Overexpression of Corin Ameliorates Kidney Fibrosis through Inhibition of Wnt/ß-Catenin Signaling in Mice.

The Wnt/ß-catenin pathway represents a promising therapeutic target for mitigating kidney fibrosis. Corin possesses the homologous ligand binding site [Frizzled-cysteine-rich domain (Fz-CRD)] similar to Frizzled proteins, which act as receptors for Wnt. The Fz-CRD has been found in eight different proteins, all of which, except for corin, are known to bind Wnt and regulate its signal transmission. We hypothesized that corin may inhibit the Wnt/ß-catenin signaling pathway and thereby reduce fibrogenesis. Reduced expression of corin along with the increased activity of Wnt/ß-catenin signaling was found in unilateral ureteral obstruction (UUO) and ureteral ischemia/reperfusion injury (UIRI) models. In vitro, corin bound to the Wnt1 through its Fz-CRDs and inhibit the Wnt1 function responsible for activating ß-catenin. Transforming growth factor-ß1 inhibited corin expression, accompanied by activation of ß-catenin; conversely, overexpression of corin attenuated the fibrotic effects of transforming growth factor-ß1. In vivo, adenovirus-mediated overexpression of corin attenuated the progression of fibrosis, which was potentially associated with the inhibition of Wnt/ß-catenin signaling and the down-regulation of its target genes after UUO and UIRI. These results suggest that corin acts as an antagonist that protects the kidney from pathogenic Wnt/ß-catenin signaling and from fibrosis following UUO and UIRI.

Management and Clinical Outcomes of Membranous Nephropathy, IgA Nephropathy, and Minimal Change Disease Two Years Post-Kidney Biopsy.

INTRODUCTION: This study evaluated the phenotypic and pathology characteristics of patients undergoing kidney biopsy at a single center, while also determining the frequency and factors associated with clinical outcomes. METHODS: The incidence and distribution of biopsy-proven kidney diseases in 2000-2019 were surveyed. Consecutive individuals diagnosed with membranous nephropathy (MN), immunoglobulin A nephropathy (IgAN), and minimal change disease (MCD) between August 2015 and December 2019 were enrolled in the prospective 2-year follow-up study. Outcomes included remission of proteinuria and kidney disease progression events. Multivariable-adjusted Cox proportional hazards model was applied. RESULTS: 4,550 kidney biopsies were performed in 2000-2019, showing a noticeable increase in the proportion of MN. 426 patients were enrolled in the follow-up cohort. 346 (81.2%) achieved remission of proteinuria, 39 (9.2%) suffered kidney disease progression and 51.3% of them were diagnosed with IgAN. Kidney pathological diagnosis (MN vs. MCD: hazard ratio [HR], 0.42; 95% confidence interval [95% CI], 0.31-0.57; IgAN vs. MCD: 0.58; 0.39-0.85), levels of 24-h urine protein at biopsy (1.04; 1.00-1.08) and presence of nodular mesangial sclerosis (0.70; 0.49-0.99) were significantly correlated with remission of proteinuria after adjusting for baseline variables. 24-h urine protein levels at biopsy (1.14; 1.04-1.25) and the presence of crescents (2.30; 1.06-4.95) were the independent risk factors for kidney disease progression events after adjusting for baseline variables. CONCLUSION: The increasing frequency of MN has been affirmed over the past 2 decades. The therapeutic status, clinical outcomes, and factors influencing these outcomes were presented in this single-center study for the three primary glomerular diseases.

Risk factors and early prediction of cardiorenal syndrome type 3 among acute kidney injury patients: a cohort study.

