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Background During the run-in phase of the TESTING study, approximately half of patients with IgA nephropathy (IgAN) were excluded due to proteinuria below 1 g/24 h after intensive supportive therapy. The long-term prognosis of these patients needs further investigation.Methods 112 screening failed patients in the TESTING study from 10 centers in China were enrolled in this retrospective study. The prognosis of 88 patients, who were excluded because of proteinuria below 1 g/24 h, was analyzed by Landmark Kaplan-Meier analysis. The composite kidney endpoint was defined by a ≥ 50% reduction in eGFR, ESKD (eGFR

Background Acute kidney injury (AKI) is a severe postoperative complication in patients undergoing major surgery. Proton pump inhibitors (PPIs) are used preoperatively as prophylaxis for postoperative gastrointestinal bleeding. Whether preoperative PPI use is associated with an increased risk of postoperative AKI remains uncertain.Methods This retrospective cohort study used electronic medical records from the clinical data warehouse of Peking University First Hospital to screen all adult hospitalizations undergoing major surgery between 1 January 2018 and 31 December 2020. Exposure was preoperative PPI use, defined as PPI use within 7 days before major surgery. The primary outcome was postoperative AKI, defined as AKI occurring within 7 days after major surgery; secondary outcomes included in-hospital AKI and in-hospital mortality.Results A total of 21,533 patients were included in the study (mean [SD] age, 57.8 [15.0] years; 51.2% male), of which 944 (4.4%) were prescribed PPI within 7 days before major surgery (PPI users). Overall, 72 PPI users (7.6%) and 356 non-users (1.7%) developed postoperative AKI. After adjustment, preoperative PPI use was associated with an increased risk of postoperative AKI (adjusted OR, 1.47; 95% CI, 1.04–2.07) and in-hospital AKI (adjusted OR, 1.41; 95% CI, 1.03–1.94). Moreover, subgroup analyses showed that the risk of PPI on postoperative AKI was amplified by the concomitant use of non-steroidal anti-inflammatory drugs or diuretics. No significant difference was observed between preoperative PPI use and in-hospital mortality in the fully adjusted model (adjusted OR 1.63; 95% CI, 0.55–4.85).Conclusions Preoperative PPI use was associated with an increased risk of AKI in patients undergoing major surgery. This risk may be enhanced by the concomitant use of other nephrotoxic drugs. Clinicians should weigh the pros and cons before initiating PPI prophylaxis.

IntroductionGalactose-deficient IgA1 (GdIgA1) is critical in the formation of immunodeposits in IgA nephropathy (IgAN), whereas the origin of GdIgA1 is unknown. We focused on the immune response to fecal microbiota in patients with IgAN. MethodsBy running 16S ribosomal RNA gene sequencing, we compared IgAN samples to the control samples from household-matched or non-related individuals. Levels of plasma GdIgA1 and poly-IgA complexes were measured, and candidate microbes that can either incite IgA-directed antibody response or degrade IgA through specific IgA protease activities were identified.ResultsThe IgAN group showed a distinct composition of fecal microbiota as compared to healthy controls. Particularly, high abundance of Escherichia-Shigella was associated with the disease group based on analyses using receiver operating characteristic (area under curve, 0.837; 95% CI, 0.738–0.914), principle coordinates, and the linear discriminant analysis effect size algorithm (linear discriminant analysis score, 4.56; p < 0.001). Accordingly, the bacterial levels directly correlated with high titers of plasma GdIgA1(r = 0.36, p < 0.001), and patients had higher IgA1 against stx2(2.88 ± 0.46 IU/mL vs. 1.34 ± 0.35 IU/mL, p = 0.03), the main antigen of Escherichia-Shigella. Conversely, the healthy controls showed relatively higher abundance of the commensal bacteria that produce IgA-degrading proteases. Particularly, the abundance of some intestinal bacteria expressing IgA proteases showed an inverse correlation with the levels of plasma GdIgA1 in IgAN.ConclusionOur data suggest that mucosal IgA production, including those of GdIgA1, is potentially linked to the humoral response to gut Escherichia-Shigella as one of the sources of plasma GdIgA1. Conversely, the IgA protease-producing microbiota in the gut are suppressed in patients with IgAN.

IntroductionActivation of complement through the alternative pathway (AP) has a key role in the pathogenesis of IgA nephropathy (IgAN). We previously showed, by intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE), C57BL/6 mice develop mild kidney damage in association with glomerular IgA deposition. To further address complement activity in causing glomerular histological alterations as suggested in the pathogenesis of IgAN, here we used mice with factor H mutation (FHW/R) to render AP overactivation in conjunction with LCWE injection to stimulate intestinal production of IgA.MethodsDose response to LCWE were examined between two groups of FHW/R mice. Wild type (FHW/W) mice stimulated with LCWE were used as model control.ResultsThe FHW/R mice primed with high dose LCWE showed elevated IgA and IgA-IgG complex levels in serum. In addition to 100% positive rate of IgA and C3, they display elevated biomarkers of kidney dysfunction, coincided with severe pathological lesions, resembling those of IgAN. As compared to wild type controls stimulated by the same high dose LCWE, these FHW/R mice exhibited stronger complement activation in the kidney and in circulation.DiscussionThe new mouse model shares many disease features with IgAN. The severity of glomerular lesions and the decline of kidney functions are further aggravated through complement overactivation. The model may be a useful tool for preclinical evaluation of treatment response to complement-inhibitors.

IntroductionIgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally. While nephrotic syndrome (NS) is uncommon in IgAN, its significance remains unclear.MethodsWe conducted a retrospective analysis of 170 IgAN patients, classifying them into NS (n = 85) and non-NS (n = 85) groups. Our study aims to compare their clinical characteristics, treatment responses, and prognoses. Patients were selected based on renal biopsy from 2003 to 2020. Propensity score matching ensured comparability. Clinical, pathological, and immunological data were analyzed. Composite endpoints were defined as end-stage kidney disease (ESKD) or a 30% decline in estimated glomerular filtration rate (eGFR).ResultsNS patients showed higher eGFR (74.3 ± 36.8 vs. 61.5 ± 33.6 mL/min.1.73 m2, p = 0.02), severe hematuria (35.0 (4.7,147.5) vs. 4.0 (1.8,45,0) cells/μl, p

BackgroudRecent trials suggest sodium-glucose cotransporter 2 inhibitors (SGLT2i) significantly reduced proteinuria in patients with IgA nephropathy (IgAN). While little was known its efficacy in clinical practice especially in those already received full dose reninangiotensin-aldosterone system (RAAS) inhibitors.MethodsA cohort of 93 Chinese patients with biopsy-proven IgAN and persistent proteinuria underwent full supportive therapy, including optimal blood pressure control and full dose angiotensin-converting enzyme–inhibitor or angiotensin receptor blocker therapy. Proteinuria reduction at three and six months after initiating SGLT2i therapy was analyzed.ResultsA total of 93 patients were enrolled in this study and 62 of them completed the six-month follow-up. After SGLT2i administration, a significant reduction in proteinuria was observed, with a decrease of 22.9% (p 0.05). Notably, a consistent antiproteinuric effect of SGLT2i was observed across various settings, including different age groups, baseline levels of proteinuria/eGFR, use of immunosuppressive agents, and the presence of comorbid diabetes and hypertension (all p values >0.05).ConclusionThe proteinuria was significantly reduced after SGLT2i administration in IgAN patients with full dose angiotensin-converting enzyme–inhibitor or angiotensin receptor blocker therapy. Importantly, the antiproteinuric effect of SGLT2i was observed independently of immunosuppressive agent therapy, age, baseline eGFR and proteinuria levels, as well as the history of hypertension and diabetes.

Abstract Background IgA nephropathy is the most common glomerular disease and is a common cause of progression to end-stage renal disease in patients with kidney diseases. Proteinuria levels are critical for the prognosis of patients with IgA nephropathy, but many patients are still unable to effectively control their proteinuria levels after receiving RAAS blockers. Antimalarial drugs have shown good efficacy in the treatment of kidney disease in previous studies; however, there have been no strictly designed randomized controlled trials to confirm the clinical efficacy of artesunate for treating IgA nephropathy patients. Therefore, we designed this clinical trial to compare the effect of artesunate versus placebo in patients with IgA nephropathy. Methods This study is a randomized, double-blind, three-group-parallel, placebo-controlled clinical trial. One hundred and twenty eligible IgA nephropathy patients at risk of progression will be randomly divided into the artesunate 100-mg group, artesunate 50-mg group, and placebo group. Changes in proteinuria and renal function will be measured 6 months after the intervention. The levels of Gd-IgA1 and anti-Gd-IgA1 in the patient’s blood will also be tested to explore the possible immune mechanisms. Discussion Clinical evidence supporting artesunate treatment of IgA nephropathy is currently lacking, and we expect that the results of this trial will provide high-quality clinical evidence for artesunate as a treatment option for IgA nephropathy in the future. Trial registration Chinese Clinical Trial Registry ChiCTR2000038104 . Registered on 10 September 2020

Introduction: We aimed to investigate whether a lower starting dose of roxadustat (∼1–1.4 mg/kg) converted from erythropoiesis-stimulating agent (ESA) could achieve a comparable hemoglobin (Hb) target (≥100 and ≤120 g/l) compared with the standard weight-based dose (∼1.5–2 mg/kg) at week 12 through a peritoneal dialysis (PD) cohort. Methods: A 12-week multicenter randomized, parallel-controlled, open-label, pilot clinical trial enrolled adult patients who had undergone PD treatment for >3 months with renal anemia. Participants were randomized in blocks of 4 in a 1:1 ratio to either the standard-dose group (n = 50) or the low-dose group (n = 50). The primary end point was the proportion of patients achieving the Hb target at week 12. Results: Baseline demographic and clinical characteristics of the 2 groups were comparable. There was no difference in the proportion of patients who met the Hb target at week 12, that is, 26 patients (52%) versus 31 patients (62%) in the low-dose group and standard-dose group, respectively (P = 0.31). The Hb levels significantly increased in both groups from baseline to week 12; the median change of Hb levels was 5.0 (0.0–14.3) g/l (P < 0.001) for the standard-dose group and 6.0 (−3.3 to 16.3) g/l for the low-dose group (P = 0.005) (P = 0.581 for between groups). Conclusion: This study suggests that a lower starting dose of roxadustat effectively achieves the Hb target as standard-dose does among patients on PD. (ClinicalTrials.gov number, NCT04454879).

