such as viability and function, retained high islet quality. In vivo, a minimal mass of 70 BSA treated islets showed their ability to control glycemia levels in diabetic mice by bringing the average blood glucose to mg/dL compared to mg/dL without BSA. Our results show that the simple addition of BSA to the isolation protocol constitutes a reliable and reproducible method for increasing islet yield. Also adding BSA to the transplantation medium improves islet function in vivo. The method outlined here can reduce the overall number of animals needed per experiment and also reduce the time and resources needed for islet preparation.

Socioeconomic Factors Affect Disparities in Access to Liver Transplant for Hepatocellular Cancer

Linda L. Wong, Brenda Y. Hernandez, and Cheryl L. Albright — Tue, 04 Dec 2012 11:50:38 +0000

Objective. The incidence/death rate of hepatocellular cancer (HCC) is increasing in America, and it is unclear if access to care contributes to this increase. Design/Patients. 575 HCC cases were reviewed for demographics, education, and tumor size. Main Outcome Measures. Endpoints to determine access to HCC care included whether an eligible patient underwent liver transplantation. Results. Transplant patients versus those not transplanted were younger (55.7 versus 61.8 yrs, ), males (89.3% versus 74.4%, ), and having completed high school (10.1% versus 1.2%, ). There were differences in transplant by ethnicity, insurance, and occupation. Transplant patients with HCC had higher median income via census classification ($54,383 versus $49,383, ) and self-reported income ($48,948 versus $38,800, ). Differences in access may be related to exclusion criteria for liver transplant, as Pacific Islanders were more likely to have tumor size larger than 5 cm compared to Whites and have BMI > 35 (20.7%) compared to Whites (6.4%) and Asians (4.7%). Conclusions. Ethnic differences in access to transplant are associated with socioeconomic status and factors that can disqualify patients (advanced disease/morbid obesity). Efforts to overcome educational barriers and screening for HCC could improve access to transplant.

Brain Natriuretic Peptide Production and Secretion in Inflammation

Tsuneo Ogawa and Adolfo J. de Bold — Wed, 28 Nov 2012 15:16:47 +0000

Gene expression and secretion of the cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are simultaneously upregulated in various cardiac disorders such as congestive heart failure, ischemic heart disease, and hypertensive heart disease, in which hemodynamic or neuroendocrine changes are key components in the progression of disease. However, during acute cardiac allograft rejection, plasma BNP levels are increased but not those of ANF. Successful treatment of the rejection episode decreases the elevated plasma BNP to prerejection values suggesting that substances related to inflammation may selectively influence BNP gene expression. Indeed, cytokines such as TNFα and IL-1β selectively stimulate cardiac BNP at the transcriptional and translational levels in cardiomyocyte cultures without affecting ANF. This selective BNP increase is seen in vivo, in addition to acute cardiac allograft rejection, in several circumstances where inflammation significantly contributes to the pathogenesis of disease such as in sepsis and in acute myocarditis.

Renal Function and NODM in De Novo Renal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS

Sun, 25 Nov 2012 09:37:24 +0000

Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD , SD ) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, ) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; ); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.

Peripheral Regulatory Cells Immunophenotyping in Kidney Transplant Recipients with Different Clinical Profiles: A Cross-Sectional Study

Mon, 19 Nov 2012 15:14:19 +0000

Regulatory Foxp3-expressing T cells (Tregs), IL-10-producing B cells (Bregs), and IDO-expressing dendritic cells (DCregs) downregulate inflammatory processes and induces peripheral tolerance. These subpopulations also might participate in maintaining allograft immunological quiescence in kidney transplant recipients (KTRs) with an excellent long-term graft function under immunosuppression (ELTGF). The aim of the study was to characterize and to enumerate peripheral Tregs, Bregs, and DCregs in KTR with an ELTGF for more than 5 years after transplant. Fourteen KTR with an ELTGF, 9 KTR with chronic graft dysfunction (CGD), and 12 healthy donors (HDs) were included in the study. CD19+-expressing peripheral B lymphocytes were purified by positive selection. IL-10-producing B cells, CD4+/CD25hi, and CD8+/CD28− Tregs, as well as CCR6+/CD123+/IDO+ DCs, were quantitated by flow cytometry. IL-10-producing Bregs (immature/transitional, but not CD19+/CD38hi/CD24hi/CD27+B10 cells), CCR6+/CD123+/IDO+ DCs, and Tregs from ELTGF patients had similar or higher percentages versus HD (). By contrast, number of Tregs, DCregs, and Bregs except for CD27+B10 cells from CGD patients had lower levels versus HD and ELTGF patients (). The findings of this exploratory study might suggest that in ELTGF patients, peripheral tolerance mechanisms could be directly involved in the maintenance of a quiescent immunologic state and graft function stability.

