肾内科领域文献阅读汇编

Pregnancy represents a critical period during which the maternal cardiovascular system adapts to profound haemodynamic and metabolic demands. When these adaptive mechanisms are impaired, adverse pregnancy outcomes (APOs)-including hypertensive disorders of pregnancy, gestational diabetes, pre-term birth, small-for-gestational-age birth, and pregnancy loss-occur. Extensive epidemiological evidence demonstrates that APOs are not isolated obstetric events but early clinical markers of cardiometabolic dysfunction that identify women at increased risk of coronary artery disease, heart failure, stroke, chronic kidney disease, and premature cardiovascular mortality. Shared mechanisms include endothelial dysfunction, inflammation, and insulin resistance, establishing a continuum between obstetric complications and later cardiovascular disease. Early post-partum studies reveal persistent hypertension, adverse cardiac remodelling, and metabolic abnormalities that mediate much of the long-term excess cardiovascular risk. These findings redefine the 'fourth trimester' as a preventive window in which timely blood pressure surveillance, metabolic screening, and lifestyle optimization can yield durable cardiovascular benefit. Integrated cardio-obstetric care models, digital follow-up, and systematic transition to primary care are crucial for maintaining long-term prevention. Addressing persistent gaps in limited provider awareness, fragmented follow-up, and disparities across socially disadvantaged populations remains critical. Recognizing pregnancy complications as indicators of underlying cardiovascular vulnerability offers an opportunity to shift prevention upstream and promote lifelong cardiovascular health for women.

GIM/FP/GP: [Formula: see text] Cardiology: [Formula: see text] Endocrinology: [Formula: see text] Nephrology: [Formula: see text].

GIM/FP/GP: [Formula: see text] Nephrology: [Formula: see text] Hematology: [Formula: see text].

The cardiovascular-kidney-liver-metabolic (CKLM) framework represents the multi-organ interplay of systemic metabolic disorders that drive the global burden of cardiovascular diseases (CVD). This study is a descriptive epidemiological analysis of the Global Burden of Disease Study 2023 that examines the trends in mortality and disability-adjusted life years (DALYs) associated with atherosclerotic CVD, chronic kidney disease (CKD), type 2 diabetes (T2D), obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), from 1990 to 2023, across 204 countries and territories. Epidemiological trends were stratified by age, sex, region, and sociodemographic index (SDI). In 2023, the global CKLM burden contributed to 626.7 million DALYs, with an age-standardized DALY rate of 6944.3 per 100,000 population. Atherosclerotic CVD was the largest contributor to the CKLM burden (3924.2 [95% Uncertainty Interval {UI}: 3666.9-4181.4]), followed by obesity (1500.0 [95% UI: 730.4-2206.5]), T2D (956.7 [95% UI: 794.4-1142.4]), CKD (523.8 [95% UI: 468.0-590.1]), and MASLD (39.6 [95% UI: 31.2-49.9]). From 1990 to 2023, CKLM-related age-standardized DALYs fell 24.4%, primarily driven by improvements in atherosclerotic CVD (41.5% decrease), while rapid increases were seen in T2D (37.5% increase) and obesity (23.3% increase). Disparities in CKLM burden exist across SDI, geography, and age-sex categories. Improvements in the global CKLM burden, driven by gains in CVD prevention, are offset by the rising burden of upstream CKLM drivers including obesity, T2D, CKD and MASLD. Population-focused strategies for prevention need to target shared risk factors driving the CKLM syndemic to achieve the greatest reduction in overall morbidity and mortality. This research was supported by the NMRC Research Transition Award and the CSDU Clinician-Scientist Grant.

AbstractIron deficiency is common in patients with chronic kidney disease (CKD). Contemporary guidelines recommend the use of iron therapy only in the presence of anemia. However, patients with CKD are at increased risk of heart failure, and the coexistence of both conditions is associated with impaired quality of life, reduced physical function, and increased mortality compared with either condition alone. In this Tomorrow's Trial article, we review current evidence for intravenous iron in CKD and heart failure and propose the design of a randomized trial of intravenous iron, independent of hemoglobin, to assess its effects on mortality, heart failure, and physical function.

The aim for this study was to describe adverse outcomes after Charcot neuro-osteoarthropathy (CNO) diagnosis in adults with diabetes and examine variation by clinical and sociodemographic characteristics. A regional, registry-based cohort study was conducted using linked routinely collected health care data from adults with diabetes and a first recorded CNO diagnosis in the National Health Service Greater Glasgow and Clyde, Scotland (2015-2024). Outcomes were all-cause emergency hospitalization, lower-extremity amputation, all-cause mortality, and amputation-free survival. Time-to-event methods and multivariable regression were used to estimate event probabilities and tested associations with clinical characteristics. From 127,513 adults with diabetes, 140 individuals with a first recorded CNO diagnosis were identified; their mean age was 59 years, and 67% were men. During a median 4.6-year follow-up, 123 patients (87.9%) had an emergency admission, 44 (31.4%) underwent lower-extremity amputation (minor or major), and 53 (37.9%) died. The estimated 5-year survival was 67%, while 5-year amputation-free survival was 44% (median 4.04 years). Advanced chronic kidney disease (stages 4 and 5) was associated with higher risk across outcomes. High or active foot-risk status was independently associated with lower-extremity amputation (subdistribution hazard ratio 8.52; 95% CI 2.05-35.45) and shorter amputation-free survival (hazard ratio (HR) 2.09; 95% CI 1.15-3.80), and older age was independently associated with higher mortality rate (HR 3.04; 95% CI 1.50-6.16). Adverse outcomes in CNO were frequent and occurred early after diagnosis, with high rates of emergency hospitalization, amputation, and death. These findings support CNO as a marker of systemic vulnerability and highlight the need for prioritized surveillance and multidisciplinary management in routine clinical care.

Genome-wide association studies (GWAS) for kidney function have mainly focused on creatinine-based glomerular filtration rate (eGFRcrea), which is affected by variation in muscle mass. Moreover, the genetic basis of the sexual dimorphism of chronic kidney disease is underexplored. We performed a GWAS meta-analysis for creatinine clearance (CrCl), a muscle mass-independent measure of kidney function, in 58,976 individuals of European ancestry from the Lifelines Cohort Study, including sex-specific analyses. We identified 16 independent loci with 21 genome-wide significant lead single-nucleotide polymorphisms (SNPs) associated with CrCl, two of which had not been reported previously in kidney function GWASs: rs146465192, located near the RP1-249F5.3 gene (effect allele frequency (EAF) 0.01, P = 3.38 × 10-9) and rs117014836, located near the AGPAT4 gene (EAF 0.02, P = 5.42 × 10-9). Both loci were also significantly associated with eGFRcrea in Lifelines, but not in previously published eGFR GWASs. In silico annotations revealed that rs146465192 was associated with plasma levels of IGF2R protein, whereas rs117014836 was associated with blood expression of AGPAT4 transcript. Furthermore, we identified two significant female-specific CrCl loci: rs8002366 (GPC6 locus) and rs12908437 (IGF1R locus), associated with GPC6 expression in kidney and IGF1R expression in blood, respectively. Our first large-scale GWAS of CrCl revealed two new genetic variants among both sexes and two female-specific variants influencing kidney function and highlighting the value of CrCl as a muscle mass-independent phenotype.