Background: Glomerular deposition of C4d is a widely used biomarker for activation of the lectin pathway in the complement system and is reported to be associated with kidney progression in immunoglobulin A nephropathy (IgAN). The aim of this study was to evaluate whether glomerular C4d deposition, as a new biomarker, improves the prediction of kidney prognosis in IgAN. Study Design: Systematic review and meta-analysis. Setting & Population: Patients with biopsy-proven primary IgAN without age limitations.Selection Criteria for Studies: Cross-sectional or cohort studies reporting the prevalence of glomerular C4d deposition or evaluating its association with IgAN progression. Predictor: Glomerular C4d deposition. Outcome: Composite progression event of a >30% decline in estimated glomerular filtration rate or end-stage kidney disease. Results: 12 studies with 1,251 patients were included. The prevalence of glomerular C4d deposition was 34% (95% CI, 27%-41%), with large heterogeneity (I2 = 86%; P

Introduction: Understanding heterogeneity in the prognosis of chronic kidney disease (CKD) has implications in management of patients. We aimed to evaluate the comparative risk of end-stage kidney disease (ESKD), cardiovascular (CV) events, and death among patients with CKD in China. Methods: In total, 3,700 patients with CKD stage 1–4 were recruited from 39 clinical centers in China between 2011 and 2016. New occurrence of ESKD, CV events, and all-cause mortality was recorded until the end of 2017. The crude incidence rate was calculated for each outcome. Ratios of incidence between different outcomes were generated with 95% confidence interval (CI) estimated by 1,000 times of bootstrapping. Multivariable adjusted Cox regression models accounting for competing risk between the outcomes were used to evaluate the association of risk factors with the outcomes. Results: The population mean age was 50 ± 14 years, with 58.2% male and 60.3% of glomerulonephritis. After a median follow-up of 4.65 years (interquartile range [IQR]: 3.71–5.60 years) for ESKD, 4.76 years (IQR: 3.97–5.76 years) for CV events, and 4.84 years (IQR: 3.97–5.76 years) for death, the incidence rates of the 3 outcomes were 3.1, 1.5, and 0.92/100 patient-years, respectively. The ratio for the incidence of ESKD and CV events was 2.15 (95% CI: 1.87, 2.53) and that for incidence of ESKD and death was 3.41 (95% CI: 2.88, 4.08). Significant differences regarding the ratios were detected through levels of age, history of CV disease, the estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (uACR), and etiology of CKD. In the Cox regression model adjusting for traditional CV and kidney-specific risk factors, older age was associated with a higher risk of CV events and death but a lower risk of ESKD (hazard ratios [HRs] = 1.45 [95% CI: 1.29, 1.64], 1.48 [95% CI: 1.29, 1.70], and 0.78 [95% CI: 0.73, 0.84] per 10 year increase, respectively). By comparison, reduced eGFR was associated with a higher risk of ESKD and death, rather than CV events (HRs = 3.62 [95% CI: 2.96, 4.43], 1.30 [95% CI: 1.02, 1.66], and 1.22 [95% CI: 0.99, 1.49] per 30.26 mL/min/1.73 m2 increase, respectively). Similar patterns were seen for increased uACR (HRs = 1.42 [95% CI: 1.30, 1.55], 1.17 [95% CI: 1.05, 1.30], and 1.07 [95% CI: 0.99, 1.17] per 1 natural log-transformed value increase, respectively). Conclusion: ESKD was more likely to occur than CV events and death in the population with CKD stage 1–4 in China. Traditional risk factors contributed differently to the comparative risk of the outcomes.

Abstract Background Clinical decision support systems including both electronic alerts and care bundles have been developed for hospitalized patients with acute kidney injury. Methods Electronic databases were searched for randomized, before-after and cohort studies that implemented a clinical decision support system for hospitalized patients with acute kidney injury between 1990 and 2019. The studies must describe their impact on care processes, patient-related outcomes, or hospital length of stay. The clinical decision support system included both electronic alerts and care bundles. Results We identified seven studies involving 32,846 participants. Clinical decision support system implementation significantly reduced mortality (OR 0.86; 95 % CI, 0.75–0.99; p = 0.040, I2 = 65.3 %; n = 5 studies; N = 30,791 participants) and increased the proportion of acute kidney injury recognition (OR 3.12; 95 % CI, 2.37–4.10; p