Detection of Postoperative Intestinal Ischemia in Small Bowel Transplants

Hanne Birke-Sorensen — Sun, 04 Nov 2012 07:57:24 +0000

Small bowel transplantation is acknowledged as auto- and allotransplantation. In both instances, there is up to a 4%–10% risk of postoperative ischemia, and as the small bowel is extremely susceptible to ischemia, the timely diagnosis of ischemia is important. The location of the transplant, whether it is buried in the abdominal cavity or in the neck region, increases the challenge, as monitoring becomes more difficult and the consequences of neglect more dangerous. All methods for the early detection of postoperative ischemia in small bowel transplants are described together with the requirements of the ideal monitoring method. A small bowel transplant can be inspected directly or indirectly; the blood flow can be monitored by Doppler or by photoplethysmography, and the consequences of the blood flow can be monitored. The ideal monitoring method should be reliable, fast, minimally invasive, safe, objective, easy, cheap, and comfortable. No monitoring methods today fulfill the criteria of the ideal monitoring method, and evidence-based guidelines regarding postoperative monitoring cannot be made. The choice of whether to implement monitoring of ischemia—and if so, which method to choose—has to be made by the individual surgeon or center.

Gene Transfer of Heme Oxygenase-1 Using an Adeno-Associated Virus Serotype 6 Vector Prolongs Cardiac Allograft Survival

Tue, 16 Oct 2012 08:49:30 +0000

Introduction. Allograft survival can be prolonged by overexpression of cytoprotective genes such as heme oxygenase-1 (HO-1). Modifications in vector design and delivery have provided new opportunities to safely and effectively administer HO-1 into the heart prior to transplantation to improve long-term graft outcome. Methods. HO-1 was delivered to the donor heart using an adeno-associated virus vector (AAV) with a pseudotype 6 capsid and vascular endothelial growth factor (VEGF) to enhance myocardial tropism and microvascular permeability. Survival of mouse cardiac allografts, fully or partially mismatched at the MHC, was determined with and without cyclosporine A. Intragraft cytokine gene expression was examined by PCR. Results. The use of AAV6 to deliver HO-1 to the donor heart, combined with immunosuppression, prolonged allograft survival by 55.3% when donor and recipient were completely mismatched at the MHC and by 94.6% if partially mismatched. The combination of gene therapy and immunosuppression was more beneficial than treatment with either AAV6-HO-1 or CsA alone. IL-17a, b, e and f were induced in the heart at rejection. Conclusions. Pretreatment of cardiac allografts with AAV6-HO-1 plus cyclosporine A prolonged graft survival. HO-1 gene therapy represents a beneficial adjunct to immunosuppressive therapy in cardiac transplantation.

Tricuspid Valve Regurgitation after Orthotopic Heart Transplantation: Prevalence and Etiology

Sun, 14 Oct 2012 18:43:28 +0000

Background. Tricuspid valve regurgitation (TR) after orthotopic heart transplantation (OHT) is common. The aims of this study were to determine the prevalence of TR after OHT, to examine the correlation between its development and various variables, and to determine its outcomes. Methods. All 163 OHT patients who were followed up between 1988 and 2009 for a minimal period of 12 months were divided into those with no TR/mild TR and those with at least mild-moderate TR, as assessed by doppler echocardiography. These groups were compared regarding preoperative hemodynamic variables, surgical technique employed, number of endomyocardial biopsies, number of acute cellular rejections, incidence of graft vasculopathy, and clinical outcomes. Results. At the end of the followup (average 8.2 years) significant TR was evident in 14.1% of the patients. The development of late TR was found by univariate, but not multivariate, analysis to be significantly correlated with the biatrial surgical technique () and the presence of graft vasculopathy (). TR development was found to be correlated with the need for tricuspid valve surgery but not with an increased mortality. Conclusions. The development of TR after OHT may be related to the biatrial anastomosis technique and to graft vasculopathy.

