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Long-term renal tolerance of cyclosporin A treatment in adult idiopathic nephrotic syndrome. Repeat renal biopsies and serial serum creatinine measurements were done in 36 adults who were treated for steroid-dependent or -resistant idiopathic nephrotic syndrome with 5.54 ± 0.81 mg/kg/day of cyclosporin A (CsA). Pre-CsA renal biopsy (RB1) had been carried out 11.6 ± 12.2 months prior to CsA treatment. It showed minimal glomerular changes (MCD) in 22, and 1 to 16 glomeruli with lesions of focal segmental glomerulosclerosis (FSGS) per biopsy in 14. Pretreatment serum creatinine levels were (μmol/liter) 97.6 ± 39.4 and were higher in FSGS (117.1 ± 48.3) than in MCD (85.2 ± 26.9; P < 0.04). Repeat biopsy (RB2) was done after 19.6 ± 15.2 months (6 to 78) of CsA treatment. At this time, in 15 patients the minimal glomerular lesions observed on RB1 were unchanged, whereas in 7 patients lesions of FSGS were now visible. In patients with FSGS on RB1 and RB2, serum creatinine at the end of CsA treatment was 130.6 ± 60.1 µmol/liter, significantly greater (P = 0.022) than the corresponding levels in the subset with MCD (87.3 ± 24.8). The contrast between the remarkable stability of renal function in the patients with MCD and the worsening of renal function in the subgroup with FSGS was explained in the latter by an aggravation of renal histologic lesions, with a greater number of glomeruli with FSGS, of obsolescent glomeruli, and of interstitial fibrosis/infiltrates. This aggravation of the primary renal disease was observed in some cases where CsA had obtained partial or even complete remission. Few of the tubular lesions and of vascular changes were typical of CsA toxicity but rather suggested development of the primary renal disease. In contrast, although some increase in the degree of tubulointerstitial lesions was observed on RB2, the rating of such lesions was much less severe in patients whose renal biopsy showed persistently normal glomeruli after exposure to CsA. Overall, the most severe interstitial/vascular lesions were observed in patients treated with the highest CsA dosages, and the “cut-off” of dosage safety appeared to be 5.5 mg/kg/day. Two patients died during the study period. Long-term surveillance of the extant 34 patients showed that 8, all of whom had FSGS, evolved to end-stage renal failure due to progression of their primary renal disease after ending CsA treatment. Four patients were failures of CsA and returned to conventional therapy. CsA treatment was continued for 12 to 60 months in fourteen patients who achieved remission. This treatment was progressively tapered to a stop and they remained in remission without CsA (follow-up 8 months to 6 years), indicating that in CsA responsive nephrotic patients, mainly those with MCD, CsA dependency is far from being the rule after a period of remission longer than one year. Statistical analysis found three strong predictive factors of histological CsA nephrotoxicity: a dosage greater than 5.5 mg/kg/day, presence of renal insufficiency prior to treatment, and the percentage of glomeruli with lesions of FSGS on initial renal biopsy. Conversely, in MCD with normal renal function treated with less than 5.5 mg/kg/day, no correlation was found between the development of tubulointerstitial/vascular lesions and duration of CsA treatment. We conclude that: (1) treatment of MCD with normal renal function, using a dosage of CsA up to 5.5. mg/kg/day is safe and efficient; (2) conversely, FSGS with pre-existing incipient renal insufficiency and tubulointerstitial lesions should be considered as relatively hazardous; (3) repeat biopsy after a year of treatment is necessary to determine whether treatment can be safely continued or should be stopped; and (4) when prolonged remission has been obtained with CsA treatment of more than a year, progressive tapering of the drug to a stop is often followed by stable remission, a finding which should lead to reconsidering the notion of “CsA dependency” in CsA-responsive idiopathic nephrotic syndrome. |
