Thickening of Glomerular Basement Membrane Is Associated with Long-Term Prognosis in Patients with IgA Nephropathy

Key Points IgA nephropathy (IgAN) patients with thickening of glomerular basement membrane had a higher risk of progressing to ESKD independent of international risk-prediction tool in IgAN. Thickening of glomerular basement membrane in IgAN patients was positively correlated with mesangial hyperplasia. Background Glomerular basement membrane (GBM) ultrastructural abnormalities are common in IgA nephropathy (IgAN); however, few studies have focused on clinical significance and prognostic value of GBM ultrastructural changes in IgAN patients. Methods A retrospective longitudinal cohort with 1006 biopsy-proven primary IgAN patients was collated. GBM thickness and texture of each case were assessed under transmission electron microscope. The primary end point was ESKD. Cox proportional hazards regression model was built to determine risk factors. Immunofluorescent staining was performed on patient kidney biopsy samples to validate the correlation between mesangial proliferation and abnormal GBM thickness. Twenty single nucleotide polymorphisms independently associated with IgAN in previous genome-wide association studies were genotyped in 617 patients, and whole exome sequencing was performed in 56 patients to investigate potential variants underlying GBM ultrastructural changes. Results Of 1006 patients, 52% were female, and the mean age was 37.3±12.3 years old. Among all patients, 80 (8%) had abnormal thickness of GBM including 29 (3%) thickening of GBM and 51 (5%) thinning of GBM. Abnormal GBM texture was found in 25 (2%) patients. During a mean follow-up time of 46.4 months, 91 (9%) patients progressed to ESKD. By Cox regression analyses, we demonstrated that thickening of GBM at biopsy increased the risk of ESKD before (hazard ratio [HR], 3.64; 95% confidence interval [CI], 1.47 to 7.55) and after adjusted by Oxford Scoring (HR, 2.92; 95% CI, 1.12 to 6.48) or international risk-prediction tool in IgAN (HR, 3.51; 95% CI, 1.41 to 7.29). Relevance analyses showed that GBM thickening was positively correlated with mesangial hyperplasia and proliferation, but not genetic variants in IgAN patients. Conclusions Thickening of GBM correlated with mesangial hyperplasia and proliferation was associated with ESKD in IgAN patients, demonstrating the potential of incorporating ultrastructural changes into the pathologic evaluation system of IgAN.