Inborn errors of immunity (IEI), formerly termed primary immunodeficiencies, are increasingly recognized as disorders of immune dysregulation rather than infection susceptibility alone. With over 500 validated genes in the 2024 International Union of Immunological Societies (IUIS) classification and approximately one-quarter of patients presenting without infection, autoimmunity, autoinflammation, lymphoproliferation, and malignancy are now core features. The kidney is affected across at least 22 IEI categories, yet renal involvement remains under-recognized. This review proposes a mechanistic framework for IEI-associated kidney disease, encompassing: complement dysregulation (C3 glomerulopathy, atypical hemolytic uremic syndrome from CFH/CFI/C3 variants); immune complex–mediated and monogenic lupus nephritis (C1q, C2, C4, DNASE1L3, and TREX1 defects); autoinflammatory and type I interferonopathy–driven nephropathy; infection-related glomerulonephritis (common variable immunodeficiency [CVID], chronic granulomatous disease); lymphoproliferative and immune-dysregulation syndromes causing interstitial nephritis (ALPS, CTLA-4 and LRBA deficiency); and syndromic IEI with intrinsic structural disease. We outline a stepwise diagnostic approach integrating clinical red flags, complement and immune profiling, kidney biopsy with immunofluorescence and electron microscopy, and genetic testing, emphasizing that genetic diagnosis should precede immunosuppression. The therapeutic landscape is shifting from empirical immunosuppression toward precision medicine, including complement inhibitors (iptacopan, pegcetacoplan, Food and Drug Administration–approved for C3 glomerulopathy in 2025), JAK inhibitors for interferonopathies, leniolisib for activated PI3Kδ syndrome, CTLA4-Ig agents, and curative hematopoietic stem cell transplantation and emerging gene therapy. An illustrative case from Europe’s largest kidney transplant center illustrates a girl with Schimke immuno-osseous dysplasia (SMARCAL1 mutation) presenting with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis who underwent kidney transplantation following bone marrow transplant. Recognizing IEI in unexplained nephropathy, combining biopsy with complement and genetic profiling, and early nephrology–immunology collaboration are key to improving renal outcomes and enabling potentially curative therapy.
