Invited Commentary by Dr. Surya Seshan

Minimal change disease (MCD) is the most common cause of steroid-responsive glomerular disease with selective proteinuria. A number of animal models (induced by puromycin, protamine sulfate, etc) were developed to elucidate some of the biochemical pathogenetic mechanisms involved in MCD, including loss of charge selectivity and podocyte injury. None have been able to completely mimic the human form of MCD because of certain limitations, one being only partial steroid responsiveness in the puromycin model, suggesting other glucocorticoid-resistant pathways may be operative.

The present review by Chugh et al in the American Journal of Kidney Diseases is based on original studies in their laboratory. It documents new and exciting information in molecular pathogenesis of MCD. The authors have shown qualitative and quantitative changes in podocyte expression of ANGPTL4, an angiopoietin-like glycoprotein, in MCD and have linked it to the development of clinical and pathologic features. This was confirmed by measuring increased serum and urine levels of ANGPTL4 protein, particularly a positively charged form with high isoelectric point (pI) and glomerular localization, in patients with MCD. In their carefully planned experiments using transgenic rat models (aP2-ANGPTL4 and NPHS2 (podocin)-ANGPTL4), Chugh et al demonstrated elevated levels of neutral and cationic high pI ANGPTL4 primarily secreted by podocytes preceding the actual foot process fusion. This molecule diffuses through the glomerular basement membrane (GBM) and binds to its protein, neutralizing the anionic charges. They have also elegantly shown the localization of high pI ANGPTL4 within the GBM and under the foot processes, employing immunogold ultrastructural technique. This GBM binding was then correlated functionally with the onset of proteinuria. However, because of the weak relationship with the reduced anionic charge to the magnitude of proteinuria, they postulate that both charge-dependent and charge-independent mechanisms may occur with the GBM binding of ANGPTL4.

Chugh et al have carefully woven their fascinating story further in demonstrating that the abnormal ANGPTL4 is inadequately sialylated, gaining interaction with the negatively charged heparan sulfate glycosaminoglycan of the normal GBM. This abnormal protein was subsequently amenable for sialylation with N-acetyl-D-mannosamine (ManNAc), which resulted in substantial decline in proteinuria in both in vitro and in vivo experiments. Based on their results, they propose a novel biochemical target and have opened new avenues of investigation in modifying the approach towards management of MCD. The potential use of ManNAc as a sialylation-based therapeutic agent to supplement steroid therapy in children is especially appealing because of its ability to decrease proteinuria while minimizing prolonged steroid therapy. As the authors aptly point out, attempts to extrapolate these results and bring it to the bedside are limited by several unanswered questions. These include the disparity in the temporal onset of massive proteinuria in humans, additional factors that may facilitate high pI ANGPTL4 binding to GBM, and lastly, possible triggers that up-regulation podocyte ANGPTL4 expression in MCD.

Surya Seshan, MD
Professor of Pathology, Weill Cornell Medical Center

To view the entire article, please visit AJKD.