BACKGROUND:Atrasentan, a selective endothelin A receptor antagonist, reduced proteinuria in the prespecified interim analysis (week 36) of the ALIGN trial in adults with IgA nephropathy. We assessed whether atrasentan slowed estimated glomerular filtration rate (eGFR) decline after 2·5 years' treatment. METHODS:We performed a randomised, double-blind, placebo-controlled, phase 3 trial (133 sites, 20 countries). Adults with biopsy-proven IgA nephropathy, eGFR of at least 30 mL/min per 1·73 m2, and urinary protein excretion of at least 1·0 g/day while receiving renin-angiotensin system inhibition were enrolled (main stratum). An exploratory stratum enrolled participants also receiving an SGLT2 inhibitor. Participants were randomly assigned (1:1) to oral atrasentan 0·75 mg once daily or placebo for 132 weeks, followed by a 4-week off-treatment follow-up. The key secondary endpoint was change from baseline to week 136 in eGFR in the main stratum, assessed in all randomised patients (excluding data after intercurrent events, defined as initiation of restricted or alternative IgA nephropathy medications or kidney replacement therapy). Safety was assessed in all randomised patients who received at least one dose of study treatment. ALIGN is registered with ClinicalTrials.gov, NCT04573478; the double-blind section is complete, and the open-label extension is ongoing. FINDINGS:Between March 15, 2021, and April 28, 2023, 404 participants were randomly assigned (main stratum: 340; SGLT2 inhibitor stratum: 64). In the main stratum, change from baseline in eGFR at week 136 was -7·5 mL/min per 1·73 m2 (95% CI -9·2 to -5·8) with atrasentan and -9·9 mL/min per 1·73 m2 (-11·7 to -8·1) with placebo (between-group difference 2·4 mL/min per 1·73 m2; 95% CI -0·1 to 4·8; p=0·057). The between-group difference in eGFR change from baseline at end of treatment (week 132) was 2·6 mL/min per 1·73 m2 (95% CI 0·1-5·0), and the difference in total eGFR slope (baseline to week 136) was 1·4 mL/min per 1·73 m2 per year (95% CI 0·5-2·3). In the SGLT2 inhibitor stratum, the difference in eGFR change from baseline at week 136 between atrasentan and placebo was 9·1 mL/min per 1·73 m2 (95% CI 3·0-15·2). Treatment-emergent adverse events were well balanced between atrasentan and placebo, with no new safety signals. In the main stratum, fluid retention adverse events occurred in 24 (14%) of 169 patients receiving atrasentan and 20 (12%) of 170 receiving placebo. INTERPRETATION:Atrasentan reduced proteinuria and preserved kidney function after 2·5 years. This effect was present with or without concomitant SGLT2 inhibitor use. Atrasentan was well tolerated. FUNDING:Novartis.

Non-steroidal mineralocorticoid receptor antagonists (NS-MRAs) have emerged as a novel therapeutic class while minimizing the endocrine adverse effects associated with steroidal MRAs, such as spironolactone and eplerenone. Finerenone, the first clinically approved NS-MRA, exhibits high receptor selectivity, minimal off-target hormonal activity, and exerts potent anti-inflammatory and antifibrotic actions that complement renin-angiotensin system inhibition and sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy. The pivotal FIDELIO-DKD and FIGARO-DKD trials demonstrated clinically meaningful reductions in kidney disease progression and cardiovascular composite outcomes in patients with type 2 diabetes and albuminuric chronic kidney disease (urine albumin-creatinine ratio ≥ 30 mg/g), the pooled FIDELITY analysis confirmed consistent cardiorenal benefits across diverse risk strata. Hyperkalaemia remains a principal safety concern and requires potassium monitoring and dose adjustments in routine practice. Emerging short-term data on albuminuria suggest the additional benefits of concomitant SGLT2 inhibitor therapy, although definitive outcome evidence for combination strategies is still evolving. Ongoing clinical programs further extend the therapeutic scope of finerenone to heart failure with preserved ejection fraction, non-diabetic chronic kidney disease, and type 1 diabetes. Collectively, NS-MRAs provide a mechanistically distinct strategy targeting inflammation and fibrosis and represent an important therapeutic advance in integrated cardiorenal-metabolic risk reduction.

