Summary: Cell wall polysaccharide biosynthesis enzymes play important roles in plant growth, development and stress responses. The functions of cell wall polysaccharide synthesis enzymes in plant growth and development have been well studied. In contrast, their roles in plant responses to environmental stress are poorly understood. Previous studies have demonstrated that the rice cell wall cellulose synthase‐like D4 protein (OsCSLD4) is involved in cell wall polysaccharide synthesis and is important for rice growth and development. This study demonstrated that the OsCSLD4 function‐disrupted mutant nd1 was sensitive to salt stress, but insensitive to abscisic acid (ABA). The expression of some ABA synthesis and response genes was repressed in nd1 under both normal and salt stress conditions. Exogenous ABA can restore nd1‐impaired salt stress tolerance. Moreover, overexpression of OsCSLD4 can enhance rice ABA synthesis gene expression, increase ABA content and improve rice salt tolerance, thus implying that OsCSLD4‐regulated rice salt stress tolerance is mediated by ABA synthesis. Additionally, nd1 decreased rice tolerance to osmotic stress, but not ion toxic tolerance. The results from the transcriptome analysis showed that more osmotic stress‐responsive genes were impaired in nd1 than salt stress‐responsive genes, thus indicating that OsCSLD4 is involved in rice salt stress response through an ABA‐induced osmotic response pathway. Intriguingly, the disruption of OsCSLD4 function decreased grain width and weight, while overexpression of OsCSLD4 increased grain width and weight. Taken together, this study demonstrates a novel plant salt stress adaptation mechanism by which crops can coordinate salt stress tolerance and yield.

IgA nephropathy (IgAN) is characterized by infections followed by episodic gross hematuria. Deficiency of mannose-binding lectin (MBL) is associated with recurrent infection in many diseases, but controversy exists regarding the role of MBL in IgAN. Here, we measured MBL2 variants and MBL levels in 749 patients with IgAN and 489 healthy controls. Overall, 5.2% (39 of 749) of patients with IgAN had MBL deficiency (MBL levels <100 ng/ml), among whom LYPB/LYPB and LXPA/LYPB were the predominant MBL2 haplotypes (82%; 32 of 39). We found a nonlinear association between MBL levels and renal outcome in IgAN. Patients with IgAN and MBL deficiency had a higher incidence of prodromic infections and gross hematuria than those with sufficient MBL levels (100–3540 ng/ml). Moreover, MBL deficiency independently associated with poor renal outcome in IgAN after multiple adjustments (hazard ratio, 5.18; 95% confidence interval, 2.50 to 10.72; P3540 ng/ml) had more severe proteinuria and a higher proportion of crescents, although the association with IgAN progression did not reach statistical significance after adjustments. In conclusion, MBL deficiency and MBL excess may both have deleterious effects on IgAN progression, which suggests that MBL contributes to IgAN pathogenesis through multiple mechanisms.

A recent genome–wide association study of IgA nephropathy (IgAN) identified 1q32, which contains multiple complement regulatory genes, including the complement factor H (CFH) gene and the complement factor H–related (CFHRs) genes, as an IgAN susceptibility locus. Abnormal complement activation caused by a mutation in CFHR5 was shown to cause CFHR5 nephropathy, which shares many characteristics with IgAN. To explore the genetic effect of variants in CFHR5 on IgAN susceptibility, we recruited 500 patients with IgAN and 576 healthy controls for genetic analysis. We sequenced all exons and their intronic flanking regions as well as the untranslated regions of CFHR5 and compared the frequencies of identified variants using the sequence kernel association test. We identified 32 variants in CFHR5, including 28 rare and four common variants. The distribution of rare variants in CFHR5 in patients with IgAN differed significantly from that in controls (P=0.002). Among the rare variants, in silico programs predicted nine as potential functional variants, which we then assessed in functional assays. Compared with wild-type CFHR5, three recombinant CFHR5 proteins, CFHR5-M (c.508G>A/p.Val170Met), CFHR5-S (c.533A>G/p.Asn178Ser), and CFHR5-D (c.822A>T/p.Glu274Asp), showed significantly higher C3b binding capacity (CFHR5-M: 109.67%±3.54%; P=0.02; CFHR5-S: 174.27%±9.78%; P<0.001; CFHR5-D: 127.25%±1.75%; PA/p.Leu259Termination) showed less C3b binding (56.89%±0.57%; P<0.001). Our study found that rare variants in CFHR5 may contribute to the genetic susceptibility to IgAN, which suggests that CFHR5 is an IgAN susceptibility gene.