Chronic kidney disease (CKD) is closely intertwined with obesity, diabetes, hypertension, dyslipidemia, and cardiovascular disease. In 2023, the American Heart Association formally recognized these interconnections as a unified entity, the cardiovascular-kidney-metabolic (CKM) syndrome. The CKM syndrome brings renewed attention to the importance of CKD in cardiovascular disease and reinforces the need for effective, evidence-based, interdisciplinary approaches to diagnose and prevent its intersecting components. The Kidney Disease: Improving Global Outcomes (KDIGO) organization has long led efforts to synthesize knowledge and translate evidence to practice in this area through the lens of the kidney. This review highlights KDIGO clinical practice guidelines and controversies conference publications that directly address the CKM syndrome. These include guidelines addressing CKD, blood pressure, diabetes, and lipids; an upcoming guideline addressing heart failure in CKD; and controversies conference reports addressing obesity and CKD prevention. Overarching themes include the importance of early detection and intervention; comprehensive, personalized management of kidney and cardiovascular risk; and multidisciplinary care. Through integrated, evidence-based, disease-specific guidelines and reports, KDIGO has established a robust framework for the management of people at risk for or with CKM syndrome as well as priorities for ongoing research.

General population distributions of lipoprotein(a) (Lp(a)) are well-characterized. However, less is known about its distributions and associated event rates within high-risk populations, including individuals with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and varying levels of subclinical atherosclerosis and calcific aortic valve disease. Yet, such insights will facilitate clinical implementation of Lp(a) testing and enhance the design of clinical trials with Lp(a)-lowering agents. Data from 5,129 participants in the population-based Rotterdam Study were used to assess Lp(a) distributions, prevalence of Lp(a) levels exceeding thresholds used in ongoing trials (i.e. >150, >175, and >200 nmol/L), accompanying numbers needed to screen (NNS), and major adverse cardiovascular event (MACE) rates across high-risk groups. Lp(a) distributions were right skewed across all groups. Among participants with ASCVD, 13.5% (11.9-15.3%) had Lp(a) >150 nmol/L and 6.5% (5.3-7.8%) had >200 nmol/L, with corresponding NNS 7.4 and 15.4. Similar distributions were observed between participants with coronary artery calcium (CAC) score >300 and participants with coronary heart disease (CHD). Prevalence in participants with aortic valve calcification (AVC) scores >300 was double that of the general population: 20.2% (13.0-27.4) at >150 nmol/L and 11.8% (6.6-19.0) at >200 nmol/L, with the lowest NNS across all groups (5.0-8.5). MACE rates varied by group and increased progressively with higher Lp(a) thresholds. Lp(a) distributions and MACE rates substantially vary across high-risk groups in the general population. These findings can facilitate design and recruitment strategies of studies with emerging Lp(a)-lowering therapies, while also aiding in identification of populations who may benefit from such therapies.

Hypertension is a common attributable cause of chronic kidney disease (CKD). Mineralocorticoid receptor overactivation can lead to hypertension and contributes to CKD progression. In FIND-CKD, finerenone reduced kidney function decline in participants with CKD without diabetes. This prespecified FIND-CKD analysis assessed finerenone efficacy and safety in participants with hypertensive nephropathy. Adults with estimated glomerular filtration rate (eGFR) 25-<90 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 200-3500 mg/g were randomized 1:1 to once-daily finerenone or placebo. Hypertensive nephropathy was investigator-reported. Total eGFR slope from baseline to Month 32 was assessed, along with a kidney-cardiovascular composite of sustained ≥57% eGFR decline, kidney failure, hospitalization for heart failure, or cardiovascular death. Of 1584 randomized participants, 459 (29.0%) had hypertensive nephropathy. Mean blood pressure (± SD) was 134/80 ± 14/10 mmHg, mean eGFR was 44 ± 15 mL/min/1.73 m2, median UACR was 797 mg/g (Q1, Q3: 566, 1247). In participants with hypertensive nephropathy, finerenone slowed total eGFR decline versus placebo by 0.65 mL/min/1.73 m2/year (95% CI: 0.02, 1.29; P = .044) and was associated with a reduction in composite kidney-cardiovascular outcome events (HR: 0.61; 95% CI: 0.38, 0.99; P = .045). These effects were consistent irrespective of baseline systolic blood pressure (SBP) (P-interaction: eGFR slope, 0.96; composite outcome, 0.91). Finerenone reduced SBP by -3.5 mmHg and UACR by 33% at Month 6 vs placebo. Hyperkalaemia occurred more frequently with finerenone (17.1%) than placebo (9.8%); related discontinuation was uncommon (1.3% vs 0.0%, respectively). Finerenone slowed eGFR decline and reduced kidney-cardiovascular outcome risk in participants with hypertensive nephropathy, supporting its use in this population. ClinicalTrials.gov registration: NCT05047263.

The cardiovascular-kidney-metabolic (CKM) syndrome framework integrates the shared pathophysiology of cardiovascular disease, excess adiposity, diabetes, and chronic kidney disease into a unified staging framework. Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic stem cells harbouring somatic mutations, has been linked to several CKM components, but its relationship with CKM syndrome is unknown. UK Biobank participants without a history of hematologic malignancy were included. Exposures included any CHIP, large CHIP, and major gene-specific CHIP subtypes. Outcomes were CKM stage and progression to stage 4 CKM syndrome during follow-up. Associations of CHIP with CKM stage and progression were tested using multivariable-adjusted logistic and Cox regression, respectively. Proteomic mediation analyses prioritized circulating proteins associated with CKM progression. Among 451,460 participants (mean [SD] age, 56.5 [8.1] years; 245,055 females [54.3%]), 15,486 (3.4%) had CHIP. CHIP was associated with higher CKM stage, driven by associations with non-DNMT3A CHIP, including TET2 (adjusted OR [aOR], 1.10; 95% CI, 1.00-1.20; false discovery rate [FDR]-corrected P = 0.045) and JAK2 CHIP (aOR, 1.68; 95% CI, 1.20-2.35; FDR-corrected P = 0.003). Over a median (IQR) 13.5 (12.6-14.3) years of follow-up, CHIP was independently associated with progression to stage 4 CKM, again driven by associations with non-DNMT3A CHIP subtypes (aHR, 1.24; 95% CI, 1.17-1.31; FDR-corrected P < 0.001). Proteomic mediators of progression to stage 4 CKM in non-DNMT3A CHIP were enriched for immune and inflammatory signalling pathways. These findings identify non-DNMT3A CHIP as a marker of CKM progression and support inflammatory mechanisms linking CHIP to CKM syndrome.

This observational study investigated whether patients with coronary heart disease (CHD) in Europe are achieving the standards set by prevention and rehabilitation guidelines. Variability was studied: (i) between countries; (ii) between geographical risk regions; and (iii) attendance at cardiac rehabilitation (CR) with outcomes. Observational study between September 2024- February 2026 in 160 hospitals across 27 countries. Geographical risk regions were defined as high, moderate or low based on WHO cardiovascular mortality data. Among 8590 patients with CHD (23.7% female), 17.1% were current smokers, 32.0% were obese and 33.5% reported low physical activity. 59.8% were above blood pressure target (systolic ≥ 130 and/or diastolic ≥ 80 mmHg), 82.7% were above LDL-C target (≥ 1.4 mmol/l), 32.8% had known diabetes of whom 42.2% had HbA1c ≥ 7% and 30.6% had chronic kidney disease. Prevalences of these risk factors were all highest in countries from high risk regions. 29.1% of patients attended at least one CR session, with country variability ranging from 0% to 79%, and differing by risk region (55.9% low risk, 29.7% moderate risk and 10.2% high risk; p < 0.001). Attendance at CR programme was associated with significantly better lifestyles, risk factor control and use of cardioprotective drugs. Most European patients are not achieving targets set by prevention guidelines. There is marked variability in CR attendance, evidence of inverse care with lowest attendance in highest risk regions, despite better outcomes for CR. These results inform the challenges for implementation of the first ESC guideline on CR.

