Clinicopathological characteristics and pedigree analysis of patients with coexisting Alport syndrome and immunoglobulin A nephropathy

Alport syndrome (AS) and immunoglobulin A nephropathy (IgAN) are both disorders associated with haematuria and renal impairment. Distinguishing IgAN from AS based on the clinicopathological features is difficult in some cases. Growing evidence indicates that pathogenic COL4A3–COL4A5 variants are common genetic abnormalities underlying both phenotypes. Notably, the coexistence of histological features characteristic of both AS and IgAN is not uncommon. We compared 11 patients with concurrent AS and IgAN with patients with AS alone and IgAN alone, who were individually matched by sex and age at renal biopsy. Galactose-deficient immunoglobulin A1 (Gd-IgA1) immunostaining of paraffin-embedded biopsy sections was performed for the patients with concurrent AS and IgAN. Three clinical pedigrees were constructed based on clinical manifestations, family histories, and genetic sequencing data. Clinicopathological characteristics were comparable between patients with concurrent AS and IgAN and those with AS or IgAN alone, except for a few specific parameters. Patients with concurrent AS and IgAN exhibited greater renal interstitial foam cell infiltration and lower serum IgA levels than those with IgAN alone. The KM55 antibody nonspecifically recognised IgA-related immune complexes involved in the pathogenicity of Gd-IgA1 in patients with concurrent AS and IgAN. Individual and familial co-occurrence of AS and IgAN was observed in three pedigrees harbouring COL4A3 / COL4A4 variants, including likely pathogenic variants and variants of uncertain significance. Conventional systemic glucocorticoids demonstrated favourable therapeutic efficacy in reducing proteinuria in two patients with concurrent AS and IgAN. One patient with concurrent AS and IgAN received sequential therapy with conventional systemic glucocorticoids, rituximab, and targeted ileal-release budesonide. Oedema and striae distensae occurred during both the systemic glucocorticoids and budesonide treatment phases, and the patient attained partial remission after receiving rituximab. Greater attention should be paid to the co-occurrence of AS and IgAN to avoid underdiagnosis or misdiagnosis. The role of type IV collagen variants accompanying glomerular basement membrane lesions in IgAN pathogenesis remains unclear and warrants further investigation. Utilising supportive care in combination with steroid and targeted therapies represents a potentially effective treatment strategy for patients with concurrent AS and IgAN. Nevertheless, treatment decisions should be individualised.