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L C Vázquez, A P González, J Juega, A Hernández-Gallego, D López, L Cañas, I Bancu, J Bonet, R Lauzurica
INTRODUCTION: Nodular arteriolar hyalinosis (NAH) is a typical, although not specific, histological finding of calcineurin inhibitor toxicity (CNIT). The objective of our study was to assess the reason why some patients showing strong NAH in renal graft biopsies who underwent calcineurin inhibitor (CNI) withdrawal presented very poor outcome whereas others improved graft function. MATERIAL AND METHODS: We performed 207 renal graft biopsies between January 2011 and May 2014 due to clinical criteria...
October 2015: Transplantation Proceedings
M J Vitalone, B Ganguly, S Hsieh, R Latek, E J Kulbokas, R Townsend, M M Sarwal
Calcineurin inhibitor (CNI) use may lead to allograft injury and compromised renal function. Gene expression profiles of 12-month kidney biopsies from a Phase 3 study of belatacept and a CNI comparator, cyclosporine (CsA), were compared with expression profiles of a set of historical, demographically matched, preimplantation control biopsies. Gene set enrichment analysis was used to test each set of differentially expressed genes (DEGs) for the enrichment of an in vitro-derived CNI toxicity (CNIT) gene set and published gene sets associated with chronic allograft injury (CAI), immune modulation and tissue remodeling...
August 2014: American Journal of Transplantation
D G Maluf, C I Dumur, J L Suh, J K Lee, E P Cathro, A L King, L Gallon, K L Brayman, V R Mas
The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated by: (1) identifying specific CNIT molecular pathways that associate with allograft injury (cross-sectional study) and (2) assessing the contribution of the identified CNIT signature in the progression to CAD with IF/TA (longitudinal study). Kidney biopsies from well-selected transplant recipients with histological diagnosis of CNIT (n = 14), acute rejection (n = 13) and CAD with IF/TA (n = 10) were evaluated...
May 2014: American Journal of Transplantation
Matthew Oetjens, William S Bush, Kelly A Birdwell, Holli H Dilks, Erica A Bowton, Joshua C Denny, Russell A Wilke, Dan M Roden, Dana C Crawford
Calcineurin-inhibitors CI are immunosuppressive agents prescribed to patients after solid organ transplant to prevent rejection. Although these drugs have been transformative for allograft survival, long-term use is complicated by side effects including nephrotoxicity. Given the narrow therapeutic index of CI, therapeutic drug monitoring is used to prevent acute rejection from underdosing and acute toxicity from overdosing, but drug monitoring does not alleviate long-term side effects. Patients on calcineurin-inhibitors for long periods almost universally experience declines in renal function, and a subpopulation of transplant recipients ultimately develop chronic kidney disease that may progress to end stage renal disease attributable to calcineurin inhibitor toxicity (CNIT)...
2014: Pacific Symposium on Biocomputing
Uttara Das, Kaligotla Venkata Dakshinamurty
Chronic allograft nephropathy (CAN) is a major cause of late kidney allograft loss. Everolimus, a novel proliferation signal inhibitor, ameliorates CAN by its antiproliferative or apoptosis-enhancing effects. This study aims to evaluate the safety and efficacy of everolimus in renal transplant recipients with calcineurin inhibitor (CNI) withdrawal either due to CAN or cal-cineurin inhibitor toxicity (CNIT). A total 21 patients with CAN or CNIT converted from CNI to everolimus were prospectively studied from 2006 to 2009...
September 2013: Saudi Journal of Kidney Diseases and Transplantation
Christoph Metalidis, Evelyne Lerut, Maarten Naesens, Dirk R J Kuypers
BACKGROUND: Susceptibility to calcineurin inhibitor nephrotoxicity (CNIT) after solid organ transplantation could be related to an interindividual variability in renal expression and function of the metabolizing cytochrome P450 3A5 (CYP3A5) isoenzyme and of the multidrug efflux transporter P-glycoprotein (P-gp, ABCB1). METHODS: We compared renal expression of CYP3A5 and P-gp, measured by immunohistochemistry, in 32 renal allograft biopsies with de novo arteriolar hyalinosis as a sign of CNIT with a control group, consisting of normal protocol allograft biopsies (n=50) and protocol biopsies demonstrating alloimmune injury (n=21)...
May 27, 2011: Transplantation
Alok Sharma, Sumeet Jain, Ruchika Gupta, Sandeep Guleria, Sanjay Agarwal, Amit Dinda
BACKGROUND: Calcineurin inhibitors (cyclosporine and tacrolimus) are important constituents of post renal transplant immunosuppression. However, renal toxicity limits their utility. Histological features of calcineurin inhibitor toxicity (CNIT) have been the subject of few studies using protocol biopsy samples, and consensus on diagnostic criteria is still evolving. AIMS: To analyze the spectrum of histological changes in protocol renal allograft biopsies with evidence of CNIT and identify additional features that are likely to help the pathologist in arriving at a diagnosis...
