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OBJECTIVE: To develop and validate a protein risk score for predicting chronic kidney disease (CKD) in patients with diabetes and compare its predictive performance with a validated clinical risk model (CKD Prediction Consortium [CKD-PC]) and CKD polygenic risk score. RESEARCH DESIGN AND METHODS: This cohort study included 2,094 patients with diabetes who had proteomics and genetic information and no history of CKD at baseline from the UK Biobank Pharma Proteomics Project. Based on nearly 3,000 plasma proteins, a CKD protein risk score including 11 proteins was constructed in the training set (including 1,047 participants; 117 CKD events). RESULTS: The median follow-up duration was 12.1 years. In the test set (including 1,047 participants; 112 CKD events), the CKD protein risk score was positively associated with incident CKD (per SD increment; hazard ratio 1.78; 95% CI 1.44, 2.20). Compared with the basic model (age + sex + race, C-index, 0.627; 95% CI 0.578, 0.675), the CKD protein risk score (C-index increase 0.122; 95% CI 0.071, 0.177), and the CKD-PC risk factors (C-index increase 0.175; 95% CI 0.126, 0.217) significantly improved the prediction performance of incident CKD, but the CKD polygenic risk score (C-index increase 0.007; 95% CI −0.016, 0.025) had no significant improvement. Adding the CKD protein risk score into the CKD-PC risk factors had the largest C-index of 0.825 (C-index from 0.802 to 0.825; difference 0.023; 95% CI 0.006, 0.044), and significantly improved the continuous 10-year net reclassification (0.199; 95% CI 0.059, 0.299) and 10-year integrated discrimination index (0.041; 95% CI 0.007, 0.083). CONCLUSIONS: Adding the CKD protein risk score to a validated clinical risk model significantly improved the discrimination and reclassification of CKD risk in patients with diabetes. [ABSTRACT FROM AUTHOR]

Evidence supports the use of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) in patients with hypertension and stage 3 or milder chronic kidney disease (CKD). This systematic review and individual-level meta-analysis summarizes the evidence supporting the use of the medications in patients with hypertension and more advanced CKD. Background: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. Purpose: To examine the association of ACEi or ARB treatment initiation, relative to a non–ACEi or ARB comparator, with rates of KFRT and death. Data Sources: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. Study Selection: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2. Data Extraction: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m 2), albuminuria (urine albumin–creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. Data Synthesis: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m 2 , of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). Limitation: Individual participant–level data for hyperkalemia or acute kidney injury were not available. Conclusion: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42022307589) [ABSTRACT FROM AUTHOR]

Background: The sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown. Objective: We performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex. Design: Prospective randomized placebo-controlled trial. Participants: A total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200–5000 mg/g) with and without type 2 diabetes. Intervention: Dapagliflozin 10 mg versus placebo once daily. Main Measures: Primary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality. Key Results: Median follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope. Conclusions: Dapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit. Trial Registry: clinicaltrials.gov NIH Trial Registry Number: NCT03036150 [ABSTRACT FROM AUTHOR]

