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Background. Diabetic nephropathy (DN) is the leading cause of ESRD. Emerging evidence indicated that proteinuria may not be the determinant of renal survival in DN. The aim of the current study was to provide molecular signatures apart from proteinuria in DN by an integrative bioinformatics approach. Method. Affymetrix microarray datasets from microdissected glomerular and tubulointerstitial compartments of DN, healthy controls, and proteinuric disease controls including minimal change disease and membranous nephropathy were extracted from open-access database. Differentially expressed genes (DEGs) in DN versus both healthy and proteinuric controls were identified by limma package, and further defined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Hub genes were checked by protein-protein interaction networks. Results. A total of 566 glomerular and 581 tubulointerstitial DEGs were identified in DN, which were commonly differentially expressed compared to normal controls and proteinuric disease controls. The upregulated DEGs in both compartments were significantly enriched in GO biological process associated with fibrosis, inflammation, and platelet dysfunction, and largely located in extracellular space, including matrix and extracellular vesicles. Pathway analysis highlighted immune system regulation. Hub genes of the upregulated DEGs negatively correlated with estimated glomerular filtration rate (eGFR). While the downregulated DEGs and their hub genes in tubulointerstitium were enriched in pathways associated with lipid metabolism and oxidation, which positively correlated with eGFR. Conclusions. Our study identified pathways including fibrosis, inflammation, lipid metabolism, and oxidative stress contributing to the progression of DN independent of proteinuria. These genes may serve as biomarkers and therapeutic targets.

BackgroundExperimental studies have demonstrated that hypersecretion of growth hormone (GH) is associated with development of glomerular sclerosis. However, clinical case of such condition is very rare. Here we presented a case of focal segmental glomerulosclerosis (FSGS) associated with acromegaly.Case presentationA 63-year-old man was diagnosed as nephrotic syndrome with minimal change disease for 2 years. Prednisone 1 mg/kg/day for 9 months led to no response. After admission, the second kidney biopsy indicated FSGS (NOS variant). On admission, his acromegalic features were noticed and he complained with a 20-year history of soft tissue swelling of hands and feet. Serum GH and insulin-like growth factor 1 (IGF-1) concentrations were both elevated significantly. An oral glucose tolerance test showed inadequate suppression of serum GH. The presence of a pituitary macroadenoma with a diameter of 1.4 cm by MRI confirmed the diagnosis of acromegaly. Then, the tumor was subtotally removed by trans-sphenoidal surgery. Partial remission of proteinuria was achieved 3 months after surgery and maintained during follow-up, with gradual reduce of corticosteroid.ConclusionsThis rare case suggested that the hypersecretion of GH may participate, at least in part, in FSGS development and progression. Early diagnosis and treatment of acromegaly is beneficial.

Background 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. Methods 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. Results 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). Conclusions 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.

Humanin (HN), a mitochondrial derived peptide, plays cyto-protective role under various stress. In this study, we aimed to investigate the effects of HNGF6A, an analogue of HN, on osteoblast apoptosis and differentiation and the underlying mechanisms. Cell proliferation of murine osteoblastic cell line MC3TC-E1 was examined by CCK8 assay and Edu staining. Cell apoptosis was detected by Annexin V assay under H2O2 treatment. The differentiation of osteoblast was determined by Alizarin red S staining. We also tested the expression of osteoblast phenotype related protein by real-time PCR and Western blot. The interaction between Circ_0001843 and miR-214, miR-214 and TAFA5 was examined by luciferase report assay. Circ_0001843 was inhibited by siRNA and miR-214 was suppressed by miR-214 inhibitor to determine the effects of Circ_0001843 and miR-214 on cell proliferation, apoptosis, and differentiation. HNGF6A, an analogue of HN, exerted cyto-protection and osteogenesis-promotion in MC3T3-E1 cells. The expression of osteoblast phenotype related protein was significantly induced by HNGF6A. Additionally, HNGF6A treatment decreased Circ_0001843 and increased miR-214 levels, as well as inhibited the phosphorylation of p38 and JNK. We further found that Circ_0001843 directly bound with miR-214, which in turn inhibited the phosphorylation of p38 and JNK. Furthermore, both Circ_0001843 overexpression and miR-214 knockdown significantly decreased the cyto-protection and osteogenic promotion of HNGF6A. In summary, our data showed that HNGF6A protected osteoblasts from oxidative stress-induced apoptosis and osteoblast phenotype inhibition by targeting Circ_0001843/miR-214 pathway and the downstream kinases, p38 and JNK.

