Controlled-Dose Versus Fixed-Dose Mycophenolate Mofetil for Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials [feedly]

 
 

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Controlled-Dose Versus Fixed-Dose Mycophenolate Mofetil for Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Although mycophenolate mofetil (MMF) is recommended at a fixed dose, there is increasing interest in controlled-dose (CD) MMF based on therapeutic drug monitoring. We systematically evaluated published randomized controlled trials (RCTs) on the efficacy and safety of CD versus fixed-dose MMF for kidney transplant recipients. Methods: The electronic databases Medline, Embase, and Cochrane Library (up to June 2012) were searched to identify relevant RCTs. Two reviewers independently applied the study selection criteria, examined the study quality, and extracted the data. Dichotomous measures were expressed as relative risk (RR) and continuous outcomes were expressed as weighted mean difference, both with 95% confidence intervals (CIs). All statistical analyses were performed using Review Manager 5.1.6. Results: Four RCTs met our selection criteria and included 1755 de novo recipients. The differences between CD and fixed-dose MMF in treatment failure (RR, 0.95; 95% CI, 0.82-1.10; P=0.52), serum creatinine clearance (weighted mean difference, 2.46; 95% CI, -1.15 to 6.07; P=0.18), total gastrointestinal adverse events (RR, 1.23; 95% CI, 0.65-2.35; P=0.53), diarrhea (RR, 1.08; 95% CI, 0.92-1.25; P=0.35), anemia (RR, 1.24; 95% CI, 0.95-1.64; P=0.12), leukopenia (RR, 1.12; 95% CI, 0.93-1.35; P=0.25), thrombocytopenia (RR, 0.80; 95% CI, 0.47-1.36; P=0.41), and malignancy (RR, 0.61; 95% CI, 0.27-1.38; P=0.23) were not statistically significant. Furthermore, total infections were more frequent in the CD group (36.0% vs. 30.9%; RR, 1.16; 95% CI, 1.03-1.30; P=0.01). Conclusions: Based on current evidence, CD MMF administration cannot be recommended as routine practice for kidney transplant recipients. Therapeutic drug monitoring for MMF may be targeted toward high-risk recipients, who should be identified in future studies. (C) 2013 Lippincott Williams & Wilkins, Inc.

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Fracture Risk in Kidney Transplant Recipients: A Systematic Review [feedly]

 
 

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Fracture Risk in Kidney Transplant Recipients: A Systematic Review

Background: Fractures in men and women after kidney transplantation are associated with morbidity (including acute and chronic pain), mortality, and high economic costs. Methods: We systematically reviewed cohort studies that provided estimates on incidence and risk factors for fracture in kidney transplant recipients. We abstracted data in duplicate and assessed the methodological quality of each study on a 17-point scale (17 representing the highest quality). Results: We screened 2715 articles, reviewed 81, and included 10 studies totaling 262,678 recipients (study mean, 26,268 recipients; range, 61-77,430). The average follow-up ranged from 1.7 to 5.3 years. The study quality scores ranged from 8 to 13. Fracture sites varied by study resulting in a highly variable incidence rate ranging from 3.3 to 99.6 fractures per 1000 person-years. Similarly, the 5-year cumulative incidence for fracture varied ranging from 0.85% to 27%. Common factors associated with an increased fracture risk were older age, female sex, the presence of diabetes, and receipt of dialysis before transplantation. Other less common but statistically significant risk factors were a previous history of fracture and receipt of a kidney from a deceased (vs. living) donor. Conclusions: There is poor consensus on the incidence and risk factors for fractures in kidney transplant recipients. Previous studies vary substantially in quality, fracture definitions, and the characteristics of recipients studied. Future research should clarify fracture incidence and risk, which will inform the design of future prevention trials and guide prognostication. (C) 2013 Lippincott Williams & Wilkins, Inc.

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Oral Paricalcitol Reduces the Prevalence of Posttransplant Hyperparathyroidism: Results of an Open Label Randomized Trial [feedly]

 
 

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Oral Paricalcitol Reduces the Prevalence of Posttransplant Hyperparathyroidism: Results of an Open Label Randomized Trial

