IgG4-Related Kidney Disease and IgG4-Related Retroperitoneal Fibrosis: An Update on Diagnosis and Treatment

Renal involvement of IgG4-related disease (IgG4-RD), collectively termed IgG4-related kidney disease (IgG4-RKD), most commonly manifests as tubulointerstitial nephritis (TIN) but can also manifest as membranous glomerulonephritis (MGN) and acute interstitial nephritis (AIN) as a histologic subtype of IgG4-related TIN (IgG4-TIN). IgG4-related retroperitoneal fibrosis (IgG4-RPF) can cause obstructive kidney disease with or without active parenchymal IgG4-RKD. IgG4-RD is a clinicopathological diagnosis, requiring correlation of clinical, laboratory, radiological, and histological findings to identify features of IgG4-RD and rule out mimickers. Histopathologic features of IgG4-RD in tissue include a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, typically accompanied by so-called "storiform" fibrosis. Important mimics of IgG4-RKD include infection, malignancy, antineutrophil cytoplasmic autoantibody (ANCA)-associated disease, idiopathic multicentric Castleman disease, Rosai-Dorfman-Destombes disease and Sjögren Disease (SjD). Mimickers of IgG4-RPF include lymphoma, Erdheim-Chester disease, and idiopathic RPF. IgG4-RKD and IgG4-RPF are responsive to the systemic therapies used for IgG4-RD in general. Corticosteroids are the traditional first line therapy; however, B cell-targeted therapies, including rituximab, inebilizumab, and obexelimab are more potent and less toxic than steroids. Further trials are currently being conducted on newer medications that target signaling pathways and immune cells involved in the pathogenesis of IgG4-RD. Early recognition and treatment are critical to prevent irreversible organ damage. This review summarizes the current understanding of the pathogenesis, clinical spectrum, diagnostic approach, and management strategies for IgG4-RD, IgG4-RKD, and IgG4-RPF.