Both IgA nephropathy and IgA vasculitis, formerly known as Henoch-Schӧnlein purpura, are immune deposition diseases. IgA nephropathy is caused by the deposition of aberrantly formed poly-IgA complexes from blood circulation to the kidney glomerulus; IgA vasculitis is characterized by IgA-dominant immune deposits to small vessels of the skin and other organs, including the kidney. Therefore, measuring the disease-causing poly-IgA contents in the plasma is needed to study these conditions. However, while clinical tests for the level of total plasma IgA are routinely performed, methods for specific detection of poly-IgA contents are unavailable in clinical medicine. In this protocol, we describe a practical solution for measuring poly-IgA in patient samples. The new method is based on the biological selectivity of IgA Fcα receptor I (FcαRI/CD89) toward poly-IgA species, in contrast to its relatively low affinity for normal monomeric IgA. By devising recombinant CD89 ectodomain as the “capturing” probe, we validated the feasibility of the assay for measuring plasma poly-IgA levels in a 96-well format. The methodology was able to differentiate plasma samples of IgA nephropathy, or related IgA vasculitis, from those of other autoimmune kidney disease types or from healthy controls. Moreover, the measured poly-IgA indices not only correlated with the severity of IgA nephropathy, but the levels also trended lower following corticosteroid or immunosuppressant treatments of patients. Therefore, we anticipate the new assay will provide useful measurements of the IgA nephropathy disease activity index for stratifying disease severity or for evaluating treatment response.Graphical abstract:

Introduction: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. It involves both genetic and environmental factors, among which DNA methylation, the most studied epigenetic modification, was shown to play a role. Here, we assessed genome-wide DNA methylation and gene expression profiles in 2 pairs of IgAN-discordant monozygotic (MZ) twins, in order to characterize methylation changes and their potential influences on gene expression in IgAN. Methods: Genome-wide DNA methylation and gene expression profiles were evaluated in peripheral blood mononuclear cells obtained from 2 IgAN-discordant MZ twins. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were detected, and an integrated analysis was performed. Finally, functional enrichment analysis was done for DMR-associated genes and DEGs. Results: Totally 521 DMRs were detected for 2 IgAN-discordant MZ twins. Among them, 9 DMRs were found to be mapped to genes that differentially expressed in 2 MZ twins, indicating the potential regulatory mechanisms of expression for these 9 genes (MNDA, DYSF, IL1R2, TLR6, TREML2, TREM1, IL32, S1PR5, and ADGRE3) in IgAN. Biological process analysis of them showed that they were mostly involved in the immune system process. Functional enrichment analysis of DEGs and DMR-associated genes both identified multiple pathways relevant to inflammatory and immune responses. And DMR-associated genes were significantly enriched in terms related to T-cell function. Conclusions: Our findings indicate that changes in DNA methylation patterns were involved in the pathogenesis of IgAN. Nine target genes detected in our study may provide new ideas for the exploration of molecular mechanisms of IgAN.

Introduction: Two prediction models for IgA nephropathy (IgAN) using clinical variables and the Oxford MEST scores were developed and validated in 2 multiethnic cohorts. Additional external validation is required. Methods: Biopsy-proven Chinese and Argentinian patients with IgAN were included. The primary outcome was defined as a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease. C-statistics and stratified analyses were used for model discrimination, coefficient of determination (R2D) for model fit, and calibration plots for model calibration. Baseline survival function was also evaluated. Results: A total of 1275 patients were enrolled, with a mean age of 34 (interquartile range: 27–42) years, 50% of whom (638 of 1275) were men. Use of renin-angiotensin system blockers was higher than in previously reported cohorts, whereas other variables were comparable. The C-statistic of the models was 0.81, and R2D was higher than reported. Survival curves in the subgroups (

Introduction: Galactose-deficient IgA1 (Gd-IgA1) and related IgA/IgG immune complexes have been identified as the key drivers in the pathogenesis of IgA nephropathy (IgAN). However, their roles in the development of secondary IgAN are still unknown. Methods: In this study, we measured the plasma Gd-IgA1 level, IgA/IgG complex, and Gd-IgA1 glomerular deposits in 100 patients with various kinds of secondary IgAN. Plasma Gd-IgA1 was measured using a lectin-based enzyme-linked immunosorbent assay, and Gd-IgA1 in glomerular deposits was examined by double immunofluorescent staining using its specific monoclonal antibody KM55. Results: Patients with secondary IgAN presented with higher plasma Gd-IgA1 levels compared to healthy controls (median, 354.61 U/ml; interquartile range [IQR], 323.93, 395.57 U/ml vs. median, 303.17 U/ml; IQR, 282.24, 337.92 U/ml, P < 0.001) or patients with other kidney diseases (median, 314.61 U/ml; IQR, 278.97, 343.55 U/ml, P < 0.001). A similar trend was observed in plasma IgA/IgG immune complexes or IgA1. There were no differences between secondary and primary IgAN in plasma Gd-IgA1 levels (median, 378.54 U/ml; IQR, 315.96, 398.33 U/ml, P = 0.700) and IgA1-IgG complex levels (median, 18.76 U/ml; IQR, 14.51, 22.83 U/ml vs. median, 19.11 U/ml; IQR, 13.21, 22.37 U/ml, P = 0.888). Co-localized IgA1 and Gd-IgA1 of both secondary and primary IgAN indicated that they both share the feature of Gd-IgA1 deposits on the glomerular mesangium. Conclusion: Our study strongly suggests that secondary IgAN shares a similar galactose-deficient IgA1-oriented pathogenesis with primary IgAN. Keywords: galactose-deficient IgA1, IgA, immune complex, nephropathy, secondary IgA nephropathy