BACKGROUND: Type 3 cardiorenal syndrome (CRS type 3) triggers acute cardiac injury from acute kidney injury (AKI), raising mortality in AKI patients. We aimed to identify risk factors for CRS type 3 and develop a predictive nomogram. METHODS: In this retrospective study, 805 AKI patients admitted at the Department of Nephrology, Second Hospital of Shanxi Medical University from 1 January 2017, to 31 December 2021, were categorized into a study cohort (406 patients from 2017.1.1-2021.6.30, with 63 CRS type 3 cases) and a validation cohort (126 patients from 1 July 2021 to 31 Dec 2021, with 22 CRS type 3 cases). Risk factors for CRS type 3, identified by logistic regression, informed the construction of a predictive nomogram. Its performance and accuracy were evaluated by the area under the curve (AUC), calibration curve and decision curve analysis, with further validation through a validation cohort. RESULTS: The nomogram included 6 risk factors: age (OR = 1.03; 95%CI = 1.009-1.052; p = 0.006), cardiovascular disease (CVD) history (OR = 2.802; 95%CI = 1.193-6.582; p = 0.018), mean artery pressure (MAP) (OR = 1.033; 95%CI = 1.012-1.054; p = 0.002), hemoglobin (OR = 0.973; 95%CI = 0.96--0.987; p < 0.001), homocysteine (OR = 1.05; 95%CI = 1.03-1.069; p < 0.001), AKI stage [(stage 1: reference), (stage 2: OR = 5.427; 95%CI = 1.781-16.534; p = 0.003), (stage 3: OR = 5.554; 95%CI = 2.234-13.805; p < 0.001)]. The nomogram exhibited excellent predictive performance with an AUC of 0.907 in the study cohort and 0.892 in the validation cohort. Calibration and decision curve analyses upheld its accuracy and clinical utility. CONCLUSIONS: We developed a nomogram predicting CRS type 3 in AKI patients, incorporating 6 risk factors: age, CVD history, MAP, hemoglobin, homocysteine, and AKI stage, enhancing early risk identification and patient management.

Effects of oral alkali drug therapy on clinical outcomes in pre-dialysis chronic kidney disease patients: a systematic review and meta-analysis.

BACKGROUND: Metabolic acidosis accelerates the progression of chronic kidney disease (CKD) and increases the mortality rate. Whether oral alkali drug therapy benefits pre-dialysis CKD patients is controversial. We performed a meta-analysis of the effects of oral alkali drug therapy on major clinical outcomes in pre-dialysis CKD patients. METHODS: We systematically searched MEDLINE using the Ovid, EMBASE, and Cochrane Library databases without language restriction. We included all eligible clinical studies that involved pre-dialysis CKD adults and compared those who received oral alkali drug therapy with controls. RESULTS: A total of 18 eligible studies, including 14 randomized controlled trials and 4 cohort studies reported in 19 publications with 3695 participants, were included. Oral alkali drug therapy led to a 55% reduction in renal failure events (relative risk [RR]: 0.45; 95% confidence interval [CI]: 0.25-0.82), a rate of decline in the estimated glomerular filtration rate (eGFR) of 2.59 mL/min/1.73 m2 per year (95% CI, 0.88-4.31). There was no significant effect on decline in eGFR events (RR: 0.34; 95% CI: 0.09-1.23), proteinuria (standardized mean difference: -0.32; 95% CI: -1.08 to 0.43), all-cause mortality events (RR: 0.90; 95% CI: 0.40-2.02) and cardiovascular (CV) events (RR: 1.03; 95% CI: 0.32-3.37) compared with the control groups. CONCLUSION: Based on the available and low-to-moderate certainty evidence, oral alkali drug therapy might potentially reduce the risk of kidney failure events, but no benefit in reducing all-cause mortality events, CV events, decline in eGFR and porteninuria.

Mechanism of action of Tripterygium wilfordii for treatment of idiopathic membranous nephropathy based on network pharmacology.

BACKGROUND: Although thunder god vine (Tripterygium wilfordii) has been widely used for treatment of idiopathic membranous nephropathy (IMN), the pharmacological mechanisms underlying its effects are still unclear. This study investigated potential therapeutic targets and the pharmacological mechanism of T. wilfordii for the treatment of IMN based on network pharmacology. METHODS: Active components of T. wilfordii were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. IMN-associated target genes were collected from the GeneCards, DisGeNET, and OMIM databases. VENNY 2.1 was used to identify the overlapping genes between active compounds of T. wilfordii and IMN target genes. The STRING database and Cytoscape 3.7.2 software were used to analyze interactions among overlapping genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of the targets were performed using Rx64 4.0.2 software, colorspace, stringi, DOSE, clusterProfiler, and enrichplot packages. RESULTS: A total of 153 compound-related genes and 1485 IMN-related genes were obtained, and 45 core genes that overlapped between both categories were identified. The protein-protein interaction network and MCODE results indicated that the targets TP53, MAPK8, MAPK14, STAT3, IFNG, ICAM1, IL4, TGFB1, PPARG, and MMP1 play important roles in the treatment of T. wilfordii on IMN. Enrichment analysis showed that the main pathways of targets were the AGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. CONCLUSION: This study revealed potential multi-component and multi-target mechanisms of T. wilfordii for the treatment of IMN based on network pharmacological, and provided a scientific basis for further experimental studies.

