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      Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients

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          Background

          Calcineurin inhibitor–associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients.

          Methods

          This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m 2 or greater improvement in estimated glomerular filtration rate from randomization to month 24.

          Results

          The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m 2 or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012).

          Conclusions

          Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus.

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          The natural history of chronic allograft nephropathy.

          Brian Nankivell, Richard J Borrows, Caroline L S Fung … (2003)
          With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure. We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter. Two distinctive phases of injury were evident as chronic allograft nephropathy evolved. An initial phase of early tubulointerstitial damage from ischemic injury (P<0.05), prior severe rejection (P<0.01), and subclinical rejection (P<0.01) predicted mild disease by one year, which was present in 94.2 percent of patients. Early subclinical rejection was common (affecting 45.7 percent of biopsy specimens at three months), and the risk was increased by the occurrence of a prior episode of severe rejection and reduced by tacrolimus and mycophenolate therapy (both P<0.05) and gradually abated after one year. Both subclinical rejection and chronic rejection were associated with increased tubulointerstitial damage (P<0.01). Beyond one year, a later phase of chronic allograft nephropathy was characterized by microvascular and glomerular injury. Chronic rejection (defined as persistent subclinical rejection for two years or longer) was uncommon (5.8 percent). Progressive high-grade arteriolar hyalinosis with luminal narrowing, increasing glomerulosclerosis, and additional tubulointerstitial damage was accompanied by the use of calcineurin inhibitors. Nephrotoxicity, implicated in late ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings. By 10 years, severe chronic allograft nephropathy was present in 58.4 percent of patients, with sclerosis in 37.3 percent of glomeruli. Tubulointerstitial and glomerular damage, once established, was irreversible, resulting in declining renal function and graft failure. Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes. Copyright 2003 Massachusetts Medical Society
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            Post-transplant renal function in the first year predicts long-term kidney transplant survival.

            Barbara Bresnahan, Christine B Tolleris, Alison A. McBride … (2002)
            Improvements in long-term kidney graft survival have been recently noted. However, the reasons for this were unclear. This study examined post-transplant renal function within the first year as an independent variable influencing long-term survival. The influence of demographic characteristics (age, sex, race); transplant variables (cadaver versus living donor, cold ischemia time, HLA mismatching, delayed graft function and transplant year), and post-transplant variables (immunosuppressive agents for the prevention of acute rejection, clinical acute rejection and post-transplant renal function in the first year) on graft survival were analyzed for 105,742 adult renal transplants between 1988 and 1998. Renal function in the first year was expressed as serum creatinine at six months and one year and delta creatinine (change in serum creatinine between 6 months and 1 year). Graft half-life was used to measure long-term survival. During this 11-year period, the one-year serum creatinine values for cadaver recipients steadily improved, from 1.82 +/- 0.82 mg/dL in 1988 to 1.67 +/- 0.82 mg/dL in 1998 (P and < or =50 years. The Relative Hazard (RH) for graft failure was 1.63 (1.61, 1.65; P < 0.0001) with each increment of 1.0 mg/dL of serum creatinine at one year post-transplant and it increased to 2.26 (2.2, 2.31; P < 0.0001) when the Delta creatinine was 0.5 mg/dL. The RH reduction for graft failure was substantially lower for the years 1993, 1996, 1997 and 1998 when post-transplant renal function was not included in the model (P < 0.05). However, the RH reduction per year was not different when post-transplant creatinine was included in the model, 1.01 (0.94 to 1.05; P = 0.89). In conclusion, one-year creatinine and Delta creatinine values predict long-term renal graft survival. Recent improvements in graft half-life are related to conservation of renal function within the first year post-transplantation.
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              Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial.

              Daniel Brennan, F Schena, Josep M Campistol … (2009)
              The efficacy and safety of converting maintenance renal transplant recipients from calcineurin inhibitors (CNIs) to sirolimus (SRL) was evaluated. Eight hundred thirty renal allograft recipients, 6 to 120 months posttransplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue CNI (n=275) or convert from CNI to SRL (n=555). Primary endpoints were calculated Nankivell glomerular filtration rate (GFR; stratified at baseline: 20-40 vs. >40 mL/min) and the cumulative rates of biopsy-confirmed acute rejection (BCAR), graft loss, or death at 12 months. Enrollment in the 20 to 40 mL/min stratum was halted prematurely because of a higher incidence of safety endpoints in the SRL conversion arm. Intent-to-treat analyses at 12 and 24 months showed no significant treatment difference in GFR in the baseline GFR more than 40 mL/min stratum. On-therapy analysis of this cohort showed significantly higher GFR at 12 and 24 months after SRL conversion. Rates of BCAR, graft survival, and patient survival were similar between groups. Median urinary protein-to-creatinine ratios (UPr/Cr) were similar at baseline but increased significantly after SRL conversion. Malignancy rates were significantly lower at 12 and 24 months after SRL conversion. Post hoc analyses identified a subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11, whose risk-benefit profile was more favorable after conversion than that for the overall SRL conversion cohort. At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Transplant Direct
                Journal ID (publisher-id): TXD
                Title: Transplantation Direct
                Publisher: Lippincott Williams & Wilkins
                ISSN (Electronic): 2373-8731
                Publication date Collection: April 2016
                Publication date (Electronic): 03 March 2016
                Volume: 2
                Issue: 4
                Electronic Location Identifier: e69
                Affiliations
                [1] 1 Divisão de Nefrologia, Hospital do Rim, São Paulo, Brazil.
                [2] 2 Department of Transplantation, California Pacific Medical Center, San Francisco, CA.
                [3] 3 Department of Nephrology, Hospital Clínico San Carlos, Madrid, Spain.
                [4] 4 Internal Medicine and Nephrology, Presbyterian/St Luke's Medical Center, Denver, CO.
                [5] 5 Renal and Transplant Service, Royal Adelaide Hospital, Adelaide South, Australia.
                [6] 6 Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain.
                [7] 7 Pfizer, Global Innovative Pharma, Collegeville, PA.
                Author notes
                Correspondence: Helio Tedesco-Silva, MD, Transplante Renal-Disciplina de Nefrologia, Hospital do Rim e Hipertensão/UNIFESP, Rua Borges, Lagoa, 960-11o andar, São Paulo, Brazil. ( heliotedesco@ 123456medfarm.com.br ).
                Article
                Publisher ID: TXD50058 Accession ID: 00001
                DOI: 10.1097/TXD.0000000000000579
                PMC ID: 4946511
                PubMed ID: 27500260
                SO-VID: 4e0659dc-6ac2-4641-b6a5-03cb68f62e52
                Copyright © Copyright © 2016 The Authors. Transplantation Direct. Published by Wolters Kluwer Health, Inc.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                Date received : 29 December 2015
                Date accepted : 14 January 2016
                Categories
                Subject: Kidney Transplantation
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