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. In addition to hematuria, proteinuria is observed in a considerable proportion of patients with IgAN and has proven to be a strong risk factor for disease progression. Although the exact pathogenesis of IgAN is still unclear, genetic factors are widely considered to play a role in its occurrence and development. Here, we investigated a large IgAN-associated pedigree of 47 members belonging to six generations. Two members of the family who presented with proteinuria and hematuria were diagnosed with IgAN through renal biopsy. Four other members also exhibited proteinuria or hematuria but without renal biopsy. Using whole-exome sequencing, we identified a likely pathogenic variant in WT1 (c.1397C>T; p.Ser466Phe) that cosegregated with proteinuria in the affected family members. In addition, another pathogenic variant in NPHS1 (c.3478C>T; p.Arg1160Ter) was identified; however, it did not cosegregate with abnormal proteinuria. Compared to individuals in the pedigree with only one heterozygous WT1 variant (c.1397C>T; p.Ser466Phe), the proband and her younger brother carried an additional WT1 variant (c.1433-10G>A) and presented with a more severe phenotype and rapid progression to end-stage kidney disease. Our findings suggest the WT1 missense variant (c.1397C>T; p.Ser466Phe)-induced primary podocyte injury might contribute to the proteinuria phenotype and IgAN progression in this pedigree.

Background: IgA nephropathy (IgAN) has a high degree of heterogeneity in clinical and pathological features. Among all subsets of IgAN, the pathogenesis of IgAN with minimal change disease (MCD-IgAN) remained controversial.Methods: We analyzed the clinical and pathological characteristics of MCD-IgAN patients in a retrospective cohort. Patients diagnosed with IgAN, excluding MCD-IgAN, were randomly selected as controls. Levels of plasma galactose-deficient IgA1 (GdIgA1), IgG autoantibodies against GdIgA1, GdIgA1 deposition in the glomerulus, and inflammatory reactivity of circulating poly-IgA1 complexes to cultured mesangial cells were evaluated.Results: Patients with MCD-IgAN had significantly higher levels of proteinuria and estimated glomerular filtration rate (eGFR), lower levels of albumin and urine blood cells, and milder histological lesions by a light microscope compared to IgAN patients, which bears a resemblance to MCD. Lower levels of GdIgA1 (3.41 ± 1.68 vs. 4.92 ± 2.30 μg/ml, p = 0.009) and IgG antiglycan autoantibodies (23.25 ± 22.59 vs. 76.58 ± 71.22 IU/ml, p < 0.001) were found in MCD-IgAN patients than those in IgAN controls. Meanwhile, weaker fluorescence intensities of both IgA and GdIgA1 were observed in the glomerulus of MCD-IgAN patients compared to those in IgAN patients. Furthermore, poly-IgA1 complexes from MCD-IgAN patients induced weaker inflammatory effects on cultured mesangial cells than those from IgAN patients in vitro.Conclusion: The results demonstrated that MCD-IgAN cases represent a dual glomerulopathy, namely, mild IgAN with superimposed MCD, which furthermore provides substantial evidence for the corticosteroids therapy in MCD-IgAN patients as the guidelines recommended.

IgA nephropathy is caused by deposition of circulatory IgA1 in the kidney. Hypogalactosylated IgA1 has the propensity to form poly-IgA aggregates that are prone to deposition. Herein, we purified poly-IgA from the plasma of patients with IgA nephropathy and showed that the complex is susceptible to reducing conditions, suggesting intermolecular disulfide connections between IgA units. We sought to find the cysteine residue(s) that form intermolecular disulfide. Naturally assembled dimeric IgA, also known as secretory IgA, involves a J chain subunit connected with 2 IgA1 molecules via their penultimate cysteine-471 residue on a “tailpiece” segment of IgA heavy chain. It is plausible that, with the absence of J chain, the cysteine residue of mono-IgA1 might aberrantly form a disulfide bond in poly-IgA formation. Mutagenesis confirmed that cysteine-471 is capable of promoting IgA aggregation. These discoveries prompted us to test thiol-based drugs for stabilizing cysteine. Specifically, the cystine-reducing drug cysteamine used for treatment of cystinosis showed a remarkable potency in preventing self-aggregation of IgA. When administrated to rat and mouse models of IgA nephropathy, cysteamine significantly reduced glomerular IgA deposition. Collectively, our results reveal a potentially novel molecular mechanism for aberrant formation of IgA aggregates, to which the repurposed cystinosis drug cysteamine was efficacious in preventing renal IgA deposition.

IntroductionCrescents, especially those found at a percentage greater than 50%, are often associated with rapid progression of kidney disease in IgA nephropathy (IgAN). The mechanism of crescents forming in IgAN is still unclear. In this study, we aimed to evaluate whether excess complement activation participates in the formation of crescents in IgAN.MethodsOne hundred IgAN patients with various proportions of crescents—24 with 1%–24%, 27 with 25%–49%, 21 with 50%–74% 12 with more than 75%, and 16 without crescents—were included. Urinary concentrations of mannose-binding lectin (MBL), Bb, C4d, C3a, C5a, and soluble C5b-9 (sC5b-9) were measured at the time of biopsy. Receiver operating characteristic (ROC) curves were performed to evaluate predictive ability of renal survival for urine complement activation. In addition, historical C4d, C5b-9, and C3d were stained by immunohistochemistry.ResultsIgAN patients with more than 50% crescent formation showed higher complement activation levels than the other patients (urinary C3a/creatinine (C3a/Cr): 6.7295 ng/mg, interquartile range (IQR) 1.4652–62.1086 ng/mg vs. 0.1055 ng/mg, IQR 0–1.4089 ng/mg; urinary C5a/Cr: 15.6202 ng/mg, 4.3127–66.7347 ng/mg vs. 0.3280 ng/mg, IQR 0.0859–2.4439 ng/mg; urinary sC5b-9/Cr: 98.6357 ng/mg, 8.8058–1,087.4578 ng/mg vs. 1.4262 ng/mg, 0.0916–11.0858 ng/mg, all p-values

