Monday, September 15, 2014

Renal function three years after early conversion from a calcineurin inhibitor to everolimus: Results from a randomized trial in kidney transplantation

Transplant International Renal function three years after early conversion from a calcineurin inhibitor to everolimus: Results from a randomized trial in kidney transplantation

Abstract

In a 36-month, open-label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post-transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to month 36 was 1.3 (14.0)mL/min with everolimus versus -1.7 (15.4)mL/min in controls (p=0.210).. In patients who remained on treatment, mean mGFR improved from randomization to month 36 by 7.9 (11.5)mL/min with everolimus (n=37) but decreased by 1.4 (14.7)mL/min in controls (n=62) (p=0.001). During months 12–36, death-censored graft survival was 100%, patient survival was 98.9% and 96.7% in the everolimus and control groups respectively, and 13.0% and 11.1% of everolimus and control patients, respectively, experienced mild biopsy-proven acute rejection. Protocol biopsies in a limited number of on-treatment patients showed similar interstitial fibrosis progression Donor specific antibodies were present at month 36 in 6.3% (2/32) and 18.0% (9/50) of on-treatment everolimus and control patients with available data (p=0.281). Adverse events were comparable, but discontinuation was more frequent with everolimus (33.7% versus 10.0%). Conversion from cyclosporine to everolimus at seven weeks post-transplant was associated with a significant benefit in renal function at three years when everolimus was continued.

This article is protected by copyright. All rights reserved.




http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Ftri.12437

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Monday, September 8, 2014

Limitations of Hemoglobin A1c for the Diagnosis of Posttransplant Diabetes Mellitus.

Transplantation - Published Ahead-of-Print Limitations of Hemoglobin A1c for the Diagnosis of Posttransplant Diabetes Mellitus.

Background: Posttransplant diabetes mellitus (PTDM) is usually detected 2 to 3 months after transplantation by fasting plasma glucose (fPG) >=7.0 mmol/L (>=126 mg/dL) and/or 2 hr post-challenge plasma glucose >=11.1 mmol/L (>=200 mg/dL) during an oral glucose tolerance test (OGTT). Recently, glycosylated hemoglobin (HbA1c) of 6.5% or higher (>=47.5 mmol/mol) has been proposed as an alternative diagnostic criterion (the HbA1c criterion). We aimed to assess the sensitivity of applying the HbA1c criterion alone or in combination with a single measurement of fPG of 7.0 mmol/L or higher (>=126 mg/dL) at 10 weeks after transplantation as screening tests for the diagnosis of PTDM. Methods: From 1999 to 2011, measurements of fPG, HbA1c, and OGTT were performed in 1,619 nondiabetic renal transplant recipients. Results: The HbA1c criterion detected 38.0% of patients with PTDM diagnosed with the standard diagnostic criteria. The specificity was 86.3%. When the HbA1c threshold value was lowered to 6.2% (44.3 mmol/mol), sensitivity increased to 57.8% with a corresponding reduced specificity of 80.4%. A combination of the HbA1c criterion and fPG of 7.0 mmol/L or higher (126 mg/dL) at 10 weeks after transplantation improved diagnostic precision with a sensitivity of 77.7% and a specificity of 96.1%. Conclusion: The proposed diagnostic HbA1c criterion failed to detect most cases of PTDM, and one of four cases of PTDM was detected by OGTT alone. This indicates that the HbA1c threshold value likely needs to be lowered for renal transplant recipients and supports continued use of OGTT as a diagnostic tool for detection of PTDM. (C) 2014 by Lippincott Williams & Wilkins


http://pdfs.journals.lww.com/transplantjournal/9000/00000/Limitations_of_Hemoglobin_A1c_for_the_Diagnosis_of.98033.pdf

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Graft and Patient Survival Outcomes of a Third Kidney Transplant.

Transplantation - Published Ahead-of-Print Graft and Patient Survival Outcomes of a Third Kidney Transplant.

