Long-term effects on renal function of dose-reduced calcineurin inhibitor and sirolimus in cardiac transplant patients.
ABSTRACT Calcineurin inhibitor (CNI)-associated renal insufficiency is common after cardiac transplantation (CTX); however, the addition of sirolimus allows for CNI dose reduction and this strategy may limit CNI renal toxicity. This study examines the long-term effects of such a strategy. METHODS: Patients from a single center who had CTX from 1990 to 2007 and who were converted to sirolimus and a dose-reduced CNI were compared to group-matched controls maintained on CNI and an antiproliferative agent. RESULTS: One hundred and fifty-five patients (79 sirolimus and 76 controls) were included and had similar baseline characteristics. Sirolimus was started a mean of 1429 d post-CTX and maintained for a mean of 823 d. Reason for conversion to sirolimus was renal insufficiency (34%), vasculopathy (29%), recurrent rejection (19%), and other (18%). The eGFR was not different between groups at baseline (44.7 mL/min/1.73 m(2) vs. 46.0, p = 0.64) or at any point during follow-up: 90 d, 180 d, 1 yr, 2 yr, and 3 yr. conclusion: Patients converted to a regimen of sirolimus and a dosed-reduced CNI have stable renal function over the following three yr, but do not have an improvement in renal outcomes compared to patients maintained on full dose CNI.
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ABSTRACT: Calcineurin inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this prospective study was to evaluate the safety and efficacy of a completely CNI-free immunosuppressive regimen [mycophenolate mofetil (MMF) and sirolimus (Sir)] in HTx-recipients with late post-transplant renal impairment. Since 2001, 30 HTx-patients (25 men, 6 women; 0.2-14.2 years after transplantation) with CNI-based immunosuppression and a serum creatinine >1.9 mg/dl were included in the study. Creatinine and cystatin levels were monitored to detect renal function. Conversion was started with 6 mg Sir or 500 mg MMF according to the pre-existing regimen and was continued with the dose adjusted to achieve target trough levels between 8 and 14 ng/ml (Sir) or 1.5 and 4 microg/ml (mycophenolate). Subsequently, the CNIs were tapered down and stopped. Clinical follow-up included endomyocardial biopsies, echocardiography and laboratory studies. Additionally, every HTx-patient treated at our centre between 1996 and 2001 due to chronic renal failure without immunosuppressive conversion and fulfilling the inclusion criteria were retrospectively analysed and acted as control group. Patient demographics and 1-year survival [93 (conversion) vs 90% (control)] were compared. No acute rejection episode was detected in either group. Renal function improved significantly in the conversion group (creatinine: 3.18+/-0.71 vs 2.22+/-0.79 mg/dl, P=0.001; cystatin pre- vs post-conversion: 2.95+/-1.06 vs 2.02+/-1.1 mg/l, P=0.01). In three patients haemodialysis therapy was stopped completely after conversion. In the control group renal impairment was deteriorating, creatinine increased from 2.44+/-0.8 to 3.28+/-1 mg/dl (P=0.01). In 10 out of 33 patients chronic haemodialysis had to be initiated within 1 year. Although side effects of CNI-free immunosuppression were common (76%), no patient had to be excluded due to adverse effects. Conversion from CNI-based immunosuppression to MMF and Sir in HTx-patients with chronic renal failure was safe, preserved graft function and improved renal function.European Journal of Cardio-Thoracic Surgery 04/2004; 25(3):333-41. · 2.67 Impact Factor
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ABSTRACT: Chronic renal dysfunction is a common occurrence after heart transplantation in patients treated with calcineurin inhibitors (CIs). We evaluated the renal-sparing effects of converting stable heart transplant patients with renal dysfunction from a CI to sirolimus. Beginning in 2000, heart transplant patients with renal dysfunction were converted from a CI to sirolimus. CI was abruptly discontinued and sirolimus added at 5 mg twice a day for 2 days and then 2 mg daily. The treatment goal was a 24-hour level of 6 to 12 ng/ml. All patients were also managed with mycophenolate mofetil (MMF) at 1,000 mg twice daily. Eighty from a total of 235 cardiac transplant patients were converted to sirolimus. The average time post-transplant for conversion was 4.78 years (range 3 days to 16 years). The average age at transplant was 55.43 years (range 15 to 70). At a mean of 304 days post-conversion, the mean serum creatinine (sCr) decreased from 2.04 +/- 0.57 mg/dl pre-conversion to 1.64 +/- 0.48 mg/dl (p < 0.001). In patients whose sCr was <2.5 mg/dl before conversion, the mean SCr level decreased from 1.81 +/- 0.39 to 1.62 +/- 0.5 mg/dl post-conversion (p = 0.01), with no patient developing end-stage renal disease (ESRD). Four patients with sCr > or =2.5 developed ESRD requiring dialysis despite conversion. In the remaining 15 patients with sCr > or =2.5 mg/dl, the sCr decreased from 2.85 +/- 0.29 to 1.73 +/- 0.43 mg/dl (p = 0.001). Conversion to sirolimus from CI is safe and has a renal-sparing effect in the management of heart transplant patients with chronic renal dysfunction. Based on these results, sirolimus has a role as a first-line immunosuppressive agent in heart transplant patients with renal dysfunction.The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 11/2005; 24(11):1863-7. · 3.54 Impact Factor
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ABSTRACT: Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil +/- steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0-5.7) preswitch to 0.23 g/day (0-9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.American Journal of Transplantation 04/2008; 8(4):854-61. · 6.19 Impact Factor