Hematuria is the most typical presentation of immunoglobulin A nephropathy (IgAN); however, its role in disease progression is still controversial. This study aimed to evaluate the association of hematuria and progression of IgAN.Retrospective cohort study.A cohort of 1,333 patients with IgAN treated at a Chinese referral hospital with a median follow-up of 45 months.Microhematuria was evaluated in fresh urine using a fully automated urine particle analyzer (automated method) and urine sediment examination by a skilled examiner (manual method). Hematuria was characterized as a time-varying attribute; namely, average hematuria level was calculated for every 6-month period for each patient during follow-up. Remission was defined as average red blood cell count ≤5/high-power field (manual method) or ≤28 red blood cells/μL (automated method) during the first 6 months of follow-up.Composite event of 50% decline in estimated glomerular filtration rate or development of kidney failure.Multivariable cause-specific hazards models to analyze the relationship between hematuria and the composite kidney disease progression event.Time-varying hematuria during follow-up was an independent risk factor for the composite kidney disease progression event (HR, 1.46; 95% CI, 1.13-1.87; P = 0.003). Hematuria remission during the 6 months after diagnosis was associated with a significantly lower rate of the composite kidney disease progression event (HR, 0.41; 95% CI, 0.28-0.61; P 0.001). A significant interaction was detected between remission of proteinuria and remission of hematuria during the first 6 months (P 0.001). The association between remission of hematuria and kidney disease progression was detectable (HR, 0.46; 95% CI, 0.32-0.68) within the subpopulation with persistent proteinuria (protein excretion1.0 g/d during the first 6 months), but not among patients whose proteinuria had remitted (HR, 0.64; 95% CI, 0.31-1.29; P = 0.2). The 2 techniques for hematuria evaluation were strongly and significantly linearly correlated (r = 0.948; P 0.001), and results using these 2 methods were consistent.A single-center retrospective study. Proportional hazards regression incorporating time-varying covariates may create time-varying confounding. The predictive value of reductions in hematuria was not directly evaluated.Level of hematuria was independently associated with kidney disease progression, whereas hematuria remission was associated with improved kidney outcomes in IgAN among patients with persistent proteinuria. Additionally, to monitor IgAN progression, automated methods to evaluate hematuria hold promise as a replacement for manual evaluation of urinary sediment.

Introduction 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

AIM Studies investigating the association between blood phosphorus and renal outcomes yielded inconsistent results, and studies from Asian population are extremely limited. We initiated the present cohort study, aiming to prospectively examine the association between blood phosphorus and adverse renal outcomes in a prospective chronic kidney disease (CKD) cohort of Chinese patients majorly with glomerulonephritis. METHODS A total of 1430 patients were involved in the study. Linear regression analyses were used to assess the relationship between phosphorus and the slope of estimated glomerular filtration rate (eGFR). Cox regression analyses were used to assess the association between phosphorus and composite outcomes, which were defined as the presence of at least one of: eGFR halving, end stage renal disease, or death. RESULTS During follow-up for an average of 41.4 months, 196 patients developed composite outcomes. The time-average plasma phosphorus was independently associated with the slope of eGFR (β = -0.18, 95% CI: -4.42 to -2.19, P

Background The effects of statin administration on kidney disease outcomes remain controversial. We undertook a systematic review and meta-analysis to assess the efficacy of statins on kidney outcomes. Study Design We conducted a meta-analysis of randomized controlled trials (RCTs) using MEDLINE (1946 to August 31, 2015), EMBASE (1966 to August 31, 2015), and the Cochrane Library database (no date restriction). Setting & Population Adults who were not receiving dialysis, for whom kidney disease outcomes were reported. Selection Criteria for Studies RCTs in which statins were given for at least 6 months and kidney outcomes were measured. Intervention Statins versus control, including placebo, usual care, and different types or doses of statins. Outcomes Kidney failure events, rate of change in estimated glomerular filtration rate (eGFR) per year, change in proteinuria or albuminuria, and, in patients with chronic kidney disease, major cardiovascular events. Results 57 eligible studies with 143,888 participants were included. Statin treatment did not produce an apparent beneficial effect for kidney failure events (OR, 0.98; 95% CI, 0.87-1.10; P =0.7) or end-stage renal disease events (OR, 0.98; 95% CI, 0.90-1.07; P =0.7). However, mean difference for rate of decline in eGFR (0.41 [95% CI, 0.11-0.70] mL/min/1.73m 2 per year slower in statin recipients) and standardized mean difference for change in proteinuria or albuminuria (−0.65 [95% CI, −0.94 to −0.37] standard deviation units, statin recipients vs controls) were statistically significant. In addition, statin therapy significantly reduced the risk for cardiovascular events (OR, 0.69; 95% CI, 0.61-0.79; P Limitations Inclusion of several post hoc analyses from large RCTs and substantial heterogeneity in secondary outcome analyses. Conclusions Statin therapy does not reduce the risk for kidney failure events in adults not receiving dialysis for whom kidney disease outcomes were reported, but may modestly reduce proteinuria and rate of eGFR decline.

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.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).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; P0.001). 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; P0.001).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.