Exenatide Pretreatment Improved Graft Function in Nonhuman Primate Islet Recipients Compared to Treatment after Transplant Only

Thu, 27 Sep 2012 17:25:53 +0000

The GLP-1 receptor agonist, exenatide, has previously been shown to improve insulin secretion, protect beta cells from apoptosis, and promote beta cell regeneration. We propose that pretreatment with exenatide will promote islet graft survival and improve graft function. Pancreatectomized cynomolgus monkeys underwent islet allotransplantation and were treated with exenatide beginning on day 0 or day −2. A third group of animals was treated with an immunosuppressive regimen while a fourth group remained untreated. Fasting blood glucose (FBG) was used to evaluate graft function along with intravenous glucose tolerance tests (IVGTTs) performed at study endpoint (day 10 for untreated and posttransplant exenatide or day 90 for pretreatment exenatide and immunosuppression). The average FBG for pre-treated animals day 5 following transplant was mg/dl, compared to mg/dl for animals treated only following transplant, 59.4 mg/dl for animals treated with immunosuppression, and mg/dl for untreated animals. IVGTTs performed at study endpoint showed normal glucose and insulin curves in the pre-treated exenatide and immunosuppression groups only, with beta cell function actually improving after transplant in the pre-treated group. We conclude, therefore, that exenatide pre-treatment can successfully maintain islet graft survival in nonhuman primates.

The Mode of Pretransplant Dialysis Does Not Affect Postrenal Transplant Outcomes in African Americans

Wed, 12 Sep 2012 11:52:06 +0000

Background. In previous reports with a majority of Caucasian patients, peritoneal dialysis (PD) before kidney transplantation has been associated with poor outcomes and higher rates of graft thrombosis and infectious complications than hemodialysis (HD). We report our experience on the outcomes of prerenal transplant peritoneal dialysis in predominantly (73%) African American patient population. Methods. A retrospective data analysis of 401 kidney transplants performed at our center from 2000 to 2006 was performed. Adult recipients with at least three months of pretransplant HD or PD were included. Results. There were 339 patients on HD and 62 patients on PD. There was no difference in graft (𝑃=0.51) and patient survival (𝑃=0.52) at 1, 3, and 5-years. Patients on HD were more likely to experience delayed graft function than PD (38.8% versus 17.7%, 𝑃<0.005). There was no difference in the incidence of vascular thrombosis or posttransplant infectious complications. When only the African American patients in the two groups were compared, there were no differences in graft or patient survival. Conclusions. Pretransplant peritoneal dialysis is associated with excellent patient and renal allograft outcomes in African Americans and does not predispose them to an increased risk of infectious or thrombotic complications.

Evaluation of Protocol Biopsy Utility 12 Months after Renal Transplantation: A Multicenter Observational Analysis

Wed, 05 Sep 2012 08:08:59 +0000

The clinical merit of surveillance kidney graft biopsies remains controversial. A retrospective, multicenter analysis evaluated 12-month surveillance biopsies (SB, 154 patients) versus no SB (NSB, 138 patients (11 with diagnostic biopsy)) in patients >18 months posttransplant with estimated GFR (eGFR) ≥30 mL/min. The primary objective was to describe renal function at 18 months post-transplant in patients with or without SB at month 12. Globally, most recipients in both cohorts were at low immunological risk (<10% of patients with PRA ≥30%). The immunosuppressive regimen remained unchanged following more than half of SB that exhibited chronic lesions (18/33, 54.5%). Mean (SD) eGFR at month 18 (primary endpoint) was 56 (19) mL/min/1.73 m² with SB and 54 (15) mL/min/1.73 m² with NSB (𝑃=0.48). In the SB group, slight nonspecific changes were observed in 51 cases, rejection (acute or chronic) in 6 cases, CNI-related toxicity in 15 cases, recurrence of initial disease in two cases, and interstitial fibrosis/tubular atrophy (IF/TA) in 83 cases (71.6%), of which 35 cases (30.2%) were grade II/III lesions. eGFR <50 mL/min/1.73 m² at month 6 predicted IF/TA grade II or III (OR 3.85, 95% CI 1.64, 9.05, 𝑃<0.002). SB at 12 months posttransplant did not prompt significant modification of immunosuppression, and no renal benefit was observed.

