Collagen IV and Podocyte-Related Gene Variants in Patients with Concurrent IgA Nephropathy and Thin Basement Membrane Nephropathy

Abstract

Introduction: IgA nephropathy is the most common primary glomerulonephritis among adults in clinic. Thin basement membrane nephropathy is often underestimated or even omitted if it coincides with IgA nephropathy. Therefore, it is necessary to study the epidemiological, clinical, and molecular characteristics of the concurrence of this entity.

Methods: Eight patients with concurrent IgA nephropathy and thin basement membrane nephropathy (IgA-T) were retrospectively analyzed based on their clinicopathological characteristics. Genetic analysis was performed using whole-exome sequencing and Sanger's sequencing. Data of the patients with IgA nephropathy and normal basement membrane (IgA-N) and variants in the local in-house database were used as controls. All candidate variants were assessed in silico.

Results: The clinical manifestations of patients with IgA-T were hematuria, proteinuria, and renal insufficiency. Histopathological analysis showed mild mesangial hyperplasia, focal segmental glomerulosclerosis, podocyte activation, and foot process fusion. Crescent was rarely seen. COL4A and/or podocyte cytoskeleton and mitochondria-related gene variants were detected in seven IgA-T patients. Three patients exhibited pathogenic variants of COL4A, including a new variant. All IgA-T and one IgA-N patient possessed ITGB4 and/or PLEC variants, but there was no corresponding genotype-phenotype relationship. Six patients possessed other podocyte cytoskeleton and mitochondria-related gene variants such as NPHS2, SRGAP1, MYO1E, MYO1C, WT1, and COQ9, which were first reported in patients with IgA-T and were not in controls. Altogether, there were no significant differences in the degrees of proteinuria, serum creatinine, and eGFR during the follow-up period of 5-10 years, but there was a significant difference in the degree of proteinuria between IgA-T patients with podocyte-related gene variants and IgA-N patients. In the IgA-T group, patients with podocyte-related gene variants seemed predisposed to progress than patients without those variants, with higher proteinuria and serum creatinine and reduced eGFR.

Conclusion: Concurrent thin basement membrane nephropathy and/or heterozygous COL4A gene pathogenic variants do not necessarily predict the short-term progress of sporadic IgA nephropathy in adults. Predisposition factors for this disease progression should be considered for detecting the variants of COL4A and podocyte cytoskeleton and mitochondria-related genes simultaneously, which also manifests the complexity and heterogeneity of IgA nephropathy with concurrent thin basement membrane nephropathy.

Keywords: Collagen IV; Cytoskeleton; IgA; Podocyte; Thin basement membrane nephropathy.