OBJECTIVE: We assessed the relationship of body weight time in target range (TTR) with composite kidney outcome in people with overweight/obesity and type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: Included in this study were 3,601 participants with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was defined as the proportion of time during the first 4 years that body weight was within the weight loss target (a weight loss of ≥7% from baseline). The primary outcome was composite kidney outcome, defined as eGFR decline ≥30% from baseline and to a level <60 mL/min/1.73 m2 at follow-up visit, or end-stage kidney disease. RESULTS: During a median follow-up of 8.0 years, 435 cases of composite kidney outcome were documented. Body weight TTR during the first 4 years was inversely associated with the subsequent risk of composite kidney outcome (per SD increment; adjusted hazard ratio [HR] 0.81; 95% CI 0.70–0.93). Accordingly, the adjusted HRs (95% CI) of composite kidney outcome were 1.00 (reference), 0.73 (0.54–1.00), 0.71 (0.52–0.99), and 0.54 (0.36–0.80) for participants with body weight TTR of 0%, >0% to <29.9%, 29.9% to <69.7%, and 69.7% to <100%, respectively. Similar results were found for a doubling of the urine albumin to creatinine ratio (secondary outcome). CONCLUSIONS: A higher body weight TTR, with a weight loss target of losing ≥7% of initial weight, was associated with a lower risk of kidney outcomes in participants with overweight/obesity and T2DM. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a common feature in various chronic kidney diseases (CKD). Tubular cell damage is a main characterization which results from dysregulated fatty acid oxidation (FAO) and lipid accumulation. Cannabinoid Receptor 2 (CB2) contributes to renal fibrosis, however, its role in FAO dysregulation in tubular cells is not clarified. In this study, we found CB2 plays a detrimental role in lipid metabolism in tubular cells. CB2 knockout mice were adopted to establish a folic acid-induced nephropathy (FAN) model. CB2-induced FAO dysfunction, lipid deposition, and fibrogenesis were assessed in vivo and vitro. To explore molecular mechanisms, β-catenin inhibitors and peroxisome proliferator-activated receptor alpha (PPARα) activators were also used in CB2-overexpressed cells. The mediative role of β-catenin in CB2-inhibited PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) activation was analyzed. CB2 activates β-catenin signaling, resulting in the suppression of PPARα/PGC-1α axis. This decreased FAO functions and led to lipid droplet formation in tubular cells. CB2 gene ablation effectively mitigated FAO dysfunction, lipid deposition and uremic toxins accumulation in FAN mice, consequently retarding renal fibrosis. Additionally, inhibition to β-catenin or PPARα activation could greatly inhibit lipid accumulation and fibrogenesis induced by CB2. This study highlights CB2 disrupts FAO in tubular cells through β-catenin activation and subsequent inhibition on PPARα/PGC-1α activity. Targeted inhibition on CB2 offers a perspective therapeutic strategy to fight against renal fibrosis. [Display omitted] • Impaired fatty acid oxidation linked to renal fibrosis in CKD • Cannabinoid receptor 2 disrupts FAO, promotes lipid deposit via β-catenin activation. • CB2/β-catenin inhibits renal FAO by suppressing PPARα/PGC-1α axis [ABSTRACT FROM AUTHOR]

The mechanisms underlying fibrogenic responses after injury are not well understood. Epithelial cell cycle arrest in G2/M after injury is a key checkpoint for determining wound-healing leading to either normal cell proliferation or fibrosis. Here, we identify a kidney- and liver-enriched circular RNA, circBNC2, which is abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insult. Loss of circBNC2 is at least partially mediated by upregulation of DHX9. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrate that circBNC2 acts as a negative regulator of cell G2/M arrest by encoding a protein that promotes formation of CDK1/cyclin B1 complexes. Restoring circBNC2 in experimentally-induced male mouse models of fibrotic kidney and liver, decreases G2/M arrested cell numbers with secretion of fibrotic factors, thereby mitigating extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increased G2/M arrest of epithelial cells are recapitulated in human ischemic reperfusion injury (IRI)-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that restoring circBNC2 might represent a potential strategy for therapeutic intervention in epithelial organ fibrosis. G2/M arrest of epithelial cells leads to fibrosis with unclear mechanisms. This study identifies a protein-encoding circRNA, circBNC2, which inhibits epithelial cells G2/M arrest to prevent fibrotic maladaptive repair in damaged kidney and liver, revealing a potential intervention target for fibrosis. [ABSTRACT FROM AUTHOR]

Loss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases. As Klotho is a large transmembrane protein, it is challenging to harness it as a therapeutic remedy. Here we report the discovery of a Klotho-derived peptide 1 (KP1) protecting kidneys by targeting TGF-β signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-β receptor 2 (TβR2) and disrupting the TGF-β/TβR2 engagement. As such, KP1 blocked TGF-β-induced activation of Smad2/3 and mitogen-activated protein kinases. In mouse models of renal fibrosis, intravenous injection of KP1 resulted in its preferential accumulation in injured kidneys. KP1 preserved kidney function, repressed TGF-β signaling, ameliorated renal fibrosis and restored endogenous Klotho expression. Together, our findings suggest that KP1 recapitulates the anti-fibrotic action of Klotho and offers a potential remedy in the fight against fibrotic kidney diseases. Klotho is an anti-ageing protein whose expression is downregulated in chronic kidney disease, but the large size of the protein makes it challenging to deliver therapeutically. Here, the authors develop a Klotho-derived peptide, and show that it recapitulates the anti-fibrotic action of Klotho and prevents kidney fibrosis in mice by targeting TGF-β signalling. [ABSTRACT FROM AUTHOR]