Background There are few studies describing the prevalence and immune features of people with subclinical mesangial immunoglobulin A (IgA) deposition in the Chinese population. We sought to investigate the prevalence of mesangial IgA deposition among kidney donors and the immune characteristics of donors with mesangial IgA deposition. Methods Fifty blood-related living donors with zero-hour allograft biopsies obtained at Peking University First Hospital were enrolled. Galactose-deficient IgA1 (Gd-IgA1) in glomerular deposits was examined by double immunofluorescent staining using the specific monoclonal antibody KM55. Plasma IgA, IgA1, Gd-IgA1 and antibodies directed against Gd-IgA1 were measured using enzyme-linked immunosorbent assay. Results Thirteen of 50 (26%) donors had mesangial IgA deposition, which was confirmed by both immunofluorescence and electron microscopy. The levels of plasma IgA, IgA1 and Gd-IgA1 were all increased in donors with IgA deposition compared with those without IgA deposition (mean ± SD, 3.54 ± 0.505 versus 2.356 ± 0.265 mg/ml, p = 0.049; 3.003 ± 0.4048 versus 2.356 ± 0.265 mg/ml, p = 0.057; and 4.719 ± 0.4357 versus 3.356 ± 0.4707 ug/ml, p = 0.0440, respectively). Colocalized IgA1 and Gd-IgA1 indicated that there were galactose-deficient IgA1 deposits in the glomerular mesangium. While donors with IgA deposition showed lower levels of IgG anti-glycan antibodies than patients with IgA nephropathy (37.71 ± 8.886 versus 78.86 ± 5.155 units/ml, p = 0.001). Conclusions The immune features of donors with IgA deposition, including IgA1 and Gd-IgA1 deposition, were similar to those of patients with IgA nephropathy, but donors with IgA deposition had lower levels of antiglycan antibodies, which may explain the subclinical status of IgA deposition in donors. Mesangial IgA deposition was common in the Chinese blood related donors cohort, further large study with both living and cadaveric donor kidneys was still needed to confirm these findings.

BackgroundImmunoglobulin A (IgA) vasculitis nephritis (IgAV-N) is the most common secondary IgA nephropathy (IgAN). Many studies have demonstrated that galactose-deficient IgA1 (Gd-IgA1) in the IgA1 hinge region is associated with the development and also progression of primary IgAN. In this study, we aimed to evaluate the roles of Gd-IgA1 in kidney disease progression in a large Chinese cohort of IgAV-N patients.MethodsThis cohort study enrolled 112 patients with IgAV-N, 15 patients with IgA vasculitis (IgAV) without kidney involvement and 108 patients with IgAN. Plasma IgA1 and Gd-IgA1 levels at kidney biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was a 30% decline in estimated glomerular filtration rate or end-stage renal disease or death.ResultsThe levels of Gd-IgA1 in IgAV-N and IgAN patients were higher than in healthy controls (mean ± SD, 302.86 ± 54.93 U/mL versus 303.16 ± 59.43 U/mL versus 281.30 ± 43.74 U/mL, respectively; P = 0.047), as well as compared with those with IgAV without kidney involvement (272.65 ± 53.14 U/mL; P = 0.036). After adjusting clinical data, higher levels of Gd-IgA1 were found to be independently associated with a greater risk for kidney failure [hazard ratio (HR) = 1.703 per 1 SD, 95% confidence interval (CI) 1.233–2.352; P = 0.001]. Compared with the first Gd-IgA1 quartile group (as reference), the fourth Gd-IgA1 quartile group retained a predictive value for poor renal outcome (HR = 3.740, 95% CI 1.204–11.619; P = 0.023).ConclusionsThese data indicate that Gd-IgA1 levels were similarly elevated in adult patients with IgAN and those with IgAV-N. Moreover, increased Gd-IgA1 levels were associated with both the development and progression of IgAV-N, as observed in IgAN.

Contains fulltext : 202673.pdf (Publisher’s version ) (Open Access) The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy.

Figure S5. Forest plot for the change of serum creatinine. (DOCX 44 kb)

The codes of Winbugs for the full Bayes methods. (DOCX 14 kb)

Figure S1. Risk of bias graph. (DOCX 55 kb)

Figure S2. Risk of bias summary. (DOCX 975 kb)

Table S3. Subgroup Analysis of Outcomes and Adverse Events. (DOCX 20 kb)

Assessment domains of risk of bias. (DOCX 16 kb)

Table S1. Summary of Characteristics of Included Trials and Patients. (DOCX 15 kb)

Table S2. Characteristics of Included Trials and Patients. (DOCX 33 kb)

Figure S3. Forest plot for all-cause death and cardiovascular death. (DOCX 102 kb)