Improving Global Outcomes (KDIGO) has published the Clinical Practice Guidelines (CPG) on managing diabetes in CKD in 2022 and the CPG for managing blood pressure in CKD in 2020. KDIGO organized a guideline implementation summit targeting the Asia-Pacific region in Kuala Lumpur in 2024 with the aim to understand existing barriers and challenges in implementation of the two CPGs and to propose possible solutions, tailored to the country or region's income level to bridge existing gaps in guideline implementation. The implementation summit discussion covered 4 key themes: i) lifestyle intervention; ii) adoption of comprehensive team-based integrated care model; iii) achievement of various treatment targets albuminuria screening and monitoring of kidney disease; and iv) implementation of guideline-directed medical therapies. The Summit was attended by co-chairs of the KDIGO CPGs on diabetes and blood pressure management in CKD, with nephrologists, endocrinologists, primary care physicians, dietitians, a health economist, and patient partners from 13 Asia-Pacific countries or regions. This conference report summarizes the key challenges in the CPG implementation for diabetes, hypertension in people with CKD in Asia-Pacific region, and provides a strategic framework of actions to overcome these barriers.

Metabolic syndrome describes a set of risk factors that can eventually lead to the occurrence of cardiovascular and cerebrovascular disease. Metabolic syndrome has emerged as a significant global health issue, associated with various metabolic diseases, including obesity, diabetes, hypertension, dyslipidemia, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, and other metabolic disorders. Here, we summarize the intricate mechanisms including insulin resistance, chronic low-grade inflammation, oxidative stress, and epigenetic modifications, and how they contribute to the disease progression of metabolic syndrome. The gut-adipose tissue axis in the progression of metabolic syndrome is emphasized here, mainly involving adipocyte-derived extracellular vesicles and adipokines, as well as specific gut microbiota and their secreted factors, such as lipopolysaccharide, short-chain fatty acids, endocannabinoids, bile acids, aryl hydrocarbon receptor ligands, and tryptophan derivatives. Furthermore, the contemporary management for metabolic syndrome mainly includes some established pharmacological treatments such as GLP-1 receptor agonists, SGLT2 inhibitors, and RAAS inhibitors, as well as promising emerging therapies targeting the gut-adipose tissue axis such as lifestyle modifications, prebiotics, probiotics, synbiotic supplements, FMT, bariatric surgery, CB1R antagonists, and novel pharmacological agents. These strategies may pave the way for the development of effective treatments for metabolic diseases in future research.

Despite decades of investigation, effective therapies for medial arterial calcification in chronic kidney disease remain lacking. Emerging therapeutic targets increasingly extend beyond systemic drivers of calcification and now seek to address direct vascular cellular mechanisms and the calcium-phosphate mineralization itself. In this issue, Öztürk et al. describe platelet-derived growth factor receptor β activation as a potent mediator of chronic kidney disease-induced vascular smooth muscle cell osteogenic differentiation and calcification, supporting vascular cell targeting as an emerging therapeutic axis in chronic kidney disease-associated medial arterial calcification.

Ground-level ozone pollution has emerged as a significant environmental risk factor for diabetic kidney diseases, yet the underlying mechanisms and potential interventions remain poorly defined. This study investigated the nephrotoxic effects of ozone in a diabetic model, wherein male db/db mice were exposed to ozone (0.25 or 1.0 ppm) for 8 weeks. Moreover, dapagliflozin (DAPA) and Yishen Huashi Granules (YSHS), pharmaceutical agents commonly used to treat metabolic and renal diseases, were applied to investigate their therapeutic potential against ozone-caused kidney insult. Our data demonstrated that ozone exposure could exacerbate hyperglycemia and structural renal damage, including glomerular basement membrane thickening, podocyte fusion, and fibrogenesis. Furthermore, ozone exposure disrupted the splenic Th17/Treg balance, enhanced IL-17 production, and promoted renal inflammation through upregulating RORγt/IL-17A signaling pathway. These findings suggested that ozone exposure could accelerate diabetic nephropathy progression by reshaping the systemic immune landscape. Notably, DAPA and YSHS, especially their combination, showed the potential to mitigate kidney injury by ozone through synergistically restoring glucose homeostasis, Th17/Treg balance and RORγt/IL-17 signaling to suppress systemic and local inflammation. This study provided valuable insights into the nephrotoxic effects associated with ozone exposure, and offered a reference for the development of intervention strategies targeting pollutant-driven metabolic kidney disease and the formulation of environmental regulations.

Exposure to fine particulate matter (PM2.5) is associated with renal injury and chronic kidney disease (CKD) progression, yet its mechanisms remain incompletely understood. In this study, we exposed mice to urban PM2.5 at an environmentally relevant dose via the respiratory tract and combined this with renal ischemia-reperfusion injury (IRI) to systematically assess its effects on kidney function and structure. Meanwhile, we investigated the relevant molecular biological mechanisms underlying renal functional and structural damage mediated by the lung-kidney axis following repeated intratracheal PM2.5 exposure. The results indicated that PM2.5 exposure significantly exacerbated renal dysfunction, tubular injury, and fibrosis, accompanied by increased lipid droplet accumulation and upregulation of fibrotic markers, and adenylate cyclase 3 (ADCY3) was identified as a critical target in this pathological process. Mechanistically, PM2.5 induced systemic inflammation and elevated circulating interleukin-6 (IL-6) levels, with alveolar macrophages likely contributing as a key source. Elevated IL-6 subsequently suppressed the function of ADCY3-CREB-PGC1α signaling pathway, leading to impaired fatty acid β-oxidation (FAO), enhanced glycolysis, mitochondrial dysfunction, oxidative stress, and fibrotic progression. Functional experiments further confirmed that blocking IL-6 signaling or overexpressing ADCY3 mitigated renal tubular epithelial cell injury, lipid metabolic dysregulation, and fibrotic responses mediated by PM2.5 exposure both in vivo and in vitro. In conclusion, this study offers a new insight into the intricate molecular mechanisms through which PM2.5 exposure exacerbates renal injury and CKD progression, suggesting that the IL-6/ADCY3 signaling pathway plays a crucial role in renal injury induced by PM2.5 exposure.