October 2010: Indian Journal of Pathology & Microbiology
Dirk R J Kuypers, Maarten Naesens, Hylke de Jonge, Evelyne Lerut, Kristin Verbeke, Yves Vanrenterghem
OBJECTIVES: Prolonged calcineurin inhibitor maintenance therapy in kidney allograft recipients is complicated by the development of chronic irreversible drug-induced nephrotoxicity (CNIT). METHODS: In 304 de novo renal graft recipients, the association among tacrolimus exposure indices (dose, C(0), AUC(0-12h)), CYP3A5, CYP3A4 and ABCB1 polymorphisms, clinical covariables and de novo arteriolar hyalinization as a histologic sign of CNIT was examined. RESULTS: Tacrolimus C(0) and AUC(0-12h) at 3 and 12 months posttransplantation did not differ between patients with and without CNIT...
August 2010: Therapeutic Drug Monitoring
Alok Sharma, Sumeet Jain, Ruchika Gupta, Kishore Gopal Banerjee, Sandeep Guleria, Sanjay Kumar Agarwal, Amit Kumar Dinda
Calcineurin inhibitors (cyclosporine and tacrolimus; CNIs) continue to be used as constituents of post-transplant immunosuppression in most centers. However, renal toxicity associated with the use of these drugs remains a problem adversely affecting the long-term graft survival. Fifteen adequate protocol renal allograft biopsies, with histological features of CNI toxicity among 140 protocol biopsies performed at 1-, 6-, and 12-month post-transplant, were included. Mitochondrial alterations in the tubular epithelial cells and endothelia of glomerular, peritubular capillaries and arterioles were graded semiquantitatively and further ultrastructural morphometric evaluation of numerical density and area of the mitochondria was performed...
April 1, 2010: Transplant International: Official Journal of the European Society for Organ Transplantation
Chien-Hsing Lin, Ling-Hui Li, Sheng-Feng Ho, Tzu-Po Chuang, Jer-Yuarn Wu, Yuan-Tsong Chen, Cathy S J Fann
BACKGROUND: Copy number variations (CNVs) have recently been recognized as important structural variations in the human genome. CNVs can affect gene expression and thus may contribute to phenotypic differences. The copy number inferring tool (CNIT) is an effective hidden Markov model-based algorithm for estimating allele-specific copy number and predicting chromosomal alterations from single nucleotide polymorphism microarrays. The CNIT algorithm, which was constructed using data from 270 HapMap multi-ethnic individuals, was applied to identify CNVs from 300 unrelated Han Chinese individuals in Taiwan...
2008: BMC Genetics
Lauren Weintraub, Li Li, Neeraja Kambham, Steven Alexander, Waldo Concepcion, Kim Miller, Cynthia Wong, Oscar Salvatierra, Minnie Sarwal
CNI withdrawal may be employed as a "rescue" strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI-associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post-CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF. Mean CrCl decreased from 64.3 +/- 22 to 59...
August 2008: Pediatric Transplantation
Chien-hsing Lin, Mei-chu Huang, Ling-hui Li, Jer-yuarn Wu, Yuan-tsong Chen, Cathy S J Fann
Copy number variation (CNV) has become an important genomic structure element in the human population, and some CNVs are related to specific traits and diseases. Moreover, analysis of human genomes has been potentiated by the use of high-resolution microarrays that assess single nucleotide polymorphisms (SNPs). Although many programs have been designed to analyze data from Affymetrix SNP microarrays, they all have high false-positive rates (FPRs) in copy number (CN) analyses. Copy number analysis tool (CNAT) 4...
August 2008: Human Mutation
Neeraja Kambham, Suja Nagarajan, Sheryl Shah, Li Li, Oscar Salvatierra, Minnie M Sarwal
Calcineurin inhibitor toxicity (CNIT) is an important cause of chronic allograft nephropathy (CAN), but clinically relevant, diagnostic pathologic criteria remain to be defined. A semiquantitative, clinically correlative CNIT scoring system was developed and validated by pathologic analyses of 254 renal transplant biopsies that were obtained from 50 consecutive pediatric renal transplant recipients. Differentially weighted pathologic criteria (glomerulosclerosis, tubular atrophy, arteriolar medial hyaline, and tubular isometric vacuolization) contributed to the composite CNIT model score...
January 2007: Clinical Journal of the American Society of Nephrology: CJASN
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