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Late conversion to mycophenolate mofetil for chronic deterioration of renal allograft function
Late Conversion to Mycophenolate Mofetil for Chronic Deterioration of Renal Allograft Function L. Fritsche, H. Sperschneider, K. Budde, M. Giessing, H. Tu¨rk, T. Bo¨hler, K. Schro¨der, G. Stein, and H.-H. Neumayer
L
ONG-term survival of kidney allografts has not improved substantially over the last decade, and the development of medical regimens to improve outcome remains one of the major challenges. The most frequent cause of graft loss after the early posttransplant phase is chronic rejection, which leads to chronic progressive deterioration of renal allograft function. So far, no effective therapy for this condition has been established. For the new immunosuppressant mycophenolate mofetil (MMF) a beneficial effect has been demonstrated in several experimental models of chronic rejection. But no data are available on the clinical value of MMF for the prevention of chronic deterioration of renal allograft function.
METHODS Ever since MMF became generally available in Germany in spring 1996, data of all adult patients converted to MMF fullfilling the following criteria were registered in a shared database by three participating centers: (1) conversion to MMF later than 6 months after kidney transplantation; (2) biopsy-proven chronic rejection or chronic deterioration of graft function without signs of an etiology other than chronic rejection. All available data from the visit 6 months prior to the initiation of MMF treatment up to the most recent visit have been registered. All patients from one center that could not provide sufficiently recent follow-up reports were excluded from all analyses. During the progress of this study new patients were prospectively included into the database.
RESULTS
In 45 patients (32 male, 13 female, age 41 6 11 years) treatment with MMF was initiated 6.4 6 5.2 years after renal transplantation. Prior to conversion to MMF, 33 patients were taking azathioprine (60 6 29 mg/d). Concomitant medication consisted of prednisolone in 39 patients (average dose 7.0 6 3.4 mg/d before conversion and 6.6 6 4.0 mg/d after conversion [difference not significant]); cyclosporine (CyA) in 37 patients (average trough level 124 6 54 ng/mL before and 103 6 49 ng/mL after conversion [P , .002]); and tacrolimus in two patients.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 2229 (1998)
The decline of glomerular filtration rate (GFR) during the preceding 6 months averaged 2.7 6 3.6 mL/min per month. In the treatment period (11.5 6 6.5 months) the average loss of GFR was reduced significantly (0.23 6 1.9 mL/min per month; P 5 .001). Before conversion a proteinuria of 1.8 6 3.5 g/d was observed, which did not change significantly during treatment (1.2 6 2.1 g/d). The initial MMF dosage of 27 6 7 mg/kg per day was tapered during the observation period to 23 6 7 mg/kg per day. Dose reductions were necessary mainly due to gastrointestinal side effects. A total of 39 adverse events were observed in 28 patients, most frequently classified as gastrointestinal. In eight patients MMF had to be discontinued (reasons: gastrointestinal problems n 5 4; graft failure n 5 2; leukopenia n 5 1; anemia n 5 1). After initiation of MMF, hemoglobin concentration was significantly lower (7.5 6 1.4 mmol/L v 7.9 6 1.3 mmol/L in the last 6 months before conversion) as well as hematocrit (0.36 6 0.06 v 0.38 6 0.05), whereas thrombocyte and leukocyte counts and lymphocyte fraction remained unchanged. DISCUSSION
In the majority of patients in this uncontrolled study, the deterioration of kidney transplant function was significantly slowed after conversion to MMF. If this turns out to be a sustainable and reproducible effect, conversion to MMF might be warranted in patients with chronic rejection. In the present study, side effects of MMF remained within acceptable limits and were mostly reversible by dose reduction. In our opinion the potential of MMF to ameliorate the problem of chronic renal allograft rejection merits a controlled clinical investigation. From the Department of Nephrology and Transplantation, Department of Urology, Charite´, Berlin, Germany, and Department of Internal Medicine IV, University of Jena, Jena, Germany. Address reprint requests to L. Fritsche, Department of Nephrology and Transplantation, Charite´, 10098 Berlin, Germany.