Lactate and β-hydroxybutyrate (βHB), once regarded mainly as metabolic byproducts or alternative fuels, are now increasingly recognized as redox-active metabolites that regulate energy partitioning, mitochondrial function, and adaptive stress responses. Here, we propose a unifying framework in which lactate and βHB form a redox-coupled inter-organ circuit linking the liver, kidney, heart, and skeletal muscle. Through coordinated LDH- and BDH1-dependent reactions and monocarboxylate transport, the lactate-βHB axis integrates carbohydrate and lipid metabolism, supports dynamic fuel switching, and links distinct cytosolic and mitochondrial NAD+/NADH redox states during fasting, exercise, hypoxia, and metabolic stress. Disruption of this circuit contributes to mitochondrial dysfunction, impaired metabolic flexibility, and maladaptive redox signaling in disorders including metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. Beyond their bioenergetic roles, lactate and βHB also act as signaling metabolites that influence transcriptional, epigenetic, post-translational, and stress-response pathways, including protein lysine lactylation and β-hydroxybutyrylation, thereby linking metabolic state to cellular adaptation, tissue resilience, and long-term remodeling. Importantly, interventions including exercise, ketogenic or low-carbohydrate diets, SGLT2 inhibition, ketone-based strategies, and NAD+-enhancing approaches may help restore lactate-βHB coupling and improve redox homeostasis. This framework positions the lactate-βHB axis as a systems-level mechanism of inter-organ redox communication and provides a redox-biological basis for therapeutic targeting in metabolic and degenerative disease.

Vascular calcification is common in chronic kidney disease (CKD), contributing to increased cardiovascular morbidity and mortality. A proposed mechanism for driving vascular calcification is a phenotypic switch of vascular smooth muscle cells (VSMCs). The platelet derived growth factors (PDGFs) and their receptors (PDGFRs), particularly PDGFR-β, were shown to modulate the VSMC phenotype. However, their role in uremic vascular calcification remained unclear. To study this, we adapted an ex vivo calcification model using murine aortas to simulate uremic conditions. Next, we generated transgenic mice with a VSMC-specific, inducible expression of constitutively active PDGFR-β and established an in vivo model of accelerated vascular calcification and CKD in the transgenic mice. Compared to control conditions, incubation of mouse aortas with dialysis fluid from uremic patients on hemodialysis therapy or examination of aortas from CKD animals both revealed increased PDGFR-β phosphorylation and vascular calcification. Inhibition of PDGF signaling using soluble PDGFR-β or the small molecule tyrosine kinase inhibitor imatinib reduced uremic calcification and enhanced vascular elasticity. Next, we generated transgenic mice with a VSMC-specific, inducible expression of constitutively active PDGFR-β. The aortas of these mice exhibited increased calcification ex vivo, which was further aggravated by uremic conditions, attesting a phenotypic switch of VSMCs compared to non-transgenic littermates. Finally, increased expression of phosphorylated PDGFR-β and a VSMC phenotypic switch were detected in arteries from patients with CKD stage 5 compared to age- and sex-matched patients without CKD and with non-calcified arteries. PDGFR-β contributes to CKD-associated vascular calcification, representing a potential novel therapeutic target.

Kidneys have a limited capacity for self-repair, and injury frequently progresses to chronic kidney disease (CKD). Remarkably, successful recovery is observed in models of unilateral acute kidney injury (AKI) upon contralateral nephrectomy. Here, we aim to better understand the cellular and molecular mechanisms underlying this enhanced recovery. Six rodent studies were performed, including optimization and time-course experiments in Wistar rats and C57BL/6J mice to define left ischemia conditions, right nephrectomy delay times, and functional outcome. Kidneys were analyzed by quantitative histomorphometry (pathomics) on whole slide sections, immunostaining, and qPCR. Bulk RNA sequencing was conducted in two independent mouse time-course studies to discern repair and injury trajectories. Clonal expansion of tubular progenitor cells was assessed by lineage tracing in PAX2/Confetti mice. Tubular epithelial cell proliferative dynamics and polyploidization were analyzed using live cell cycle and DNA content profiling in PAX8/FUCCI2aR mice. Nephrectomy at day three after AKI induced full functional recovery in rats and mice, whereas longer delays (10 and 20 days) failed to prevent CKD progression. Early nephrectomy reduced tubular atrophy, fibrosis, and inflammation. Pathomics revealed distinct tubular morphological trajectories distinguishing between atrophy and repair, as adaptive signatures. Transcriptomic analyses with orthogonal validation demonstrated attenuation and reshaping of immune cell signatures and inflammatory pathways. Additionally, specific gene sets unique to nephrectomy-induced repair were identified. Lineage tracing showed that nephrectomy enhanced clonal expansion of tubular progenitor cells, beyond the levels of spontaneous repair. Cell cycle and DNA-content analysis of tubular cells demonstrated a strong polyploid response immediately after the ischemic insult, while early nephrectomy attenuated persistent tubular cell polyploidization, a contributor to CKD. Early nephrectomy in experimental AKI triggers efficient repair by modulating immune responses, promoting tubular regeneration, inducing pro-repair transcriptional reprogramming, and counteracting progression to CKD through attenuation of sustained polyploidization.

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone produced by osteocytes. In iron deficiency anemia (IDA) and chronic kidney disease (CKD), FGF23 is also produced by erythroid cells. Recent studies have suggested that rising circulating FGF23 is negatively associated with erythropoiesis in IDA and CKD. However, the distinct contributions of bone- and erythroid-produced FGF23 to anemia in IDA remain unclear. Using the conditional deletion of Fgf23 in osteocytes (Fgf23Dmp1-cKO) and in erythroid cells (Fgf23HbB-cKO) in mice fed a control or an iron-deficient (ID) diet, we first determined that in iron deficiency, osteocytes and erythroid cells are distinct sources of circulating intact FGF23 (iFGF23) and FGF23-cleaved peptides, respectively. We further showed that erythroid-specific deletion of Fgf23 corrected anemia in ID mice, whereas overexpression induced anemia in control mice, unlike osteocyte-specific deletion or overexpression of Fgf23. Importantly, erythroid-specific deletion of Furin (FurinHbB-cKO), the enzyme responsible for FGF23 cleavage, led to the increased production of iFGF23 from erythroid cells and aggravated ID-induced anemia. Furthermore, iFGF23 dose-dependently blocked the differentiation of erythroid progenitors in culture, triggering mitochondrial dysfunction that led to impaired erythropoiesis. These effects were fully suppressed by cotreatment with an FGFR1 inhibitor. Finally, erythroid-specific deletion of Fgf23 in an animal model of progressive CKD prevented the development of anemia of CKD. Collectively, our results show that erythroid-expressed FGF23 is a negative regulator of erythropoiesis that contributes to anemia via direct paracrine FGFR1 activation in erythroid precursors.

Membranous nephropathy (MN) comprises distinct subtypes driven by autoantibodies targeting podocyte-associated proteins, one of which is neural EGFL-like 1 (NELL1). Currently, the diagnosis of NELL1-associated MN relies mainly on mass spectrometry or immunostaining of kidney biopsies. Serologic testing for anti-NELL1 antibodies is not yet commercially available, but research assays including Western blotting, indirect immunofluorescence, and ELISA have recently been developed. However, these are currently performed only in research settings, and ELISA may not be sufficiently specific for primary diagnostic purposes. High-throughput immunoassays are needed for the diagnosis and monitoring of NELL1 autoantibody-positive patients with MN. Here, we developed a luciferase immunoprecipitation systems (LIPS) immunoassay to detect circulating NELL1 autoantibodies. After identifying the optimal antigenic region of NELL1, we evaluated the assay's diagnostic performance using serum samples derived from a biopsy-proven NELL1+ validation cohort. We then assessed NELL1 seropositivity in an independent NIH clinical evaluation cohort and examined antibody dynamics in longitudinal samples from selected positive cases. Initial assay development using known NELL1 positive sera demonstrated an N-terminal fragment of NELL1 protein (amino acids 1-550) fused to Gaussia luciferase yielded superior diagnostic performance compared with full-length NELL1 (810 amino acids). In a validation cohort consisting of sera from 20 biopsy-proven NELL1-positive and 20 PLA2R+/NELL1-negative patients, this LIPS assay showed 90% sensitivity and 100% specificity and showed agreement with ELISA but with better specificity. Further testing of 63 MN cases and 20 disease controls from the NIH cohort identified six NELL1-positive MN cases. Longitudinal analysis of three NELL1 seropositive cases revealed that autoantibody levels tracked proteinuria, suggesting that monitoring antibody titers may be useful in clinical management like that with PLA2R antibodies. Our NELL1 LIPS assay provides a noninvasive tool for diagnosing NELL1-associated MN, characterizing clinical subsets, and monitoring therapeutic response.

