Anti-UMOD (aa 351-380) polyclonal antibody

Mutations of the UMOD gene, which encodes the uromodulin protein, are associated with tubulointerstitial nephritis and hyperuricemia. UMOD mutations impair uromodulin folding, resulting in its retention within the endoplasmic reticulum (ER) of renal tubular cells. The aim of this study was to investigate whether mutant uromodulin accumulation in epithelial tubular cells is associated with ER stress. We characterized tubular expression of uromodulin and the ER stress surrogate marker Grp78 by immunohistochemistry in kidney biopsy specimens from 7 patients with UMOD-related kidney disease. We compared this population with 5 patients with familial tubulointerstitial nephritis not related to UMOD mutation. All biopsy specimens from patients carrying the UMOD mutation showed strong heterogeneous cytoplasmic expression of uromodulin in cells of the thick ascending limb of the loop of Henle. In the same tubules, Grp78 was highly expressed in a perinuclear pattern. In contrast, in all kidney biopsy specimens from patients without UMOD mutations, uromodulin staining showed normal apical expression and Grp78 expression was not increased. Our observations support the hypothesis that ER accumulation of mutant uromodulin may cause ER stress, providing a potential mechanism for the progression of UMOD-related kidney disease. Am J Kidney Dis. 59(1):117-121. (C) 2011 by the National Kidney Foundation, Inc.

Introduction: Focal segmental glomerulosclerosis (FSGS) is a histopathologically defined kidney lesion. FSGS can be observed with various underlying causes, including highly penetrant monogenic renal disease. We recently identified pathogenic variants of UMOD, a gene encoding the tubular protein uromodulin, in 8 families with suspected glomerular disease. Methods: To validate pathogenic variants of UMOD, we reviewed the clinical and pathology reports of members of 8 families identified to have variants of UMOD. Clinical, laboratory, and pathologic data were collected, and genetic confirmation for UMOD was performed by Sanger sequencing. Results: Biopsy-proven cases of FSGS were verified in 21% (7 of 34) of patients with UMOD variants. The UMOD variants seen in 7 families were mutations previously reported in autosomal dominant tubulointerstitial kidney disease-uromodulin (ADTKD-UMOD). For one family with 3 generations affected, we identified p.R79G in a noncanonical transcript variant of UMOD co-segregating with disease. Consistent with ADTKD, most patients in our study presented with autosomal dominant inheritance, subnephrotic range proteinuria, minimal hematuria, and renal impairment. Kidney biopsies showed histologic features of glomerular injury consistent with secondary FSGS, including focal sclerosis and partial podocyte foot process effacement. Conclusion: Our study demonstrates that with the use of standard clinical testing and kidney biopsy, clinicians were unable to make the diagnosis of ADTKD-UMOD; patients were often labeled with a clinical diagnosis of FSGS. We show that genetic testing can establish the diagnosis of ADTKD-UMOD with secondary FSGS. Genetic testing in individuals with FSGS histology should not be limited to genes that directly impair podocyte function.