Focal segmental glomerulosclerosis (FSGS) is a podocyte disease characterized by segmental sclerosis of the glomeruli[1]. Accounting for approximately 40% of glomerular kidney disease cases in adults[2], FSGS is a leading cause of kidney failure globally[3]. The current view is that FSGS is not as a single disease entity, but rather the final common pathway for a heterogeneous group of disorders with diverse etiologies[4]. To reflect this pathophysiological complexity, the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines adopted a mechanistic classification system that categorizes FSGS into primary (immune-mediated), genetic, secondary/adaptive, and undetermined forms [5]. In particular, the genetic category has rapidly expanded, with mutations in over 60 genes identified to date, revealing unexpected genotypes and broadening the phenotypic spectrum of hereditary FSGS.

UMOD is the most abundant protein in normal urine, formerly known as Tamm-Horsfall glycoprotein, which encodes uromodulin[6]. More than 100 pathogenic mutations in UMOD have been reported[7], typically causing Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD-UMOD)[8]. The classic presentation of ADTKD-UMOD includes an autosomal dominant inheritance pattern, bland urine sediment with minimal proteinuria, hyperuricemia, early-onset gout, and a slow progression to end-stage renal disease typically between the third and seventh decades of life[6, 9, 10]. Its insidious onset and often subtle urinary findings requires a high index of clinical suspicion for the diagnosis of ADTKD-UMOD, and is ultimately confirmed by genetic testing.

Notably, emerging evidence challenges the traditional view of UMOD-associated disease as a purely tubulointerstitial disorder. Recent studies have identified UMOD variants in patients with a histopathological diagnosis of FSGS, a finding that was initially unexpected given the protein's primary tubular origin[1].This suggests that the clinicopathological presentation of UMOD-related nephropathy may be more widespread than previously recognized, and some patients clinically diagnosed with FSGS may have potential UMOD mutations.

In this case, a patient with a renal biopsy confirming FSGS was found through whole-exome sequencing to carry a compound heterozygous mutation in the UMOD gene, emphasizing the diagnostic complexity and expanded the genotypic spectrum of UMOD-related disease. This case highlights the critical role of comprehensive genetic testing in the evaluation of FSGS and contributes to the evolving understanding of the phenotypic manifestations of UMOD mutations.

This article reports a case of UMOD-associated nephropathy mimicking FSGS in a male with a family history of kidney disease, which has the following enlightenments:

The patient had a 4-year history of renal disease that was notable for minimal proteinuria and stable renal function. However, the renal biopsy demonstrated severe glomerular injury. This striking discordance between clinical manifestations and pathological severity affirms the essential role of biopsy in diagnosis.

Besides, this patient had a clear family history and biopsy findings of FSGS; however, genetic testing identified a heterozygous UMOD mutation (c.113A > T; p.Asn38Ile)—a gene typically associated with tubulointerstitial disease. This case challenges the conventional pathological classification, but some investigations have observed similar phenomena. For example, Bleyer et al[11] noted in early family studies that in familial adolescent hyperuricemic nephropathy (FJHN) patients carrying UMOD gene mutations, in addition to typical tubulointerstitial lesions, some members also exhibited focal glomerulosclerosis and global sclerosis in renal pathology. Chun et al[1] investigated eight affected members of families initially believed to have FSGS, but ultimately diagnosed with ADTKD-UMOD. It indicates that UMOD gene may not only be associated with tubulointerstitial disease, but also cause segmental glomerular sclerosis through immune mediation[12], which is consistent with Trudu et al[13]. Nafar et al[14] further suggested that uromodulin might be a biomarker of FSGS. Because the renal pathology in ADTKD-UMOD is typically nonspecific on conventional biopsy, some affected individuals may be misdiagnosed with FSGS[14]. Thus, when ADTKD-UMOD is clinically suspected, uromodulin immunostaining should be performed. If a UMOD variant is subsequently found in a patient diagnosed with FSGS, reclassification as ADTKD-UMOD is appropriate[1].

For this patient's condition, a standard treatment has not been established per current guidelines. Therapies like glucocorticoids and CNIs are considered ineffective and are therefore typically avoided[15]. Due to the patient's immediate fertility needs, management was limited to supportive care. This allowed the avoidance of glucocorticoid and immunosuppressant-related side effects.

This study has a key limitation: we were unable to perform genetic testing on the patient's affected family members. This precluded confirmation of co-segregation of the UMOD variant with the disease phenotype and verification of a shared genetic etiology among all affected relatives.

In summary, this case supports that UMOD mutations can underlie an FSGS histologic phenotype. Early genetic testing in patients with FSGS and a family history is essential to prevent unnecessary immunosuppression and enable personalized treatment.