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CHRONIC RENAL ALLOGRAFT DYSFUNCTION: A ROLE FOR MYCOPHENOLATE MOFETIL? 1

2000; Wolters Kluwer; Linguagem: Inglês

10.1097/00007890-200004270-00042

1534-6080

Manuel Pascual, Winfred W. Williams Tolkoff-Rubin,

Neurological Complications and Syndromes

We read with interest two articles recently published by Weir et al. and Glicklich et al., concerning the role of mycophenolate mofetil (MMF) in patients with chronic renal allograft dysfunction (1, 2). In the last 15 years, immunosuppressive regimens consisting of cyclosporine (CsA), steroids, and azathioprine (AZA) have been used worldwide for recipients of renal allografts. Although improved early allograft survival rates have been achieved with this combination therapy, the rate of chronic allograft loss or “organ half-life” has not changed significantly from that observed in the pre-CsA era (3, 4). If survival is analyzed excluding death with a functioning kidney as a cause of graft loss, the late attrition of renal allografts has generally been attributed to “chronic rejection.” However, further evaluation of these failed allografts has emphasized that this term is a misnomer and should be replaced by “chronic allograft nephropathy” (CAN). It is now accepted that CAN is due to both immunological and nonimmunological factors, including donor organ quality, ischemic injury, hypertension, drug toxicity, and possibly hyperlipidemia (3–5). In recent years mycophenolate mofetil (MMF) has proved to be superior to AZA in preventing early acute rejection in renal recipients (6). Therefore there has been renewed optimism that conversion to MMF from AZA might prevent CAN or improve renal function in recipients with chronic allograft dysfunction due to CAN. Controversy remains, however, whether MMF is efficacious for these indications. In two preliminary studies of renal recipients with established CAN, the addition of MMF with a concomitant 40–50% decrease in CsA dosage resulted in improved renal function in most patients (1, 7). In contrast, in another study of similarly selected patients, administration of MMF alone (with no reduction of CsA dosage) did not result in improvement in renal function (2). We would like to summarize our observations in 17 patients selected for treatment with MMF for chronic renal allograft dysfunction. Between May 1996 and October 1998, 17 adult renal transplant recipients at least 6 months posttransplant with slowly deteriorating allograft dysfunction were prospectively identified. Over the 12 months before study entry the mean increase of serum creatinine was from 1.84±0.49 to 2.44±0.5 mg/dl (P <0.01). The time from transplant to study entry was 50±25 months. All patients had been maintained on CsA, prednisone, and AZA from the day of transplantation. After informed consent was obtained, AZA was discontinued, MMF at 1 g po bid was started and the CsA dose was reduced by 30%. The baseline prednisone dose (11±3.3 mg/day) was not changed. No other treatment modification was made. A renal biopsy before starting MMF was obtained in 12/17 patients. The mean age of the patients was 42±12 years. There were 10 females and 7 males, 16 Caucasians and 1 African-American. At transplant, the mean panel reactive antibody was 3.3±9.7% and the mean number of HLA mismatches was 2.8±1.9. Before study entry the patients had 1.4±1.2 episodes of biopsy-proven acute rejection and 0.24±0.5 episodes of biopsy-proven acute CsA toxicity. At study entry all the biopsy specimens revealed chronic changes consistent with CAN, including interstitial fibrosis, tubular atrophy and fibrointimal thickening of arterioles/arteries. Additionally four patients demonstrated signs of chronic CsA toxicity, i.e., nodular arteriolar hyalinosis. The mean level of proteinuria at study entry was 0.85±1.3 g/day (range 0.04–3.6 g/day) and two patients had proteinuria of more than 3 g/day. The observation period after starting MMF and reducing CsA dosage was 11 months (range 6–35 months). The dosage of MMF had to be decreased in 8/17 patients due to gastrointestinal side-effects. No episodes of acute rejection were observed after the changes in immunosuppressive therapy. In 15/17 (88%) patients there was an improvement in renal function and the mean serum creatinine decreased significantly (P <0.01) from 2.44±0.54 to 1.82±0.53 mg/dl (Table 1). Table 1: Changes in clinical parametersaThe two patients with nephrotic-range proteinuria had progressive deterioration of renal function and one patient returned to dialysis 10 months after being entered into the protocol. Both patients had received cadaveric renal transplants 46 and 63 months prior to study entry and had serum creatinines of 2.1 and 3 mg/dl at the start of MMF. Our results confirm the observations from two earlier studies that suggested beneficial effects of MMF and CsA dosage reduction in renal recipients with late allograft dysfunction (1, 7). In our series renal function improved in approximately 90% of the patients and no episodes of acute rejection were observed despite the reduction in CsA dosage. Only two patients, who had nephrotic-range proteinuria had deteriorating renal function and one progressed to end stage renal failure. Interestingly, Cosio et al. (8) have recently reported that proteinuria and focal glomerulosclerosis in patients with CAN may be used as a predictor of poor graft survival. Therefore, it is conceivable that nephrotic-range proteinuria may be defined as a marker of “nonresponse” to the immunosuppressive approach that we propose here for patients with CAN. It is important to note that addition of MMF alone may not be sufficient to improve renal function in established CAN (2). We would like to suggest that, in patients with chronic allograft dysfunction, the major beneficial action of MMF is to allow a safe reduction of CsA, thereby improving renal hemodynamics and function without being exposed to an increased risk of acute rejection. In the “CsA-steroids-AZA era,” CsA dosage reduction was associated with a signifi-cant risk of acute rejection and most transplant programs, including ours have been reluctant to decrease CsA dosage below an average of 4 mg/kg/day to avoid chronic immunological injury. Given the vasoconstrictive and profibrogenic properties of CsA, the use of new agents such as MMF that will allow CsA dosage reduction, although providing adequate immunosuppression, might be the ideal approach to treat CAN and prevent further chronic allograft injury (4). In summary, we conclude that conversion to MMF with a 30% reduction in CsA dosage is an effective therapeutic approach for patients with chronic renal allograft dysfunction due to CAN. However, prospective controlled trials with suitable control groups are needed to determine whether it is the addition of MMF, or the CsA dosage reduction, that accounts for the improvement in renal function. Such controlled studies will also help to determine whether conversion to MMF, with or without CsA dosage reduction, can result in improved graft and patient survival. Acknowledgments. The authors thank Mrs. Denise Faherty PhD, Roche Laboratories, Inc. for support of this project. Manuel Pascual2 Winfred W. Williams A. Benedict Cosimi Francis L. Delmonico Mary Lin Farrell Nina Tolkoff-Rubin