Effects of contralateral nephrectomy timing and ischemic conditions on kidney fibrosis after unilateral kidney ischemia-reperfusion injury.

Acute kidney injury (AKI) is an important cause of chronic kidney disease (CKD), but the underlying mechanisms are unclear. Animal models are tools for studying the AKI-CKD progression. Kidney ischemia-reperfusion injury (IRI) models, especially the unilateral IRI (uIRI) model with delayed contralateral kidney resection, are commonly used to induce fibrotic progression to CKD after AKI. However, in previous studies, we found that details of the operation had a significant impact on the long-term outcomes of the kidney in this uIRI model. In this study, we investigated the effects of resection timing of the contralateral intact kidney, core body temperatures during ischemia, and time length of kidney ischemia on kidney function, histological injury and kidney fibrosis after AKI, using a mouse uIRI model with delayed contralateral nephrectomy. The results showed that all these parameters significantly affected the AKI-CKD transition. The post-AKI fibrosis worsened and the survival rate declined with a longer interval between contralateral nephrectomy and uIRI, higher ischemic body temperature, or longer ischemic duration when the other two variables were fixed. In conclusion, in the uIRI model with delayed contralateral nephrectomy, kidney fibrosis after AKI is influenced by many factors. Strictly controlling the experimental conditions is very important for the stability and consistency of the model.

Oral Anticoagulant Agents in Patients With Atrial Fibrillation and CKD: A Systematic Review and Pairwise Network Meta-analysis.

OBJECTIVE: To evaluate the relative efficacy and safety of different oral anticoagulant agents (OACs) for patients with atrial fibrillation (AF) and chronic kidney disease (CKD). STUDY DESIGN: Systematic review and pairwise and Bayesian network meta-analysis. SETTING & STUDY POPULATIONS: Adult patients with AF and CKD stages 3-5D who received OACs. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials (RCTs) and observational studies that reported the efficacy and safety outcomes of subgroups with a glomerular filtration rate (GFR)<60mL/min. DATA EXTRACTION: Two reviewers independently abstracted data, assessed study quality, and rated the strength of evidence (SOE). ANALYTICAL APPROACH: Random-effects models using restricted maximum-likelihood methods were fit for the pairwise meta-analyses as well as a network meta-analysis within a Bayesian framework. RESULTS: Pairwise meta-analysis including 8 RCTs and 46 observational studies showed that direct OACs (DOACs) were superior to warfarin in preventing thromboembolic events (hazard ratio [HR], 0.86 [95% CI, 0.78-0.95]), without heterogeneity (I2=10.5%), and in reducing the risk of bleeding events (HR, 0.81 [95% CI, 0.66-0.99]), with substantial heterogeneity (I2=69.8%), in patients with AF and a GFR of 15-60mL/min. Bayesian network meta-analysis including 8 RCTs showed that dose-adjusted apixaban and a 15-mg dose of edoxaban were superior to the other OAC regimens in reducing bleeding events. Dose-adjusted apixaban was more effective than edoxaban in preventing thromboembolic events for patients with AF and GFR in the range of 25-50 or 30-50mL/min. In dialysis recipients with AF, the use of OACs increased the risk of bleeding events by 28% (HR, 1.28 [95% CI, 1.03-1.60]) without significant beneficial effects versus not using anticoagulants. LIMITATIONS: Low SOE and heterogeneity in most comparisons. CONCLUSIONS: This study suggests that DOACs are superior to warfarin for the prevention of thromboembolic events and reduction in bleeding risk in patients with AF and mild to moderate kidney disease. However, the low SOE limits the conclusions that can be drawn about the preferred DOAC. Notably, the use of OACs may increase bleeding risk without significant benefits in dialysis recipients with AF. REGISTRATION: Registered at PROSPERO with identification number CRD42018090896.

Effect of antiplatelet therapy on cardiovascular and kidney outcomes in patients with chronic kidney disease: a systematic review and meta-analysis.

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.

Estrogen receptor 1 gene polymorphisms are associated with metabolic syndrome in postmenopausal women in China.

