Initial experience with sirolimus and mycophenolate mofetil for renal rescue from cyclosporine nephrotoxicity after heart transplantation

Initial Experience With Sirolimus and Mycophenolate Mofetil for Renal Rescue From Cyclosporine Nephrotoxicity After Heart Transplantation H. Lyster, G. Panicker, N. Leaver, and N.R. Banner ABSTRACT Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. We evaluated a CNI elimination protocol in 14 patients with renal impairment at 48.3 ⫾ 36.0 months after heart transplantation. The mean serum creatinine was 321 ⫾ 107 ␮mol/L; cyclosporine (n ⫽ 13) or tacrolimus (n ⫽ 1) was discontinued with sirolimus commenced immediately, initially aiming for a target trough level of 16 (12 to 20) ng/mL. If patients were not receiving mycophenolate (MMF) this was initiated at 1 g bid. The transfer period was covered with a tapering course of corticosteroids. In addition to monitoring clinical status, hematology, biochemistry, and sirolimus levels, graft function was assessed by echocardiography, ECG, and, where indicated, endomyocardial biopsy. Renal function improved in 12 patients (with 6 having a greater than 40% decrease in serum creatinine), remained unchanged in 1, and deteriorated in 1. Two patients who were converted at 15 and 139 months after transplantation experienced grade 3A rejection. One patient experienced a fall in ejection fraction without histologic evidence of rejection. Sirolimus was discontinued in three patients because of side effects: bone marrow suppression, presumed lymphocytic pneumonitis, and generalized acneform rash complicated by an axillary abcess; 50% of patients continue on sirolimus. In conclusion, withdrawal of CNIs after heart transplantation resulted in an improvement in renal function in most patients: 43% experienced a substantial improvement. CNI elimination protocols need to be refined to reduce the risk of breakthrough rejection and to minimize side effects while protecting renal function after heart transplantation.

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ARDIAC transplantation is an established treatment option for patients with end-stage heart disease. Most centers use an immunosuppressive regimen consisting of a calcineurin inhibitor (CNI; cyclosporine or tacrolimus), together with an antiproliferative agent (azathioprine or mycophenolate mofetil) with or without corticosteroids. However, long-term CNI therapy is associated with nephrotoxicity, renal impairment is present in 31% of recipients at 5 years after transplantation.1 Newer immunosuppressive agents have become available, which are not nephrotoxic, namely, mycophenolate mofetil, sirolimus, and everolimus. The use of mycophenolate mofetil and sirolimus in combination has facilitated CNI-free immunosuppression in renal transplantation,2– 6 but currently there is limited information about this approach in heart transplantation. The objectives of this study were to determine whether CNI withdrawal is feasible using a combination of sirolimus and mycophenolate mofetil, and

whether this maneuver results in improved renal function after heart transplantation. METHODS A 12-month retrospective analysis of 14 heart transplant patients, who were switched from their CNI to sirolimus between November 2002 to May 2003. The indication for the switch was renal impairment; the mean initial serum creatinine was 321 ⫾ 107 ␮mol/L. The 14 (13 men) patients were switched at a mean of 41.6 (range 1.0 to 138.6) months after transplant. The mean age was 56 years (range 25 to 70). The calcineurin inhibitor, cyclosporine (n ⫽ 13) or tacrolimus (n ⫽ 1), was discontinued with sirolimus comFrom the Department of Cardiothoracic Transplantation, Harefield Hospital, Harefield Middlesex, United Kingdom. Address reprint requests to H. Lyster, Department of Cardiothoracic Transplantation, Harefield Hospital, Hill End Road, Harefield, Middlesex, UB96JH, United Kingdom. E-mail: h.lyster@rbh. nthames.nhs.uk

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0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.10.062

Transplantation Proceedings, 36, 3167–3170 (2004)

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Fig 1A. Serum creatinine in micromoles per liter at baseline, 1, 3, 6 and 12 months after conversion to sirolimus. B. Calcualted creatinine clearance (Cockroft and Gault) in millilitres per minute at baseline, 1, 3, 6 and 12 months after conversion to sirolimus.

mencing immediately, with a loading dose of 12 to 15 mg, initially aiming for a target trough level of 16 (12 to 20) ng/mL. With subsequent experience this target was reduced to 12 (8 to 16) ng/mL due to the incidence of side effects. Nine patients who were receiving mycophenolate mofetil at a mean daily dose of 1.75 ⫾ 0.75 g (in two divided doses), continued this medication, while those taking azathioprine (3 patients) at a mean daily dose of 33 ⫾ 11 mg, were converted to mycophenolate mofetil at an initial dose of 1 g twice daily. The mean 12-hour cyclosporine level at the time of conversion was 181 ⫾ 21 ng/mL. The transfer period was

covered with a tapering course of corticosteroids as prednisolone (1 mg/kg daily; maximum 70 mg), tapered to 0.2 mg/kg daily (maximum 15 mg) by 2 weeks and then gradually withdrawn over at least 2 months after the switch. The dose of sirolimus was adjusted with respect to levels and side effects; mycophenolate mofetil dose was reduced in response to side effects, namely, decreased white cell count or gastrointestinal symptoms. In addition to monitoring clinical status, hematology, biochemistry, and sirolimus levels, graft function was assessed by echocardiography, ECG and, when indicated, endomyocardial biopsy.