Background: The waiting time for deceased donor renal transplantation in the United States continues to grow. Retransplant candidates make up a small but growing percentage of the overall transplant waiting list and raise questions about the stewardship of scarce resources. The utility of renal transplantation among individuals with two prior renal transplants is not described in the literature, and we thus sought to determine the survival benefit associated with a third kidney transplant (3KT). Methods: Multivariable Cox regression models were created to determine characteristics associated with 3KT outcomes and the survival benefit of 3KT among recipients wait listed and transplanted within the United States between 1995 and 2009. Results: A total of 4,334 patients were waitlisted for a 3KT and 2,492 patients received a 3KT. In a multivariate analysis, 3KT demonstrated an overall patient survival benefit compared to the waitlist (hazards ratio, 0.379; 95% confidence interval, 0.302-0.475; P<0.001) for those awaiting their first, second, or third kidney transplants, although an inferior graft outcome compared to first kidney transplants. The time to survival benefit did not accrue until 8 months after transplantation. In addition, we found that the duration of second graft survival was predictive of third graft survival, such that second graft survival beyond 5 years is associated with superior 3KT graft survival. Second graft loss in 30 days or less was not associated with inferior 3KT graft survival. Conclusion: A 3KT achieves a survival benefit over remaining on the waitlist, although is associated with inferior graft outcomes compared to first kidney transplants. Graft survival of the second transplant beyond 5 years is associated with superior 3KT graft survival. (C) 2014 by Lippincott Williams & Wilkins


http://pdfs.journals.lww.com/transplantjournal/9000/00000/Graft_and_Patient_Survival_Outcomes_of_a_Third.98052.pdf

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Colchicine Levels in Chronic Kidney Diseases and Kidney Transplant Recipients using Tacrolimus

Clinical Transplantation Colchicine Levels in Chronic Kidney Diseases and Kidney Transplant Recipients using Tacrolimus

Abstract

Background

Tacrolimus is a CYP3A4 inhibitor and can alter colchicine metabolism. In this study, we aimed to evaluate plasma colchicine levels in different stages of kidney disease as well as in kidney transplant (KTx) recipients using tacrolimus.

Method

This study included 6 FMF patients with normal glomerular filtration rate (GFR) as controls, 3 patients with low GFR, 6 FMF patients on hemodialysis (HD), and 6 FMF patients who were KTx recipients using tacrolimus. After a three-day washout period, plasma colchicine levels were measured at 0 (pre-dose), 1,2,4,8, and 24 hours post-dose of 1 mg oral colchicine. Area under the curve 0-24 hours (AUC0-24) and maximum concentration (Cmax) were evaluated and compared between the groups.

Results

Colchicine AUC0-24 was 6-fold higher in HD (p<0.001) and 3-fold higher in KTx recipients (p<0.001) when compared to the control. The low GFR group had mildly higher AUC0-24 than the control group. Cmax levels were also higher in HD (p=0.011) and KTx recipient (p=0.06) groups and mildly elevated in low GFR patients in comparison to controls.

Conclusion

Colchicine AUC0-24 and Cmax were significantly increased in HD patients and KTx recipients using tacrolimus. Therefore, dose adjustments are needed to avoid toxicity in both circumstances.

This article is protected by copyright. All rights reserved.




http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Fctr.12448

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Saturday, September 6, 2014

I'm sharing "Risk of ESRD and Death in Patients with CKD Not Referred to a Nephrologist: A 7-Year Prospective Study."

I thought you would be interested in this article.

