A Novel Non-invasive Biomarker for Minimal Change Disease: Will Anti-nephrin Antibodies Be the Next Anti-PLA2R?

Novel biomarkers have been changing our understanding of glomerular disease physiology by improving our diagnostic and prognostic capabilities while opening the door to more precise therapeutic options. Most notably, the discovery of the anti-phospholipase receptor-2 antibody (anti-PLA2R Ab) in 2009 has facilitated diagnostic algorithms where some patients with high PLA2R titers may not need a kidney biopsy. Titer levels are followed clinically to monitor response to treatment and risk of relapse, whereas novel therapeutics are being developed to specifically inhibit presumed pathogenic properties of PLA2R Abs (1).

Nephrin, an important component of the slit diaphragm, has been one of the most widely studied proteins in experimental glomerular disease. The identification in 1998 of mutations in NPHS1, the gene encoding nephrin, in patients with congenital nephrotic syndrome (CNS) of Finnish type opened the door to the subsequent identification of dozens of other gene mutations impacting the glomerular filtration barrier, greatly improving our understanding of its molecular architecture (2). Interestingly, analogous to what happens in Alport syndrome, where de novo anti-glomerular basement membrane (anti-GBM) disease can develop posttransplant, children with CNS due to complete nephrin deficiency have also been reported to develop recurrent nephrosis after transplantation, where anti-nephrin antibodies develop upon exposure to this novel antigen not encountered during fetal maturation. Anti-nephrin antibodies have also been shown to cause massive albuminuria in animal models and redistribution away from the slit diaphragm in cultured podocytes. Taken together, these findings suggest a pathogenic role for anti-nephrin antibodies.

The recent study by Watts, Keller, et al. (3), published in JASN, hypothesized a role for circulating anti-nephrin antibodies in the pathogenesis of minimal change disease (MCD) (Figure 1). With the use of a custom-developed indirect enzyme-linked immunosorbent assay (ELISA) and established thresholds, the authors found 18 of 62 (29%) patients of biopsy-proven MCD and active disease showing the presence of this autoantibody in the serum. The threshold for anti-nephrin antibody positivity was set as the maximum titer (187 U/mL) detected in a healthy control population (n = 30). With the use of this standard, only 1 of 54 (2%) of PLA2R+ patients was also positive for anti-nephrin antibodies. Interestingly, anti-nephrin antibodies were reduced or completely absent in seropositive MCD patients during a complete or partial remission. Histologically, the authors identified punctate immunoglobulin G (IgG) colocalizing with nephrin, which they speculate represents in situ nephrin autoantibody binding in patients with circulating anti-nephrin antibodies. Finally, they identified a patient—with steroid-dependent childhood MCD progressing to end stage kidney disease, with no underlying genetic basis—who developed massive posttransplant recurrence of proteinuria in the setting of high pre-transplant anti-nephrin antibodies.

View Full Size

• Download Figure
• Download figure as PowerPoint slide

Overall, the possibility of anti-nephrin antibodies proving to be a novel glomerular biomarker for a subset of MCD seems attractive. However, the study had some limitations, including the fact that patients initiated therapy prior to the earliest serum sample being collected and the small sample size. Another point to mention is that the patient with anti-nephrin antibodies and posttransplant proteinuria, discussed previously, had focal segmental glomerulosclerosis (FSGS) on a pre-transplant biopsy, so this is not a straightforward MCD story. The assay will also need to be further validated and threshold value limits defined.

Nonetheless, this observation may pave the way for use of anti-nephrin antibodies, not only for diagnosis but also as a marker of response to therapy or for predicting an impending relapse or recurrence posttransplantation. It is also possible that anti-nephrin antibodies could play a role in the pathogenesis of non-genetic FSGS, particularly given shared features with MCD, but this remains to be seen.

Whereas we celebrate an important step in better understanding the pathogenesis of MCD, we still have a long way to go in establishing a definitive association, causality, and potential use in clinical nephrology.