0041-1345/98/$19.00 PII S0041-1345(98)00600-9 2229
L
ONG-term survival of kidney allografts has not improved substantially over the last decade, and the development of medical regimens to improve outcome remains one of the major challenges. The most frequent cause of graft loss after the early posttransplant phase is chronic rejection, which leads to chronic progressive deterioration of renal allograft function. So far, no effective therapy for this condition has been established. For the new immunosuppressant mycophenolate mofetil (MMF) a beneficial effect has been demonstrated in several experimental models of chronic rejection. But no data are available on the clinical value of MMF for the prevention of chronic deterioration of renal allograft function.
METHODS Ever since MMF became generally available in Germany in spring 1996, data of all adult patients converted to MMF fullfilling the following criteria were registered in a shared database by three participating centers: (1) conversion to MMF later than 6 months after kidney transplantation; (2) biopsy-proven chronic rejection or chronic deterioration of graft function without signs of an etiology other than chronic rejection. All available data from the visit 6 months prior to the initiation of MMF treatment up to the most recent visit have been registered. All patients from one center that could not provide sufficiently recent follow-up reports were excluded from all analyses. During the progress of this study new patients were prospectively included into the database.
RESULTS
In 45 patients (32 male, 13 female, age 41 6 11 years) treatment with MMF was initiated 6.4 6 5.2 years after renal transplantation. Prior to conversion to MMF, 33 patients were taking azathioprine (60 6 29 mg/d). Concomitant medication consisted of prednisolone in 39 patients (average dose 7.0 6 3.4 mg/d before conversion and 6.6 6 4.0 mg/d after conversion [difference not significant]); cyclosporine (CyA) in 37 patients (average trough level 124 6 54 ng/mL before and 103 6 49 ng/mL after conversion [P , .002]); and tacrolimus in two patients.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 2229 (1998)
The decline of glomerular filtration rate (GFR) during the preceding 6 months averaged 2.7 6 3.6 mL/min per month. In the treatment period (11.5 6 6.5 months) the average loss of GFR was reduced significantly (0.23 6 1.9 mL/min per month; P 5 .001). Before conversion a proteinuria of 1.8 6 3.5 g/d was observed, which did not change significantly during treatment (1.2 6 2.1 g/d). The initial MMF dosage of 27 6 7 mg/kg per day was tapered during the observation period to 23 6 7 mg/kg per day. Dose reductions were necessary mainly due to gastrointestinal side effects. A total of 39 adverse events were observed in 28 patients, most frequently classified as gastrointestinal. In eight patients MMF had to be discontinued (reasons: gastrointestinal problems n 5 4; graft failure n 5 2; leukopenia n 5 1; anemia n 5 1). After initiation of MMF, hemoglobin concentration was significantly lower (7.5 6 1.4 mmol/L v 7.9 6 1.3 mmol/L in the last 6 months before conversion) as well as hematocrit (0.36 6 0.06 v 0.38 6 0.05), whereas thrombocyte and leukocyte counts and lymphocyte fraction remained unchanged. DISCUSSION
In the majority of patients in this uncontrolled study, the deterioration of kidney transplant function was significantly slowed after conversion to MMF. If this turns out to be a sustainable and reproducible effect, conversion to MMF might be warranted in patients with chronic rejection. In the present study, side effects of MMF remained within acceptable limits and were mostly reversible by dose reduction. In our opinion the potential of MMF to ameliorate the problem of chronic renal allograft rejection merits a controlled clinical investigation. From the Department of Nephrology and Transplantation, Department of Urology, Charite´, Berlin, Germany, and Department of Internal Medicine IV, University of Jena, Jena, Germany. Address reprint requests to L. Fritsche, Department of Nephrology and Transplantation, Charite´, 10098 Berlin, Germany.
0041-1345/98/$19.00 PII S0041-1345(98)00600-9 2229