Stem Cells as a Tool to Improve Outcomes of Islet Transplantation

Emily Sims and Carmella Evans-Molina — Thu, 30 Aug 2012 09:32:09 +0000

The publication of the promising results of the Edmonton protocol in 2000 generated optimism for islet transplantation as a potential cure for Type 1 Diabetes Mellitus. Unfortunately, follow-up data revealed that less than 10% of patients achieved long-term insulin independence. More recent data from other large trials like the Collaborative Islet Transplant Registry show incremental improvement with 44% of islet transplant recipients maintaining insulin independence at three years of follow-up. Multiple underlying issues have been identified that contribute to islet graft failure, and newer research has attempted to address these problems. Stem cells have been utilized not only as a functional replacement for β cells, but also as companion or supportive cells to address a variety of different obstacles that prevent ideal graft viability and function. In this paper, we outline the manners in which stem cells have been applied to address barriers to the achievement of long-term insulin independence following islet transplantation.

De Novo Donor-Specific HLA Antibody Development and Peripheral CD4+CD25high Cells in Kidney Transplant Recipients: A Place for Interaction?

Thu, 23 Aug 2012 11:21:44 +0000

The aim of this study was to determine whether the abundance of regulatory T cells (Tregs) (CD4+CD25high) affects the de novo development of anti-HLA donor-specific antibodies (DSAs) in kidney transplant recipients (KTRs). Methods. Unsensitized (PRA ≤ 10%, no DSA) adult primary KTRs who received a living (83%) or deceased (17%) KT in our Institution during 2004/2005 were included. DSA testing was performed monthly, and Tregs were quantified by flow cytometry every 3 months, during the 1st year after KT. All patients received triple drug immunosuppressive therapy (CNI + MMF or AZA + PDN); 83% received anti-CD25. Results. 53 KTRs were included; 32% developed DSA during the 1st year after KT. Significantly lower 7-year graft survival was observed in those who developed DSA. No difference was observed in Treg numbers up to 9 months after KT, between DSA positive and negative. However, at 12 months after KT, DSA-negative patients had significantly higher numbers of Treg. Conclusions. Early development of DSA was not associated to variations in Treg abundance. The differences in Treg numbers observed at the late time point may reflect better immune acceptance of the graft and may be associated to long-term effects. Additional inhibitory mechanisms participating earlier in DSA development after KT deserve to be sought.

A Prospective, Multinational Pharmacoepidemiological Study of Clinical Conversion to Sirolimus Immunosuppression after Renal Transplantation

Thu, 09 Aug 2012 12:01:00 +0000

This prospective pharmacoepidemiological study examined treatment and outcomes in patients converted to sirolimus (SRL) after renal transplantation. 484 subjects in 36 centres in 7 countries were followed for up to 5 years. Principal reasons for conversion were declining graft function (146/484, 30%) and side effects of prior therapy (144/484, 30%) and the major treatment combinations after conversion were SRL ± MMF (62%), SRL + TAC (21.5%), SRL + CSA (16.5%). The cumulative probability of biopsy-confirmed acute rejection (BCAR) was 5% (𝑛=22), death-censored graft loss 12% (𝑛=56) and death 6% (𝑛=22), and there was no significant relationship to the treatment combination employed. Median calculated creatinine clearance was 48.4 (29.3, 64.5) mL/min at conversion, rising to 54.1 (41.2, 69.0) mL/min at month 1, 55.7 (39.0, 73.0) mL/min at month 12, 58.6 (39.7, 75.2) mL/min at two years and 60.9 (36.0, 77.0) mL/min at three years post-conversion. The most common adverse events were hypertension (47%), hyperlipidemia (26%), urinary tract infections (25%), anaemia (24%) and diarrhea (14%), and cardiac events, hyperlipemia and CMV infection were more common in patients converted during the first year. SRL was most frequently combined with MMF after conversion, but principal clinical outcomes were not significantly influenced by the treatment combination employed in normal practice.

