A Paired Survival Analysis Comparing Hemodialysis and Kidney Transplantation From Deceased Elderly Donors Older Than 65 Years.

Transplantation - Published Ahead-of-Print A Paired Survival Analysis Comparing Hemodialysis and Kidney Transplantation From Deceased Elderly Donors Older Than 65 Years.

Background: Kidney transplantation from deceased donors aged 65 years or older is associated with suboptimal patient and graft survival. In large registries, survival is longer after kidney transplantation than when remaining on dialysis. However, whether recipients of these old grafts survive longer than their dialysis counterparts is unknown. Methods: We retrospectively assessed the outcomes of 5,230 recipients of first deceased donor grafts transplanted during the period of 1990 to 2010 in Catalonia, 915 of whom received grafts from donors 65 years or older. In a match-pair analysis, we aimed to pair each of 915 eligible cases with one control (1:1 ratio). Each pair had the same characteristics at the time of entering dialysis program: age, sex, primary renal disease, period of dialysis onset, and cardiovascular comorbidities. We found 823 pairs. Results: Patient survival of 823 recipients of elderly donors was significantly higher than that of their 823 matched dialysis waitlisted nontransplanted partners (91.6%, 74.5%, and 55.5% vs. 88.8%, 44.2%, and 18.1%, respectively at 1, 5, and 10 years; P<0.001). The probability of death after the first year was similar (8.1% transplant vs 10.3% dialysis; P=0.137); however, analyzing the whole period, the adjusted proportional risk of death was 2.66 (95% confidence interval, 2.21-3.20) times higher for patients remaining on dialysis than for transplanted patients (P<0.001). Conclusion: Our study demonstrates that despite the fact that kidney transplantation from elderly deceased donors is associated with reduced graft and patient survival, their paired counterpart patients remaining on dialysis have a risk of death 2.66 times higher. (C) 2014 by Lippincott Williams & Wilkins


http://pdfs.journals.lww.com/transplantjournal/9000/00000/A_Paired_Survival_Analysis_Comparing_Hemodialysis.97979.pdf

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

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

• Rosborough BR, Raïch-Regué D, Liu Q, et al. 
• Adenosine Triphosphate-Competitive mTOR Inhibitors: A New Class of Immunosuppressive Agents That Inhibit Allograft Rejection. [JOURNAL ARTICLE]
• Am J Transplant 2014 Sep; 14(9):2173-2180.

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://www.unboundmedicine.com/medline/citation/25307040/Adenosine_Triphosphate_Competitive_mTOR_Inhibitors:_A_New_Class_of_Immunosuppressive_Agents_That_Inhibit_Allograft_Rejection_

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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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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 (AUC_0-24) and maximum concentration (Cmax) were evaluated and compared between the groups.

Results

Colchicine AUC_0-24 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 AUC_0-24 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 AUC_0-24 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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