BACKGROUND: Metabolic syndrome (MetS) includes obesity, diabetes, dyslipidemia and hypertension. Its incidence is rapidly increasing worldwide, particularly in postmenopausal women. Estrogens regulate glucose homeostasis and lipid metabolism via estrogen receptors 1 (ESR1) and 2 (ESR2). The current study aimed to elucidate associations of MetS with ESR1 and ESR2 gene polymorphisms in postmenopausal Chinese women. METHODS: This case-control study included 304 postmenopausal women (154 and 150 control and MetS patients, respectively). Clinical indicators related to MetS were assessed. Two ESR1 (PvuII and XbaI) and two ESR2 (RsaI and AluI) polymorphisms were evaluated by polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. RESULTS: ESR1 polymorphisms were significantly different between MetS patients and healthy controls. G allele frequency for the XbaI polymorphism was significantly higher in patients than in control patients (p = 0.004, OR = 1.610, 95%CI 1.169-2.18). The haplotypes A-T (p = 0.015) and G-C (p = 0.024) showed significant differences. The minor alleles of the XbaI and PvuII gene polymorphisms in both homozygous and heterozygous forms showed associations with elevated waist circumference, fasting serum insulin and HOMA-IR. The minor G allele in homozygous and heterozygous forms of the RsaI and AluI gene polymorphisms showed associations with elevated total cholesterol and LDL-C. CONCLUSIONS: In postmenopausal Chinese women, ESR1 polymorphism and the haplotypes A-T and G-C of XbaI-PvuII are associated with MetS, unlike ESR2 polymorphisms. Patients harboring the G allele of XbaI have elevated BMI, waist circumference, systolic and diastolic BP, FBG, HOMA-IR, total cholesterol, TG, LDL-C and NAFLD (%), and reduced HDL-C.

Comparative Effectiveness of 12 Treatment Strategies for Preventing Contrast-Induced Acute Kidney Injury: A Systematic Review and Bayesian Network Meta-analysis.

BACKGROUND: To simultaneously evaluate the relative efficacy of multiple pharmacologic strategies for preventing contrast-induced acute kidney injury (AKI). STUDY DESIGN: Systematic review containing a Bayesian network meta-analysis of randomized controlled trials. SETTING & POPULATION: Participants undergoing diagnostic and/or interventional procedures with contrast media. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials comparing the active drug treatments with each other or with hydration alone. INTERVENTION: Any of the following drugs in combination with hydration: N-acetylcysteine (NAC), theophylline (aminophylline), fenoldopam, iloprost, alprostadil, prostaglandin E1, statins, statins plus NAC, bicarbonate sodium, bicarbonate sodium plus NAC, ascorbic acid (vitamin C), tocopherol (vitamin E), α-lipoic acid, atrial natriuretic peptide, B-type natriuretic peptide, and carperitide. OUTCOMES: The occurrence of contrast-induced AKI. RESULTS: The trial network included 150 trials with 31,631 participants and 4,182 contrast-induced AKI events assessing 12 different interventions. Compared to hydration, ORs (95% credible intervals) for contrast-induced AKI were 0.31 (0.14-0.60) for high-dose statin plus NAC, 0.37 (0.19-0.64) for high-dose statin alone, 0.37 (0.17-0.72) for prostaglandins, 0.48 (0.26-0.82) for theophylline, 0.62 (0.40-0.88) for bicarbonate sodium plus NAC, 0.67 (0.54-0.81) for NAC alone, 0.64 (0.41-0.95) for vitamins and analogues, 0.70 (0.29-1.37) for natriuretic peptides, 0.69 (0.31-1.37) for fenoldopam, 0.78 (0.59-1.01) for bicarbonate sodium, and 0.98 (0.41-2.07) for low-dose statin. High-dose statin plus NAC or high-dose statin alone were likely to be ranked the best or the second best for preventing contrast-induced AKI. The overall results were not materially changed in metaregressions or subgroup and sensitivity analyses. LIMITATIONS: Patient-level data were unavailable; unable to include some treatment agents; low event rates; imbalanced distribution of participants among treatment strategies. CONCLUSIONS: High-dose statins plus hydration with or without NAC might be the preferred treatment strategy to prevent contrast-induced AKI in patients undergoing diagnostic and/or interventional procedures requiring contrast media.

