A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients

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Abstract

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m ² vs. 67.1 ml/min/1.73 m ² by ITT, which met predefined noninferiority criteria ( P = 0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.

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Most cited references 24

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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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Cancer incidence before and after kidney transplantation.

Claire Vajdic, Stephen McDonald, Margaret R E McCredie … (2006)

Immune suppression after organ transplantation is associated with a markedly increased risk of nonmelanoma skin cancer and a few virus-associated cancers. Although it is generally accepted that other cancers do not occur at increased rates, there have been few long-term population-based cohort studies performed. To compare the incidence of cancer in patients receiving immune suppression after kidney transplantation with incidence in the same population in 2 periods before receipt of immune suppression: during dialysis and during end-stage kidney disease before renal replacement therapy (RRT). A population-based cohort study of 28,855 patients with end-stage kidney disease who received RRT, with 273,407 person-years of follow-up. Incident cancers (1982-2003) were ascertained by record linkage between the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Cancer Statistics Clearing House. Standardized incidence ratios (SIRs) of cancer, using age-specific, sex-specific, calendar year-specific, and state/territory-specific population cancer incidence rates. The overall incidence of cancer, excluding nonmelanoma skin cancer and those cancers known to frequently cause end-stage kidney disease, was markedly increased after transplantation (n = 1236; SIR, 3.27; 95% confidence interval [CI], 3.09-3.46). In contrast, cancer incidence was only slightly increased during dialysis (n = 870; SIR, 1.35; 95% CI, 1.27-1.45) and before RRT (n = 689; SIR, 1.16; 95% CI, 1.08-1.25). After transplantation, cancer occurred at significantly increased incidence at 25 sites, and risk exceeded 3-fold at 18 of these sites. Most of these cancers were of known or suspected viral etiology. Kidney transplantation is associated with a marked increase in cancer risk at a wide variety of sites. Because SIRs for most types of cancer were not increased before transplantation, immune suppression may be responsible for the increased risk. These data suggest a broader than previously appreciated role of the interaction between the immune system and common viral infections in the etiology of cancer.

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Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.

F Vincenti, S Friman, E Scheuermann … (2007)

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C(2) Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C(2) monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft-Gault) was 63.6 +/- 20.7 mL/min/1.73 m(2) in the CsA-ME cohort and 65.9 +/- 23.1 mL/min/1.73 m(2) with tacrolimus (p = 0.285); mean serum creatinine was 139 +/- 58 and 133 +/- 57 mumol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome.

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Author and article information

Journal

Journal ID (nlm-ta): Transpl Int

Journal ID (iso-abbrev): Transpl. Int

Journal ID (publisher-id): tri

Title: Transplant International

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 0934-0874

ISSN (Electronic): 1432-2277

Publication date (Print): March 2014

Publication date (Electronic): 06 January 2014

Volume: 27

Issue: 3

Pages: 302-311

Affiliations

[1 ]Renal Medicine and Transplantation, Royal Prince Alfred Hospital and Sydney Medical School Sydney, NSW, Australia

[2 ]Department of Nephrology, Monash Medical Centre Melbourne, Vic., Australia

[3 ]Department of Renal Medicine, Auckland City Hospital Auckland, New Zealand

[4 ]Department of Surgery, National Cheng Kung University Hospital Tainan, Taiwan

[5 ]Division of Nephrology, University Malaya Medical Centre Kuala Lumpur, Malaysia

[6 ]Novartis Pharmaceuticals North Ryde, NSW, Australia

[7 ]Department of Nephrology, The Royal Adelaide Hospital Adelaide, SA, Australia

Author notes

Professor Steve Chadban, Transplantation, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia., Tel.: +612 9515 6600;, fax: +612 9515 6329;, e-mail: steve.chadban@ 123456sswahs.nsw.gov.au

The authors of this manuscript have conflicts of interest to disclose. Chadban S: Received research funding, honoraria or travel support from Novartis, Wyeth, Jansen, BMS and Genzyme. Kanellis J: Received research funding, honoraria or travel support from Novartis, Roche, Wyeth, BMS and Genzyme. Pilmore H: Received honoraria from Roche. Lee PC: No relevant conflicts to disclose. Lim SK: Received research funding, honorarium from Roche, Sanofi, Boehringer Ingelheim. Woodcock C: Employed by Novartis Pharmaceuticals Australia. Kurstjens N: Employed by Novartis Pharmaceuticals Australia. Eris J: Received research funding &/or honoraria &/or travel support from Novartis, Roche, Pfizer, Amgen, Astellas and Jansen Cilag. Russ G: Received research funding, honoraria or travel support from Novartis, Wyeth, Bristol-Myers Squibb and Astellas.

Article

DOI: 10.1111/tri.12252

PMC ID: 4282427

PubMed ID: 24279685

SO-VID: 9f50c3d1-046c-4089-89f4-59506e53966e

License:

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 07 July 2013

Date revision received : 21 August 2013

Date accepted : 23 November 2013

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