New-onset diabetes after transplantation (NODAT) is common after liver transplant and associated with poorer outcomes. The aim of this study was to identify risk factors for NODAT in liver transplant recipients off corticosteroids. In 225 adult nondiabetic liver transplant recipients, the mean age was 51.7 years, the majority were men (71%), and half had HCV (49%). The mean calculated MELD score at transplantation was 18.7, and 19% underwent living-donor transplant (LDLT). One year after transplantation, 17% developed NODAT, and an additional 16% had impaired fasting glucose. The incidence of NODAT in patients with HCV was 26%. In multivariate analysis, HCV, pretransplant FPG, and LDLT were significant. Each 10 mg/dL increase in pretransplant FPG was associated with a twofold increase in future development of NODAT. The incidence of NODAT after liver transplant in patients off corticosteroids is 17%. Risk factors for developing NODAT include HCV and pretransplant FPG; LDLT is protective.

Elizabeth J. Carey

Bashar A. Aqel

Thomas J. Byrne

David D. Douglas

Jorge Rakela

Hugo E. Vargas

Adyr A. Moss

David C. Mulligan

K. Sudhakar Reddy

Harini A. Chakkera

Pretransplant Fasting Glucose Predicts New-Onset Diabetes after Liver Transplantation

End Stage Renal Disease (ESRD) is an ever increasing problem worldwide. However the mechanisms underlying disease progression are not fully elucidated. This work addressed nephrotoxicity induced by the immunosuppressive agents&#x2019; cyclosporine A (CsA) and sirolimus (SRL). Nephrotoxicity is the major limiting factor in long term use of CsA. SRL causes less nephrotoxicity than CsA. Therefore investigations into the differential effects of these agents may identify potential mechanisms of nephrotoxicity and means to prevent ESRD induced by therapeutic drugs. Using ELISA, Western blotting, quantitative PCR and a reporter gene assay we detailed the differential effects of CsA and SRL in human renal mesangial cells. CsA treatment increased profibrotic TGF-<i>&#x3b2;</i>1 secretion in human mesangial cells whereas SRL did not, indicating a role for TGF-<i>&#x3b2;</i> in CsA toxicity. However we observed a synergistic nephrotoxic effect when CsA and SRL were co-administered. These synergistic alterations may have been due to an increase in CTGF which was not evident when the immunosuppressive drugs were used alone. The CsA/SRL combination therapy significantly enhanced Smad signalling and altered the extracellular matrix regulator matrix metalloproteinase 9 (MMP-9). Inhibition of the ERK 1/2 pathway, attenuated these CsA/SRL induced alterations indicating a potentially significant role for this pathway.

Séin O'Connell

Craig Slattery

Michael P. Ryan

Tara McMorrow

Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

Accurate assessment of kidney function by measurement of glomerular filtration rate (GFR) is essential to the risk assessment of prospective living kidney donors. We evaluated the performance of various estimating equations for creatinine clearance (Cockcroft-Gault), GFR (Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration), and 24-hour urine collections for creatinine clearance in obese potential kidney donors. We evaluated 164 potential kidney donors including 49 with a BMI of 30–35 and 32 with a BMI &gt;35 that have completed a routine living donor evaluation with a measured GFR. All the estimating equations performed poorly in obese donors. While 24-hour urine collections performed better, only 15% had an adequate 24-hour urine collection. Since obese kidney donors may be at higher than average risk for kidney failure, accurate assessment of kidney function in these donors is crucial to ensure their long-term health postdonation.

Nidhi Aggarwal

Anna C. Porter

Ignatius Y. S. Tang

Bryan N. Becker

Sanjeev K. Akkina

Creatinine-Based Estimations of Kidney Function Are Unreliable in Obese Kidney Donors

The discovery and use of cyclosporine since its inception into clinical use in the late 1970s has played a major role in the advancement of transplant medicine. While it has improved rates of acute rejection and early graft survival, data on long-term survival of renal allografts is less convincing. The finding of acute reversible nephrotoxicity and nephrotoxicity in nonrenal transplants has since led to the widely accepted view that there is a chronic more irreversible component to this agent as well. Since that time, there has been intense interest in finding protocols which seek to minimize and even avoid the use of calcineurin inhibitors altogether. We seek to review cyclosporine in terms of its mechanism of action, pathophysiologic, and histologic features associated with acute and chronic nephrotoxicity and recent studies looking to avoid its toxic side effects.