Background Despite renin–angiotensin–aldosterone system blockade and immunosuppressive treatment, focal segmental glomerulosclerosis (FSGS) often progresses to kidney failure. The objective of this prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease trial (DAPA-CKD) was to assess efficacy and safety of dapagliflozin in a small subgroup of participants with FSGS confirmed by kidney biopsy. Methods In DAPA-CKD, patients with an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200–5000 mg/g (22.6–565 mg/mol) were randomized to dapagliflozin 10 mg once daily or placebo as an adjunct to standard care and followed for median 2.4 years. The primary composite endpoint was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The endpoint of interest for this analysis was eGFR slope (acute effects from baseline to Week 2 and chronic effects from Week 2 to end of treatment). Results Of 104 participants with biopsy-confirmed FSGS, 45 were randomized to dapagliflozin and 59 to placebo. Mean (standard deviation) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73 m2 and median (interquartile range) UACR 1248 (749–2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomized to dapagliflozin and placebo, respectively [hazard ratio 0.62, 95% confidence interval (95% CI) 0.17, 2.17]. Dapagliflozin led to a larger acute reduction (standard error) in eGFR compared with placebo (−4.5, 95% CI −5.9 to −3.1 versus −0.9, −2.1 to 0.4 mL/min/1.73 m2/2 weeks). Thereafter, mean rates of chronic eGFR decline with dapagliflozin and placebo were −1.9 (−3.0, −0.9) and −4.0 (−4.9, −3.0) mL/min/1.73 m2/year, respectively (difference 2.0, 95% CI 0.6 to 3.5, mL/min/1.73 m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin. Conclusions Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared with placebo, although this difference was not statistically significant. [ABSTRACT FROM AUTHOR]

Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by β‐catenin in renal tubular cells. Osteopontin (OPN), especially its N‐terminal fragment (N‐OPN), was encapsulated in β‐catenin‐controlled tubular cell‐derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of β‐catenin in tubular cells (Ksp‐β‐catenin−/−) or gene ablation of CD44 (CD44−/−) greatly ameliorated renal fibrosis. Notably, N‐OPN was carried by exosome and secreted into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome‐mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by β‐catenin. [ABSTRACT FROM AUTHOR]

The relation of alkaline phosphatase (ALP) with chronic kidney disease (CKD) is still uncertain. We aimed to examine the prospective association between serum ALP and CKD progression, and the modifying effect of serum ALP on folic acid in preventing CKD progression in treated hypertensive patients. This is a post-hoc analysis of 12,734 hypertensive adults with relevant measurements and without liver disease at baseline from the renal sub-study of the China Stroke Primary Prevention Trial, where participants were randomly assigned to daily treatments of 10 mg enalapril and 0.8 mg folic acid, or 10 mg enalapril alone. The primary outcome was CKD progression, defined as a decrease in estimated glomerular filtration rate (eGFR) of ≥30% and to a level of <60 ml/min/1.73 m2 if baseline eGFR was ≥60 ml/min/1.73 m2; or a decrease in eGFR of ≥50% if baseline eGFR was <60 ml/min/1.73 m2; or end-stage renal disease. Over a median of 4.4 years, in the enalapril only group, participants with baseline serum ALP≥110IU/L (quartile 4) had a significantly higher risk of CKD progression (3.4% vs 2.3%; adjusted OR,1.61; 95%CI:1.11, 2.32), compared with those with ALP<110IU/L. For those with enalapril and folic acid treatment, compared with the enalapril only treatment, the risk of CKD progression was reduced from 3.4 to 2.1% (adjusted OR, 0.53; 95%CI:0.34, 0.83) among participants with baseline ALP≥110IU/L, whereas there was no significant effect among those with ALP<110IU/L. In hypertensive patients, higher serum ALP was associated with increased risk of CKD progression, and this risk was reduced by 47% with folic acid treatment. [ABSTRACT FROM AUTHOR]

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline.Methods: The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020.Recommendations: The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines. [ABSTRACT FROM AUTHOR]

