Coexistence of Alport syndrome with other renal pathologies has been previously reported in the literature, including atypical hemolytic uremic syndrome, IgA nephropathy, and autosomal dominant polycystic kidney disease [4,5,6,7,8]. These cases suggest that Alport syndrome, while primarily a hereditary basement membrane disorder, may occasionally occur alongside other glomerular or tubular diseases, complicating both diagnosis and management. Our case describes an unusual clinical scenario where X-linked Alport syndrome coexists with biopsy-proven IC-MPGN.

Alport syndrome is a genetic disorder caused by mutations in genes encoding the α3, α4, or α5 chains of type IV collagen. It leads to structural abnormalities in the glomerular basement membrane (GBM) [9]. It typically manifests with hematuria, proteinuria, sensorineural hearing loss, and progressive renal failure [9]. The COL4A5 c.1871G > A (p.Gly624Asp) variant identified in our patient is one of the most common pathogenic variants in Europe. This mutation is considered hypomorphic, associated with a milder Alport phenotype, slower progression to ESRD, and often milder extrarenal features [10]. This aligns with the relatively late-onset renal failure in our patient, and the absence of severe ocular involvement. Importantly, genetic testing in the patient’s daughter and nephew revealed the same COL4A5 c.1871G > A mutation in heterozygous form, supporting X-linked inheritance. However, the patient’s father and sister, both with kidney failure, were not genetically tested, which limits the strength of familial segregation analysis. Nevertheless, the identification of the same mutation in two younger family members adds weight to the diagnosis of X-linked Alport syndrome in this case.

By contrast, IC-MPGN is an immune complex-mediated disease characterized histologically by mesangial hypercellularity, GBM duplication, mesangial interposition, endocapillary proliferation and immunofluorescence positivity for immunoglobulins and complement factors [3]. Distinguishing true immune complex GN from nonspecific immune deposits seen in hereditary nephropathies remains a diagnostic challenge. Nasr et al. reported Alport patients whose renal biopsies revealed immune complex-like staining patterns; however, none fulfilled histologic criteria for active GN [11]. The authors proposed that such deposits may represent nonspecific trapping of circulating immune reactants within the thickened and structurally abnormal glomerular capillary walls, especially in advanced Alport pathology [11]. However, in our case, renal biopsy showed typical features of MPGN and immune complex deposition along with active urinary abnormalities and progressive proteinuria. These findings support a true immune complex–mediated process rather than passive deposition. Negative DNAJB9 staining helped exclude fibrillary GN.

A previous report by Ding et al. described the coexistence of C3 glomerulopathy and a COL4A5 mutation, supporting the notion that structural defects in the GBM may predispose patients to secondary immune-mediated injury or reveal underlying complement dysregulation [4]. Although true overlap between Alport syndrome and immune complex GN remains rare, such cases raise important questions about whether basement membrane abnormalities facilitate immune complex deposition, or if these conditions occur coincidentally in genetically susceptible individuals. In our case, therapeutic management was further complicated by steroid-induced proximal myopathy, which led to discontinuation of immunosuppressive treatment, emphasizing the clinical challenges associated with dual glomerular pathologies and treatment-limiting comorbidities.

This case underscores the importance of renal biopsy, even when a hereditary nephropathy is suspected, especially if the disease course is atypical or progressive. It also supports the use of genetic testing in patients with a positive family history or extrarenal features. Recognizing dual pathologies is crucial, as they may carry distinct prognostic and therapeutic implications. Accurate diagnosis requires integration of clinical, histological, immunofluorescence, and genetic findings, all of which are vital to guide personalized patient management.