Hypertension is a major attributed cause of chronic kidney disease (CKD) and kidney failure, yet the cellular mechanisms linking chronic hemodynamic and neurohormonal stress to progressive nephron loss remain incompletely defined. Interpretation is further complicated by the clinical heterogeneity and limited pathological validation of hypertensive nephrosclerosis. Autophagy and mitophagy are important intracellular quality-control pathways and have been increasingly implicated in hypertensive kidney injury. In this review, we critically appraise the available evidence using a multidimensional ACGEM framework that evaluates autophagy/mitophagy measurement (A), cell-type resolution (C), genetic manipulation (G), experimental causality (E), and disease-model relevance (M) as independent dimensions. The available literature does not support a uniform increase or decrease in autophagy during hypertensive kidney disease. Rather, autophagic responses appear to depend on renal cell type, hypertensive stimulus, disease stage, and the component of the pathway being measured. In podocytes, chronic angiotensin II exposure provides evidence of impaired autophagic flux with a protective role for intact autophagy, whereas mineralocorticoid stress can induce a compensatory increase in autophagic flux. Tubular studies likewise suggest protective roles for effective autophagic and mitochondrial quality control, although direct cell-specific causal evidence in hypertensive models remains limited. Across the field, most studies rely on static autophagy-associated markers and bulk kidney measurements, while dynamic flux assessment, cell-specific genetic approaches, and direct evaluation of lysosomal competence remain uncommon. Observations from APOL1-associated kidney disease, chronic interstitial nephritis in agricultural communities, proteinuric overload, aging, and obesity provide mechanistic or pathological precedent for lysosomal vulnerability but do not constitute direct evidence for classical hypertensive nephrosclerosis. We therefore propose, as a falsifiable working hypothesis rather than an established mechanism, that lysosomal clearance may become rate limiting in a subset of hypertensive CKD. Testing this model will require longitudinal, cell-type-resolved flux measurements, direct assessment of lysosomal function, and pathological validation in biopsy-confirmed human hypertensive nephrosclerosis.

Background:Sarcopenia affects approximately 30%-40% of patients with end-stage kidney disease (ESKD) undergoing maintenance hemodialysis (HD), a prevalence substantially higher than that observed in community-dwelling older adults. Muscle wasting in this population is driven by chronic inflammation, amino acid losses during dialysis, and anabolic resistance, which blunt muscle protein synthesis despite nutritional intake or exercise. Leucine, a branched-chain amino acid that activates mechanistic target of rapamycin complex 1 signaling, plays a key role in muscle anabolism but is often depleted in patients undergoing HD. This pilot study evaluated the feasibility and preliminary effects of combining leucine supplementation with exercise on muscle-related outcomes in ESKD patients. Methods:In this single-center randomized pilot trial, 24 patients undergoing maintenance HD were assigned to either exercise alone or exercise plus leucine supplementation for 12 weeks. The intervention group received 6 g/day of leucine in beverage and capsule form. The primary outcome was the change in handgrip strength. Secondary outcomes included physical performance measures (gait speed, five-times sit-to-stand, and Short Physical Performance Battery), skeletal muscle mass indices, body composition, and biochemical markers. Exploratory analyses included responder analysis and metabolomic correlation analysis in an independent cohort. Results:Baseline characteristics were generally comparable between groups. The intervention group showed higher responder rates for handgrip strength and gait speed compared with the exercise-only group, while modest increases in skeletal muscle index were observed only in the intervention group. Several biochemical markers, including total protein, blood urea nitrogen, creatinine, and red blood cell count, showed directional increases in the intervention group. Independent metabolomic profiling demonstrated lower circulating leucine levels and disrupted amino acid correlations in HD patients compared with healthy controls. Conclusion:Adjunct leucine supplementation combined with exercise showed preliminary improvements in muscle function and selected biochemical markers in patients with ESKD undergoing HD. These findings support the potential role of leucine-based nutritional strategies in mitigating sarcopenia in this population, although larger and longer-term trials are required to confirm efficacy.

