Conversion to Low-Dose Tacrolimus or Rapamycin 3 Months After Kidney Transplantation: A Prospective, Protocol Biopsy-Guided Study

doi:10.1016/j.transproceed.2011.01.033

Transplantation Proceedings

Volume 43, Issue 2, March 2011, Pages 519-523

https://doi.org/10.1016/j.transproceed.2011.01.033 Get rights and content

Abstract

Long-term survival of kidney allografts is primarily limited by a progressive decline in function characterized by the presence of interstitial fibrosis (IF) and tubular atrophy (TA) on biopsy. Since chronic calcineurin-inhibitor (CNI) drug toxicity has been implicated as a significant cause of IF/TA, a major effort in transplantation has been to decrease or eliminate CNI therapy. We now report the clinical and histological consequences of converting renal transplant recipients at 3 months to either very low levels of tacrolimus (TAC; 4–6 ng/mL) or sirolimus (SRL; 6–10 ng/mL) therapy. Fifty-eight enrollees in this prospective randomized trial received low-dose (2.9 ± 0.6 mg/kg) rabbit antithymocyte globulin induction followed by standard doses of TAC (10–15 ng/mL), mycophenolic acid, and low-dose steroids for 3 months. Protocol biopsies were performed at implantation and 3 and 12 months. Six patients had evidence of either borderline changes (n = 5) or grade 1A rejection (n = 1) on the 3-month protocol biopsy and were not randomized. Only one patient had clinically evident rejection that occurred after randomization to SRL. One patient in each group had borderline changes at 12 months. Renal function (estimated glomerular filtration rate) was equivalent in both groups at 12 months (TAC 74 ± 15 vs SRL 66 ± 18 mL/min, P = .22). Chronic allograft damage index scores at 1 year were similar in both groups (TAC 2.8 ± 2.4 vs SRL 2.0 ± 2.7, P = .71). The percentage of patients with IF/TA scores greater than 2 at 1 year was low in both groups (TAC 12% vs SRL 9%, P = .78). Therefore, in a low-risk population defined as having a normal 3-month protocol biopsy, TAC levels can be successfully decreased to very low concentrations. One-year graft function and histology were equally well maintained with either low-dose TAC or SRL immunosuppression.

Section snippets

Patients

This randomized prospective clinical trial was conducted at Buffalo General Hospital, Kaleida Health Care System, with informed consent and approval from the Institutional Review Board of SUNY, University at Buffalo. Adult patients who received their first kidney transplant were eligible to participate. Exclusion criteria included a class I panel-reactive antibody > 30%, simultaneous transplant of a second solid organ, history of malignancy, active pregnancy, total cholesterol > 300 mg/dL,

Results

A total of 58 patients were enrolled in the study. Six patients were removed from the study after the 3-month protocol biopsy because of subclinical inflammation; five had borderline changes and one had grade 1A rejection. Therefore, 52 patients were randomized at 3 months to either the LoTAC or SRL arm. The demographics for the two groups of randomized patients are shown in Table 1. The two groups were well matched except for a greater percentage of expanded criteria donor (ECD) kidneys

Discussion

Prolonging renal allograft survival remains one of the most important challenges in kidney transplantation. Indeed, long-term kidney transplant survival rates for both living and deceased donor transplants have not kept pace with the striking improvements achieved in short-term outcomes.⁵ A major cause of long-term allograft injury, fibrosis and functional decline, is CNI toxicity.⁶ This study examines the effect of reducing TAC levels or conversion to SRL at 3 months on renal allograft

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Cited by (16)

Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis
2016, American Journal of Transplantation
Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta‐analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate‐ to high‐strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard‐dose regimens; moderate‐strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate‐ to high‐strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine‐based strategies and low‐risk populations. Additional research is needed with tacrolimus‐based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient‐centered outcomes.
Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model
2014, Biochemical Pharmacology
Citation Excerpt :
CsA (Sandimmune Neoral®) was provided by Novartis Pharma (Lisbon, Portugal), while SRL (Rapamune) by Wyeth Europe Ltd (Berkshire, UK). The true blood concentration of CsA (367.0 ± 45.5 ng/ml) and SRL (7.8 ± 1.9 ng/ml) treatments were within the range of those achieved in humans under the same immunosuppressive regimens, while the recommended therapeutic windows are 200–400 ng/ml for CsA and 6–10 ng/ml for SRL [17]. A glucose tolerance test (GTT) was performed in fasted rats, 3 days before sacrifice.
Cyclosporin A (CsA) and sirolimus (SRL) are immunosuppressive agents (IAs) associated with dyslipidemia, insulin resistance and new onset diabetes after transplantation (NODAT). However, the molecular mechanisms involved are not fully understood. We investigated the effects of six-week treatment of either CsA or SRL on glucose and lipid metabolism in Wistar rats. The results show that, compared with vehicle-treated rats, SRL-treated rats were significantly lighter starting at week 5. CsA or SRL caused glucose intolerance, increased storage of lipids in the liver and skeletal muscle, and decreased the insulin-stimulated glucose uptake in isolated adipocytes. Furthermore, these agents significantly decreased genes involved in insulin action and glucose uptake, such as, IRS-1, Glut4 and Glut1, and increased genes and/or proteins involved in hepatic lipogenesis and gluconeogenesis, while decreasing them in adipose tissue. After either treatment PGC1α gene expression was down regulated in skeletal muscle, an important player in fatty acid oxidation. Moreover, there was an increase in IL-6 gene expression in adipose tissue in the SRL-treated rats, suggesting stimulation of lipolysis. The results of the present study suggest that CsA and SRL lead to metabolic alterations in liver, muscle and adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
Comparison of cyclosporine and sirolimus effects on serum creatinine level over five years after kidney transplantation
2013, Transplantation Proceedings
Conversion from cyclosporine to sirolimus (SRL) after organ transplantation may improve renal function. The current study considers the effects of conversion during a 5-year period.
Among 98 primary kidney recipients, 88 completed the study on cyclosporine (n = 59) or SRL (n = 29) treatment. Conversion to SRL was performed between 3 and 6 months post-transplantation. The serum creatinine level was tested on 1 day as well as 3, 6, 9, 12, 15, 18, 21, 24, 36, 48, and 60 months after transplantation. The data were analyzed using student t test, chi square, repeated measures, and a mixed model for multivariate analysis.
The mean serum creatinine levels in the cyclosporine and SRL groups were 1.78 ± 0.68 and 1.62 ± 1.01, respectively (P = .04). Using repeated measure analysis, there was an interaction between time and the drug (P = .039). A separate comparison showed that serum creatinine levels were significantly different between the 2 groups at time points 11 and 12. Using multivariate analysis to control the possible effect of demographic or clinical features, we confirmed that conversion was the most significant explanation for the renal function improvement.
Compared with cyclosporine, we observed a preference for SRL as the maintenance immunosuppressant after renal transplantation.
Wound complications frequency in heart transplant recipients on mammalian target of rapamycin inhibitors: A meta-analysis
2023, International Wound Journal
Autologous bone marrow-derived mesenchymal stem cells for interstitial fibrosis and tubular atrophy: a pilot study
2021, Renal Failure
Campath, calcineurin inhibitor reduction, and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial
2018, American Journal of Transplantation

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: This work was supported by an investigator-initiated research grant, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.

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Renal transplantationComplication: RenalConversion to Low-Dose Tacrolimus or Rapamycin 3 Months After Kidney Transplantation: A Prospective, Protocol Biopsy-Guided Study

Abstract

Section snippets

Patients

Results

Discussion

Changes in quality of life after renal transplantation

Transplant Proc

Which renal transplant candidates should accept marginal kidneys in exchange for a shorter waiting time on dialysis?

Clin J Am Soc Nephrol

US Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States

Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era

Am J Transplant

The natural history of chronic allograft nephropathy

N Eng J Med

Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity

Clin Transplant

Minimizing immunosuppression, an alternative approach to reducing side effects: objectives and interim result

Clin J Am Soc Nephrol

Calcineurin inhibitor minimization in the symphony study: observational results 3 years after transplantation

Am J Transplant

Renal transplantation
Complication: Renal
Conversion to Low-Dose Tacrolimus or Rapamycin 3 Months After Kidney Transplantation: A Prospective, Protocol Biopsy-Guided Study