Abstract

Postkidney transplant hyperparathyroidism is a significant problem. Vitamin D receptor agonists are known to suppress parathyroid hormone (PTH) secretion. We examined the effect of oral paricalcitol on posttransplant secondary hyperparathyroidism by conducting an open label randomized trial in which 100 incident kidney transplant recipients were randomized 1:1 to receive oral paricalcitol, 2 μg per day, for the first year posttransplant or no additional therapy. Serial measurements of serum PTH, calcium and bone alkaline phosphatase, 24-h urine calcium and bone density were performed. The primary endpoint was the frequency of hyperparathyroidism 1-year posttransplant. Eighty-seven patients completed the trial. One-year posttransplant, 29% of paricalcitol-treated subjects had hyperparathyroidism compared with 63% of untreated patients (p = 0.0005). Calcium supplementation was discontinued in two control and 15 treatment patients due to mild hypercalcemia or hypercalcuria. Paricalcitol was discontinued in four patients due to hypercalcuria/hypercalcemia and in one for preference. Two subjects required decreasing the dose of paricalcitol to 1 μg daily. Hypercalcemia was asymptomatic and reversible. Incidence of acute rejection, BK nephropathy and renal function at 1 year were similar between groups. Moderate renal allograft fibrosis was reduced in treated patients. Oral paricalcitol is effective in decreasing posttransplant hyperparathyroidism and may have beneficial effects on renal allograft histology.

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Efficacy, Outcomes, and Cost-Effectiveness of Desensitization Using IVIG and Rituximab [feedly]

 
 

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Efficacy, Outcomes, and Cost-Effectiveness of Desensitization Using IVIG and Rituximab

Background: Transplantation rates are very low for the broadly sensitized patient (panel reactive antibody [PRA]>80%; HS). Here, we examine the efficacy, outcomes, and cost-effectiveness of desensitization using high-dose intravenous immunoglobulin (IVIG) and rituximab to improve transplantation rates in HS patients. Methods: From July 2006 to December 2011, 207 HS (56 living donors/151 deceased donors) patients (donor-specific antibody positive, PRA>80%) were desensitized using IVIG and rituximab. After desensitization, responsive patients proceeded to transplantation with an acceptable crossmatch. Cost and outcomes of desensitization were compared with dialysis. Results: Of the 207 treated patients, 146 (71%) were transplanted. At 48 months, patient and graft survival by Kaplan–Meier were 95% and 87.5%, respectively. The total 3-year cost for patients treated in the desensitization arm was $219,914 per patient compared with $238,667 per patient treated in the dialysis arm. Thus, each patient treated with desensitization is estimated to save the U.S. healthcare system $18,753 in 2011 USD. Overall, estimated patient survival at the end of 3 years was 96.6% for patients in the desensitization arm of the model (based on Cedars-Sinai survival rate) compared with 79.0% for an age, end-stage renal disease etiology, and PRA matched group of patients remaining on dialysis during the study period. Conclusions: We conclude that desensitization with IVIG+rituximab is clinically and cost-effective, with both financial savings and an estimated 17.6% greater probability of 3-year survival associated with desensitization versus dialysis alone. However, the benefits of desensitization and transplantation are limited by organ availability and allocation policies.

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Randomized Trial of Everolimus-Facilitated Calcineurin Inhibitor Minimization Over 24 Months in Renal Transplantation [feedly]

 
 

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Randomized Trial of Everolimus-Facilitated Calcineurin Inhibitor Minimization Over 24 Months in Renal Transplantation

Background: Strategies allowing calcineurin inhibitor minimization while maintaining efficacy may improve renal transplant outcomes. Methods: A2309 was a 24-month, phase IIIb, open-label trial of 833 de novo renal transplant recipients randomized to everolimus, targeting trough concentrations of 3–8 or 6–12 ng/mL plus reduced-exposure cyclosporine A (CsA) or to mycophenolic acid (MPA) 1.44 g per day plus standard-exposure CsA. All patients received basiliximab±corticosteroids. The incidence of the primary composite efficacy endpoint and its components (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up), renal function (serum creatinine and estimated glomerular filtration rate), and adverse events (AEs) were compared at 24 months; as per the protocol, these analyses were not noninferiority. Results: Composite efficacy failure rates (95% confidence interval for difference vs. MPA) were 32.9% (−2.2%, 13.0%), 26.9% (−7.9%, 6.8%), and 27.4% at month 24 in the everolimus 3–8 and 6–12 ng/mL and MPA groups, respectively. Mean estimated glomerular filtration rate (Modification of Diet in Renal Disease) at month 24 was 52.2 (−2.1, 5.5 mL/min/1.73 m2), 49.4 (−4.8, 2.7 mL/min/1.73 m2), and 50.5 mL/min/1.73 m2, respectively. AEs were generally mild to moderate in severity and comparable between the groups. AEs leading to discontinuation were reported in 28.5% (P=0.03 vs. MPA), 30.6% (P=0.007 vs. MPA), and 20.5% of patients receiving everolimus 3–8 and 6–12 ng/mL and MPA, respectively. Conclusions: Everolimus trough concentrations targeted to 3–8 ng/mL, along with a greater than 60% reduction in CsA exposure, was associated with comparable efficacy and renal function versus MPA plus standard-exposure CsA over the 2-year period. A significantly higher incidence of AEs led to discontinuation in the everolimus groups compared with the MPA group.