Podocyte injury and apoptosis are central drivers of progressive glomerular dysfunction in chronic kidney disease (CKD). Urine-derived stem cells (UDSCs) are kidney-proximal multipotent cells with reported renoprotective properties, but their effects on ADR (adriamycin)-induced podocyte apoptosis and the influence of dosing frequency remain incompletely defined. In vitro, conditionally immortalized human podocytes (CIHP-1) were exposed to ADR (dose–response 0.1–2.0 µM; time-course up to 48 h) was used for establishing podocyte apoptosis model. Human UDSCs were isolated from urine, expanded and characterized. Indirect transwell co-culture was performed for evaluating reno-protection effect of UDSCs. In vivo, BALB/c mice received 10 mg/kg ADR through intravenous (IV) injection on day 0; UDSCs (1× 10^6 cells/mouse) were administered starting day 7 as either a single dose or three daily doses. Endpoints included urine albumin/creatinine ratio (ACR), histology, TEM, immunostaining, and renal bulk transcriptomics. ADR induced early NF-κB activation and NLRP3/IL-1β increase followed by p53 and caspase-3 activation in CIHP-1. UDSC transwell co-culture attenuated NF-κB, NLRP3, IL-1β and caspase-3 induction, reduced cytochrome-c release, and preserved nephrin expression and F-actin architecture. In vivo, ADR increased ACR and produced glomerular injury with foot-process effacement; both single and repeated UDSC dosing reduced ACR and ameliorated histologic damage. Repeated dosing produced broader transcriptomic suppression of ferroptosis, ribosome biogenesis, and senescence/SASP-associated pathways compared with a single dose. UDSCs attenuate ADR-induced podocyte inflammation and apoptosis and promote structural and functional renal recovery. Dosing frequency shapes transcriptomic responses, with repeated dosing inducing broader anti-senescence signatures. These findings support further mechanistic investigation and translational development of UDSC therapy for CKD.

BACKGROUND:The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), inflammatory indices derived from routine complete blood counts, and red cell distribution width (RDW) have been proposed as prognostic markers in chronic kidney disease (CKD). However, whether the inflammatory ratios retain independent prognostic value once erythrocyte homeostasis is considered, and whether their performance varies across the spectrum of erythrocyte heterogeneity captured by RDW, remains uncertain. METHODS:This retrospective cohort study included 2,654 adults with non-dialysis CKD followed at a single tertiary center between 2015 and 2022. Optimal biomarker cut-off values were determined by receiver operating characteristic analysis based on 3-year all-cause mortality. Associations of RDW, NLR, and PLR with dialysis-free survival and overall survival were assessed using Kaplan-Meier analysis and multivariable Cox proportional hazards models adjusted for age, sex, kidney function, comorbidities, and nutritional and metabolic parameters. RDW-stratified analyses and formal interaction testing were performed to to determine whether NLR retains independent prognostic value within RDW-defined subgroups. Parallel analyses restricted to patients with eGFR < 60 mL/min/1.73 m2 were performed as a sensitivity analysis and reported as supplementary material. RESULTS:During a median follow-up of 2,413 days, 451 patients (17.0%) initiated dialysis and 239 (9.0%) died. In multivariable Cox analyses of the whole cohort, NLR did not retain an independent association with either dialysis initiation (HR 1.03, 95% CI 0.84-1.26; p = 0.771) or all-cause mortality (HR 1.23, 95% CI 0.92-1.64; p = 0.162). However, a statistically significant RDW × NLR interaction was observed for overall survival (p for interaction = 0.006): NLR was independently associated with mortality in the low RDW subgroup (HR 2.07, 95% CI 1.25-3.45; p = 0.006) but not in the high RDW subgroup (HR 0.88, 95% CI 0.62-1.26; p = 0.494). PLR did not retain independent prognostic value in any analysis, whereas RDW remained the only marker independently associated with all-cause mortality in the overall multivariable model (HR 1.72, 95% CI 1.31-2.26; p < 0.001). Fine-Gray competing-risks models yielded virtually identical estimates, and findings were consistent in the eGFR < 60 mL/min/1.73 m2 subgroup. CONCLUSIONS:In patients with non-dialysis CKD, NLR independently predicts all-cause mortality specifically in patients with preserved RDW, but loses incremental prognostic information once RDW is already elevated. These findings argue against the uncritical use of NLR as a universal prognostic marker in CKD and support an RDW-stratified, outcome-specific framework for applying inflammatory ratios in routine risk stratification.