Abstract Background The benefits and risks of antiplatelet therapy for patients with chronic kidney disease (CKD) remain controversial. We undertook a systematic review and meta-analysis to investigate the effects of antiplatelet therapy on major clinical outcomes. Methods We systematically searched MEDLINE, Embase, and the Cochrane Library for trials published before April 2019 without language restriction. We included rrandomized controlled trials that involved adults with CKD and compared antiplatelet agents with controls. Results Fifty eligible trials that included at least one event were identified, providing data for 27773patients with CKD, including 4518 major cardiovascular events and 1962 all-cause deaths. Antiplatelet therapy produced a 15% (OR, 0.85; 95% CI 0.74–0.94) reduction in the odds of major cardiovascular events (P = 0.002), a 48% reduction for access failure events (OR, 0.52; 95% CI, 0.31–0.73), but had no significantly effect on all-cause death (OR, 0.87; 95% CI, 0.71–1.01) or kidney failure events (OR, 0.87; 95% CI, 0.32–1.55). Adverse events were significantly increased by antiplatelet therapy, including major (OR, 1.33; 95% CI, 1.11–1.59) or minor bleeding (OR, 1.66; 95% CI, 1.27–2.05). Among every 1000 persons with CKD treated with antiplatelet therapy for 12 months, 23 major cardiovascular events will be prevented while nine major bleeding events will occur. Conclusions Major prevention with antiplatelet agents (cardiovascular events and access failure), might outweigh the risk of bleeding, and there seemed to be an overall net benefit. Individual evaluation and careful monitoring are required.

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is characterized by excessive activation of the immune system due to infection, autoimmune diseases, or malignancy. As an aggressive and life-threatening clinical syndrome, HLH secondary to peritoneal dialysis associated peritonitis (PDAP) has never been reported. Case presentation A 34-year-old female peritoneal dialysis (PD) patient was hospitalized for fever, progressively multi-organ damage (including cytopenias, abnormalities of coagulation and liver enzyme) after an episode of organism-specific peritonitis. She was refractory to the broad-spectrum antimicrobial agent. Further tests found hemophagocytosis on the bone marrow examination, and extremely high level of sIL2-R and impaired activity of NK cell. The diagnosis of HLH was eventually established. After HLH-specific therapy, this patient recovered and discharged. Conclusions The present case suggests that clinicians should to be aware of HLH in those patients apparently suspected with refractory or relapsing peritonitis, especially those accompanied with persist fever, hyperferritinemia, and cytopenias. HLH-specific therapy and supportive care should be applied without delay.

Abstracts Background The magnitude effects of human leukocyte antigen (HLA) mismatching on post-transplant outcomes of kidney transplantation remain controversial. We aim to quantitatively assess the associations of HLA mismatching with graft survival and mortality in adult kidney transplantation. Methods We searched PubMed, EMBASE and the Cochrane Library from their inception to December, 2016. Priori clinical outcomes were overall graft failure, death-censored graft failure and all-cause mortality. Results A total of 23 cohort studies covering 486,608 recipients were selected. HLA per mismatch was significant associated with increased risks of overall graft failure (hazard ratio (HR), 1.06; 95% confidence interval (CI), 1.05–1.07), death-censored graft failure (HR: 1.09; 95% CI 1.06–1.12) and all-cause mortality (HR: 1.04; 95% CI: 1.02–1.07). Besides, HLA-DR mismatches were significant associated with worse overall graft survival (HR: 1.12, 95% CI: 1.05–1.21). For HLA-A locus, the association was insignificant (HR: 1.06; 95% CI: 0.98–1.14). We observed no significant association between HLA-B locus and overall graft failure (HR: 1.01; 95% CI: 0.90–1.15). In subgroup analyses, we found recipient sample size and ethnicity maybe the potential sources of heterogeneity. Conclusions HLA mismatching was still a critical prognostic factor that affects graft and recipient survival. HLA-DR mismatching has a substantial impact on recipient’s graft survival. HLA-A mismatching has minor but insignificant impact on graft survival outcomes.