Background: Several clinical practice guidelines noted the potential benefits of urate-lowering therapy (ULT) on cardiovascular disease (CVD) and chronic kidney disease (CKD) progression, however effect of this regimen remains much uncertainty. In this systematic review, we aimed to evaluate the efficacy of ULT on major adverse cardiovascular events(MACEs), all-cause mortality and kidney failure events. Methods: We systematically searched MEDLINE, Embase, and the Cochrane databases for trials published through April 2019. We included prospective, randomized, controlled trials assessing the effects of ULT on cardiovascular or renal outcomes. We extracted published data and did a meta-analysis of urate-lowering therapy on relative risks (RRs) of major adverse cardiovascular events, all-cause mortality, kidney failure events, and adverse events. Summary estimates of RR reductions were calculated with a random effects model. Findings: We identified 28 trials including a total of 9194 participants, of which 5070 participants received ULT, 4104 participants received placebo, usual-care or no treatment. Finally, 1279 MACEs, 377 deaths and 87 kidney failure events were recorded. Among all the population with 3103 (34·18%) participants having chronic kidney disease and 5718 (61·14%) having cardiovascular disease or stroke, ULT reduced the risk of MACEs [risk ratio (RR) 0·80, 95% confidence interval (CI) 0·67-0·95; I2 = 42·7%] and all-cause mortality (RR 0·80, 95% CI 0·66-0·97; I2 =0·0%), but had no effect on kidney failure (RR 1·04, 95%CI 0·43-2·42; I2 =64·4%). There was no significant difference (RR=0·99, 95% CI 0·95 to 1·03; I2 =55·7%) in the risk of adverse events between the participants receiving ULT and the control group. Interpretation: ULT has a beneficial effect on reducing the risk of MACEs and all-cause mortality. However, there is insufficient evidence to support an effect of ULT in reducing risk of kidney failure events. Funding Statement: This work was funded by National Key Research and Development Program of China (2018YFC1314004). JL was supported by the grant from the National Natural Science Foundation of China (no. 81270795), JZ was supported by the National Natural Science Foundation of China (81874401). Dr Badve is supported by a John Chalmers Clinical Research Fellowship with the support of Servier from The George Institute for Global Health. Declaration of Interests: Dr Badve reports grants from the National Health and Medical Research Council of Australia, personal fees from Bayer AG and Amgen Australia, and nonfinancial support from Bayer AG. Other authors listed in this paper declare no competing interests. Ethics Approval Statement: This study is registered with PROSPERO, number CRD42018104227.

Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. The global estimated prevalence of CKD is 13.4% (11.7–15.1%), and patients with end-stage kidney disease (ESKD) needing renal replacement therapy is estimated between 4.902 and 7.083 million. Through its effect on cardiovascular risk and ESKD, CKD directly affects the global burden of morbidity and mortality worldwide. The global increase in this disease is mainly driven by the increase in the prevalence of diabetes mellitus, hypertension, obesity, and aging. But in some regions, other causes such as infection, herbal and environmental toxins are still common. The large number of deaths for poor access to renal replacement therapy in developing countries, and also large increase of patients with ESKD in future, will produce substantial financial burden for even the most wealthy countries. Cost-effectiveness of preventive strategies to reduce the disease burden should be evaluated in relation to the local economic development and resource. Strategies reducing the cardiovascular risk in CKD still need further evaluation in large trials especially including patients with advanced kidney disease or end-stage kidney disease.

In September 2017, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference titled Blood Pressure in Chronic Kidney Disease (CKD). The purpose of the meeting was to consider which recommendations from the 2012 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD should be reevaluated based on new evidence from clinical trials. Participants included a multidisciplinary panel of clinical and scientific experts. Discussions focused on the optimal means for measuring blood pressure (BP) as well as managing BP in CKD patients. Consistent with the 2012 Guideline, the conference did not address BP management in patients on maintenance dialysis.

s 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. Electronic supplementary material The online version of this article (10.1186/s12882-018-0908-3) contains supplementary material, which is available to authorized users.

Summary Background Recent hypertension guidelines have reversed previous recommendations for lower blood pressure targets in high-risk patients, such as those with cardiovascular disease, renal disease, or diabetes. This change represents uncertainty about whether more intensive blood pressure-lowering strategies are associated with greater reductions in risk of major cardiovascular and renal events. We aimed to assess the efficacy and safety of intensive blood pressure-lowering strategies. Methods For this updated systematic review and meta-analysis, we systematically searched MEDLINE, Embase, and the Cochrane Library for trials published between Jan 1, 1950, and Nov 3, 2015. We included randomised controlled trials with at least 6 months' follow-up that randomly assigned participants to more intensive versus less intensive blood pressure-lowering treatment, with different blood pressure targets or different blood pressure changes from baseline. We did not use any age or language restrictions. We did a meta-analysis of blood pressure reductions on relative risk (RR) of major cardiovascular events (myocardial infarction, stroke, heart failure, or cardiovascular death, separately and combined), and non-vascular and all-cause mortality, end-stage kidney disease, and adverse events, as well as albuminuria and progression of retinopathy in trials done in patients with diabetes. Findings We identified 19 trials including 44 989 participants, in whom 2496 major cardiovascular events were recorded during a mean 3·8 years of follow-up (range 1·0–8·4 years). Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4–22]), myocardial infarction (13% [0–24]), stroke (22% [10–32]), albuminuria (10% [3–16]), and retinopathy progression (19% [0–34]). However, more intensive treatment had no clear effects on heart failure (15% [95% CI −11 to 34]), cardiovascular death (9% [–11 to 26]), total mortality (9% [–3 to 19]), or end-stage kidney disease (10% [–6 to 23]). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1·2% per year in intensive blood pressure-lowering group participants, compared with 0·9% in the less intensive treatment group (RR 1·35 [95% CI 0·93–1·97]). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2·68 [1·21–5·89], p=0·015), but the absolute excess was small (0·3% vs 0·1% per person-year for the duration of follow-up). Interpretation Intensive blood pressure lowering provided greater vascular protection than standard regimens. In high-risk patients, there are additional benefits from more intensive blood pressure lowering, including for those with systolic blood pressure below 140 mmHg. The net absolute benefits of intensive blood pressure lowering in high-risk individuals are large. Funding National Health and Medical Research Council of Australia.