Background:The role of apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) in renal fibrosis development remains unclear. This study aimed to investigate the role of APE1/Ref-1 deficiency on renal fibrosis and elucidate the underlying mechanisms using a unilateral ureteral obstruction (UUO) mouse model and HK-2 cells in vitro. Methods:Male wild-type and heterozygous APE1/Ref-1+/- mice underwent UUO or sham surgery. Renal tissue was collected at 7 and 14 days after UUO. APE1/Ref-1 expression, histological changes, fibrosis markers (collagen I, α-smooth muscle actin [α-SMA], vimentin, transforming growth factor-β1 [TGF-β1]), macrophage infiltration (F4/80, CD68), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) were assessed. In human kidney-2 (HK-2) cells, APE1/Ref-1 was knocked down using small interfering RNA, and epithelial-mesenchymal transition (EMT) markers (vimentin, α-SMA) were evaluated following TGF-β1 stimulation. Results:UUO upregulated APE1/Ref-1 expression in wild-type mice, but this was attenuated in heterozygous APE1/Ref-1+/- mice. While both genotypes displayed tubular injury, no significant differences in tubular injury scores or renal function markers were observed. Heterozygous APE1/Ref-1+/- mice exhibited exacerbated renal fibrosis compared to wild-type mice, as shown by increased collagen I, α-SMA, TGF-β1, and vimentin levels. Macrophage infiltration (CD68, F4/80) was significantly elevated in heterozygous APE1/Ref-1+/- mice after UUO. Increased 8-OHdG and TUNEL-positive cells indicated enhanced oxidative damage and apoptosis in heterozygous APE1/Ref-1+/- mice. In HK-2 cells, APE1/Ref-1 knockdown induced the upregulation of vimentin and α-SMA, suggesting a role in EMT regulation. Conclusion:APE1/Ref-1 deficiency exacerbates fibrosis, macrophage infiltration, and apoptosis. APE1/Ref-1 also modulates EMT in vitro, highlighting its protective function in chronic kidney disease.

Diabetic kidney disease (DKD) involves oxidative stress-driven damage to glomeruli (Gloms) and proximal convoluted tubules (PCT). NAD(P)H: quinone oxidoreductase 1 (NQO1) regulates redox balance, but its compartment-specific role remains unclear. Streptozotocin (STZ)-induced hyperglycemia increased albuminuria and foot process effacement, with NQO1 KO (NKO) mice exhibiting greater podocyte injury than WT, indicating exacerbated glomerular damage. To investigate the underlying mechanisms, we conducted compartment-specific transcriptomic Gene Set Enrichment Analysis (GSEA) in Gloms and PCT. In Gloms, ribosome biogenesis and immune pathways were upregulated in WT-STZ compared to WT but suppressed in NKO-STZ compared to STZ, indicating impaired protein synthesis and immune regulation in NQO1 deficiency. In PCT, ribosome activity, oxidative phosphorylation, glutathione metabolism, and cytoskeletal pathways were elevated in WT-STZ compared to WT but suppressed in NKO-STZ compared to WT-STZ. However, ribosome activity was relatively less affected than in Gloms. Additionally, adherens junction activation was more pronounced in WT-STZ Gloms than in NKO mice Gloms, suggesting a compensatory mechanism to maintain podocyte foot process integrity. This response involved key cytoskeletal genes, including Actg1, Ctnna1, Tjp1, Rhoa, and Iqgap1. These findings highlight compartment-specific adaptive responses to STZ-induced hyperglycemia and underscore NQO1's role in regulating these adaptations. Our results suggest that enhancing NQO1 activity may restore redox balance and preserve nephron integrity, supporting its potential as a therapeutic target for DKD. Furthermore, the observed compartment-specific responses highlight the need for precision redox therapies tailored to glomerular and tubular vulnerabilities.

Objectives: The impact of initial emergency room (ER) factors on survival and renal function in critically ill patients undergoing continuous renal replacement therapy (CRRT) remains unclear. This study aimed to evaluate whether these initial factors influence survival and renal recovery in such patients. Methods: This single-center, retrospective study included 190 critically ill patients admitted to the intensive care unit (ICU) via the ER for CRRT between 1 March 2018, and 31 May 2021. Clinical parameters, including urine output, estimated glomerular filtration rate (eGFR), and serum neutrophil gelatinase-associated lipocalin (NGAL), were assessed. The primary outcomes were 30-day and 90-day mortality, while secondary outcomes included 30-day and 90-day RRT-free durations. Results: Patients with low urine output (LUO, defined as the average of <0.5 mL/kg/h over 6 h) were significantly associated with higher 30-day and 90-day mortality rates. Multivariable Cox regression analysis revealed that the LUO group had an increased risk of 30-day and 90-day mortality (hazard ratios: 1.935 and 2.141, respectively) compared to the high urine output (HUO, defined as the average of ≥0.5 mL/kg/h over 6 h) group. No significant association was observed between mortality and initial eGFR or plasma NGAL levels. However, the HUO group and patients with initial eGFR ≥ 30 mL/min/1.73 m2 had longer RRT-free durations at 30 and 90 days. Plasma NGAL levels did not significantly correlate with RRT-free durations. Conclusions: Initial 6-h urine output in the ER is a significant predictor of 30-day and 90-day mortality in critically ill patients undergoing CRRT.