Pregnancy and Kidney Outcomes in Patients With IgA Nephropathy: A Cohort Study.

BACKGROUND: The outcomes of pregnancy in immunoglobulin A nephropathy (IgAN) are controversial. This cohort study assessed the effects of pregnancy on kidney disease progression and risk factors for adverse pregnancy outcomes in patients with IgAN. STUDY DESIGN: A cohort study. SETTING & PARTICIPANTS: Women of child-bearing age with IgAN and minimum follow-up of 1 year after biopsy from December 2003 to September 2014. PREDICTORS: Pregnancy, treated as a time-dependent variable; baseline (at time of biopsy) estimated glomerular filtration rate (eGFR), proteinuria, blood pressure, and kidney pathology (Oxford MEST classification). OUTCOMES: Kidney disease progression event, defined as 30% decline in eGFR or end-stage kidney disease; rate of eGFR decline; and adverse pregnancy outcomes, including severe preeclampsia and fetal loss. RESULTS: Of 413 patients enrolled, 266 (64.4%), 101 (24.5%), 40 (9.6%), and 6 (1.5%) had chronic kidney disease (CKD) stages 1, 2, 3, and 4, respectively. During follow-up, 104 had 116 pregnancies, of which 110 continued beyond week 20; 309 patients did not become pregnant. After adjustment for age, eGFR, mean arterial pressure, proteinuria, and pathology class at the time of biopsy, subsequent pregnancy among patients with CKD stages 3 to 4, but not CKD stages 1 to 2, was associated with faster eGFR decline (-7.44 vs -3.90mL/min/1.73m2 per year; P=0.007) and increased incidence of kidney progression events (HR, 5.14; 95% CI, 1.16-22.74) compared with patients who did not become pregnant. LIMITATIONS: Relatively small sample size and single-center experience. CONCLUSIONS: Pregnancy accelerated kidney disease progression in women with IgAN and CKD stage 3, but not in those at stage 1 or 2.

Intermedin attenuates renal fibrosis by induction of heme oxygenase-1 in rats with unilateral ureteral obstruction.

BACKGROUND: Intermedin [IMD, adrenomedullin-2 (ADM-2)] attenuates renal fibrosis by inhibition of oxidative stress. However, the precise mechanisms remain unknown. Heme oxygenase-1 (HO-1), an antioxidant agent, is associated with antifibrogenic effects. ADM is known to induce HO-1. Whether IMD has any effect on HO-1 is unclear. Herein, we determined whether the antifibrotic properties of IMD are mediated by induction of HO-1. METHODS: Renal fibrosis was induced by unilateral ureteral obstruction (UUO) performed on male Wistar rats. Rat proximal tubular epithelial cell line (NRK-52E) was exposed to rhTGF-ß1 (10 ng/ml) to establish an in vitro model of epithelial-mesenchymal transition (EMT). IMD was over-expressed in vivo and in vitro using the vector pcDNA3.1-IMD. Zinc protoporphyrin (ZnPP) was used to block HO-1 enzymatic activity. IMD effects on HO-1 expression in the obstructed kidney of UUO rat and in TGF-ß1-stimulated NRK-52E were analyzed by real-time RT-PCR, Western blotting or immunohistochemistry. HO activity in the obstructed kidney, contralateral kidney of UUO rat and NRK-52E was examined by measuring bilirubin production. Renal fibrosis was determined by Masson trichrome staining and collagen I expression. Macrophage infiltration and IL-6 expression were evaluated using immunohistochemical analysis. In vivo and in vitro EMT was assessed by measuring α-smooth muscle actin (α-SMA) and E-cadherin expression using Western blotting or immunofluorescence, respectively. RESULTS: HO-1 expression and HO activity were increased in IMD-treated UUO kidneys or NRK-52E. The obstructed kidneys of UUO rats demonstrated significant interstitial fibrosis on day 7 after operation. In contrast, kidneys that were treated with IMD gene transfer exhibited minimal interstitial fibrosis. The obstructed kidneys of UUO rats also had greater macrophage infiltration and IL-6 expression. IMD restrained infiltration of macrophages and expression of IL-6 in UUO kidneys. The degree of EMT was extensive in obstructed kidneys of UUO rats as indicated by decreased expression of E-cadherin and increased expression of α-SMA. In vitro studies using NRK-52E confirmed these observations. EMT was suppressed by IMD gene delivery. However, all of the above beneficial effects of IMD were eliminated by ZnPP, an inhibitor of HO enzyme activity. CONCLUSION: This study demonstrates that IMD attenuates renal fibrosis by induction of HO-1.

