A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children

Abstract

For over 30 years cyclophosphamide (CYC) and chlorambucil (CHL) have been used to treat children with relapsing steroid-sensitive nephrotic syndrome (SSNS). A meta-analysis on treatment protocols, efficacy, and side effects of CYC and CHL was performed from the literature. Thirty-eight studies comprising 1,504 children and 1,573 courses of cytotoxic drug therapy were systematically evaluated. Relapse-free survival rates increased with the cumulative dosage of CHL and CYC and were higher in children with frequently relapsing than steroid-dependent NS. The fatality rate of the treatment was approximately 1%. Leukopenia occurred in one-third of patients treated with either drug. Severe bacterial infections developed in 1.5% of the patients under CYC and in 6.8% under CHL. Seizures were observed in 3.6% of children treated with CHL. Malignancies were observed in 14 children after high doses of either drug. Females rarely developed permanent gonadal damage. However, no safe threshold for a cumulative amount of CYC was found in males, but there was a marked increase in the risk of oligo- or azoospermia with higher cumulative doses. From this meta-analysis we recommend CYC 2-3 mg/kg body weight for 8-12 weeks as the standard scheme. CHL has higher rates of severe side effects and should be considered a second-line drug.

Gonad evaluation in male systemic lupus erythematosus

“…Meistrich et al (41) showed that a cumulative dose of IV CYC Ͼ7.5 gm/m 2 was associated with azoospermia. Our findings are in accordance with those of previous studies in cancer and nephrotic syndrome that showed a decrease in spermatozoa production following IV CYC treatment, due to dysfunction of the germinal epithelium (7,8). It has been shown that spermatogenesis is suppressed within 90-120 days by IV CYC treatment, resulting in abnormal semen analysis findings (42).…”

“…Male gonad evaluation requires a complete urologic examination in order to determine semen alterations due to increasing age (3,4), genital system abnormalities (e.g., varicocele, orchitis, testicular cancer, mumps) (5), influence of drugs (particularly intravenous cyclophosphamide [IV CYC]) (6)(7)(8)(9), and antisperm antibodies (10). There is, however, no systematic study in the literature assessing the overall gonad function in male SLE patients and its relevance for sperm abnormalities.…”

Clinical Course of Steroid Sensitive Nephrotic Syndrome in Children: Outcome and Outlook

“…In particular, the association between young age and recurrent SSNS has previously been reported by [3,5,[7][8][9]. In our study, the two youngest ages (from 1.5 to <3 and from three to <6 years) were stably significant relapse prognostic variables in both Cox and multinomial regression models.…”

Fertility preservation in patients receiving cyclophosphamide therapy for renal disease

“…Dosing limits for steroid-dependent NS range from 168-252 mg/kg of CPO, which corresponds to the gonadotoxic dose limit in males [18]. This dosing limit was initially established in 1981 in a long-term follow-up study by Trompeter et al in which they evaluated adult males who had been treated with CPO as children, with doses limited to 3 mg/kg CPO for an 8-week course (168 mg/kg) [19].…”

“…These authors found that despite lower ejaculate volume and sperm densities and a higher percentage of immotile and abnormal spermatozoa compared to healthy controls, these abnormalities were not severe enough to suggest permanent infertility [19]. The treatment regimen recommended for steroiddependent NS is a dose of 2-3 mg/kg/day CPO given orally for 8-12 weeks [18]. Ueda et al recommend a dose of 2 mg/kg/day given orally for 8 weeks and demonstrated no significant benefit in extending the duration of therapy beyond 8 weeks, with comparable relapse-free rates at the 5-year follow-up and similar relapse-free intervals between the two durations of therapy [20].…”