Low CD4/CD8 Ratio in Bronchus-Associated Lymphoid Tissue Is Associated with Lung Allograft Rejection

Wed, 08 Aug 2012 08:22:32 +0000

Background. Bronchus-associated lymphoid tissue (BALT) has been associated with lung allograft rejection in rat transplant models. In human transplant recipients, BALT has not been linked to clinically significant rejection. We hypothesize that the immunohistochemical composition of BALT varies with the presence of acute lung allograft rejection. Methods. We retrospectively examined 40 human lung allograft recipients transplanted from 3/1/1999 to 6/1/2008. Patients were grouped by frequency and severity of acute rejection based on International Society of Heart Lung Transplant (ISHLT) criteria. Transbronchial biopsies were reviewed for BALT by a blinded pathologist. BALT if present was immunohistochemically stained to determine T-and B-cell subpopulations. Results. BALT presence was associated with an increased frequency of acute rejection episodes in the first year after transplantation. Patients with a lower CD4/CD8 ratio had an increased rejection rate; however, BALT size or densities of T-cell and B-cell subpopulations did not correlate with rejection rate. Conclusion. The presence of BALT is associated with an increased frequency of rejection one year after transplant. The lower the CD4/CD8 ratio, the more acute rejection episodes occur in the first year after transplantation. The immunohistochemical composition of BALT may predict patients prone to frequent episodes of acute cellular rejection.

Islet 𝜷-Cell Mass Preservation and Regeneration in Diabetes Mellitus: Four Factors with Potential Therapeutic Interest

Jose Manuel Mellado-Gil, Nadia Cobo-Vuilleumier, and Benoit R. Gauthier — Sun, 05 Aug 2012 10:21:25 +0000

Islet β-cell replacement and regeneration are two promising approaches for the treatment of Type 1 Diabetes Mellitus. Indeed, the success of islet transplantation in normalizing blood glucose in diabetic patients has provided the proof of principle that cell replacement can be employed as a safe and efficacious treatment. Nonetheless, shortage of organ donors has hampered expansion of this approach. Alternative sources of insulin-producing cells are mandatory to fill this gap. Although great advances have been achieved in generating surrogate β-cells from stem cells, current protocols have yet to produce functionally mature insulin-secreting cells. Recently, the concept of islet regeneration in which new β-cells are formed from either residual β-cell proliferation or transdifferentiation of other endocrine islet cells has gained much interest as an attractive therapeutic alternative to restore β-cell mass. Complementary approaches to cell replacement and regeneration could aim at enhancing β-cell survival and function. Herein, we discuss the value of Hepatocyte Growth Factor (HGF), Glucose-Dependent Insulinotropic Peptide (GIP), Paired box gene 4 (Pax4) and Liver Receptor Homolog-1 (LRH-1) as key players for β-cell replacement and regeneration therapies. These factors convey β-cell protection and enhanced function as well as facilitating proliferation and transdifferentiation of other pancreatic cell types to β-cells, under stressful conditions.

A Knotless Technique for Kidney Transplantation in the Mouse

Song Rong, Alfor G. Lewis, Uta Kunter, Hermann Haller, and Faikah Gueler — Tue, 17 Jul 2012 09:55:50 +0000

Mouse models of kidney transplantation are important to study molecular mechanisms of organ transplant rejection as well as to develop new therapeutic strategies aimed at improving allograft survival. However, the surgical technique necessary to result in a viable allograft has traditionally proven to be complex and very demanding. Here, we introduce a new, simple, and rapid knotless technique for vessel anastomosis wherein the last stitch of the anastomosis is not tied to the short end of the upper tie as in the classical approach but is left free. This is a critical difference in that it allows the size of the anastomosis to be increased or decreased after graft reperfusion in order to avoid stenosis or bleeding, respectively. We compared the outcome of this new knotless technique (𝑛=175) with the classical approach (𝑛=122) in terms of local thrombosis or bleeding, time for anastomosis, and survival rates. By this modification of the suture technique, local thrombosis was significantly reduced (1.1% versus 6.6%), anastomosis time was less, and highly reproducible kidney graft survival was achieved (95% versus 84% with the classical approach). We believe that this knotless technique is easy to learn and will improve the success rates in the technically demanding model of mouse kidney transplantation.