Papulonodular mucinosis, Guillain-Barré syndrome and nephrotic syndrome in a patient with systemic lupus erythematosus: a case report.

BACKGROUND: Awareness of the spectrum of clinical manifestations of systemic lupus erythematosus (SLE), especially uncommon changes, is essential for diagnosis and effective management of patients. CASE PRESENTATION: A 26-year-old Chinese man with SLE initially manifested cutaneous papulonodular mucinosis and developed acute Guillain-Barré syndrome and class V lupus nephritis 2 years later. His cutaneous nodules had not been idententified for 2 years and were resected by surgical procedures twice until SLE was diagnosed. The kidney biopsy revealed class V lupus nephritis. The patient responded well to a short course of intravenous immunoglobulins and his muscle strength almost completely recovered. So far, he has undergone five cycles of cyclophosphamide combined with hydroxychloroquine and tapering prednisone, resulting in partial remission of lupus nephritis and disappearance of hypocomplementemia. CONCLUSION: We reported a rare case of male patient with SLE with manifestation of class V lupus nephritis, Guillain-Barré syndrome and papulonodular mucinosis.

Intermedin inhibits unilateral ureteral obstruction-induced oxidative stress via NADPH oxidase Nox4 and cAMP-dependent mechanisms.

NADPH oxidase Nox4-derived reactive oxygen species (ROS) play important roles in renal fibrosis. Our previous study demonstrated that intermedin (IMD) alleviated unilateral ureteral obstruction (UUO)-induced renal fibrosis by inhibition of ROS. However, the precise mechanisms remain unclear. Herein, we investigated the effect of IMD on Nox4 expression and NADPH oxidase activity in rat UUO model, and explored if these effect were achieved through cAMP-PKA pathway, the important post-receptor signal transduction pathway of IMD, in TGF-ß1-stimulated rat proximal tubular cell (NRK-52E). Renal fibrosis was induced by UUO. NRK-52E was exposed to rhTGF-ß1 to establish an in vitro model of fibrosis. IMD was overexpressed in the kidney and in NRK-52E by IMD gene transfer. We studied UUO-induced ROS by measuring dihydroethidium levels and lipid peroxidation end-product 4-hydroxynonenal expression. Nox4 expression in the obstructed kidney of UUO rat or in TGF-ß1-stimulated NRK-52E was measured by quantitative RT-PCR and Western blotting. We analyzed NADPH oxidase activity using a lucigenin-enhanced chemiluminescence system. We showed that UUO-stimulated ROS production was remarkably attenuated by IMD gene transfer. IMD overexpression inhibited UUO-induced up-regulation of Nox4 and activation of NADPH oxidase. Consistent with in vivo results, TGF-ß1-stimulated increase in Nox4 expression and NADPH oxidase activity was blocked by IMD. In NRK-52E, these beneficial effects of IMD were abolished by pretreatment with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89), a PKA inhibitor, and mimicked by a cell-permeable cAMP analog dibutyl-cAMP. Our results indicate that IMD exerts anti-oxidant effects by inhibition of Nox4, and the effect can be mediated by cAMP-PKA pathway.

Effect of Statins on Kidney Disease Outcomes: A Systematic Review and Meta-analysis.

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<0.001) in patients with chronic kidney disease. 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.

Intermedin protects against renal ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress.

