Handbook of Dialysis, 4th edition John T.DaugirdasPeter G.BlakeTodd S.Ing2006800softcover, $65 ISBN 9780781752534

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Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis

Background: Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients. Methods: Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts. Results: Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (Cmax) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC(0-t)) fell within the required range (0.80-1.25) for cyclosporine (Cmax 0.91; 90% CI 0.86-0.95; and AUC(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (Cmax 1.17; 90% CI 1.09-1.24; and AUC(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (Cmax 0.98; 90% CI 0.96-1.01; and AUC(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death. Conclusions: Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed. © 2016 S. Karger AG, Basel

PowerPoint Slides for: Bioavailability, Efficacy and Safety of Generic Immunosuppressive Drugs for Kidney Transplantation: A Systematic Review and Meta-Analysis

<i>Background:</i> Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients. <i>Methods:</i> Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts. <i>Results:</i> Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (Cmax) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC(0-t)) fell within the required range (0.80-1.25) for cyclosporine (Cmax 0.91; 90% CI 0.86-0.95; and AUC(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (Cmax 1.17; 90% CI 1.09-1.24; and AUC(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (Cmax 0.98; 90% CI 0.96-1.01; and AUC(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death. <i>Conclusions:</i> Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed

Supplementary Material for: Association of Functional Kallikrein-1 Promoter Polymorphisms and Acute Kidney Injury: A Case-Control and Longitudinal Cohort Study

<p><b><i>Background:</i></b> Kallikrein-1 (KLK1) is a highly conserved serine protease that is expressed in the kidney and involved in blood pressure regulation. The activity of this enzyme is diminished in acute kidney injury (AKI). <b><i>Methods:</i></b> We first evaluated the potential role of functional multiallelic <i>KLK1</i> promoter gene polymorphisms in a case-control study of 481 subjects (214 hospitalized patients with AKI of mixed causes and 267 healthy subjects). The complex, multiallelic G/C-rich repeat region of the proximal <i>KLK1</i> promoter was determined by direct Sanger/capillary resequencing. <b><i>Results:</i></b> 16 alleles were identified in a complex, polymorphic G/C-rich region of the <i>KLK1</i> proximal promoter; 5 of these alleles (F, G, H, I, and K) were associated with development of AKI. Alleles I and G were classified as risk-alleles (unadjusted OR 1.86; 95% CI 1.23, 2.81; p = 0.003), whereas alleles F, H, and K were classified as protective-alleles (unadjusted OR 0.32; 95% CI 0.22, 0.46; p < 0.001) according to their directional association with development of AKI. After adjustment for sex, race, preexisting chronic kidney disease and APACHE II score, the <i>KLK1</i> risk-allele (I or G) carrier state was associated with the composite of ≥2-fold increase in serum creatinine, oliguria, or dialysis requirement (adjusted OR 2.71; 95% CI 1.14, 6.44; p = 0.02). The <i>KLK1</i> risk-allele carrier state was also marginally associated with the composite of ≥2-fold increase in serum creatinine, oliguria, dialysis requirement, or in-hospital death (adjusted OR 2.33; 95% CI 0.98, 5.52; p = 0.06). <b><i>Conclusions:</i></b><i>KLK1</i> promoter polymorphisms are associated with development of AKI and adverse outcomes. Further studies are needed to validate these findings.</p

Supplementary Material for: Cinacalcet for Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: A Meta-Analysis of Randomized Controlled Trials

<b><i>Background:</i></b> Cinacalcet could decrease serum calcium, phosphate, and parathyroid hormone (PTH) in previous meta-analyses. However, the effect of cinacalcet on the new biomarkers such as fibroblast growth factor-23 (FGF-23), bone markers, and vascular calcification are still unestablished. We conducted a meta-analysis to examine the effects of cinacalcet on all laboratory and clinical spectrums of chronic kidney disease-mineral bone disorders (CKD-MBD). <b><i>Methods:</i></b> A systematic literature search was conducted in MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov to identify randomized controlled trials (RCTs) comparing the effect of cinacalcet relative to standard treatment on CKD-MBD surrogate markers and clinical outcomes. Random-effect models were used to compute the weighted mean difference for continuous variables and the risk ratio for binary variables. <b><i>Results:</i></b> Twenty-four RCTs (10,031 dialysis patients) were identified. Besides lowering effects on calcium, phosphate, and PTH, cinacalcet significantly reduced bone resorptive marker (tartrate-resistant acid phosphatase 5b) but unaltered bone formation markers (bone alkaline phosphatase and osteocalcin). Cinacalcet also resulted in significant higher risk of hypocalcemia, nausea, vomiting, and diarrhea. Cinacalcet significantly lowered serum FGF-23 level, although unaltered all-cause mortalities. <b><i>Conclusions:</i></b> Use of cinacalcet in dialysis patients improves several CKD-MBD-related surrogate markers. However, the benefit on all-cause mortalities was not demonstrated

Microbiological contamination of a hemodialysis center water distribution system Contaminação microbiológica no sistema de distribuição de água de um centro de hemodiálise

The microbiological monitoring of the water used for hemodialysis is extremely important, especially because of the debilitated immune system of patients suffering from chronic renal insufficiency. To investigate the occurrence and species diversity of bacteria in waters, water samples were collected monthly from a hemodialysis center in upstate São Paulo and tap water samples at the terminal sites of the distribution system was sampled repeatedly (22 times) at each of five points in the distribution system; a further 36 samples were taken from cannulae in 19 hemodialysis machines that were ready for the next patient, four samples from the reuse system and 13 from the water storage system. To identify bacteria, samples were filtered through 0.22 µm-pore membranes; for mycobacteria, 0.45 µm pores were used. Conventional microbiological and molecular methods were used in the analysis. Bacteria were isolated from the distribution system (128 isolates), kidney machine water (43) and reuse system (3). Among these isolates, 32 were Gram-positive rods, 120 Gram-negative rods, 20 Gram-positive cocci and 11 mycobacteria. We propose the continual monitoring of the water supplies in hemodialysis centers and the adoption of effective prophylactic measures that minimize the exposure of these immunodeficient patients to contaminated sources of water.<br>O monitoramento microbiológico da água utilizada no procedimento de hemodiálise é de extrema importância, principalmente devido à imunodebilidade dos pacientes com insuficiência renal crônica. Nosso objetivo foi verificar qualitativa e quantitativamente a presença de bactérias na água de um centro de hemodiálise do interior do Estado de São Paulo. Foram realizadas 22 coletas de cada um dos cinco pontos do sistema de distribuição; 36 amostras de 19 máquinas de hemodiálise, prontas para utilização; quatro amostras do sistema de reuso e 13 amostras do sistema de armazenamento de água, empregando-se a técnica da membrana filtrante com poros de 0,22 µm para bactérias e de 0,45 µm para micobactérias. A identificação foi realizada através de métodos microbiológicos convencionais e de biologia molecular. Isolados bacterianos foram obtidos de sistema de distribuição (128), águas das máquinas (43) e sistema de reuso (3). Entre os isolados 32 foram de bacilos Gram-positivos, 120 bacilos Gram-negativos, 20 Cocos Gram-positivos e 11 micobactérias. Neste estudo, sugerimos que suprimentos de água para o Centro de Hemodiálise devam ser monitorados, adotando-se medidas profiláticas eficazes que minimizem a exposição destes pacientes imunodeficientes a fontes aquáticas ambientais contaminadas