Autoimmune Podocytopathies: A Novel Sub-Group of Diseases from Childhood Idiopathic Nephrotic Syndrome
Authors: Qing Ye, Anqun Chen, En Yin Lai, Jianhua Mao
Journal: Journal of the American Society of Nephrology (2022)

A recent study reported that autoantibodies targeting Nephrin were detected in the sera of adults and children with minimal change disease.1 Researchers believe that this autoantibody is related to the outcome of the disease, and the research results have provided strong support for the autoimmune etiology of nephrotic syndrome. We think this is significant and interesting research. At present, the etiology and pathogenesis of idiopathic nephrotic syndrome (INS) are still unclear, and podocyte dysfunction/decrease in number is its main pathologic feature. According to the classic view, the pathogenesis of INS is mainly autoimmune imbalance, which is mainly manifested by abnormal T lymphocyte function and the production of some glomerular permissibility factors. Nevertheless, these mechanisms are not enough to explain the pathogenesis of impaired glomerular filtration barrier and the nephrotic range proteinuria. In recent years, evidence of abnormal B lymphocyte function causing INS has been accumulating. The most robust evidence came from the fact that Rituximab and Ofatumumab targeting B cells would be effective in patients with steroid-sensitive nephrotic syndrome or steroid-resistant nephrotic syndrome with minimal change disease or focal segmental glomerular sclerosis in pathology. We recently added evidence for this theory, finding mononuclear cells in peripheral blood of patients with nephrotic syndrome and found apparent B cell disorder in these patients.2 B cells mainly function through the antibodies secreted after they are transformed into plasma cells. Therefore, since 2017, our team began screening and identifying antipodocyte autoantibodies in the serum of children with INS. At first, we detected an autoantibody against podocyte Annexin A2 protein in the serum, and the detection rate was 17.8%.3 Further mouse models proved that it could cause proteinuria in vivo. Mechanism research shows that Annexin A2 antibody can promote the phosphorylation of Annexin A2 Tyr24 and act on the Rho/ROCK signaling pathway to cause the rearrangement of podocyte skeleton, thus causing podocyte damage. After that, we comprehensively studied the podocyte autoantibody spectrum in the serum of patients with INS by two-dimensional electrophoresis and mass spectrometry. Fortunately, we finally screened out 14 target antigens of autoantibodies, including eight target antigens of podocyte autoantibodies specific to children with nephrotic syndrome and six target antigens of highly expressed podocyte autoantibodies in children with nephrotic syndrome.4 Clinical research finally determined that there are seven kinds of podocyte autoantibodies that are most related to the onset of nephrotic syndrome, and approximately 66% of children with nephrotic syndrome have these podocytes autoantibodies.4 Further analysis shows a positive correlation between the urine protein content of children with nephrotic syndrome and the titer of these podocyte autoantibodies in the same period. When urine protein turns negative, podocyte autoantibodies also decrease in patients effectively treated with steroid and/or immunosuppressants. Our study and the opinion of Watts et al.1 both suggest the existence of autoimmune podocytopathies. Based on the above series of findings, we put forward the concept of Autoimmune podocytopathies.4 We do believe it is a novel subgroup of diseases of childhood nephrotic syndrome. These patients show a high level of podocyte autoantibodies in serum. However, unlike idiopathic membranous nephropathy in adults, no apparent immune complex deposits can be observed in the glomerulus. Disclosures A. Chen reports scientific advisor or membership as and ISN-KI editorial board intern. All remaining authors have nothing to disclose. Funding This study was supported by the key project of provincial ministry co-construction, Health science and Technology project plan of Zhejiang Province (WKJ-ZJ-2128), Key Laboratory of Women's Reproductive Health Research of Zhejiang Province (grant: ZDFY2020-RH-0006), the National Natural Science Foundation of China (grant: U20A20351) and Key Research and Development Plan of Zhejiang Province (grant: 2021C03079).