Pegcetacoplan is a novel C3/C3b inhibitor with potential as a treatment for C3 glomerulopathy (C3G) and primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), both caused by complement system dysfunction. We conducted a real-world observational cohort study to evaluate the efficacy and safety of pegcetacoplan in pediatric and adult patients, largely resistant to conventional immunosuppression. These patients were treated outside clinical trials and identified through the CompCure registry and an international survey. Changes in urine protein-to-creatinine ratio (uPCR), estimated glomerular filtration rate (eGFR), and serum C3 at one, three, six and twelve months were evaluated. 25 patients (18 C3 glomerulonephritis, 3 Dense Deposit Disease, 4 primary IC-MPGN) initiated pegcetacoplan therapy at a median age of 14.9 years at a median 2.7 years after diagnosis. Median uPCR at baseline was 3.5 g/g, mean eGFR was 74 ml/min per 1.73 m2, and 19 of 25 patients had low serum C3. After pegcetacoplan initiation we observed a rapid and sustained reduction of proteinuria: uPCR decreased by 81% in six months, with 68% of patients achieving under 1 g/g and 12% achieving complete and 64% partial remission. Serum C3 increased to the normal or supranormal range in all but one case with suspected non-adherence. The eGFR significantly increased by month three (9.4 ml/min per 1.73 m2) and six (12 ml/min per 1.73m2) and remained stable at twelve months in patients with available follow-up data. Sequential biopsies available in four cases showed variable changes, ranging from complete disappearance to persistence of C3 deposits, of chronic lesions, and occasional tubulo-epithelial damage. No serious adverse events occurred during 222 months of cumulative exposure. Pegcetacoplan demonstrated rapid and sustained efficacy with good safety despite two potential drug-related concerns in C3G and primary IC-MPGN, highlighting its potential for broader application and the need for further research to optimize patient selection and treatment strategies.

Treatments that deplete or modulate B cells are in use or being investigated for several immune-mediated glomerular diseases. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference in Panama City, Panama, in June 2025 to review current evidence and identify key gaps in knowledge and research needs to effectively apply such therapies. Availability, effectiveness, and safety of B cell-targeted therapies vary substantially across glomerular diseases. In IgA nephropathy, anti-CD20 therapy (rituximab) has shown limited efficacy, although inhibitors of survival factors BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) and anti-CD38 antibodies can lead to reduction in proteinuria and reduction in decline in estimated glomerular filtration rate. In contrast, for membranous nephropathy, anti-CD20 antibodies have become first-line therapy, achieving at least partial remission in most patients by 18 months. In steroid-dependent nephrotic syndrome, rituximab effectively prevents relapses, particularly in children, though benefits are transient. For lupus nephritis, newer approaches including obinutuzumab and chimeric antigen receptor (CAR) T cell therapy have shown promising results, with CAR T cells introducing the possibility of being free of disease activity and treatment for a prolonged time. In antineutrophil cytoplasmic antibody-associated glomerulonephritis, rituximab has proven effective for both induction and maintenance therapy, with ongoing trials investigating CAR T cell approaches. Safety considerations of B cell-targeting therapies vary by intensity of therapy, with conventional anti-CD20 therapy showing favorable safety profiles and CAR T cell therapy requiring careful patient selection because of the potential for cytokine release syndrome and other serious adverse events. Validating biomarkers for patient selection and monitoring is a critical research need, along with optimizing treatment protocols and determining optimal therapy duration.

Kidney Disease: Improving Global Outcomes (KDIGO) updated its clinical practice guideline for the management of glomerular diseases in 2021, more than a decade after the first glomerular diseases guideline was published, reflecting slow progress in drug development. But since then, novel therapies for several glomerular diseases have been successfully tested and approved by regulatory agencies, none more so than IgA nephropathy (IgAN). To keep pace with new therapies, the IgAN guideline was updated again in 2025. After this revision came to press, 3 additional IgAN treatments received accelerated approval by the US Food and Drug Administration. Because the presumptive mechanisms of action of 2 of these new therapies are mechanistically different from those of previously approved drugs, the KDIGO IgAN Work Group felt that a brief commentary outlining where the new therapies may fit into the overall IgAN treatment strategy was warranted in lieu of a full guideline update, pending additional evidence for these and other therapies.

C3 glomerulopathy-primary immune complex membranoproliferative glomerulonephritis (C3G/IC-MPGN) is an ultrarare disease spectrum associated with a significant health burden and for which there is a huge unmet need for safe and effective treatment. The underlying pathophysiology is dysregulation and overactivation of the alternative complement pathway. Two new therapeutic agents, iptacoplan and pegcetacoplan, that target proximal steps in the cascade, have demonstrated to be effective and have been approved for use in patients with C3G alone and with C3G/IC-MPGN, respectively. A key challenge to the nephrology community is how to incorporate these disease-modifying drugs into clinical practice in a timely and equitable manner. This report summarizes the deliberations and recommendations that emerged from the SEISMIC (Addressing access issues in diagnosis and treatment of C3G nephropathy and IC-MPGN) summit in July 2025. The meeting assembled a broad panel of experts and patients and addressed the following three aims: 1) define issues in proper and timely diagnosis of this complex disease spectrum, 2) assess management strategies in light of the availability of this new class of therapeutic agents, and 3) identify barriers to access to care and treatment with these new therapeutic agents and design strategies to surmount them.

In systemic lupus erythematosus (SLE) and other autoimmune diseases, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play critical roles through three receptors, i.e., BAFF-Receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI), and B-cell maturation antigen (BCMA), promoting the survival of self-reactive B cells and supporting their differentiation into antibody-producing cells. Several biologic therapies with anti-BAFF and anti-BAFF/APRIL agents induce profound suppression of immunoglobulin production and B-cell survival with variable safety profiles. While belimumab has demonstrated significant improvement of overall disease activity in clinical trials, some cases of de novo lupus nephritis have been reported suggesting a potential lack of protection in certain cases. The sustained reduction in B cell populations expressing regulatory markers, alongside a rapid decline in IL-10 levels following belimumab initiation, suggests that BAFF may have a previously underappreciated role in supporting the development or function of regulatory B cells (Bregs). Given the complex receptor interactions of BAFF and APRIL, as well as the heterogeneous phenotype of regulatory B cells and their different mechanisms for regulating the immune response, the involvement of BAFF in regulatory immune responses remains difficult to fully elucidate. This review explores the current evidence on the anti-BAFF/APRIL therapies and examines the unresolved question of whether BAFF exerts a context-dependent role in supporting regulatory B cell function.