Dustin Tedesco

Lukas Haragsim

Cyclosporine: A Review

Uterine transplantation has been proposed as a possible solution to absolute uterine factor infertility untreatable by any other option. Since the first human attempt in 2000, various teams have tried to clarify which immunosuppressant would be most suitable for protecting the allogeneic uterine graft while posing a minimal risk to the fetus. Cyclosporine A (CsA) is an immunosuppressant widely used by transplant recipients. It is currently being tested as a potential immunosuppressant to be used during UTn. Its effect on the mother and fetus and its influence upon the graft during pregnancy have been of major concern. We review the role of CsA in UTn and its effect on pregnant transplant recipients and their offspring.

Srdjan Saso

Karl Logan

Yazan Abdallah

Louay S. Louis

Sadaf Ghaem-Maghami

J. Richard Smith

Giuseppe Del Priore

Use of Cyclosporine in Uterine Transplantation

Measurements of Cyclosporine (CsA) systemic exposure permit its dose adjustment in allogenic stem cell transplantation recipients to prevent graft-versus-host disease. CsA LSSs were developed and validated from 60 ASCT patients via multiple linear regressions. All whole-blood samples were analyzed by fluorescence polarization immunoassay (FPIA-Axym). The 10 models that have used CsA concentrations at a single time point did not have a good fit with AUC<sub  >0&#x2013;12</sub> (<svg style="vertical-align:-0.30096pt;width:63.375px;" id="M1" height="14.15" version="1.1" viewBox="0 0 63.375 14.15" width="63.375"  xmlns="http://www.w3.org/2000/svg">
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Hanene ELjebari

Nadia Ben Fradj

Issam Salouage

Emna Gaies

Sameh Trabelsi

Nadia Jebabli

Mohamed Lakhal

Tarek Ben Othman

Anis Kouz

Estimation of Abbreviated Cyclosporine A Area under the Concentration-Time Curve in Allogenic Stem Cell Transplantation after Oral Administration

Tubular epithelial cells play a central role in the pathogenesis of chronic nephropathies. Previous toxicogenomic studies have demonstrated that cyclosporine- (CsA-) induced epithelial phenotypic changes (EPCs) are reminiscent of an incomplete epithelial to mesenchymal transition (EMT) in a TGF-<i>&#x3b2;</i>-independent manner. Furthermore, we identified endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity during CsA exposure. Because c-jun-N-terminal kinase (JNK), which is activated during ER stress, is implicated in kidney fibrogenesis, we undertook the current study to identify the role of JNK signaling in EPCs induced by CsA. In primary cultures of human renal epithelial cells, CsA activates JNK signaling, and the treatment with a JNK inhibitor reduces the occurrence of cell shape changes, E-cadherin downregulation, cell migration, and Snail-1 expression. Our results suggest that CsA activates JNK signaling, which, in turn, may participate in the morphological alterations through the regulation of Snail-1 expression.

Nicolas Pallet

Eric Thervet

Dany Anglicheau

c-Jun-N-Terminal Kinase Signaling Is Involved in Cyclosporine-Induced Epithelial Phenotypic Changes

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<p><em>Journal of Transplantation</em> publishes research related to heart, lung, kidney, liver, pancreas and stem cell transplantation as well as focusing on the histocompatibility, related side effects and complications of those transplantations.</p>


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Journal of Transplantation - Table of contents 2012

title

Journal of Transplantation publishes research related to heart, lung, kidney, liver, pancreas and stem cell transplantation as well as focusing on the histocompatibility, related side effects and complications of those transplantations.

Journal of Transplantation