Background and objectives We undertook a systematic review and meta-analysis of published cohort studies and case-control studies to estimate ( 1 ) the risk of pregnancy complications among patients with CKD versus those without CKD and ( 2 ) the risk of CKD progression among pregnant patients versus nonpregnant controls with CKD. Design, setting, participants, & measurements We searched electronic databases for studies published between 1946 and 2014, and we reviewed articles using validity criteria. Random-effects analytical methods were used. Results Twenty-three studies (14 with data for adverse pregnancy outcomes and 9 for renal outcomes) with 506,340 pregnancies were included. Pregnancy with CKD had greater odds of preeclampsia (odds ratio [OR], 10.36; 95% confidence interval [95% CI], 6.28 to 17.09), premature delivery (OR, 5.72; 95% CI, 3.26 to 10.03), small for gestational age/low birth weight (OR, 4.85; 95% CI, 3.03 to 7.76), cesarean section (OR, 2.67; 95% CI, 2.01 to 3.54), and failure of pregnancy (OR, 1.80; 95% CI, 1.03 to 3.13). Subgroup analysis showed that odds of preeclampsia ( P 0.01) and premature delivery ( P 0.01) were higher in women with nondiabetic nephropathy compared with diabetic nephropathy, and the odds of preeclampsia ( P =0.01) and premature delivery ( P 0.01) were higher in women with macroproteinuria compared with microproteinuria. The median for follow-up time for renal events was 5 years (interquartile range, 5–14.7 years). There were no significant differences in the occurrence of renal events between CKD pregnant women and those without pregnancy (OR, 0.96; 95% CI, 0.69 to 1.35). Subgroup analysis showed that publication year, sample size, follow-up years, type of primary disease, CKD classification, level of serum creatinine at baseline, proteinuria, and level of systolic BP did not modify the renal outcomes. Conclusions The risks of adverse maternal and fetal outcomes in pregnancy are higher for women with CKD versus pregnant women without CKD. However, pregnancy was not a risk factor for progression of renal disease in women with CKD before pregnancy.

Aim To validate the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines risk stratification system based on the combination of estimated glomerular filtration rate (eGFR) and proteinuria. Methods This was a cohort study. A total of 1219 study population were recruited. Estimated GFR and proteinuria measured by using 24 h urine protein excretion rate (PER) were predictors. Adverse outcomes included all-cause mortality (ACM) and end-stage renal disease (ESRD). Follow-up was done by regular visit, telephone interview and electronic medical records. Results Over a median follow-up of 4.6 years, 153 (12.6%) and 43 (3.5%) patients experienced ESRD and ACM, respectively. On multivariable analysis, the adjusted hazard ratio for ESRD and ACM (compared with patients with eGFR > 60 mL/min per 1.73 m2) was of 29.8 and 3.6 for those with eGFR of 15–29 mL/min per 1.73 m2, respectively. The adjusted hazard ratio for ESRD and ACM (compared with patients with PER 500 mg/24h. Higher KDIGO guidelines risk categories (indicating lower eGFR or higher proteinuria) were associated with a graded increase in the risk for the ESRD (P

Summary Background End-stage kidney disease is a leading cause of morbidity and mortality worldwide. Prevalence of the disease and worldwide use of renal replacement therapy (RRT) are expected to rise sharply in the next decade. We aimed to quantify estimates of this burden. Methods We systematically searched Medline for observational studies and renal registries, and contacted national experts to obtain RRT prevalence data. We used Poisson regression to estimate the prevalence of RRT for countries without reported data. We estimated the gap between needed and actual RRT, and projected needs to 2030. Findings In 2010, 2·618 million people received RRT worldwide. We estimated the number of patients needing RRT to be between 4·902 million (95% CI 4·438–5·431 million) in our conservative model and 9·701 million (8·544–11·021 million) in our high-estimate model, suggesting that at least 2·284 million people might have died prematurely because RRT could not be accessed. We noted the largest treatment gaps in low-income countries, particularly Asia (1·907 million people needing but not receiving RRT; conservative model) and Africa (432 000 people; conservative model). Worldwide use of RRT is projected to more than double to 5·439 million (3·899–7·640 million) people by 2030, with the most growth in Asia (0·968 million to a projected 2·162 million [1·571–3·014 million]). Interpretation The large number of people receiving RRT and the substantial number without access to it show the need to both develop low-cost treatments and implement effective population-based prevention strategies. Funding Australian National Health and Medical Research Council.

