How to Cure Autoimmune GN and Podocytopathies

Autoimmune GN and podocytopathies are immune-mediated kidney diseases with different clinical presentations and histotypes. Traditionally, proteinuria and histotypes are used for prognosis prediction and hence define intensity of immunotherapy. Renin-angiotensin system and sodium-glucose transporter 2 inhibitors are considered as "supportive care," and control of proteinuria seems a primary treatment goal without reasoning the cause of proteinuria. We propose to refine these concepts based on the shared pathophysiology of these diseases: ( 1 ) Disease acuity as the primary determinant of therapy. Rapidly progressive GN, relapsing GN, and chronic GN require different priorities. Rapidly progressive GN depends on the level and nephrotoxicity of the involved antibodies and complement activation and may require immediate complement inhibition, and antibody removal from the circulation before a B-cell-targeting therapy is initiated to control de novo autoantibody production. ( 2 ) Relapsing or chronically active disease need long-term control of immunologic activity with a B-cell-targeting monotherapy, in case of single autoreactive lymphocyte clones, for example, in antineutrophil cytoplasmic antibodies vasculitis or antinephrin/anti-M-type phospholipase A2 receptor-nephrotic syndrome. By contrast, diseases with numerous autoantigens/clones, i.e ., lupus nephritis or antiphospholipid syndrome should benefit from combination therapies, similar to kidney transplantation. ( 3 ) All forms of GN and most relapsing podocytopathies lead to glomerulosclerosis and nephron loss, i.e ., CKD. This implies CKD management following the latest Kidney Disease Improving Global Outcomes CKD risk matrix and treatment recommendations. In relapsing GN/podocytopathies, CKD care is the second treatment priority; in chronic GNs, it becomes the first treatment priority in contrast to "supportive care." In relapsing and chronic disease, proteinuria levels may represent activity, CKD, or both; hence, proteinuria alone does not inform treatment choices. This review aims to overcome existing hurdles by redefining treatment priorities in GNs and podocytopathies based on the underlying autoimmune pathomechanisms to define immunotherapy and by implementing CKD care for conceptual clarity and better long-term outcomes.