Risk variants G1 and G2 of APOL1 confer a markedly increased risk of chronic kidney disease (CKD) in individuals of African ancestry, yet disease expression requires secondary insults such as inflammation or hypoxia. How these stressors intersect with APOL1 risk variants to drive podocyte injury and cell death remains poorly defined. To identify pathways that modify APOL1 variant-induced cytotoxicity under hypoxic stress, we performed an unbiased, genome-wide RNA interference (RNAi) screen in cells expressing APOL1 G1 or G2. Candidate genes were validated using targeted genetic manipulation, pharmacologic interventions, and subcellular localization and structure-function analyses. The RNAi screen identified multiple peroxisomal biogenesis (PEX) genes as modifiers of APOL1 G1 or G2 cytotoxicity, with PEX gene silencing markedly exacerbating cell death during hypoxia. This implicates impaired peroxisomal homeostasis as a previously unappreciated vulnerability in APOL1-associated cellular injury. In contrast, genetic or pharmacologic enhancement of peroxisomal function significantly attenuated cytotoxicity induced by either APOL1 risk variant. Mechanistically, we identified a functional peroxisomal targeting signal at the C-terminus of APOL1 that mediates hypoxia-dependent trafficking to peroxisomes. Disruption of this targeting signal reduced peroxisomal localization of APOL1 G1/G2 variants and mitigated cytotoxicity, linking peroxisomal trafficking to variant-specific injury. Our findings identify peroxisomal dysfunction as an important determinant of APOL1 G1/G2-mediated cytotoxicity under hypoxic stress. By establishing a mechanistic connection between hypoxia, peroxisomal biology, and APOL1 risk variants, our work highlights peroxisomes as a therapeutically actionable pathway to limit podocyte injury and CKD progression in genetically susceptible population.

Aberrant O-linked glycosylation of the IgA hinge segment resulting in galactose-deficient IgA1 (Gd-IgA1) is frequently observed in patients with IgA nephropathy (IgAN), and it is hypothesized to be pathogenic. Here, we genetically disrupted the expression of galactosyltransferase 1 (C1galt1) to elevate Gd-IgA1 levels in mice and examine its role in glomerular deposition. We previously established a mouse model expressing the human IgA1 heavy chain via an IGHA1-knock-in allele. To investigate the role of aberrant glycosylation, we introduced a B cell-specific deletion of c1galt1 into this model. Circulating Gd-IgA1 levels were measured, and kidney phenotypes were evaluated under physiological conditions and following inflammatory stimulation. Furthermore, using a passive mouse model, we compared the glomerular deposition potential of IgA1 derived from various human sources, including serum, ileocecal mucus, as well as from patients with myeloma. B cell-specific deletion of c1galt1 resulted in markedly elevated circulating Gd-IgA1 levels under both physiological conditions and inflammatory stimulation (Lactobacillus casei cell wall extract and complete Freund's adjuvant), and these mice exhibited impaired B cell development and reduced IgA production in both systemic circulation and intestinal mucosa. Correspondingly, glomerular IgA deposition remained limited under physiological conditions and was not substantially enhanced following inflammatory stimulation. In contrast, mucosa-derived IgA1 from patients with IgAN induced significantly stronger mesangial deposition than serum- or myeloma-derived IgA1, despite having a similar or lower Gd-IgA1 content. Our findings support Gd-IgA1 as a correlate of mucosal immune activation rather than a direct pathogenic driver. Instead, tissue origin and immune context are likely key determinants of IgA1 deposition and pathogenic potential.

Managing pruritus in hemodialysis patients is challenging. Nemolizumab, a monoclonal antibody targeting IL-31, has demonstrated efficacy in atopic dermatitis and prurigo nodularis with fast reduction of pruritus. To evaluate nemolizumab safety and efficacy for treatment of chronic kidney disease-associated pruritus (CKD-aP). This was a 12-week randomized, placebo-controlled study of nemolizumab (30 mg or 60 mg) Q4W in 258 hemodialysis patients with CKD-aP. Endpoints assessed safety, and efficacy on pruritus, sleep disturbances and quality of life (QoL). The primary endpoint (proportion of patients with ≥4-point-improvement in Worst Itch-Numerical Rating Scale [WI-NRS] at week 12) was not met for either nemolizumab dose (60 mg: 47.7% [P=0.0686], 30 mg: 38.5% [P=0.37]) versus placebo (32.4%). Patient-reported itch-related QoL improved on Skindex-10 in the 60 mg group vs placebo (nominal P<0.01). Onset of action on itch was rapid. At week 4, ≥4-point-improvement in WI-NRS was achieved in 24.3% to 26.6% (nemolizumab) compared with 7.4% (placebo). Adverse events related to study drug were comparable among groups. The primary limitation was the relatively small sample size and duration of follow-up (12 weeks); longer studies would be required to evaluate safety and efficacy of long-term treatment. Although the primary endpoint was not met, the trial demonstrated a favorable safety profile and signals of reduced pruritus and improved itch-related QoL in patients with CKD-aP over 12 weeks.

There is a need for improved glycemia monitoring tools for people with type 2 diabetes (T2D) and end-stage kidney failure (ESKF). This prospective, randomized, crossover trial compared the efficacy of real-time continuous glucose monitoring (rtCGM) with capillary blood glucose (CBG) testing in adults with T2D and ESKF undergoing hemodialysis. The primary outcome was percentage of time below range (%TBR) <70 mg/dL. The %TBR <70 mg/dL was not significantly different between groups (mean 1.17% ± 1.8 vs. 1.29% ± 2.7; P = 0.28). Compared with CBG testing, percentage time in range (%TIR) was higher (63.4% ± 24 vs. 54.5% ± 23) and mean glucose lower (173.6 ± 37 vs. 187.7 ± 38 mg/dL) after the rtCGM intervention, while percentage time above range (%TAR) >180 mg/dL (35.3% ± 25 vs. 44.3% ± 23) and >250 mg/dL decreased (12.3% ± 15 vs. 18.8% ± 19) (all P ≤ 0.01). In adults with T2D and ESKF undergoing hemodialysis, TBR was minimal and not influenced by rtCGM use. Compared with CBG testing, %TIR and %TAR improved during the rtCGM intervention. Future studies are needed to confirm the benefits of rtCGM in this population.

Respiratory syncytial virus (RSV) causes substantial morbidity in older adults. Patients receiving hemodialysis are particularly vulnerable due to impaired immunity and chronic health care exposure. Data on RSV vaccine immunogenicity in this population are lacking. We conducted an observational study of 20 patients receiving hemodialysis (median age 78.4 years; 55% female; median dialysis duration 23 months) who received a single dose of the RSV vaccine Arexvy. Blood samples were obtained at baseline and at weeks two, five, eight, 16, and 32. RSV-specific IgG was quantified by ELISA, and cellular responses were assessed by multiparameter flow cytometry. Fifteen sex- and age-matched individuals with normal kidney function were included as a control group. At baseline, 14 of 20 patients were seropositive (IgG over 11 Standard Units (SU); median 12.6 SU). IgG titters remained stable through week 5, rose significantly at week eight (16.8 SU), peaked at week 16 (17.5 SU), and declined to 14.6 SU at week 32, remaining above baseline. In contrast, healthy control individuals, vaccinated with Arexvv, showed increasing RSV-IgG antibody levels already after two weeks. Antibody levels correlated negatively with dialysis duration, and patients with under one year of dialysis had significantly higher titers. RSV-specific CD4+ T cells increased at week two, with most producing IFN-γ, IL-2, or TNF, and returned to baseline by week eight. B cell responses included expansion of plasmablasts (weeks five-eight) and early increases in switched memory B cells. Cytokine profiling showed modest changes (IL-23, TNF and IL12p70 increased; IL-8 decreased). Arexvy elicited robust humoral and cellular responses in patients receiving hemodialysis. Attenuated antibody responses with longer dialysis duration suggest dialysis vintage as a key determinant of vaccine efficacy in this high-risk population. The increase in anti-RSV IgG antibody levels was significantly delayed in patients receiving hemodialysis compared with control individuals.