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Survival Advantage of Kidney Transplantation Over Dialysis in Patients With Hepatitis C: A Systematic Review and Meta-Analysis [feedly]

 
 

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Survival Advantage of Kidney Transplantation Over Dialysis in Patients With Hepatitis C: A Systematic Review and Meta-Analysis

Background: The clinical outcomes of hepatitis C infection in kidney transplantation and maintenance dialysis patients remain controversial. Here, we conducted a systematic review and meta-analysis that aimed at comparing 5-year mortality rates between waiting list and kidney transplantation patients with hepatitis C infections. Methods: We searched Medline, EMBASE, and Scopus databases published since inception to June 2011 and found nine studies with 1734 patients who were eligible for pooling. Eligible studies were cohort studies that analyzed adult end-stage renal disease patients with hepatitis C virus infection and compared death rates between waiting list and kidney transplantation. The crude risk ratio of death along with its 95% confidence interval was estimated for each study. Data were independently extracted by two reviewers. Results: The pooled risk ratio of death at 5 years by using a random-effect model was 2.19 (95% confidence interval, 1.50–3.20), which significantly favored the kidney transplantation when compared with the waiting list. There was evidence of heterogeneity of death rates across studies (χ2=22.6; df=8; P=0.004). From the metaregression model, age and male gender could be the source of heterogeneity or variation of treatment effects. A major cause of death in the waiting list was cardiovascular diseases, whereas infection was a major cause in the transplant group. There was no evidence of publication bias suggested by an Egger test. Conclusions: This systematic review suggested that hepatitis C virus–infected patients who remain on dialysis are at higher risk of death when compared with those who received kidney transplantations.

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Tacrolimus Predose Concentrations Do Not Predict the Risk of Acute Rejection After Renal Transplantation: A Pooled Analysis From Three Randomized-Controlled Clinical Trials(†) [feedly]

 
 

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Tacrolimus Predose Concentrations Do Not Predict the Risk of Acute Rejection After Renal Transplantation: A Pooled Analysis From Three Randomized-Controlled Clinical Trials(†)

• Bouamar R, Shuker N, Hesselink DA, et al. 
• Tacrolimus Predose Concentrations Do Not Predict the Risk of Acute Rejection After Renal Transplantation: A Pooled Analysis From Three Randomized-Controlled Clinical Trials(†) [JOURNAL ARTICLE]
• Am J Transplant 2013 Mar 8.
• AbstractPublisher Full Text

Therapeutic drug monitoring (TDM) for tacrolimus (Tac) is universally applied. However, the concentration-effect relationship for Tac is poorly defined. This study investigated whether Tac concentrations are associated with acute rejection in kidney transplant recipients. Data from three large trials were pooled. We used univariate and multivariate analysis to investigate the relationship between biopsy-proven acute rejection (BPAR) and Tac predose concentration at five time points (day 3, 10 and 14, and month 1 and 6 after transplantation). A total of 136/1304 patients experienced BPAR, giving an overall incidence of 10.4%. We did not find any significant correlations between Tac predose concentrations and the incidence of BPAR at the different time points. In the multivariate analysis, only delayed graft function (DGF) and the use of induction therapy were independently correlated with BPAR, with an odds ratio of 2.7 [95% CI: 1.8-4.0; p < 0.001] for DGF and 0.66 [95% CI: 0.44-0.99; p = 0.049] for induction therapy. The other variables, including the Tac predose concentrations, were not statistically significantly associated with BPAR. We did not find an association between the Tac predose concentrations measured at five time points after kidney transplantation and the incidence of acute rejection occurring thereafter. Based on this study it is not possible to define the optimal target concentrations for Tac.

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The First Transplant Kidney Biopsy Ever Performed [feedly]

 
 

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The First Transplant Kidney Biopsy Ever Performed

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Primary CNS Posttransplant Lymphoproliferative Disease (PTLD): An International Report of 84 Cases in the Modern Era [feedly]

 
 

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Primary CNS Posttransplant Lymphoproliferative Disease (PTLD): An International Report of 84 Cases in the Modern Era

Abstract

We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32–5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29–13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56–29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.

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Joseph Edward Murray, M.D., 1919–2012: Pioneering Transplant and Reconstructive Plastic Surgeon and Scientist, Nobel Laureate, Humanitarian—An Appreciation [feedly]

 
 

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Joseph Edward Murray, M.D., 1919–2012: Pioneering Transplant and Reconstructive Plastic Surgeon and Scientist, Nobel Laureate, Humanitarian—An Appreciation

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