Renal ischemia-reperfusion injury (IRI) is a key driver of the progression from acute kidney injury (AKI) to chronic kidney disease (CKD), primarily through mechanisms involving oxidative stress, ferroptosis, and inflammation that promote fibrotic remodelling. This study investigates the therapeutic potential of MIT-001, a mitochondria-targeted reactive oxygen species (ROS) scavenger, in mitigating renal IRI. In vitro, MIT-001 attenuated ferroptotic cell death and fibrotic responses in HK-2 cells challenged with TGF-β or RSL3. MIT-001 restored GPX4 expression and activity, activated Nrf2 signalling, reduced lipid ROS and suppressed fibrogenic markers (α-SMA, Snail, collagen IV), while preserving E-cadherin levels. In a bilateral renal IRI mouse model, administration of MIT-001 significantly improved renal function and histology. Oxidative stress (DHE staining), apoptosis (TUNEL) and ferroptosis (4-HNE, xCT, GPX4) were markedly reduced. Additionally, MIT-001 inhibited the NF-κB/HMGB1 inflammatory axis and enhanced antioxidant defence via the Nrf2/HO-1 pathway, resulting in decreased immune infiltration and fibrosis. These findings demonstrate that MIT-001 confers renal protection by concurrently targeting oxidative stress, ferroptosis and inflammation, underscoring its promise as a therapeutic strategy to prevent AKI-to-CKD progression.

Objectives: This study aimed to classify fasting blood glucose (FBG) trajectories by sex and examine their associations with the risk of chronic kidney disease (CKD). Methods: Using data from the National Health Insurance Service-National Sample Cohort in Korea, participants aged 40 years and above, without CKD or diabetes mellitus (DM), were followed from 2002 to 2009. Based on their FBG trajectories, participants were categorized into two classes and stratified by sex. CKD incidence rates were analyzed according to these FBG trajectories, and the impact of additional risk factors on CKD incidence was assessed. Results: A total of 91,131 participants were analyzed. Among individuals classified in Class 1, FBG levels gradually increased from 90.7 (men) and 88.7 (women) in 2002 to 96.6 (men) and 93.2 (women) in 2009. In contrast, participants classified as Class 2 exhibited a rapid increase in FBG levels, rising from 106 (men) and 106 (women) in 2002 to 144 (men) and 132 (women) in 2009. The incidence of CKD increased over time in both men and women classified as Class 2 compared to Class 1, with respective hazard ratios (HR) of 1.35 for men and 1.53 for women. Additionally, increased age, hypertension, and body mass index (BMI) were independently associated with an elevated risk of CKD. Conclusions: The Class 2 group demonstrated a significantly higher incidence of CKD compared to the Class 1 group. This finding indicates the need for the proactive management of individuals with relatively high FBG levels featuring rapid FBG increases in order to mitigate the risk of CKD development.