Background: The role of serum uric acid (SUA) level in the progression of Immunoglobulin A nephropathy (IgAN) remains controversial. Methods: In a cohort of 1,965 cases with biopsy-proven IgAN, we examined the associations of SUA concentration with the primary outcome of a composite of all-cause mortality or kidney failure (defined as a reduction of estimated glomerular filtration rate [eGFR] by 40% from baseline, requirements for dialysis and transplantation), or the outcome of kidney failure alone, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. Results: At baseline, the mean age was 33.37 ± 11.07 years, eGFR was 101.30 ± 30.49 mL/min/1.73 m2, and mean uric acid level was 5.32 ± 1.76 mg/dL. During a median of 7-year follow-up, 317 cases reached the composite outcome of all-cause mortality (5 deaths) or kidney failure (36 cases of dialysis, 5 cases of renal transplantation, and 271 cases with reduction of eGFR by 40% from baseline). After adjustment for demographic and IgAN specific covariates and treatments, a higher quartile of uric acid was linearly associated with an increased risk of the primary outcome (highest versus lowest quartile, hazard ratio [HR] 2.39; 95% CI 1.52–3.75) and kidney failure (highest versus lowest quartile, HR 2.55; 95% CI 1.62–4.01) in the Cox proportional hazards regression models. In the continuous analysis, a 1 mg/dL greater uric acid level was associated with 16% increased risk of primary outcome (HR 1.16, 95% CI 1.07–1.25) and 17% increased risk of kidney failure (HR 1.17, 95% CI 1.08–1.27), respectively, in the fully adjusted model. The multivariate ­logistic regression analyses for the sensitive analyses drew consistent results. In the subgroup analyses, significant interactions were detected that patients with mean arterial pressure (MAP) < 90 mm Hg or mesangial hypercellularity had a higher association of SUA with the incidence of the primary outcome than those with MAP ≥90 mm Hg or those without mesangial hypercellularity respectively. Hyperuricemia was not significantly associated with the risk of developing the primary outcome in elder patients (≥32 years old), patients with eGFR < 90 mL/min or with tubular atrophy/interstitial fibrosis. Conclusions: SUA level may be positively associated with the progression of IgAN. It was noticeable that the association of hyperuricemia with IgAN progression was less significant in patients with elder age, lower eGFR, or tubular atrophy/interstitial fibrosis, which may be due to some more confounders in association with the IgA progression in these patients. Future prospective studies are warranted to confirm these findings and to investigate the underlying mechanisms.

Table S2. The PRISMA checklist. (DOCX 90 kb)

Additional file 1: Table S1. Adjusted HRs of the association of ESRD with crescents in more than 1/6 of glomeruli. Table S2. Univariate analysis of crescents with eGFR decline rate (ml/min/1.73Â m2/year).

Figure S1. Meta-regression of HLA mismatches on graft failure for primary determinant confounders (A: Sample size; B: Data source; C: Donor source; D: Geographical locations). (DOCX 608 kb)

Table S3. Newcastle-Ottawa Scale (NOS) score for evaluation of study quality. (DOCX 73 kb)

Supplemental Methods. (DOCX 45 kb)

Figure S2. Funnel plot and Egger test for publication bias among studies that evaluated association HLA per mismatch and overall graft failure. (A: Funnel plot; B: Egger test). (DOCX 81 kb)

Table S1. The MOOSE checklist. (DOCX 103 kb)

Figure S4. Forest plot after stratification for sample size (â Ľ10,000 vs

Figure S3. Forest plot that evaluated the impact of 1 or 2 HLA-DR mismatches versus 0 mismatches on overall graft failure. (DOCX 587 kb)

Background: Hydroxychloroquine (HCQ) is a well-known immunomodulator that is useful as in the treatment for lupus because of its inhibitory effect on toll-like receptors and cytokines, which are speculated to play a role in the pathogenesis of Immunoglobulin A (IgA) nephropathy (IgAN). However, there was only one study that investigated the effect of HCQ on proteinuria in patients with IgAN. Methods: Ninety patients with IgAN who received HCQ in addition to optimized dosage of renin-angiotensin-aldosterone system inhibitors (RAASi) were recruited for this study, and 90 matched historical controls who received RAASi alone were selected from our registry by the propensity score matching method. Their clinical data were compared at baseline and during follow-up till the termination of HCQ or addition of immunosuppressive agents. Results: The median baseline proteinuria level of the 90 patients who received HCQ was comparable with the RAASi-alone group (1.5 [1.2, 2.1] vs. 1.5 [1.2, 1.9] g/day, p = 0.74). At 6 months post-study initiation, the median proteinuria level in the HCQ group was lower than that in the RAASi-alone group (0.8 [0.7, 1.2] vs. 1.2 [0.8, 1.8] g/day, p = 0.02). The percentage by which proteinuria was reduced in the HCQ group was significantly higher than that in the RAASi-alone group (–43% [–57, –12] vs. –19% [–46, 17], p = 0.01). No serious adverse effects were documented during treatment with HCQ. Conclusion: The addition of HCQ to RAASi resulted in a significant and safe reduction in proteinuria in patients with IgAN.