Objective: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) study demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status.Research Design and Methods: We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200-5,000 mg/g. The primary composite end point was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death.Results: Of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or prediabetes.Conclusions: Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status. [ABSTRACT FROM AUTHOR]

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long‐term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time‐to‐event models were used to quantify the association between plasma exposure and long‐term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28–0.85) for kidney events and 1.13 (95% CI: 1.03–2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population. [ABSTRACT FROM AUTHOR]

Aims  Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death. Methods and results  DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n  = 2152) or placebo (n  = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P  = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo. Conclusion  In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether atrasentan plasma exposure explains between‐patient variability in urinary albumin‐to‐creatinine ratio (UACR) response, a surrogate for kidney protection, and B‐type natriuretic peptide (BNP) response, a surrogate for fluid expansion. Methods: Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run‐in period. Individual area under the concentration‐time‐curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. Results: The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th‐97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was −36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th‐97.5th P: −76.2% to 44.5%; BNP, 2.5th‐97.5th P: −71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P <.01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P <.01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). Conclusion: Atrasentan plasma exposure varied among individual patients and partially explained between‐patient variability in efficacy and safety response. [ABSTRACT FROM AUTHOR]

Background Data on the association between visit-to-visit variability (VVV) in blood pressure (BP) and the risk of chronic kidney disease (CKD) in general treated hypertensive patients were limited. We aimed to evaluate the relation of VVV in BP with the development of CKD, and examine any possible effect modifiers in hypertensive patients without prior cardiovascular diseases (CVDs) or CKD. Methods This is a post hoc analysis of the Renal Sub-study of the China Stroke Primary Prevention Trial (CSPPT). A total of 10 051 hypertensives without CVD and CKD and with at least six visits of BP measurements from randomization to the 24-month visit were included. The main VVV in BP was expressed as standard deviation (SD). The primary outcome was the development of CKD, defined as a decrease in estimated glomerular filtration rate ≥30% and to a level of <60 mL/min/1.73 m2, or end-stage renal disease. Results The median treatment duration was 4.4 years. After multivariable adjustment, including baseline systolic blood pressure (SBP) and mean SBP during the first 2-year treatment period, there was a significantly positive relationship of SD of SBP with the risk of CKD development (per SD increment; odds ratio, 1.27; 95% confidence interval: 1.10–1.46). The results were similar for coefficient of variation (CV) of SBP. Results across various subgroups, including age, sex, SBP at baseline, treatment compliance, concomitant antihypertensive medications and mean SBP during the first 24-month treatment period, were consistent. Conclusions SBP variability, irrespective of mean BP level, was significantly associated with the development of CKD in general treated hypertensive patients. [ABSTRACT FROM AUTHOR]

Background The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. Methods In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol). Results Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n  = 2510) were ischaemic/hypertensive nephropathy (n  = 687) and chronic glomerulonephritis (n  = 695), of which immunoglobulin A nephropathy (n  = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR). Conclusions Participants with a wide range of underlying kidney diseases receiving renin–angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2–4 and increased albuminuria, with and without T2D. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line (HKC‐8) to examine the expression of C‐X‐C motif chemokine receptor 4 (CXCR4) and β‐catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up‐regulated in tubules, with a concomitant activation of β‐catenin. CXCR4 expression level was positively correlated with the expression of β‐catenin target MMP‐7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β‐catenin signalling, protected against tubular injury and renal fibrosis. CXCR4‐induced renal fibrosis was inhibited by treatment with ICG‐001, an inhibitor of β‐catenin signalling. In HKC‐8 cells, overexpression of CXCR4 induced activation of β‐catenin and deteriorated cell injury. These effects were inhibited by ICG‐001. Stromal cell–derived factor (SDF)‐1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC‐8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF‐1α‐induced activation of β‐catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β‐catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades. [ABSTRACT FROM AUTHOR]

Background Recent cardiovascular outcome trials have shown that sodium–glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes. Methods DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2–4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin–angiotensin system inhibitor at enrolment. Results After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05). Conclusion DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes. [ABSTRACT FROM AUTHOR]

