Nephropathy in IgG4-related Systemic Disease

Abstract

Lymphoplasmacytic sclerosing pancreatitis ("autoimmune" pancreatitis) is the best-known manifestation of an unusual corticosteroid-sensitive systemic fibrosclerotic disease that is associated with high plasma immunoglobulin G4 (IgG4) and tissue infiltration with IgG4-secreting plasma cells. Pancreatic and biliary manifestations of this condition are well-reported, but reports of other systemic involvement are few. We report here a case of initially unrecognized autoimmune pancreatitis followed 5 years later by a focal sclerosing lymphoplasmacytic tubulointerstitial nephritis and concurrent membranous nephropathy. The patient presented with hypertension, a raised serum creatinine, proteinuria, elevated serum IgG4, and eosinophilia. Immunolabeling of renal tissue showed numerous IgG4 positive plasma cells with peritubular and glomerular subepithelial IgG4 deposition. On steroid therapy serum IgG4 levels normalized, the eosinophilia resolved, and there was improvement in symptomatic wheeze, dry eyes, serum creatinine, and liver function tests. This case highlights a distinctive and potentially treatable form of interstitial nephritis manifesting from a systemic immune disorder, and provides circumstantial evidence to support the notion that dysregulated IgG4 can precipitate the development of a form of membranous nephropathy.

An abundance of IgG4+ plasma cells is not specific for IgG4-related tubulointerstitial nephritis

“…In IgG4-TIN, renal biopsy is usually contemplated to evaluate an asymptomatic rise in serum creatinine, proteinuria, renal enlargement, and/or focal renal parenchymal lesions. [6][7][8][9][10][11] As with other forms of IgG4-SD, IgG4-TIN is often accompanied by serological findings consistent with an immune complex disorder, including marked elevation of serum IgG, particularly IgG4, 6,[8][9][10][11] the presence of ANA and other autoantibodies, 6,8,11 and hypocomplementemia. 6,8,10,11 When examined by enhanced CT, the renal parenchymal lesions are typically focal or multifocal and expansile, sometimes mimicking cancer.…”

“…In published reports, most cases of IgG4-TIN accompany other lesions of IgG4-SD [5][6][7][8][9][10][11] (Table 1), particularly those in pancreas, hepatobiliary system, lymph nodes, and/or salivary glands. This has been our experience as well, but in all of the IgG4-TIN reference biopsy samples reviewed in this study, IgG4-SD first came to light as a result of the kidney biopsy.…”

“…6,8,10,11 When examined by enhanced CT, the renal parenchymal lesions are typically focal or multifocal and expansile, sometimes mimicking cancer. 5,6 Histologically, IgG4-TIN is characterized by the presence of IgG4 þ PC-rich lymphoplasmacytic infiltrates, obliterative, expansile sclerosis, 6,7,8 and often by peritubular and/or interstitial immune deposits, including IgG4 deposits. 6 Numerous IgG4 þ PC are virtually always present in the infiltrates of IgG4-TIN, 6 as they are in other IgG4-SD lesions, 2,3 but the criteria and specificity of this finding for IgG4-TIN has not been examined.…”

“…[2][3][4][5] The presence of numerous IgG4-positive plasma cells (IgG4 þ PC) in the inflammatory infiltrate is a histological hallmark of IgG4-SD. [1][2][3][4] Case reports consistently emphasize this finding in IgG4-TIN, 6,7 but there have been no detailed studies of plasma cell IgG isotype-labeling in other settings of interstitial nephritis to determine the specificity of this finding. Furthermore, little is known about whether or to what extent unrecognized variants of IgG4-TIN might account for some cases of idiopathic interstitial nephritis seen in a renal biopsy service.…”

IgG4-Associated Tubulointerstitial Nephritis: Two Case Reports and a Literature Review

“…Additionally, IgG4-related TIN may have concurrent glomerular diseases. Membranous nephropathy (MN), another IgG4-dominant disease (10,(23)(24)(25)) is most commonly observed in patients with IgG4-related TIN. In Case 1, the patient's daughter had been diagnosed with idiopathic membranous nephropathy.…”