Ultrasound-assisted pH-shifting integrates alkaline pH-induced protein unfolding, ultrasound-assisted dispersion, and neutralization-driven reassembly to regulate the formation of multicomponent biopolymer nanoparticles. This study investigated the effects of ultrasound-assisted pH-shifting on the structural characteristics, colloidal stability, and gastrointestinal delivery performance of rutin-loaded zein-soy protein isolate-inulin nanoparticles (ZSI-R). Compared with pH-shifting alone, ultrasound-assisted pH-shifting produced ZSI-R nanoparticles with a higher encapsulation efficiency (92.20 ± 1.48%), smaller particle size, a more negative zeta potential, and greater resistance to centrifugal, ionic, and storage stresses. Spectroscopic and diffraction results suggested that the combined treatment induced protein conformational reorganization, altered noncovalent interactions among zein, soy protein isolate, inulin, and rutin, and promoted the incorporation of rutin in an amorphous state within the nanoparticle matrix. The apparent dispersibility of rutin increased from 137.47 ± 1.80 μg/mL for free rutin to 1791.99 ± 10.27 μg/mL for ZSI-R nanoparticles prepared by ultrasound-assisted pH-shifting. During gastrointestinal evaluation, these nanoparticles showed slower gastric-phase dialysis-based diffusion and an intestinal bioaccessibility of 80.70%. Changes in particle size, zeta potential, infrared spectra, and fluorescence profiles were consistent with digestion-associated changes in the composition and microenvironment of the particle-digesta interface. Overall, under the experimental conditions used in this study, ultrasound-assisted pH-shifting improved the encapsulation, colloidal stability, apparent dispersibility, and gastrointestinal delivery performance of rutin in zein-soy protein isolate-inulin nanoparticles.

Occlusive arterial disease continues to be a leading contributor to morbidity and mortality, and the ongoing lack of small-diameter vascular grafts (<6 mm) significantly restricts surgical interventions. In this work, we present a new core/shell fibrous vascular graft (C/S PE) created through coaxial electrospinning, consisting of a polycaprolactone (PCL) core and a cardiac extracellular matrix (cECM)-enriched shell designed for ex vivo endothelialization. Proteomic profiling confirmed that the cECM preserved angiogenic and cell-adhesive components capable of guiding vascular lineage commitment. To enhance luminal cellular organization prior to implantation, a dynamic ex vivo perfusion strategy was applied to induce mesenchymal stem cell differentiation under gradually increasing shear conditions designed to emulate early physiological adaptation. This approach enabled the formation of a confluent endothelial-like layer after two weeks. RNA-seq analysis revealed activation of pathways associated with endothelial proliferation, angiogenesis, extracellular matrix remodeling, etc. Following implantation in the rat abdominal aorta model, the ex vivo endothelialized (C/S PE-EC) grafts maintained 100% patency and progressive host-driven remodeling characterized by endothelial regeneration, smooth muscle layer formation, and a shift toward a pro-healing macrophage phenotype. Importantly, the C/S PE (EC) grafts reached nearly complete endothelial coverage and functional eNOS expression within one month, suggesting the synergistic role of biomimetic matrix composition and biomechanical conditioning in accelerating vascular integration. By integrating synthetic strength, ECM bioactivity, and stem cell-derived endothelialization, this approach offers a promising pathway toward clinically translatable small-diameter vascular grafts, particularly appropriate for scheduled procedures such as Fontan surgery and hemodialysis access.

Peritoneal fibrosis (PF), a major complication of long-term peritoneal dialysis (PD), is characterized by excessive extracellular matrix (ECM) deposition mediated by activated myofibroblasts (MyoFs). While mesenchymal transition of mesothelial cells has been widely studied, the cellular origins of MyoFs remain incompletely defined. Recent evidence suggests pericytes-mural cells surrounding microvessels-may contribute to fibrosis in other organs, but their role in PF pathogenesis is undefined. This study aimed to clarify pericyte-myofibroblast transition (PMT) as a key mechanism of PF, investigate the role of platelet-derived growth factor receptor-β (PDGFRβ) signaling in orchestrating PMT, and evaluate the therapeutic potential of natural triterpenoid asiaticoside (ASI) against PDGFRβ-driven fibrosis. Through single-cell RNA sequencing of chlorhexidine gluconate (CG)-induced PF mice, we identified two MyoFs subpopulations (Fibro5 and Fibro7) exhibiting pericyte lineage signatures, with trajectory inference confirming their differentiation from pericytes during fibrosis. Pharmacological and genetic approaches demonstrated that PDGFRβ signaling orchestrates PMT, as evidenced by upregulated α-smooth muscle actin (α-SMA), PDGFRβ, and ECM markers (Collagen I, fibronectin) in PF mice and TGF-β1/PDGF-BB-stimulated mouse peritoneal microvascular pericytes. Remarkably, ASI attenuated PF by suppressing PDGFRβ expression by 50 % and disrupting pericyte-endothelial interactions, which led to a marked reduction in peritoneal thickness (by ∼ 69 %) and collagen deposition (by ∼ 78 %). Proteomics analysis provided a perspective for analyzing the downstream mechanisms. Mechanistically, ASI mimicked PDGFRβ knockout effects, reducing MyoFs accumulation and abrogating PDGFRβ-induced Erk and Pi3k/Akt activation. Our findings repositioned pericytes as pivotal contributors to PF and proposed ASI as a therapeutic agent against PDGFRβ-driven PMT, which provided a new perspective for antifibrotic strategies.

Prophylactic antimicrobial drugs are routinely administered for most surgical procedures worldwide. However, the benefit may be modest and supported by low-certainty evidence, while little is known about safety in contemporary practice. Observational study in 26 UK hospitals between 2022 and 2024. Eligible patients were aged ≥18 years undergoing any of six common surgical procedures. The exposure was the number of antimicrobial doses administered before, during or after surgery to prevent infection. The primary outcome was surgical site infection (SSI) within 30 days after surgery. Secondary outcomes were antimicrobial side effects (diarrhoea, hearing loss, tinnitus, vertigo, acute kidney injury), all post-operative infections and all post-operative complications. Data are presented as mean (SD), median (IQR) or risk differences (RD) with 95% confidence intervals. Of 13,720 patients, 13,646 were included in the analysis. Mean age was 59 (20) years and 9059/13,646 (66%) patients were women. 13,246/13,646 (97.1%) patients received antimicrobial prophylaxis (median of 2 (1-2) doses). 1097/13,646 (8.0%) patients experienced an SSI. Increasing number of antimicrobial prophylaxis doses was not associated with a reduction in SSI (1 dose: RD -0.2% [-2.5 to 2.2]; to >10 doses: 0.6% [-2.4 to 3.6]). There was a dose-related increase in antimicrobial side effects (1 dose: RD -1.4% [-3.9 to 1.0], to >10 doses: 4.2% [0.4-7.9]) and complications (1 dose: RD -0.2% [-4.2 to 3.8], to >10 doses: 6.2% [0.5-11.8]). 875/13,646 (6.4%) patients experienced antimicrobial-related side effects compared to an expected incidence of 2.2%. Overall infection rates did not differ with increasing antimicrobial doses. Study registration: ISRCTN15775657. In this study, increasing doses of antimicrobial prophylaxis did not improve SSI prevention. Antimicrobial side effect rates were much higher than expected, especially among patients receiving more doses. Adherence to antimicrobial prophylaxis protocols could improve side effect rates without an increase in the incidence of SSI. British Journal of Anaesthesia (WKR0-2020-0020); National Institute for Health and Care Research (NIHR): (CL-2021-19-501), (NIHR305701), (DRF-2020-301454), (DRF-2018-11-ST2-062), (NIHR RP-PG-0218-20001).