Background In immunoglobulin A nephropathy (IgAN), complement activation occurs in both the systemic circulation and in situ (glomerular). A recent IgAN-genome-wide association study (GWAS) identified 1q32 as an IgAN susceptible locus that contained the complement regulatory protein coding gene complement factor H (CFH). Here, we explored the combined genetic effects of coding and noncoding variants in CFH, rs6677604 and rs800292 on complement activation in IgAN. Methods In total, 1,194 IgAN patients and 900 healthy controls who were the same as the Beijing Discovery Cohort in our recent IgAN-GWAS were recruited. The genotyping information of rs800292 and rs6677604 were extracted from GWAS data, while the information regarding plasma C3 levels and mesangial C3 deposits were collected from medical records. Results We found both rs800292-GG and rs6677604-GG were risk genotypes for complement activation in IgAN patients, as represented by lower plasma C3 levels in IgAN patients with rs800292-GG and a higher intensity of glomerular C3 deposits in those with rs6677604-GG, respectively. Additionally, IgAN patients with 2 risk genotypes (rs800292-GG and rs6677604-GG) showed a higher degree of complement activation compared to those with no risk genotypes (rs800292-AA/AG and rs6677604-AA/AG), as represented by both lower plasma C3 levels and a higher intensity of glomerular C3 deposits. Moreover, when compared to rs800292 or rs6677604 alone, the combined genetic effects of rs800292 and rs6677604 showed a stronger association with IgAN susceptibility. Conclusions Our findings suggested that both coding and noncoding variants in CFH acted synergistically to regulate the degree of complement activation and thereby contributed to IgAN susceptibility.

Background Accumulating evidences proved the important roles of circulating IgA1-containing immune complexes (cIgA1) in IgA nephropathy (IgAN). Galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG antibody have been identified as major components in cIgA1. Before, Gd-IgA1 was reported as a vital factor in IgAN, partly via of its pathogenic role to induce mesangial cells activation. However, we still lack direct evidences to clarify the biological effect of glycan-specific IgG antibody in IgAN. Methods In the present study, we enrolled 35 IgAN patients and 17 age- and sex-matched healthy controls. Using uniform aberrant glycosylated IgA1 molecules, and IgG from different individuals, we in vitro prepared IgG-ddIgA1 complexes, and compared the biological differences among these immune complexes regarding their proliferative and inflammatory effects on mesangial cells. Results IgG-ddIgA1 complexes from both patients with IgA nephropathy (IgAN-IgG-dd-IgA1) and healthy controls (HC-IgG-dd-IgA1) could induce the proliferation of mesangial cells and up-regulate expression of MCP-1, IL-6 and CXCL1. The levels of mesangial cells proliferation induced by IgAN-IgG-dd-IgA1 were significantly higher than those induced by HC-IgG-dd-IgA1 (1.10 ± 0.05 vs. 1.03 ± 0.03; p

Importance Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain. Objective To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression. Design, Setting, and Participants The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred. Interventions Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months. Main Outcomes and Measures The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years. Results After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P Conclusions and Relevance Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial.

International audience; Epitopes of phospholipase A2 receptor (PLA2R), the target antigen in idiopathic membranous nephropathy (iMN), must be presented by the HLA-encoded MHC class II molecules to stimulate autoantibody production. A genome-wide association study identified risk alleles at HLA and PLA2R loci, with the top variant rs2187668 within HLA-DQA1 showing a risk effect greater than that of the top variant rs4664308 within PLA2R1. How the HLA risk alleles affect epitope presentation by MHC class II molecules in iMN is unknown. Here, we genotyped 261 patients with iMN and 599 healthy controls at the HLA-DRB1, HLA-DQA1, HLA-DQB1, and HLA-DPB1 loci with four-digit resolution and extracted the encoded amino acid sequences from the IMGT/HLA database. We predicted T cell epitopes of PLA2R and constructed MHC-DR molecule-PLA2R peptide-T cell receptor structures using Modeler. We identified DRB1*1501 (odds ratio, 4.65; 95% confidence interval [95% CI], 3.39 to 6.41; P

Chronic kidney disease (CKD) stage 3 was divided into stage G3a and stage G3b in the 2013 Kidney Disease Improving Global Outcomes guidelines. Whether it is appropriate to regard 45 mL/min/per 1.73 m2 as the threshold value of G3a/G3b staging and whether dividing CKD stage 3 into G3a/G3b plays a useful role in assessing the prognosis of patients with IgA nephropathy (IgAN) remain unknown. Three hundred and ninety patients from the First Affiliated Hospital of Zhengzhou University and Peking University First Hospital diagnosed with IgAN in CKD stage 3 were enrolled and successfully followed up. Cox proportional hazards model was used to analyze hazard ratios of reaching the composite endpoints (doubling of serum creatinine, end-stage renal disease: estimated glomerular filtration rate (eGFR)