Abstract Background A working group on the Oxford classification of IgA nephropathy (IgAN) recently reported that crescents detected in kidney tissue predicted a worse renal outcome. However, this finding must be validated in independent cohorts before it can be widely applied to clinical practice. Methods Biopsy-proven IgAN patients were continuously recruited from two large renal centers in China from 1989 to 2014. All patients were followed for more than 1 year unless end stage renal disease (ESRD) occurred within 12 months. Crescents were defined as focal cellular or fibrocellular crescent formations. IgAN patients without detectable crescents were recruited to the C0 group. Patients with crescents in less than or more than 1/4 of all glomeruli were recruited to the C1 or C2 group, respectively. Primary outcome was defined as the time to ESRD, and the secondary outcome was defined as the time to an estimated glomerular filtration rate (eGFR) decline equal to or greater than 50% or to ESRD. Results In total, 1152 IgAN patients were recruited in this study. Among all patients, 53.7% were in the C0 group, 38.8% were in the C1 group, and 7.5% were in the C2 group. Compared to patients in the C0 group, patients in the C1 or C2 group were younger, had more urinary protein excretion and lower eGFR, and presented with more severe mesangial hypercellularity, endocapillary proliferation or tubular atrophy/interstitial fibrosis. After 45 months of follow-up, ESRD had occurred in 80 (12.9%), 46 (10.3%) and 18 (20.9%) of patients in the C0, C1 and C2 groups, respectively. By multivariable Cox regression analysis, inclusion in the C1 (HR = 1.07, 95% CI 0.71–1.63), C2 (HR = 0.84, 95% CI 0.41–1.73), or C1 or C2 group (HR = 1.02, 95% CI 0.68–1.52) was not associated with a higher rate of ESRD than inclusion in the C0 group after adjusting for age, gender, eGFR, mean arterial pressure (MAP), MEST scores, and immunosuppressive treatment. However, in patients with nephrotic-range proteinuria, patients in either the C1 or C2 group had a higher rate of the primary outcome, ESRD (HR = 2.54, 95% CI 1.14–5.66) after adjusting for age, gender, eGFR, MAP, MEST scores, and immunosuppressive treatment. Similar results were found when we evaluated the association between crescents and the secondary outcome. Conclusions IgAN patients with crescents had more severe clinical and pathological manifestations than those without crescents. However, we failed to replicate the association between crescents and renal function progression in Chinese IgAN patients followed for more than 1 year.

Few data are available on the risk of SAEs in corticosteroid users in IgAN populations. We describe the prevalence and risk factors of corticosteroid-related SAEs in a Chinese cohort. Methods: A total of 1034 IgAN patients were followed up in our renal center from 2003 to 2014. Prevalence of corticosteroid use and corticosteroid-related SAEs were noted. Logistic regression was used to search for risk factors of SAEs in corticosteroid users. Results: Of the 369 patients with steroids therapy, 46 patients (12.5%) with 58 events suffered SAEs, whereas only 18 patients (2.7%) without corticosteroids suffered SAEs (OR: 5.45; 95% CI: 3.07–9.68; P

Focal segmental glomerulosclerosis (FSGS) lesions are similar in characteristics to S lesions of the Oxford classification of IgA nephropathy (IgAN) and may predict poor prognosis. In the present study, we aimed to explore the association between plasma soluble urokinase receptor (suPAR) levels and S lesions and podocytes damage in IgAN patients.We enrolled 569 IgAN patients with follow-up data and detected plasma suPAR levels at renal biopsy by enzyme-linked immunosorbent assay.Plasma suPAR levels in IgAN patients with or without S lesions did not differ significantly (P = 0.411). However, suPAR levels were positively correlated with proteinuria (r = 0.202, P < 0.001), and negatively correlated with estimated glomerular filtration rate (eGFR, r = -0.236, P < 0.001). In the partial correlation to adjust for eGFR, plasma suPAR levels remained positively correlated with proteinuria (r = 0.112, P = 0.023). In a Cox proportional hazards model, higher levels of plasma suPAR were not associated with poor renal outcome. Plasma suPAR levels of IgAN and primary FSGS patients with nephrotic syndrome were not significantly different (P = 0.306). Plasma suPAR levels in patients with extensive effacement of the epithelial cell foot processes of glomerular podocytes were significantly higher than those with segmental effacement on the basis of comparable eGFR (P = 0.036).In IgAN patients, plasma suPAR levels were not associated with S lesions. However, they were positively associated with proteinuria and negatively associated with eGFR. In addition, plasma suPAR levels were positively associated with the effacement degree of the foot processes, which might partially contribute to the development of proteinuria in patients with IgAN.