Aims: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin‐to‐creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. Materials and Methods: SONAR is a randomized, double‐blind, placebo‐controlled trial with approximately 3500 participants who have stage 2–4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin‐angiotensin system inhibitor. Results: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non‐responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end‐stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). Conclusion: SONAR aims to determine whether atrasentan added to guideline‐recommended therapies safely reduces the risk of CKD progression and delays the onset of end‐stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial “surrogate” response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Whether diabetes and genetic susceptibility of kidney diseases modifies the relationship between ultra-processed foods (UPF) consumption and incident chronic kidney disease (CKD) remains uncertain. We aimed to investigate the association between UPF consumption and new-onset CKD in participants with and without diabetes, and explore whether genetic risks of kidney diseases may modify the association. 153,985 participants who were free of CKD at baseline and provided 24-h dietary recalls in the UK Biobank were included. UPF was defined according to the NOVA classification. The energy contribution of UPF was calculated by dividing the energy intake of UPF by the total energy intake. The study outcome was new-onset CKD, ascertained by self-report data and data linkage with primary care, hospital admissions, and death registry records. During a median follow-up of 12.1 years, 4,058 participants developed new-onset CKD. There was a significant positive association between UPF consumption and new-onset CKD in total participants (per 10% increment, adjusted hazard ratio (HR) 1.04; 95% confidence interval (CI) [1.01;1.06]. The positive association between UPF consumption and risk of new-onset CKD was significantly stronger in participants with diabetes (per 10% increment, adjusted HR 1.11 [1.05;1.17]) than in those without diabetes (per 10% increment, adjusted HR 1.03 [1.00;1.05]; P -interaction = 0.005). Genetic risks of kidney diseases did not significantly modify the positive association in those with or without diabetes (all P -interactions > 0.05). There was a significantly stronger positive association between UPF consumption and new-onset CKD in participants with diabetes compared with those without diabetes. [ABSTRACT FROM AUTHOR]

Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model) or sham operation were treated for 2 weeks with a normal-(0.4% NaCl), or high-salt (4% NaCl) diet. We employed TiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for phosphoproteomic profiling of left ventricular free walls in these animals. A total of 1724 unique phosphopeptides representing 2551 non-redundant phosphorylation sites corresponding to 763 phosphoproteins were identified. During normal salt feeding, 89 (54%) phosphopeptides upregulated and 76 (46%) phosphopeptides downregulated in chronic renal failure rats relative to sham rats. In chronic renal failure rats, high salt intake induced upregulation of 84 (49%) phosphopeptides and downregulation of 88 (51%) phosphopeptides. Database searches revealed that most of the identified phospholproteins were important signaling molecules such as protein kinases, receptors and phosphatases. These phospholproteins were involved in energy metabolism, cell communication, cell differentiation, cell death and other biological processes. The Search Tool for the Retrieval of Interacting Genes analysis revealed functional links among 15 significantly regulated phosphoproteins in chronic renal failure rats compared to sham group, and 23 altered phosphoproteins induced by high salt intake. The altered phosphorylation levels of two proteins involved in heart damage, lamin A and phospholamban were validated. Expression of the downstream genes of these two proteins, desmin and SERCA2a, were also analyzed. [ABSTRACT FROM AUTHOR]

Aim:Lipolysis in fat tissue plays an important role in the development of metabolic disturbances, a characteristic feature of chronic kidney disease (CKD). In the present study, we tested the hypothesis that the inhibition of endoplasmic reticulum (ER) stress could alleviate lipolysis in white adipose tissue in a rat model of CKD.Methods:A rat model of CKD was established by a method of reduced renal mass (RRM). Lipolysis was measured as the release of glycerol in ex vivo fat pads and cultured primary adipocytes. The activity of lipases and markers of ER stress were measured by Western blotting and immunoprecipitation.Results:Our data showed that lipolysis in visceral white adipose tissue was increased in RRM rats compared with control rats. In addition, increased phosphorylation of hormone-sensitive lipase (HSL) and binding of adipose triglyceride lipase (ATGL) to comparative gene identification-58 (CGI-58) protein were observed in the RRM rats. The phosphorylation of ER stress markers, including IRE1α, PERK, and eukaryotic initiation factor (eIF) 2α, and the expression of ER stress marker 78 kDa glucose-regulated protein (GRP78) were significantly increased in RRM rats. Treatment with an inhibitor of ER stress partially but significantly alleviated lipolysis, and this alleviation was accompanied by reduced binding of ATGL to CGI-58.Conclusion:Our results showed that enhanced lipolysis and ER stress occurred in visceral white adipose tissue in a rat model of CKD. Moreover, inhibition of ER stress significantly alleviated lipolysis. These findings suggest that ER stress is a potential therapeutic target for the metabolic disturbances associated with CKD. [ABSTRACT FROM AUTHOR]

