A significant reduction in the incidence of relapse of steroid-sensitive nephrotic syndrome has been shown in a controlled trial of cyclophosphamide given during steroid-maintained remission. Toxicity was very minor, and the regimen constitutes a useful advance in management of these patients. The trial had two special features: the use of a semisequential analysis permitting planned repeated access to the trial data and the demonstration of a therapeutic effect of one drug while the manifestations of the disease were completely suppressed by another.

While not evaluated as a high-quality study, this trial did have a significant effect on practice as it was the first to show a potential beneficial action of an alkylating agent on relapses in steroid-sensitive, relapsing MCD in children. The trial was well designed, and all patients were followed, making an analysis by intention to treat superfluous. The analysis was sequential, but the P values were not corrected for multiple analyses. All patients (ages 2.9–12.9 years) had steroid-sensitive and frequently relapsing disease (due to MCD, confirmed by renal biopsy) and were in a steroid-induced remission at the time steroids were tapered with or without a pre-taper regimen of oral cyclophosphamide (CYC) (8 weeks at 3 mg/kg/day). Although the duration of steroid treatment was slightly longer in the CYC group, this most likely did not influence the results. After 4 months of observation, 3/15 patients that received CYC and 11/15 that had received steroids only had relapses (p < 0.02). After 1 year of observation, 2/10 patients that had received CYC relapsed, while 9/10 patients that tapered steroids without CYC had relapsed. Adverse side effects were minimal (mild alopecia). Leukopenia was seen in only one patient treated with CYC. The duration of CYC treatment (and cumulative dose) proved to be important in subsequent studies [4, 5]. The cumulative dose of CYC in this study was about 168 mg/kg, below the threshold believed to produce gonadal damage and well below the level associated with an increased risk for neoplasia.

This study provided a new way to reduce the harmful effects of repeated courses of glucocorticoids in multiple relapsing MCD. Concerns about the potential for subtle genetic damage from the CYC were well recognized by the authors and many studies were subsequently performed to try to establish the minimum effective dose and to examine other less toxic regimens [4, 6]. But this study, despite its weaknesses in design and analysis, did have a profound influence practice. Although 40 years later alkylating agents are much less frequently used as steroid-sparing agent in frequently relapsing and steroid-dependent MCD, due to the development of less “toxic” regimens (see below), they still have a role to play in highly selected cases [1]. Less data is available in adults with multiple relapsing MCD, but CYC is also suggested as a steroid-sparing agent in this group as well [7–9].

To compare the efficacy (induction of remission) and safety of cyclosporine (CsA) with those of supportive therapy in patients with steroid-resistant idiopathic nephrotic syndrome (INS), we organized an open, prospective, randomized, multicentric, controlled study for parallel groups, stratified for adults and children. Forty-five patients with steroid-resistant INS were randomly assigned to supportive therapy or CsA (5 mg/kg/day for adults, 6 mg/kg/day for children) for 6 months, then tapered off by 25 % every 2 months until complete discontinuation. Four patients were lost to follow-up. During the first year, 13/22 CsA-treated patients versus 3 of 19 controls attained remission of the nephrotic syndrome (P < 0.001). A symptom score was assessed at time 0 and at 6 months. The mean score significantly decreased in the CsA group (P < 0.001), but remained unchanged in the controls. At month 6, the mean urinary protein excretion, the mean serum proteins, and the plasma cholesterol had significantly improved in the CsA group but were not changed in the controls. There were no significant differences in serum creatinine and creatinine clearance between treatments (interaction time* treatments, P = 0.089 and P = 0.935, respectively) at month 6 versus basal. The CsA-related side effects were mild; no significant difference in blood pressure between the two groups was seen at any time. This study shows that CsA can bring about remission in some 60 % of patients with steroid-resistant INS. In patients with normal renal function and without severe hypertension, CsA at the therapeutic scheme adopted did not produce severe renal or extrarenal toxicity.

This study was among the first to suggest a short-term beneficial effect of cyclosporin (CsA) on “steroid-resistant” idiopathic nephrotic syndrome in adults (n = 24) and children (n = 17). Not surprisingly a lesion of FSGS was found in 28/51 cases (55 %). The number of MCD cases is higher than one might have expected – many of these cases may have been “misdiagnosed” FSGS. “Steroid resistance” was defined as continued nephrotic syndrome after only 6 weeks (adults) or 5 weeks (children) of treatment with high-dose steroids. This may have been too short by contemporary standards, thus adding a potential bias to the observed remission rates post CsA treatment. The control groups received supportive therapy only, but “rescue treatment” with steroids was permitted, adding another element of potential bias. Treatment with CsA was at 5 mg/kg/day in adults and 6 mg/kg/day in children with trough blood levels of 250–600 ng/ml with dosage adjustments for impairment of renal function. After 6 months, the CsA was stopped in the absence of a remission or continued in reduced levels for an additional 6 months in those who did remit. The cumulative probability of obtaining a complete or partial remission (CR + PR) of nephrotic syndrome at 1 year was 0.65 in the CsA group and only 0.16 in the control group (p < .0.001). Thirty-eight percent of the “responders” remained in remission for at least 12 months. No differences in renal function were observed during the treatment interval in either, but in four subjects in the control group and one in the CsA group developed progress in renal impairment or ESRD within 2 years of follow-up. Adverse events were mild and reversible in both groups.

While some potential for bias is present and short follow-up precluded examination of effects on ESRD, overall this trial supports the widely held view that CsA does play a role in management of steroid-resistant nephrotic syndrome, mainly due to FSGS. The high frequency of CR and PR observed would likely predict avoidance of ESRD over the long term unless CsA nephrotoxicity from repeated courses adds an element of iatrogenic kidney injury. The average baseline serum creatinine in the CsA group was only 0.83 ± 0.09 mg/dl, so no inferences can be made regarding the efficacy or safety of CsA treatment when renal function is impaired (serum creatinine >1.5 mg/dl) at the time treatment is begun. KDIGO does suggest that CsA be considered in management of steroid-resistant FSGS [1], in doses not to exceed 5 mg/kg/day, but prolonged therapy may be required, adding to the risk of nephrotoxicity, especially at the higher dosage levels.