Targeted Antibiotic Prophylaxis for Lung Transplantation in Cystic Fibrosis Patients Colonised with Pseudomonas aeruginosa Using Multiple Combination Bactericidal Testing

Mon, 16 Jul 2012 08:08:16 +0000

Early infection is a recognised complication after lung transplantation in patients with cystic fibrosis (CF). Our centre uses multiple combination bactericidal testing (MCBT) when determining appropriate peritransplant prophylactic regimens. To evaluate our strategy, we compared the incidence of posttransplant infection in patients whose peritransplant antimicrobial regimens were determined using MCBT versus standard sensitivity testing. Patients with CF who were infected with Pseudomonas aeruginosa and underwent lung transplantations between 2000 and 2010 were included. Data was collected from clinical records and our microbiology database. Microorganisms cultured were mapped against antibiotic resistance, method of sensitivity testing, and antibiotics administered peritransplant. 129 patients were identified (mean age 28, male : female, 63 : 66). Fifty patients (38.8%) had antibiotics determined by MCBT. Two patients in the MCBT group developed septicaemia, 13 in the conventional group (𝑃≤0.05, 2-tailed Fisher's test). Sepsis was attributable to P. aeruginosa in one patient from the MCBT group and seven patients in the conventional group (𝑃=0.15). P. aeruginosa was recovered from the posttransplant pleural fluid of one patient who received MCBT-guided prophylaxis, six patients in the conventional group (𝑃=0.25). Patients given antibiotics based on MCBT had significantly lower rates of septicaemia and lower rates of empyema.

The Major Histocompatibility Complex in Transplantation

Wed, 20 Jun 2012 10:25:07 +0000

The transplant of organs is one of the greatest therapeutic achievements of the twentieth century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the principal target of the immune response is the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells. However, we should not forget that the innate and adaptive immunities are closely interrelated and should be viewed as complementary and cooperating. When a human transplant is performed, HLA (human leukocyte antigens) molecules from a donor are recognized by the recipient's immune system triggering an alloimmune response Matching of donor and recipient for MHC antigens has been shown to have a significant positive effect on graft acceptance. This paper will present MHC, the innate and adaptive immunities, and clinical HLA testing.

CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”

Thu, 07 Jun 2012 10:58:23 +0000

Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients.

Progression from Sustained BK Viruria to Sustained BK Viremia with Immunosuppression Reduction Is Not Associated with Changes in the Noncoding Control Region of the BK Virus Genome

Mon, 04 Jun 2012 09:24:07 +0000

Changes in the BK virus archetypal noncoding control region (NCCR) have been associated with BK-virus-associated nephropathy (BKVAN). Whether sustained viremia, a surrogate for BKVAN, is associated with significant changes in the BK-NCCR is unknown. We performed PCR amplification and sequencing of (1) stored urine and (2) plasma samples from the time of peak viremia from 11 patients with sustained viremia who participated in a 200-patient clinical trial. The antimetabolite was withdrawn for BK viremia and reduction of the calcineurin inhibitor for sustained BK viremia. DNA sequencing from the 11 patients with sustained viremia revealed 8 insertions, 16 transversions, 3 deletions, and 17 transitions. None were deemed significant. No patient developed clinically evident BKVAN. Our data support, at a genomic level, the effectiveness of reduction of immunosuppression for prevention of progression from viremia to BKVAN.

Identification of Risk Factors for Vascular Thrombosis May Reduce Early Renal Graft Loss: A Review of Recent Literature

Anna Krarup Keller, Troels Munch Jorgensen, and Bente Jespersen — Thu, 31 May 2012 09:01:06 +0000

Renal graft survival has improved over the past years, mainly owing to better immunosuppression. Vascular thrombosis, though rare, therefore accounts for up to one third of early graft loss. We assess current literature on transplantation, identify thrombosis risk factors, and discuss means of avoiding thrombotic events and saving thrombosed grafts. The incidence of arterial thrombosis was reported to 0.2–7.5% and venous thrombosis 0.1–8.2%, with the highest incidence among children and infants, and the lowest in living donor reports. The most significant risk factors for developing thrombosis were donor-age below 6 or above 60 years, or recipient-age below 5-6 years, per- or postoperative hemodynamic instability, peritoneal dialysis, diabetic nephropathy, a history of thrombosis, deceased donor, or >24 hours cold ischemia. Multiple arteries were not a risk factor, and a right kidney graft was most often reported not to be. Given the thrombosed kidney graft is diagnosed in time, salvage is possible by urgent reoperation and thrombectomy. Despite meticulous attentions to reduce thrombotic risk factors, thrombosis cannot be entirely prevented and means to an early detection of this complication is desirable in order to save the kidneys through prompt reoperation. Microdialysis may be a new tool for this.