This study investigated whether proteinuria not only could serve as a marker of renal outcome but also could monitor the renoprotection of renin–angiotensin system (RAS) inhibitor treatment in patients with nondiabetic chronic kidney disease (CKD). Data from the Renoprotection of Optimal Antiproteinuric Doses (ROAD) trial were used to examine the contribution of the antiproteinuric effect of benazepril and losartan on renal outcome (the primary composite end point of doubling of serum creatinine and end-stage renal disease or death) in 339 Chinese nondiabetic CKD patients with overt proteinuria and renal insufficiency. The degree of proteinuria at month 6 of treatment (residual proteinuria) and during follow-up (time-average proteinuria) showed a close relationship with renal end points. Lowering of proteinuria reduced the risk of renal progression in patients with high, as well as low, proteinuria at baseline. After adjustment for baseline risk markers, therapy-induced change in these variables at month 6 and during follow-up—high residual proteinuria and time-average proteinuria (≥1.0 g/d)—remained the independent predictors for renal end points. Therefore, minimization of proteinuria at least to less than 1.0 g/d should be a therapeutic goal in the management of nondiabetic patients with heavy proteinuria and renal insufficiency. [ABSTRACT FROM PUBLISHER]

It remains unclear whether inflammatory bowel disease is associated with long-term risk of chronic kidney disease (CKD) and acute kidney injury (AKI) in the general population. A total of 417,302 participants, including 2,940 patients with ulcerative colitis and 1,261 patients with Crohn's disease, without previous CKD and AKI at baseline (2006–2010) from the UK Biobank were included. The study outcomes included incident CKD and AKI, ascertained by self-report data and data linkage with primary care, hospital admissions, and death registry records. Analysis was conducted in 2022. During a median follow-up of 12.5 years, 13,564 and 14,331 participants developed CKD and AKI, respectively. Compared with the hazard ratio for non-inflammatory bowel diseases, the hazard ratios for CKD and AKI related to inflammatory bowel diseases were 1.57 (95% CI=1.37, 1.79) and 1.96 (95% CI=1.74, 2.20) after adjustments for age, sex, and race and were 1.32 (95% CI=1.15, 1.51) and 1.70 (95% CI=1.51, 1.91) after further adjustments for biological, behavioral, and socioeconomic factors in addition to mental health and self-rated health. Similar results were found for patients with Crohn's disease (adjusted hazard ratio=1.38 (95% CI=1.09, 1.75) for CKD and 1.62 [95% CI=1.30, 2.02] for AKI) and those with ulcerative colitis (adjusted hazard ratio=1.29 (95% CI=1.09, 1.51) for CKD and 1.71 [95% CI=1.49, 1.97] for AKI) in the fully adjusted models. Genetic risks of kidney diseases did not significantly affect the association of inflammatory bowel disease with incident CKD and AKI (both p -interactions>0.05). The association between inflammatory bowel disease and the risk of incident CKD (p -interaction=0.010) and AKI (p -interaction<0.001) were stronger in younger participants than in older participants. Inflammatory bowel disease was associated with higher risks for CKD and AKI, independent of genetic risks of kidney diseases. [ABSTRACT FROM AUTHOR]