Background: Hemodialysis patients face a high mortality risk, requiring effective clinical assessments. In these patients, muscle wasting due to protein-energy wasting (PEW) leads to increased frailty, which is strongly associated with worse outcomes, including higher mortality. As muscle mass declines, so does functional capacity, making regular assessment of both muscle mass and function critical for prognostic evaluation. Handgrip strength (HGS) offers a quick and reliable measure of muscle strength and functional capacity. In this study, we focused on the impact of HGS on survival in hemodialysis patients, analyzing its relationship with muscle mass and BMI. Methods: This retrospective cohort study included 408 dialysis patients (221 males, 187 females) who underwent bioimpedance spectroscopy (BIS) and HGS assessments between March 2021 and August 2023. Data collected included BIS profiles, HGS, dialysis status, age, complete blood count, blood chemistry, mortality, and CONUT scores. Results: Cox proportional hazards regression analysis revealed that lean tissue index (LTI) (HR 3.30, 95% CI 1.75–6.19), body mass index (BMI) (HR 2.65, 95% CI 1.17–6.01), and handgrip strength (HGS) (HR 4.22, 95% CI 2.05–8.70) were significant predictors of survival in the overall dialysis patient cohort. Gender-specific analysis showed that in males, both LTI (HR 4.81, 95% CI 1.89–12.23) and HGS (HR 5.45, 95% CI 2.18–13.61) significantly predicted survival. In females, HGS (HR 6.01, 95% CI 2.42–14.94) was a significant predictor, while LTI was also significant (HR 3.22, 95% CI 1.24–8.40, p = 0.017). In the multivariate Cox proportional hazards analysis, which adjusted for age, diabetes mellitus (DM), hypertension (HTN), BMI, fat tissue index (FTI), LTI, serum albumin, C-reactive protein (CRP), and CONUT score, HGS remained a significant predictor of survival in female dialysis patients (HR 2.77, 95% CI 1.00–7.65, p = 0.049). Conclusions: HGS has been identified as an important factor for survival in dialysis patients, particularly in female patients, independent of muscle mass and BMI.

Obesity and adipose tissue are commonly regarded as detrimental factors linked to adverse outcomes, including cardiovascular and metabolic diseases. However, the obesity paradox is obesity that may provide survival benefits for chronic diseases including patients undergoing hemodialysis. Fat mass can be a surrogate marker for nutrition status in patients undergoing hemodialysis. Thus, this study evaluated subcutaneous fat and all-cause mortality in patients initiating hemodialysis. A total of 123 patients initiating hemodialysis were included in this study. MATLAB (version R2014a) was used to identify subcutaneous fat area (SFA) and visceral fat area (VFA) in computed tomography images for the analysis of body composition. The survival rate was calculated using Cox regression analysis. The Kaplan-Meier survival rates were 70.0% and 85.7% in the low and high subcutaneous fat area (SFA) groups, respectively (log rank, p = 0.021). In Cox analysis, the low SFA group showed high risk for all-cause mortality than the high SFA group (hazard ratio (HR) 3.541, 95% CI 1.358-9.235, p = 0.010). In subgroup univariate analysis, the risk for all-cause mortality was higher in patients with low SFA and diabetes than those with high SFA and diabetes (HR 3.541, 95% CI 1.358-9.235, p = 0.010). In multivariate analysis, the risk for all-cause mortality was higher in patients with low SFA and diabetes than those with high SFA and diabetes (HR 4.615, 95% CI 1.484-14.351, p = 0.008). Conclusively, low SFA increases the risk of 2-year all-cause mortality, and SFA analysis can provide information for risk evaluation for patients initiating hemodialysis.

Background: Hypothermia has been previously reported to ameliorate acute renal injury induced by ischemia–reperfusion injury (IRI). However, its protective effects against subsequent renal fibrosis remain unclear. Objectives: The aim of this study was to determine whether hypothermia provides protection against renal ischemia–reperfusion injury (IRI), and to elucidate the molecular mechanisms involved. Methods: We used a model of renal fibrosis after ischemia–reperfusion injury in mice. C57BL/6 mice were divided into the following groups: control mice and ischemia–reperfusion injury mice (at 37 °C and at 32 °C). Their kidneys were harvested on day 1, day 3, and day 7 after IRI. The molecular mechanisms were evaluated. Results: The blood urea nitrogen (BUN) levels, serum creatinine (s-Cr) levels, and the histologic renal injury scores were significantly lower in the 32 °C IRI group than in the 37 °C ischemia–reperfusion injury group. In the hypothermic IR group, TGF-β and α-SMA were significantly decreased, while the PGC-1α level was significantly increased. Cold preparation increased the PGC-1α levels in HK2 cells. In TGF-β-treated HK2 cells, cold preparation decreased α-SMA and collagen IV levels. In addition, siPGC-1α in HK2 cells increased α-SMA and collagen IV, despite cold preparation. Conclusions: Hypothermia attenuates renal function deterioration and renal fibrosis in renal IRI mice kidneys. PGC-1α may play a role in hypothermic protection in renal fibrosis after IRI.