BACKGROUND: Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. Endoplasmic reticulum stress (ERS) has been implicated in the pathology of renal ischemia/reperfusion (IRI). In the present study, we investigated whether IMD could reduce ERS damage after renal ischemia. METHODS: The kidneys of SD rats were subjected to 45 min of warm ischemia followed by 24 h of reperfusion. The hypoxia/reoxygenation(H/R) model in NRK-52E cells consisted of hypoxia for 1 h and reoxygenation for 2 h. IMD was over-expressed in vivo and in vitro using the vector pcDNA3.1-IMD. The serum creatinine concentration and lactate dehydrogenase (LDH) activity in the plasma were determined. Histologic examinations of renal tissues were performed with PAS staining. Real-time PCR and Western blotting were used to determine the mRNA and protein levels, respectively. Additionally, ER staining was used to detect the ERS response. RESULTS: In the rat renal IRI model, we found that IMD gene transfer markedly improved renal function and pathology and decreased LDH activity and cell apoptosis compared with the kidneys that were transfected with the control plasmid. IMD significantly attenuated the ERS stress parameters compared with IRI group. Indeed, IMD down-regulated glucose-regulated protein 78 (GRP78), C/EBP homologous protein(CHOP), and caspase 12 protein and mRNA levels. Moreover, in the NRK-52E cell H/R model, IMD overexpression prevented the apoptosis induced by H/R. Furthermore, IMD ameliorated the ER structural changes and concomitantly decreased the levels of GRP78, CHOP and caspase-12. CONCLUSION: This study revealed that IMD protects against renal IRI by suppressing ERS and ERS-related apoptosis.

Obinutuzumab as Initial or Second-Line Therapy in Patients With Primary Membranous Nephropathy.

Introduction: B-cell lymphocytes have been demonstrated to play a key role in the pathogenesis underlying membranous nephropathy (MN). The aim of this study was to evaluate the therapeutic efficacy and safety of Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody in individuals with MN. Methods: We retrospectively analyzed data from 59 consecutive patients with primary MN who provided consent to receive Obinutuzumab and were followed for at least 6 months. The primary outcomes were complete (proteinuria <0.3 g/d) or partial (proteinuria <3.5 g/d with ≥ 50% reduction) remission of proteinuria. Results: Twenty patients received Obinutuzumab as initial therapy, and 39 patients were previously treated with at least 1 immunosuppressant (second-line therapy). Fifty patients (84.7%) achieved complete remission (CR) or partial remission (PR) of proteinuria during the median follow-up of 9.4 months. The likelihood of remission was significantly higher when Obinutuzumab was used as initial therapy than as second-line therapy after adjusting for the baseline estimated glomerular filtration rate (eGFR), 24-hour urinary protein levels, and anti-phospholipase A2 receptor (PLA2R) status (adjusted hazard ratio [HR], 4.5; 95% confidence interval [CI]: 2.1-9.5, P < 0.001). Circulating CD19+ B-cell count decreased to <5 cells/µl in all patients within 2 weeks after infusion. Serum anti-PLA2R concentrations decreased to <14 relative units (RU)/ml in 43 of 48 patients with PLA2R-related MN. After Obinutuzumab administration, a significant reduction in 24-hour urine protein and increase in serum albumin were observed. No serious adverse events were observed. Conclusion: Obinutuzumab may represent a promising and well-tolerated therapeutic option for individuals with primary MN. The potential of Obinutuzumab was highlighted as an initial therapy for primary MN.

Enteric-coated Mycophenolate Sodium therApy versus cyclophosphamide for induction of Remission in Microscopic PolyAngiitis (EMSAR-MPA trial): study protocol for a randomised controlled trial.

INTRODUCTION: Several studies have demonstrated that mycophenolate mofetil (MMF) may be an excellent alternative to cyclophosphamide (CYC) or rituximab for the induction of remission in non-life-threatening anti-neutrophil cytoplasmic antibodies associated vasculitis because of its strong immunosuppressive potency and low toxicity profile. Enteric-coated mycophenolate sodium (EC-MPS) was introduced to reduce gastrointestinal adverse reactions of MMF. This study will evaluate the efficacy and safety of EC-MPS combined with glucocorticoid in patients with active and non-life-threatening microscopic polyangiitis (MPA). METHODS AND ANALYSIS: This study is a multicentre, open-label, randomised controlled, non-inferiority trial. A total of 110 patients with active and non-life-threatening MPA from 11 hospitals in Shanxi Province of China will be recruited and randomised in a 1:1 ratio to receive either EC-MPS or CYC. All patients will receive the same glucocorticoid plan. We will compare oral EC-MPS (720-1440 mg/day) with intravenous pulsed CYC (7.5-15 mg/kg) administered for 3-6 months. All patients will be switched from their assigned treatment (EC-MPS or CYC) to oral azathioprine (2 mg/kg/day) after remission has been achieved, between 3 and 6 months. Azathioprine will be continued until the study ends at 18 months. The primary end point of efficacy is the remission rate at 6 months. Follow-up will continue for 18 months in order to detect an influence of induction regimen on subsequent relapse rates. ETHICS AND DISSEMINATION: This study has received approval from the Ethics Committee of the Second Hospital of Shanxi Medical University (2022YX-026). All participants are required to provide written informed consent and no study-related procedures will be performed until consent is obtained. The results of this trial will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: ChiCTR2200063823.

