Overcoming Calcineurin Dependence in Membranous Nephropathy

Abstract

Membranous nephropathy (MN) is a common immune-mediated glomerular disease and one of the leading causes of nephrotic syndrome in Caucasian adults (1). Although in most patients the disease progresses relatively slowly, approximately 40% of patients eventually develop ESRD (2). This is particularly true for patients who remain nephrotic despite therapy (3). Several immunosuppressive treatments seem to be at least partially successful in reducing proteinuria in MN (recently reviewed in reference [4]); however, their use can be associated with a number of adverse effects, an issue that is important with a disease for which up to 30% of patients are said to achieve spontaneous remission of proteinuria and will enjoy long-term renal survival. This problem of drug toxicity can be exemplified by the use of calcineurin inhibitors (CNI; e.g. , cyclosporine, tacrolimus). In patients with MN, prospective, randomized studies with the use of CNI have demonstrated that these agents can induce remission of proteinuria (either complete or partial remission) in >70% (5–7). For reaping their maximum benefit, current recommendations are that these agents be used for a prolonged period ( e.g. , ≥12 mo) (8). Prolonged CNI treatment, however, can be complicated by a number of adverse effects, including hypertension and nephrotoxicity, the latter being dosage/duration dependent as well as age dependent. An additional problem with CNI is that almost half of patients’ disease will relapse once the drug is withdrawn (5–7,9). Prolonged low-dosage CNI could be considered for long-term maintenance of patients who are CNI dependent, with seemingly little risk of nephrotoxicity, but the risk is certainly not zero and may require using repeat renal biopsy surveillance (9). In this issue of CJASN , Segarra et al. (10) give us an alternative treatment option for patients who have MN and are CNI …