The Management of Cyclosporine-Induced Nephrotoxicity After Cardiac Transplantation

Improvement of Impaired Renal Function in Heart Transplant Recipients Treated with Mycophenolate Mofetil and Low-Dose Cyclosporine. Transplantation 2000; 69: 1586. Aleksic I, Baryalei M, Busch T, Pieske B, Schorn B, Strauch J, Sîrbu H, and Dalichau H. The introduction of cyclosporine (CsA) into cardiac transplantation in the early 1980s resulted in a remarkable improvement in 1-year survival and established the procedure as the treatment of choice for selected patients with end-stage heart failure. The acute and chronic nephrotoxic effects of CsA became apparent as experience with the drug increased (1). CsA-induced nephrotoxicity is now one of the most important long-term complications in recipients of heart transplants (the others being cardiac allograft vasculopathy and an increased incidence of malignancy) (2). The incidence of end-stage renal disease requiring dialysis or transplantation is 4–5% in large transplant centers. CsA-based immunosuppressive regimens result in fewer and milder episodes of rejection. Most episodes of rejection in heart transplant recipients occur in the first 6 months after surgery, and it seemed reasonable to withdraw CsA (and maintain patients on azathioprine and steroids) in patients who developed late nephrotoxicity. Unfortunately this approach resulted in episodes of rejection (some fatal) in several patients (3). The nephrotoxicity of CsA is dose dependent, and decreasing the CsA dose usually results in an improvement in renal function. Because acute rejection becomes progressively less likely with time after transplantation, the usual practice is to gradually decrease the CsA dose. Our approach, for instance, is to aim for a trough CsA level of 300–350 μg/L in the first 3 months, 200–300 in the next 3 months, and 150–250 μg/L until the end of the first year. Therapy is individualized thereafter depending on rejection history and renal function. Several years after transplantation, the trough CsA level is often maintained at around 100 μg/L. CsA monotherapy is uncommon in heart transplant recipients; until recently most centers combined CsA with azathioprine and prednisolone as part of a “triple therapy” regimen. In some centers, including ours, it has been normal practice to attempt steroid weaning between months 3 and 12 after transplantation. Those patients who develop significant renal dysfunction are maintained on a small dose of prednisolone (usually 5 mg/day), and the CsA dose is reduced to achieve a trough whole blood level of 100–150 ng/ml. With this approach, the incidence of renal failure is considerably less than in the early years of the transplant program. In this issue of the journal, Aleksic et al. report on a small group of patients with moderate renal dysfunction after heart transplantation. The time from transplantation varied from just under 4 months to 5 years. The CsA dose was reduced gradually to achieve a whole blood trough level of 70–120 ng/ml. All the patients were started on mycophenolate mofetil (MMF) in place of azathioprine. There were no significant episodes of rejection or infection after the change in therapy. The introduction of newer immunosuppressive drugs (like MMF and tacrolimus) into clinical practice has given the transplant physician options that were not available in the past. The safe reduction of CsA reported by Aleksic et al. is not surprising given that a similar approach has been used by workers in the field for several years without using MMF. Acute rejection is very uncommon after the first year if patients are maintained on a small dose of steroids in addition to azathioprine and low-dose CsA. A more intriguing question is whether the introduction of MMF allows CsA-free immunosuppression in a selected groups of patients with renal dysfunction due to CsA. Although this has been reported in renal transplant patients (4), no convincing evidence is available of the safety of this approach in the cardiac transplant population. Despite serial endomyocardial biopsy and/or echocardiography, there is a risk of sudden cardiac death due to rejection that has inhibited transplant physicians from discontinuing CsA. There is also doubt as to what level of renal dysfunction merits such a change in therapy. Most patients on CsA exhibit a gradual rise in serum creatinine level after the first few months of therapy; in our large posttransplantation cohort, the median creatinine level rises to a plateau of about 180 μg/L by the fourth year (5). Discontinuing CsA in all patients who reach a serum creatinine level of 200 μg/L may expose a relatively large number of patients to the risk of acute rejection. On the other hand, waiting until the creatinine level is much higher may lead to end-stage renal disease even if the offending agent (CsA) is withdrawn. From the point of view of the transplant cardiologist, it would be useful to know which patients are more likely to develop renal dysfunction when treated with CsA (age and the presence of renovascular disease may be important risk factors). This could lead to better targeted therapy, with the use of agents like MMF and low-dose CsA from the outset in those patients at greater risk. Transplant cardiologists and surgeons must also appreciate that acute rejection is now an uncommon cause of death in the heart transplant recipient. In most patients it is no longer necessary to damage the kidney to preserve cardiac function. Needless to say, meticulous attention to blood pressure control, avoidance of other nephrotoxic drugs, and liaison with our colleagues in nephrology are important facets of the approach to this problem. For the patient who develops severe renal dysfunction several years after heart transplantation perhaps it is time to consider a trial of CsA-free immunosuppression using the newer agents as adjunctive therapy.