To examine the relationship between an accelerometer-derived "weekend warrior" pattern, characterized by achieving the most moderate to vigorous physical activity (MVPA) over 1–2 days, as opposed to more evenly distributed patterns, with risk of chronic kidney disease (CKD) and acute kidney injury (AKI). 77,977 participants without prior kidney diseases and with usable accelerometer data (collected between 2013 and 2015) were included from the UK Biobank. Three physical activity patterns were compared: active weekend warrior pattern (achieving ≥150 min MVPA per week and accumulating ≥50 % of total MVPA in 1–2 days), active regular pattern (achieving ≥150 min MVPA but not meeting active weekend warrior criteria per week), and inactive pattern (<150 min MVPA per week). The study outcomes included incident CKD and AKI, ascertained through self-report data and data linkage with primary care, hospital admissions, and death registry records. During a median follow-up of 6.8 years, 1324 participants developed CKD and 1515 developed AKI. In multivariable-adjusted models, when compared with inactive participants, individuals with active weekend warrior pattern (CKD: hazard ratio [HR], 0.79, 95 % confidence interval [CI], 0.69–0.89; AKI: HR, 0.70, 95 %CI, 0.62–0.79) and those with active regular pattern (CKD: HR, 0.81, 95 %CI, 0.69–0.95; AKI: HR, 0.79, 95 %CI, 0.68–0.91) exhibited a similar and significantly lower risk of incident CKD and AKI. Similar findings were observed at the median threshold of ≥230.4 min of MVPA per week. Concentrated MVPA within 1 to 2 days is as effective as distributed ones in decreasing the risk of renal outcomes. • Both concentrated and regular exercise yielded CKD and AKI benefits. • Concentrated exercise matched the efficacy of regular ones. • The relationship persisted across various definitions of concentrated exercise. [ABSTRACT FROM AUTHOR]

Background: Depression and chronic kidney disease (CKD) often coexist. However, both the relations of depression with CKD development and CKD with depression risk were still elusive. We aimed to investigate the bidirectional relations between renal function and depression in a cohort of young and middle-aged adults.Methods: Using data from the Coronary Artery Risk Development in Young Adults study, the analysis of depressive symptoms and incident CKD (analysis 1) was performed in 3,731 participants without CKD, and the analysis of renal function and incident depression (analysis 2) was performed in 2,994 participants without depression. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (-CES-D), and depression was defined as CES-D scores ≥16 or self-reported history of depression or antidepressant medication use. CKD was defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 or urinary albumin to creatinine ratio ≥30 mg/g.Results: In analysis 1, 485 participants developed incident CKD during 61,202 person-years of follow-up, and CES-D scores (≥16 vs. <16; adjusted HR, 1.28; 95% CI, 1.04 to 1.59) were significant positive associated with incident CKD. In analysis 2, 1,029 participants developed incident depression during 42,927 person-years of follow-up, and CKD was significantly associated with a 36% increased risk of incident depression compared to non-CKD (HR, 1.36; 95% CI, 1.05 to 1.76).Limitations: Depressive symptoms were only assessed using CES-D score, which is not the gold standard for the clinical diagnosis of depression.Conclusions: This prospective cohort study monitored over 20 years indicated a bidirectional association between depression and CKD. [ABSTRACT FROM AUTHOR]

Background: Dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease. We examined the relative risk of cardiovascular and renal events in these patients and the effect of dapagliflozin on either type of event, taking account of history of cardiovascular disease.Methods: In the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), 4304 participants with chronic kidney disease were randomly assigned to dapagliflozin 10 mg once daily or placebo. The primary end point was a composite of sustained decline in estimated glomerular filtration rate ≥50%, end-stage kidney disease, or kidney or cardiovascular death. The secondary end points were a kidney composite outcome (primary end point, minus cardiovascular death), the composite of hospitalization for heart failure or cardiovascular death, and all-cause death. In a prespecified subgroup analysis, we divided patients into primary and secondary prevention subgroups according to history of cardiovascular disease.Results: Secondary prevention patients (n=1610; 37.4%) were older, were more often male, had a higher blood pressure and body mass index, and were more likely to have diabetes. Mean estimated glomerular filtration rate and median urinary albumin-to-creatinine ratio were similar in the primary and secondary prevention groups. The rates of adverse cardiovascular outcomes were higher in the secondary prevention group, but kidney failure occurred at the same rate in the primary and secondary prevention groups. Dapagliflozin reduced the risk of the primary composite outcome to a similar extent in both the primary (hazard ratio, 0.61 [95% CI, 0.48-0.78]) and secondary (0.61 [0.47-0.79]) prevention groups (P-interaction=0.90). This was also true for the composite of heart failure hospitalization or cardiovascular death (0.67 [0.40-1.13] versus 0.70 [0.52-0.94], respectively; P-interaction=0.88), and all-cause mortality (0.63 [0.41-0.98] versus 0.70 [0.51-0.95], respectively; P-interaction=0.71). Rates of adverse events were low overall and did not differ between patients with and without cardiovascular disease.Conclusions: Dapagliflozin reduced the risk of kidney failure, death from cardiovascular causes or hospitalization for heart failure, and prolonged survival in people with chronic kidney disease, with or without type 2 diabetes, independently of the presence of concomitant cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036150. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.Methods: We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.Results: The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.Conclusions: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.). [ABSTRACT FROM AUTHOR]