Background and objectives Current therapy for IgA nephropathy mainly includes renin-angiotensin system inhibitors and adding steroids for patients with persistent proteinuria. This study aimed to evaluate kidney disease progression and its risk factors in a Chinese cohort under current therapy. Design, setting, participants, & measurements Patients with IgA nephropathy followed up for at least 12 months from a prospective database were involved. Renal survival and the relationship between clinical parameters and composite kidney failure events (defined as end stage kidney failure or eGFR halving) were assessed. Results Overall, 703 patients between 2003 and 2011 were enrolled in this study, with a mean follow-up time of 45 months. Mean eGFR was 84.0 ml/min per 1.73 m 2 , systolic BP was 124 mmHg, and time-averaged mean arterial pressure was 90.0 mmHg. Median proteinuria at baseline was 1.60 g/d, and time-averaged proteinuria was 0.80 g/d. The mean rate of eGFR decline was −3.12 ml/min per 1.73 m 2 per year (95% confidence interval, −19.07 to 11.80), and annual end stage kidney failure rate was 2.3%. Multivariate Cox regression analyses revealed that baseline eGFR (hazard ratio, 0.76 per 10 ml/min per 1.73 m 2 ; 95% confidence interval, 0.66 to 0.91), proteinuria at 6 months (hazard ratio, 1.53 per g/d; 95% confidence interval, 1.27 to 1.84), and systolic BP control at 6 months (hazard ratio, 1.36 per 10 mmHg; 95% confidence interval, 1.05 to 1.77) were associated with composite kidney failure events. Baseline eGFR (regression coefficient, −0.06; 95% confidence interval, −0.07 to −0.04), time-averaged proteinuria (regression coefficient, −0.21; 95% confidence interval, −0.25 to −0.16), and time-averaged mean arterial pressure (regression coefficient, −0.15; 95% confidence interval, −0.21 to −0.09) were independent predictors of the slope of eGFR by linear regression. Conclusion Lower proteinuria and lower BP were associated with slower eGFR decline and lower risk of end stage kidney failure in patients currently being treated for IgA nephropathy.

Crescentic IgA nephropathy (IgAN), defined as >50% crescentic glomeruli on kidney biopsy, is one of the most common causes of rapidly progressive GN. However, few studies have characterized this condition. To identify risk factors and develop a prediction model, we assessed data from patients ≥ 14 years old with crescentic IgAN who were followed ≥ 12 months. The discovery cohort comprised 52 patients from one kidney center, and the validation cohort comprised 61 patients from multiple centers. At biopsy, the mean serum creatinine (SCr) level ± SD was 4.3 ± 3.4 mg/dl, and the mean percentage of crescents was 66.4%± 15.8%. The kidney survival rates at years 1, 3, and 5 after biopsy were 57.4%± 4.7%, 45.8%± 5.1%, and 30.4%± 6.6%, respectively. Multivariate Cox regression revealed initial SCr as the only independent risk factor for ESRD (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.10 to 1.57; P=0.002). Notably, the percentage of crescents did not associate independently with ESRD. Logistic regression showed that the risk of ESRD at 1 year after biopsy increased rapidly at SCr>2.7 mg/dl and reached 90% at SCr>6.8 mg/dl (specificity=98.5%, sensitivity=64.6% for combined cohorts). In both cohorts, patients with SCr>6.8 mg/dl were less likely to recover from dialysis. Analyses in additional cohorts revealed a similar association between initial SCr and ESRD in patients with antiglomerular basement membrane disease but not ANCA-associated systemic vasculitis. In conclusion, crescentic IgAN has a poor prognosis, and initial SCr concentration may predict kidney failure in patients with this disease.

The Oxford Classification of the pathology of immunoglobulin A (IgA) nephropathy, developed in 2009, is highly predictive of renal prognosis. It has been validated in different populations, but the results remain inconsistent.Systematic review and meta-analysis.Patients with biopsy-proven primary IgA nephropathy.Studies assessing the Oxford Classification of IgA nephropathy published between January 2009 and December 2012 were included following systematic searching of the MEDLINE and EMBASE databases.4 pathologic lesions of the Oxford Classification: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T).Kidney failure defined as doubled serum creatinine level, 50% decline in estimated glomerular filtration rate, or end-stage kidney disease.16 retrospective cohort studies with 3,893 patients and 570 kidney failure events were included. In a multivariate model, HRs for kidney failure were 0.6 (95% CI, 0.5-0.8; P0.001), 1.8 (95% CI, 1.4-2.4; P0.001), and 3.2 (95% CI, 1.8-5.6; P0.001) for scores of M0 (mesangial hypercellularity score ≤0.5), S1 (presence of segmental glomerulosclerosis), and T1/2 (25% tubular atrophy/interstitial fibrosis), respectively, without evidence of heterogeneity. Pooled results showed that E lesions were not associated with kidney failure (HR, 1.4; 95% CI, 0.9-2.0; P = 0.1), with evidence of heterogeneity (I(2) = 54.1%; P = 0.01). Crescent (C) lesions were associated with kidney failure (HR, 2.3; 95% CI, 1.6-3.4; P0.001), with no evidence of heterogeneity (I(2) = 14.7%; P = 0.3).All studies were retrospective. This was not an individual-patient-data meta-analysis.This study suggests that M, S, T, and C lesions, but not E lesions, are associated strongly with progression to kidney failure and thus should be included in the Oxford Classification system.