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Individual patients serum creatinine at baseline and 3 months after conversion to sirolimus.

RESULTS

Renal function improved significantly after switching to sirolimus. This occurred during the first month and was usually maintained (Fig 1A); however, there was marked variability in the response in individual patients (Fig 2). Renal function improved in 12 patients, with 6 having a greater than 40% decrease in serum creatinine (44% to 74%); 6 showed a decrease of 5% to 32% from baseline. One patient progressed to need dialysis. The calculated creatinine clearance (Cockcroft and Gault)7 improved significantly and was maintained up to 12 months postconversion (Fig. 1B). There was no correlation between improved renal function and the time after transplant at which the patient was switched to sirolimus (data not shown). Breakthrough acute rejection (ISHLT grade 3A) occurred in two patients who had been switched to sirolimus at 15 and 139 months after heart transplant. The acute rejection episodes occurred at 3 and 6 months postconversion; in both cases it occurred within 1 month after prednisolone was discontinued. There was a drop in the left ventricular ejection fraction from 50% to 27%, in one patient; however, there was no evidence of cellular rejection on biospy. These three patients were converted back to cyclosporine. One patient who discontinued sirolimus and mycophenolate mofetil as a result of bone marrow suppression (leukopenia and thrombocytopenia) complicated with infection was converted to cyclosporine. A case of presumed lymphocytic pneumonitis and gastrointestinal symptoms due to MMF is currently receiving azathioprine and prednisolone. One patient who suffered a generalized acneform rash, complicated by an axillary abscess, unresponsive to cortico-

steroid withdrawal, was converted to cyclosporine. Worsening dyslipidemia (hypertriglyceridemia) occurred in one patient, but was controlled by reducing the sirolimus dose and switching from pravastatin to atorvastatin; he is still maintained on the sirolimus and mycophenolate mofetil combination. Seven patients remain on the protocol, with a mean daily sirolimus dose of 5 mg and a mean trough level of 10.1 ng/mL. Only one is currently taking prednisolone (but no mycophenolate mofetil); six patients remain on the sirolimus and mycophenolate mofetil combination. Mycophenolate mofetil doses decreased over time from an initial 2 g daily to a mean of 1 g daily by 12 months postconversion. DISCUSSION

Conversion from cyclosporines to sirolimus-based immunosuppression produced a substantial improvement in renal function in 43% of patients. However, side effects were frequent, requiring a reduction in the target level from 16 ng/mL to 12 (8 to 16) ng/mL. Breakthrough rejection occurred in two patients; 50% of the entire cohort remain on the regimen long term. CNI-free immunosupression has been used in renal transplantation both for de novo transplants and as a rescue treatment for renal dysfunction.2– 6 However, only a few studies have been conducted in thoracic organ transplantation. Some authors have reported improved renal function,8 –10 although others have found that the renal dysfunction was permanent.11 We found a spectrum of responses with 43% of patients having an improvement greater than 40%. In contrast to other studies, some patients experienced an acute rejection episode.8 –11 In common with other

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authors, we found a high incidence of side effects,8 which may be dose related. Most of the improvement in renal function seemed to occur early, suggesting this was due to functional changes resulting from cyclosporine withdrawal.8 However, there may be an additional long-term benefit if withdrawing cyclosporine helps to prevent further structural damage to the kidneys. In addition, in the majority of patients corticosteroids were able to be withdrawn, avoiding the side effects of steroid therapy. Although non-CNI immunosuppression is possible late after heart transplantation, and can result in improved renal function, the optimum regimen is unknown. High levels of sirolimus were associated with a greater incidence of side effects, and there was a risk of breakthrough rejection after CNI withdrawal. However, 43% of patients achieved an important improvement in renal function, indicating the need for further studies of non-CNI immunosuppression.

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REFERENCES 1. ISHLT registry report 2002. http:www.ishlt.org 2. Flechner SM: Transplant Proc 35(Suppl 3A):118S, 2003 3. Wyzgal J, Paczek L, Senatorski G, et al: Transplant Proc 34:3185, 2002 4. Formica Jr RN, Lorber KM, Friedman AL, et al: Transplant Proc 35(Suppl 3A):95S, 2003 5. Flechner SM, Goldfarb D, Modlin C, et al: Transplantation 74:1070, 2002 6. Pescovitz MD, Govani M: Am J Kidney Diseases 38(Suppl 2):S16, 2001 7. Cockroft DW, Gault MH: Nephron 16:31, 1976 8. Snell G, Levvey BJ, Chin W, et al: J Heart Lung Transplant 21:540, 2002 9. Groetzner J, Meiser B, Landwehr P, et al: Transplantation 77:568, 2004 10. Groetzner J, Kaczmarek I, Landwehr P, et al: Eur J Cardiothorac Surg 25:333, 2004 11. Zakliczynski M, Nozynski J, Zakliczynska H, et al: Transplant Proc 35:2331, 2003