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532.Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65).Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease.Funding: AbbVie. [ABSTRACT FROM AUTHOR]

Renal fibrosis is the common pathological feature of various chronic kidney diseases (CKD). Tubular cell senescence plays a key role in the progression of renal fibrosis. However, the underlying mechanisms are still in mystery. In this study, we identified, Pentraxin 3 (PTX3), belonging to the Pentraxin family, is a new fibrogenic factor. PTX3 was increased in various CKD models. PTX3 was primarily localized in tubular epithelial cells and upregulated, accompanied by mitochondrial dysfunction and cellular senescence. Overexpression of PTX3 aggravated mitochondrial damage and accelerated cell senescence in tubular cells, leading to more severe fibrogenesis in kidneys. However, knockout of PTX3 significantly preserved mitochondrial homeostasis, and blocked cellular senescence in primary cultured tubular cells. Furthermore, KYA1797K, a destabilizer of β-catenin, greatly inhibited PTX3-induced mitochondrial dysfunction, tubular cell senescence, and renal fibrosis. Overexpression of PTX3 triggered nuclear translocation of β-catenin, an activating form of β-catenin. PTX3-induced mitochondrial dysfunction and tubular cell senescence were also significantly inhibited by knockdown of p16INK4A, a senescence-related protein. In a clinical cohort, we found PTX3 was increased in urine and serum in patients with CKD. Urinary PTX3 negatively correlated with eGFR. PTX3 also increased gradually following the severity of diseases, triggering the fibrogenesis. Taken together, our results provide strong evidences that PTX3 is a new fibrogenic factor in the development of renal fibrosis through β-catenin-induced mitochondrial dysfunction and cell senescence. This study further suggests PTX3 is a new diagnostic factor to renal fibrosis and provides a new therapeutic target against renal fibrosis. • PTX3 is increased in CKD models and associates with CKD progression. • PTX3 induces mitochondrial dysfunction and tubular cell senescence via β-catenin activation, resulting in renal fibrosis. • Blockade of β-catenin reduces PTX3-induced renal fibrosis both in vivo and vitro. • These studies indicate an intrinsic linkage between PTX3 and renal fibrosis via β-catenin activation. [ABSTRACT FROM AUTHOR]

Aims: Acute kidney injury (AKI) is increasingly recognized as a major risk factor leading to progression to chronic kidney disease (CKD). However, the diagnostic tools for predicting AKI to CKD progression are particularly lacking. Here, we tested the utility of contrast-enhanced ultrasound (CEUS) for predicting progression to CKD after AKI by using both mild (20-min) and severe (45-min) bilateral renal ischemia-reperfusion injury mice. Results: Renal perfusion measured by CEUS reduced to 25% ± 7% and 14% ± 6% of the pre-ischemic levels in mild and severe AKI 1 h after ischemia ( p < 0.05). Renal perfusion returned to pre-ischemic levels 1 day after mild AKI followed by restoration of kidney function. However, severe AKI caused persistent renal perfusion impairment (60% ± 9% of baseline levels) accompanied by progressive renal fibrosis and sustained decrease in renal function. Renal perfusion at days 1-21 significantly correlated with tubulointerstitial fibrosis 42 days after AKI. For predicting renal fibrosis at day 42, the area under the receiver operating characteristics curve of renal perfusion impairment at day 1 was 0.84. Similar changes in the renal image of CEUS were observed in patients with AKI-CKD progression. Innovation: This study demonstrates that CEUS enables dynamic and noninvasive detection of renal perfusion impairment after ischemic AKI and the perfusion abnormalities shown by CEUS can early predict the progression to CKD after AKI. Conclusions: These results indicate that CEUS enables the evaluation of renal perfusion impairment associated with CKD after ischemic AKI and may serve as a noninvasive technique for assessing AKI-CKD progression. Antioxid. Redox Signal. 27, 1397-1411. [ABSTRACT FROM AUTHOR]