ABSTRACT Background Age‐related primary sarcopenia and end‐stage renal disease (ESRD)–related muscle wasting are discrete entities; however, both manifest as a decline in skeletal muscle mass and strength. The etiological pathways differ, with aging factors implicated in sarcopenia and a combination of uremic factors, including haemodialysis, contributing to ESRD‐related muscle wasting. Understanding these molecular nuances is imperative for targeted interventions, and the integration of proteomic and metabolomic data elucidate these intricate processes. Methods We generated detailed clinical data and multi‐omics data (plasma proteomics and metabolomics) for 78 participants to characterise sarcopenia (n = 28; mean age, 72.6 ± 7.0 years) or ESRD (n = 22; 61.6 ± 5.5 years) compared with controls (n = 28; 69.3 ± 5.7 years). Muscle mass was measured using bioelectrical impedance analysis and handgrip strength. Five‐times sit‐to‐stand test performance was measured for all participants. Sarcopenia was diagnosed in accordance with the 2019 Consensus Guidelines from the Asian Working Group for Sarcopenia. An abundance of 234 metabolites and 722 protein groups was quantified in all plasma samples using liquid chromatography with tandem mass spectrometry. Results Muscle mass, handgrip strength and lower limb muscle function significantly lower in the sarcopenia group and the ESRD group compared with those in the control group. Metabolomics revealed altered metabolites, highlighting exclusive differences in ESRD‐related muscle wasting. Metabolite set enrichment analysis revealed the involvement of numerous metabolic intermediates associated with urea cycle, amino acid metabolism and nucleic acid metabolism. Catecholamines, including epinephrine, dopamine and serotonin, are significantly elevated in the plasma of patients within the ESRD group. Proteomics data exhibited a clearer distinction among the three groups compared with the metabolomics data, particularly in distinguishing the control group from the sarcopenia group. The ciliary neurotrophic factor receptor was top‐ranked in terms of the variable importance of projection scores. Plasma AHNAK protein levels was higher in the sarcopenia group but was lower in the ESRD group. Proteomic set enrichment analysis revealed enrichment of several pathways related to sarcopenia, such as hemopexin, defence response and cell differentiation, in sarcopenia group. Multi‐omic integration analysis revealed associations between relevant metabolites, including catecholamines, and a group of annotated proteins in extracellular exosomes. Conclusions We identified distinct multi‐omic signatures in individuals with ESRD or sarcopenia, providing new insights into the mechanisms underlying ESRD‐related muscle wasting, which differ from primary sarcopenia. These findings may support interventions for context‐dependent muscle loss and contribute to the development of targeted treatments and preventive strategies for muscle wasting.

Cognitive dysfunction is more frequent in end-stage renal disease (ESRD) patients undergoing hemodialysis compared with the healthy population, emphasizing the need for early detection. Interest in serum markers that reflect cognitive function has recently increased. Elevated serum growth differentiation factor 15 (GDF-15) levels are known to be associated with an increased risk of decreased renal function and cognitive dysfunction. This study investigated the relationship between GDF-15 and cognitive dysfunction in hemodialysis patients using a retrospective analysis of 92 individuals aged ≥ 18 years. Cognitive function was assessed using the Korean version of the Mini-Mental Status Examination (K-MMSE), categorizing patients into normal (≥24 points) and cognitive dysfunction (<24 points). As a result, serum GDF-15 concentrations were at significantly higher levels in the cognitive dysfunction group (7500.42 pg/mL, p = 0.001). Logistic regression indicated an increased risk of K-MMSE scores < 24 points when serum GDF-15 exceeded 5408.33 pg/mL. After indoxyl sulfate exposure in HT22 cells, HT22 cells survival was decreased and GDF-15 expression in HT22 cells was increased. Similarly, exposure to indoxyl sulfate in mouse brain tissue resulted in an increased expression of GDF-15. This study highlights the potential of serum GDF-15 as a marker for cognitive dysfunction in hemodialysis patients, offering a valuable screening tool. Serum GDF-15 is related to cognitive dysfunction in hemodialysis patients and may be helpful in screening for cognitive dysfunction in hemodialysis patients.

The global prevalence of CKD continues to increase, with diabetes accounting for the highest proportion. There is a lack of information on how much diabetes will affect the incidence of CKD in the eGFR group measured in the single examination.