Intermedin/adrenomedullin 2 protects against tubular cell hypoxia-reoxygenation injury in vitro by promoting cell proliferation and upregulating cyclin D1 expression.

AIM: Intermedin/adrenomedullin 2 (IMD/ADM2) is a newly discovered peptide closely related to adrenomedullin. We recently reported that IMD/ADM2 gene transfer could significantly reduce renal ischaemia/reperfusion injury. In this study, we evaluated the effect of IMD/ADM2 on cell proliferation and regeneration in a cultured rat renal tubular epithelial cell line (NRK-52E) of hypoxia-reoxygenation (H/R) injury. METHODS: The H/R model in NRK-52E cells consisted of hypoxia for 1 h and reoxygenation for 2 h. IMD/ADM2 was overexpressed in NRK-52E cells using the vector pcDNA3.1-IMD. Enzyme-linked immunosorbent assays were used to measure the concentration of IMD/ADM2 in the culture medium, and real-time PCR and Western blotting were used to determine mRNA and protein levels. In addition, luciferase reporter assays and electrophoretic mobility-shift assays were performed to measure cyclin D1 promoter activity and transcription factor activity. RESULTS: We found that IMD/ADM2 gene transfer markedly promoted cell viability and decreased lactate dehydrogenase (LDH) activity and cell apoptosis compared with that of H/R. IMD/ADM2 increased the phosphorylation of ERK and decreased the phosphorylation of JNK and P38. Furthermore, IMD/ADM2 promoted cell cycle progression with concomitant increases in the levels of cyclin D1 and cyclin E, and these effects were blocked by the inhibition of ERK, or the agonist JNK and P38. IMD/ADM2 also increased cyclin D1 promoter activity and AP-1 DNA-binding activity. CONCLUSIONS: We demonstrated that IMD/ADM2 promotes renal cell proliferation and regeneration after renal H/R injury by upregulating cyclin D1 and that this upregulation seems to be mediated by the ERK, JNK, and P38 MAPK signalling pathways.

Cardiovascular and kidney outcomes of uric acid-lowering therapy in patients with different kidney functions: study protocol for a systematic review, pairwise and network meta-analysis.

INTRODUCTION: Hyperuricaemia has been implicated in the development of kidney function in populations with chronic kidney disease; however, the benefits of urate-lowering therapy (ULT) remain uncertain in different clinical studies. The different kidney functions of enrolled populations and distinct pharmacokinetic characteristics of ULT might be of the essence for the contrasting results. In this study, we will synthesise all available data from randomised controlled trials (RCTs) and cohort studies, then evaluate the outcomes of ULT in patients stratified by different estimated glomerular filtration rate (eGFR) stratifications. Furthermore, we will attempt to explore a relatively optimal ULT regimen using a Bayesian network meta-analysis in different eGFRs. METHODS AND ANALYSIS: We searched published and unpublished data from MEDLINE, EMBASE, the Cochrane Central Register of Controlled trials and ClinicalTrials.gov website (before March 2022) for RCTs and cohort studies without language restriction. In the pairwise meta-analysis, all regimens of ULT will be pooled as a whole and compared with controls in different eGFRs. The random-effects model will be applied to generate the summary values using the software Stata V.12.0 (StataCorp). Network meta-analysis within a Bayesian framework will be conducted to explore the relative efficacy profiles of different ULTs and to find optimal ULT in different eGFRs. The software of WinBUGS V.1.4.3 and R2WinBUGS package of R V.3.1.1 will be used in the network meta-analysis. Primary outcomes will be the occurrence of major cardiovascular events and kidney failure events. Secondary outcomes will include the rate of change in eGFR per year, all-cause death, changes in serum uric acid level and major adverse events. Two authors will independently review study selection, data extraction and quality assessment. ETHICS AND DISSEMINATION: The meta-analysis does not require ethical certification. The results will be disseminated through publication in a peer-reviewed journal and through presentations at academic conferences. PROSPERO REGISTRATION NUMBER: CRD42021226163.