Significance Statement: Thinned glomerular basement membrane (tGBM) lesions, usually associated with COL4A3 / COL4A4 / COL4A5 gene variants, are not uncommon in sporadic IgA nephropathy (IgAN), but the underlying mechanism is unclear. Exome sequence analysis of 122 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) identified diagnostic COL4A3 / COL4A4 / COL4A5 gene variants in 38 patients (31.1%), with 37 different variants. Patients with IgAN-tGBM who did not have diagnostic variants showed more characteristics of IgAN, whereas those who did have diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury. These findings suggest different mechanisms in patients with IgAN-tGBM with and without diagnostic variants in these collagen genes. The research indicated the importance of COL4A3 / COL4A4 / COL4A5 variant detection in patients with IgAN-tGBM. Background: Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen—built of α 3, α 4, and α 5 chains, encoded by COL4A3 / COL4A4 / COL4A5 genes—is the major component of glomerular basement membrane (GBM). In recent years, mutations in type IV collagen–encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3 / COL4A4 / COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear. Methods: We compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3 / COL4A4 / COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA. Results: The patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3 / COL4A4 / COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes. Conclusions: COL4A3 / COL4A4 / COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions.

Renal tubular epithelial cells (TECs) can initiate an adaptive response to completely recover from mild acute kidney injury (AKI), whereas severe injury often leads to persistence of maladaptive repair and progression to kidney fibrosis. Through profiling of active DNA regulatory elements by ATAC-seq, we reveal widespread, dynamic changes in the chromatin accessibility of TECs after ischemia–reperfusion injury. We show that injury-specific domains of regulatory chromatin become accessible prior to gene activation, creating poised chromatin states to activate the consequent gene expression program and injury response. We further identify RXRα as a key transcription factor in promoting adaptive repair. Activation of RXRα by bexarotene, an FDA-approved RXRα agonist, restores the chromatin state and gene expression program to protect TECs against severe kidney injury. Together, our findings elucidate a chromatin-mediated mechanism underlying differential responses of TECs to varying injuries and identify RXRα as a therapeutic target of acute kidney injury.

Hydroxychloroquine (HCQ), a well-known immunomodulator, has recently been found to be a promising and safe anti-proteinuric agent for treating IgA nephropathy (IgAN). We aimed to compare the efficacy and safety of HCQ and corticosteroid treatment in patients with IgAN. This is a case-control study. Ninety-two patients with IgAN who received HCQ in addition to routine renin-angiotensin-aldosterone system inhibitors (RAASi) therapy were included. Ninety-two matched historical controls who received corticosteroids were selected by propensity score matching. The clinical data over 6 months were compared. Baseline proteinuria levels were comparable between the HCQ and corticosteroid groups (1.7 [1.2, 2.3] vs. 1.8 [1.3, 2.5] g/d, p = 0.96). The percentage reduction in proteinuria at 6 months was smaller in the HCQ group than in the corticosteroid group (− 48.5% [− 62.6, − 31.4] vs. -62.9% [− 81.1, − 34.9], p = 0.006). The time averaged proteinuria within the 6 months of observation was comparable for the HCQ and corticosteroid groups (1.1 [0.8, 1.5] vs. 1.1 [0.5, 1.8] g/d, p = 0.48). The cumulative frequency of patients with a 50% reduction in proteinuria during the study was also comparable between the two groups (52.2% vs. 62.0%, p = 0.25). However, six of the 92 (6.5%) patients suffered from severe adverse events (SAEs) in the corticosteroid group, while no SAEs were observed in the HCQ group (6.5% vs. 0%, p = 0.03). The antiproteinuric effect of HCQ might be slightly inferior to that of corticosteroids over 6 months in patients with IgAN who were deemed to be candidates for HCQ and not corticosteroids treatment. However, HCQ treatment was safer than corticosteroid treatment.