Background and objectives: Proteinuria is an independent predictor for IgA nephropathy (IgAN) progression. Urine albumin-to-creatinine ratio (ACR), protein-to-creatinine ratio, and 24-hour urine protein excretion (UPE) are widely used for proteinuria evaluation in clinical practice. Here, we evaluated the association of these measurements with clinical and histologic findings of IgAN and explored which was the best predictor of IgAN prognosis. Design, setting, participants, & measurements: Patients with IgAN were followed up for ≥12 months, were diagnosed between 2003 and 2012, and had urine samples available (438 patients). Spot urine ACR, protein-to-creatinine ratio, and 24-hour UPE at the time of renal biopsy were measured on a Hitachi Automatic Biochemical Analyzer 7180 (Hitachi, Yokohama, Japan). Results: In our patients, ACR, protein-to-creatinine ratio, and 24-hour UPE were highly correlated (correlation coefficients: 0.71–0.87). They showed good relationships with acknowledged markers reflecting IgAN severity, including eGFR, hypertension, and the biopsy parameter (Oxford severity of tubular atrophy/interstitial fibrosis parameter). However, only ACR presented with positive association with the Oxford segmental glomerulosclerosis/adhesion parameter and extracapillary proliferation lesions. The follow-up time was 37.0 (22.0–58.0) months, with the last follow-up on April 18, 2014. In total, 124 patients reached the composite end point (30% eGFR decline, ESRD, or death). In univariate survival analysis, ACR consistently had better performance than protein-to-creatinine ratio and 24-hour UPE as represented by higher area under the curve using time–dependent survival analysis. When adjusted for well known risk factors for IgAN progression, ACR was most significantly associated with the composite end point (hazard ratio, 1.56 per 1-SD change of standard normalized square root–transformed ACR; 95% confidence interval, 1.29 to 1.89; P<0.001). Compared with protein-to-creatinine ratio and 24-hour UPE, addition of ACR to traditional risk factors resulted in more improvement in the predictive ability of IgAN progression (c statistic: ACR=0.70; protein-to-creatinine ratio =0.68; 24-hour UPE =0.69; Akaike information criterion: ACR=1217.85; protein-to-creatinine ratio =1229.28; 24-hour UPE =1234.96; P<0.001). Conclusions: In IgAN, ACR, protein-to-creatinine ratio, and 24-hour UPE had comparable association with severe clinical and histologic findings. Compared with protein-to-creatinine ratio and 24-hour UPE, ACR showed slightly better performance in predicting IgAN progression.

Nivolumab is a fully human monoclonal antibody that inhibits programmed cell death‐1 activation. To assess covariate effects on nivolumab clearance (CL), a population pharmacokinetics model was developed using data from 6,468 patients with colorectal cancer, hepatocellular carcinoma, melanoma, non‐small cell lung cancer, renal cell carcinoma, or small cell lung cancer who received nivolumab as monotherapy or in combination with ipilimumab or chemotherapy across 25 clinical studies. Nivolumab CL was similar across the tumor types examined; CL was higher for ipilimumab 1 mg/kg every 6 weeks (by 17%) and 3 mg/kg every 3 weeks (by 29%) vs. nivolumab monotherapy. Nivolumab CL over time was partially explained by time‐varying covariates. A greater decrease in nivolumab time‐varying CL was associated with increased albumin and body weight and a responder status. Our findings support the observed association between nivolumab CL and disease severity.

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.