39�C41 Their patients had nephrotic-range proteinuria and normal or near normal renal function. Conversely, investigators from the Netherlands have described outcomes of an extended course, typically 12 months (Table 1), of daily oral cyclophosphamide and sellckchem corticosteroids in patients with nephrotic syndrome and deteriorating renal function.34,42 Table 2. Selected studies of alkylating agents in patients with IMN Both Ponticelli et al. and Jha et al. found that alternating monthly cycles of corticosteroids and an alkylating agent were more effective than supportive therapy alone for inducing remissions of proteinuria and preserving renal function.40,41 Ponticelli et al. found that substitution of cyclophosphamide for chlorambucil provides similar efficacy with an improved adverse event profile.

43 Jha et al. permitted crossover to the immunosuppressive treatment arm 24 months after randomization to supportive treatment.41 It is notable that remission rates were lower among patients who switched to immunosuppression as rescue therapy (47%) than among those who were initially randomized to immunosuppression (72%), suggesting that delay in immunosuppressive therapy until evidence of disease progression diminishes efficacy. Studies reported by du Buf-Vereijken et al. and Hofstra et al. from the Netherlands provide additional insights into the effect of delaying cytotoxic drug therapy for IMN until there is evidence of renal function deterioration.34,42,44 These investigators favor this restrictive treatment policy because it identifies patients at highest risk of progression and avoids unnecessary immunosuppression in patients with a more favorable prognosis.

A beneficial effect of this approach in attenuating deterioration of renal function was shown in the case-controlled study of high-risk IMN patients reported by du Buf-Vereijken et al.34 Renal outcomes of 65 patients treated for 1 year with oral cytoxan and steroids were compared with 24 historical matched control patients. Control patients received either no immunosuppression or treatments that have subsequently proven to be ineffective (prednisone monotherapy, intravenous cyclophosphamide, or both). Patients had an impaired GFR at baseline (median creatinine clearance of 42 ml/min per 1.73 m2) and high-grade proteinuria. Remission of proteinuria was achieved in 86% of 65 patients receiving immunosuppressive therapy (Table 2).

At 5 years, a renal survival advantage was evident in cytoxan-treated patients compared with controls (86% versus 32%; P<0.001). The renal survival of these cytoxan-treated patients at 7 years was 74%, which is somewhat lower than the 10-year renal survival of patients with normal baseline renal function treated with a cytotoxic drug regimen by Ponticelli Batimastat et al.40 (92%). Hofstra et al.