After activation, the complement system is involved in the pathogenesis of Immunoglobulin A nephropathy (IgAN). Complement factor H (CFH) is a crucial inhibitory factor of the alternative pathway of the complement system. The study investigated the effects of urinary CFH levels on IgAN progression.A total of 351 patients with IgAN participated in this study. They were followed up for an average of 51.8 ± 26.6 months. Renal outcome was defined as a composite endpoint, that included instances of end-stage renal disease (ESRD), ≥ 50% decline in estimated glomerular filtration rate (eGFR) or doubling of plasma creatinine levels. Urinary CFH levels were measured by enzyme-linked immunosorbent assay and calculated as the ratio of urinary CFH over creatinine (uCFH/uCr).In the whole cohort, uCFH/uCr values were associated with disease progression either as continuous [log(uCFH/uCr)] or categorical traits (dichotomous and quartile variables) after adjusting for eGFR, proteinuria, mean arterial blood pressure, histological grading and immunosuppressive therapy in the Cox proportional hazard model. Kaplan-Meier analysis showed that higher uCFH/uCr values at baseline predicted worse renal outcome during follow-up (log-rank, P < 0.001). Receiver operating characteristic curve (ROC) analysis showed that log(uCFH/uCr) had predictive value for renal outcome (area under curve [AUC] = 0.745), and the AUC increased to 0.805 after being incorporated into baseline eGFR and proteinuria. In subgroup analysis with eGFR ≥ 60 mL/min/1.73 m2, log(uCFH/uCr) had better predictive value (AUC = 0.724, P = 0.002) for renal outcome compared to eGFR (AUC = 0.582, P = 0.259) and proteinuria (AUC = 0.615, P = 0.114).Urinary CFH levels are associated with renal function decline and increased urinary CFH levels are a risk factor for progression of IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. In recent years, consistent efforts have been made to develop new non-invasive biomarkers for IgAN progression. In our previous in vitro study we found mesangial derived CXCL1 as a contributor for kidney injury, and observed higher urinary CXCL1 levels in patients with IgAN. It implied that the urinary CXCL1 might be a potential biomarker.In the present study, we enrolled 425 IgAN patients with follow-up data and detected their urinary CXCL1 levels at the time of renal biopsy, to explore the predictive value of urinary CXCL1 in IgAN progression. Urinary CXCL1 levels were measured using enzyme-linked immunosorbent assay.Urinary CXCL1 levels were associated with presently well established predictors of IgAN progression, including SBP (r = 0.138, p = 0.004), DBP (r = 0.114, p = 0.019), proteinuria (r = 0.155, p = 0.001), eGFR (r = -0.259, p

Podocyte loss has been reported to relate to disease severity and progression in IgA nephropathy (IgAN). However, the underlying mechanism for its role in IgAN remain unclear. Recent evidence has shown that IgA1 complexes from patients with IgAN could activate mesangial cells to induce soluble mediator excretion, and further injure podocytes through mesangial-podocytic cross-talk. In the present study, we explored the underlying mechanism of mesangial cell-induced podocyte loss in IgAN. We found that IgA1 complexes from IgAN patients significantly up-regulated the expression of CXCL1 and TGF-β1 in mesangial cells compared with healthy controls. Significantly higher urinary levels of CXCL1 and TGF-β1 were also observed in patients with IgAN compared to healthy controls. Moreover, IgAN patients with higher urinary CXCL1 and TGF-β1 presented with severe clinical and pathological manifestations, including higher 24-hour urine protein excretion, lower eGFR and higher cresentic glomeruli proportion. Further in vitro experiments showed that increased podocyte death and reduced podocyte adhesion were induced by mesangial cell conditional medium from IgAN (IgAN-HMCM), as well as rhCXCL1 together with rhTGF-β1. In addition, the over-expression of CXCR2, the receptor for CXCL1, by podocytes was induced by IgAN-HMCM and rhTGF-β1, but not by rhCXCL1. Furthermore, the effect of increased podocyte death and reduced podocyte adhesion induced by IgAN-HMCM and rhCXCL1 and rhTGF-β1 was rescued partially by a blocking antibody against CXCR2. Moreover, we observed the expression of CXCR2 in urine exfoliated podocytes in IgAN patients. Our present study implied that IgA1 complexes from IgAN patients could up-regulate the secretion of CXCL1 and TGF-β1 in mesangial cells. Additionally, the synergistic effect of CXCL1 and TGF-β1 further induced podocyte death and adhesion dysfunction in podocytes via CXCR2. This might be a potential mechanism for podocyte loss observed in IgAN.

BackgroundGuidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes.Methods and findingsWe systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years).ConclusionsIntensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data.

Abstract Background Immunoglobulin A nephropathy (IgAN), an immune-complex-mediated glomerulonephritis defined immunohistologically by the presence of glomerular IgA deposits, is the most common primary glomerular disease worldwide and a significant cause of end-stage renal disease. Familial clustering of patients with IgAN suggests a genetic predisposition. Methods In this study, 192 patients with IgAN and 192 normal controls in the Sichuan cohort and 935 patients with IgAN and 2,103 normal controls in the Beijing cohort were investigated. HLA-DRB1*01–DRB1*10 specificities were genotyped by the PCR–SSP technique in both cohorts. Based on the HLA-DRB1*04-positive results, the subtypes of HLA-DRB1*04 were analyzed using sequencing-based typing (SBT) in 291 IgAN cases and 420 matched controls. Results The frequency of HLA-DRB1*04 in the IgAN group was significantly higher than that in the control group (0.129 vs. 0.092, P = 8.29 × 10-5, odds ratio (OR) =1.381, 95% confidence interval (CI) 1.178–1.619). Other alleles at the HLA-DRB1 locus were observed with no significant differences between the case and control groups. The dominant alleles of the HLA-DRB1*04 subtypes were DRB1*0405 in both cohorts. The frequencies of HLA-DRB1*0405 and 0403 were significantly increased in the patients compared to healthy subjects. Conclusion HLA-DRB1*04 was significantly associated with primary IgAN in Chinese population. This result implies that HLA-DRB1 gene plays a major role in primary IgAN.