Clinical Journal of the American Society of Nephrology : CJASN 2014 Jul 29;

Risk of ESRD and Death in Patients with CKD Not Referred to a Nephrologist: A 7-Year Prospective Study.
Roberto Minutolo, Francesco Lapi, Paolo Chiodini, Monica Simonetti, Elisa Bianchini, Serena Pecchioli, Iacopo Cricelli, Claudio Cricelli, Gaetano Piccinocchi, Giuseppe Conte, Luca De Nicola

PMID: 25074838

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A Randomized Multicenter Trial of Paricalcitol versus Calcitriol for Secondary Hyperparathyroidism in Stages 3-4 CKD

Clinical Journal of the American Society of Nephrology current issue A Randomized Multicenter Trial of Paricalcitol versus Calcitriol for Secondary Hyperparathyroidism in Stages 3-4 CKD


Abstract

Background and objectives Calcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%–60%.

Design, setting, participants, & measurements Patients with stages 3–4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 μg/d of calcitriol or 1 μg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%–60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups.

Results Forty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (−52% with paricalcitol and −46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405;P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3–0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups.

Conclusions These results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3–4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.


http://cjasn.asnjournals.org/cgi/content/short/9/9/1620?rss=1

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Thursday, September 4, 2014

Hypervolemia and Blood Pressure in Prevalent Kidney Transplant Recipients

Transplantation - Most Popular Articles Hypervolemia and Blood Pressure in Prevalent Kidney Transplant Recipients

imageBackgroundThe prevalence and consequences of hypervolemia in kidney transplant recipients (KTRs) have not been investigated. Specifically, its impact on blood pressure (BP) and relationship with N-terminal fragment of prohormone B-type natriuretic peptide (NT-proBNP) are unknown. The objectives of this study were to establish the prevalence of hypervolemia among clinically stable KTRs, investigate the predictors of posttransplant hypervolemia, assess its impact on blood pressure, and determine its relationship with NT-proBNP. MethodsThis single-center cross-sectional study enrolled 123 clinically stable KTRs. Extracellular volume status was determined by multifrequency bioimpedance analysis. Mild and severe hypervolemia were defined as percentage volume expansion of greater than 7% and greater than 15%, respectively. Systolic BP (SBP) and diastolic BP (DBP) were measured, with mean arterial pressure (MAP) calculated. Serum NT-proBNP was quantified using a noncompetitive immunoluminometric assay. Potential demographic, nutritional, and clinical predictors of extracellular volume status, BP, and NT-proBNP levels were assessed. ResultsHypervolemia was present in 30% of KTRs, with 5% classified as severe hypervolemia. Significant predictors of volume expansion were increased sodium intake, advancing age, and reduced fat mass (P<0.01 for all associations). Hypervolemia was the only independent predictor of elevated MAP, SBP, and DBP (P<0.001 for all associations). Raised NT-proBNP levels were independently associated with both hypervolemia (P=0.01) and allograft dysfunction (P=0.03). ConclusionsHypervolemia is unexpectedly common among clinically stable KTRs. It is closely associated with elevated BP. The relationship with increased sodium intake signals potential therapeutic focus. Further study is warranted to prospectively investigate objective measures of extracellular volume status among KTRs.


http://journals.lww.com/transplantjournal/Fulltext/2014/08150/Hypervolemia_and_Blood_Pressure_in_Prevalent.16.aspx

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Tuesday, September 2, 2014

Risk of Metabolic Complications in Kidney Transplantation After Conversion to mTOR Inhibitor: A Systematic Review and Meta-Analysis.

AJT Risk of Metabolic Complications in Kidney Transplantation After Conversion to mTOR Inhibitor: A Systematic Review and Meta-Analysis.

Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the hope of minimizing calcineurin inhibitor (CNI)-induced nephrotoxicity. However, mTOR inhibitors are also associated with a range of side effects, including metabolic complications. We aimed to determine the risks of metabolic complications after the conversion from CNI to mTOR inhibitor postkidney transplant. A systematic search in PubMed up to September 2013 identified nine relevant trials (a total of 2323 patients). The primary end points were the relative risks (RRs) of new-onset diabetes after transplant (NODAT) and hypercholesterolemia. The overall RRs of NODAT and hypercholesterolemia associated with mTOR inhibitors were 1.32 (95% confidence interval [CI] 0.92-1.87) and 2.15 (95% CI 1.35-3.41), respectively, compared with CNI-based regimen. Subgroup analyses revealed no differences in the incidence of NODAT or hypercholesterolemia between sirolimus- versus everolimus-based regimen, or between early versus late conversion. Analyses of secondary outcomes revealed a higher risk of acute rejection, proteinuria and anemia, but no difference in the risk of opportunistic infections after mTOR inhibitor conversion. In conclusion, the conversion from CNI to mTOR inhibitor in low-to-moderate risk kidney transplant recipients was associated with nonsignificant trend toward increased risk of NODAT and significant increase in hypercholesterolemia, acute rejection, proteinuria and anemia.



http://www.unboundmedicine.com/medline/citation/25146383/Risk_of_Metabolic_Complications_in_Kidney_Transplantation_After_Conversion_to_mTOR_Inhibitor:_A_Systematic_Review_and_Meta_Analysis_

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A Systematic Review of Conversion From Calcineurin Inhibitor to Mammalian Target of Rapamycin Inhibitors for Maintenance Immunosuppression in Kidney Transplant Recipients.

AJT A Systematic Review of Conversion From Calcineurin Inhibitor to Mammalian Target of Rapamycin Inhibitors for Maintenance Immunosuppression in Kidney Transplant Recipients.

This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000-2012) and conference abstracts (2009-2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention-to-treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28 mL/min/1.73 m(2) , 95% confidence interval [CI] 0.21-0.36; I(2)  = 68%, p < 0.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on-treatment population, mTORi was associated with higher GFR (14.21 mL/min/1.73 m(2) , 10.34-18.08; I(2)  = 0%, p = 0.970) 2-5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34-2.22; I(2)  = 12%, p = 0.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short-term improvements in GFR in a number of studies but longer-term follow-up data of graft and patient survival are required.



http://www.unboundmedicine.com/medline/citation/25088685/A_Systematic_Review_of_Conversion_From_Calcineurin_Inhibitor_to_Mammalian_Target_of_Rapamycin_Inhibitors_for_Maintenance_Immunosuppression_in_Kidney_Transplant_Recipients_

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Adenosine Triphosphate-Competitive mTOR Inhibitors: A New Class of Immunosuppressive Agents That Inhibit Allograft Rejection

AJT - Early Adenosine Triphosphate-Competitive mTOR Inhibitors: A New Class of Immunosuppressive Agents That Inhibit Allograft Rejection

The mechanistic/mammalian target of rapamycin (mTOR) is inhibited clinically to suppress T cell function and prevent allograft rejection. mTOR is the kinase subunit of two mTOR-containing complexes, mTOR complex (mTORC) 1 and 2. Although mTORC1 is inhibited by the macrolide immunosuppressant rapamycin (RAPA), its efficacy may be limited by its inability to block mTORC1 completely and its limited effect on mTORC2. Adenosine triphosphate (ATP)-competitive mTOR inhibitors are an emerging class of mTOR inhibitors that compete with ATP at the mTOR active site and inhibit any mTOR-containing complex. Since this class of compounds has not been investigated for their immunosuppressive potential, our goal was to determine the influence of a prototypic ATP-competitive mTOR inhibitor on allograft survival. AZD8055 proved to be a potent suppressor of T cell proliferation. Moreover, a short, 10-day course of the agent successfully prolonged murine MHC-mismatched, vascularized heart transplant survival. This therapeutic effect was associated with increased graft-infiltrating regulatory T cells and reduced CD4+ and CD8+ T cell interferon-γ production. These studies establish for the first time, that ATP-competitive mTOR inhibition can prolong organ allograft survival and warrant further investigation of this next generation mTOR inhibitors.




http://onlinelibrary.wiley.com/resolve/doi?DOI=10.1111%2Fajt.12799

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