Postoperative delirium (POD) and acute kidney injury (AKI) are serious complications in older patients undergoing surgery, yet predictive model development is often constrained by single-center data limitations and privacy concerns that preclude centralized data sharing. To address these challenges, we retrospectively evaluated a simulated federated learning (FL) framework using multicenter datasets partitioned by hospital source, without sharing raw patient data across centers. A total of 7,216 non-cardiac, non-neurosurgical patients aged 65 years or older were included across five centers, with four contributing training data and one serving as an external validation site. Using a multilayer perceptron architecture, we implemented three federated algorithms and benchmarked them against local learning models (LLMs) and centralized learning models (CLMs). For POD, federated learning models (FLMs) achieved internal area under the curve (AUC) values of 0.725-0.726 and external AUCs of 0.700-0.701. For AKI, internal AUCs reached 0.780 and external AUCs ranged from 0.740 to 0.741. FLM performance was statistically comparable to CLMs (p > 0.05). These findings support federated learning as a feasible privacy-preserving strategy that achieved discrimination comparable to centralized learning for multicenter prediction of postoperative complications in older patients.

The effect of postthrombectomy blood pressure (BP) management on the development of acute kidney injury (AKI) in patients with acute ischemic stroke remains largely unexplored. This secondary analysis of the OPTIMAL-BP trial (Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control) included patients with acute ischemic stroke due to large-vessel occlusion who achieved successful endovascular thrombectomy and had a systolic BP ≥140 mm Hg. Patients were randomized to intensive (target systolic BP <140 mm Hg) or conventional (target systolic BP 140-180 mm Hg) BP management for 24 hours. The outcomes were AKI within 7 days and within 2 days, defined according to the Kidney Disease: Improving Global Outcomes criteria. In addition, we examined the associations between AKI and functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2. Multivariable logistic regression analyses were performed with adjustment for age, sex, time from stroke onset to enrollment, baseline National Institutes of Health Stroke Scale score, and baseline estimated glomerular filtration rate. Of 306 patients, 19 were excluded, and 287 patients were included in this analysis (mean age, 73.2 years; 117 [40.8%] women). AKI within 7 days occurred more frequently in the intensive management group than in the conventional group (20/147 [13.6%] versus 9/140 [6.4%]; adjusted odds ratio, 2.54 [95% CI, 1.10-6.35]). Most AKI events were stage 1 (20/29 [69.0%]). Early AKI within 2 days was also more common with intensive BP management. Patients with AKI had significantly lower rates of functional independence (4/29 [13.8%] versus 126/257 [49.0%]; adjusted odds ratio, 0.19 [95% CI, 0.05-0.55]) and higher stroke-related mortality at 3 months (11/29 [37.9%] versus 8/257 [3.1%]; adjusted odds ratio, 13.8 [95% CI, 4.14-49.64]). In a sensitivity analysis with equal creatinine ascertainment, the association with 48-hour AKI did not reach statistical significance (7/76 [9.2%] versus 2/66 [3.0%]; adjusted odds ratio, 4.20 [95% CI, 0.83-32.6]), although the absolute risk difference remained directionally consistent. Intensive BP lowering after successful endovascular thrombectomy was associated with a higher risk of AKI, even when kidney injury was predominantly mild. In addition, AKI was associated with worse neurological outcomes. These findings suggest that AKI is an important marker of systemic hemodynamic vulnerability after aggressive postendovascular thrombectomy BP lowering. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04205305.

Acute kidney injury (AKI) is a life‑threatening condition with limited preventive medications. While the transcription factor Krüppel-like factor 4 (KLF4) is critical to AKI pathophysiology, its underlying molecular mechanisms remain incompletely understood. This study investigates KLF4 from a metabolic perspective and explores the renoprotective potential of doxycycline, an FDA-approved antibiotic. In murine models of ischemia‑reperfusion (IR)‑ and cisplatin (CDDP)‑induced AKI, doxycycline administered significantly attenuated kidney injury and protected renal tubular cells from glucose deprivation- and oxygen‑glucose deprivation-induced stress in vitro. Integrative transcriptomic and metabolomic profiling revealed that AKI progression involves profound metabolic dysfunction, characterized by the downregulation of peroxisomal Acyl-CoA oxidase 3 (ACOX3) and mitochondrial Isocitrate dehydrogenase 2 (IDH2). We identified KLF4 as a dual transcriptional repressor of ACOX3 and IDH2. Mechanistically, molecular docking, surface plasmon resonance, and co-immunoprecipitation assays demonstrated that doxycycline directly binds KLF4 and promotes its ubiquitin-mediated degradation via the E3 ligase FBXO32, which restores ACOX3/IDH2-mediated fatty acid oxidation and the TCA cycle, enhancing cellular resilience against ischemic crisis. These findings define a novel KLF4‑ACOX3/IDH2 metabolic axis and highlight doxycycline as a promising repositioning candidate for AKI prevention.

Renal tubular epithelial cells are highly susceptible to mitochondrial dysfunction during acute kidney injury (AKI), in which oxidative stress and microenvironmental remodeling occur before overt functional deterioration. Hydrogen peroxide (H2O2) is an important but nonspecific redox mediator, whereas mitochondrial viscosity provides a complementary biophysical readout associated with organelle stress, protein aggregation, membrane damage, and impaired molecular diffusion. Simultaneous imaging of mitochondrial H2O2 and viscosity may therefore provide a dual-parameter strategy for interrogating redox-biophysical remodeling during AKI-associated tubular injury. Here, we developed a mitochondria-targeted dual-responsive fluorescent probe, PB-PB-B(OH)2, that enables single-excitation dual-channel imaging of H2O2-associated oxidative stress and viscosity-related microenvironmental changes. PB-PB-B(OH)2 showed H2O2-responsive green emission and viscosity-sensitive red emission with limited channel cross-interference under the tested conditions. In HK-2 cells exposed to TNF-α or LPS, the probe visualized concurrent increases in mitochondrial oxidative stress-associated green fluorescence and viscosity-related red fluorescence, which were attenuated by NAC or Nec-1s treatment. In an LPS-induced AKI mouse model, PB-PB-B(OH)2 enabled dynamic renal imaging of injury-stage-dependent redox and viscosity changes, which correlated with histological injury, renal function markers, and necroptosis-related signaling proteins. Therapeutic intervention with NAC or Nec-1s reduced both fluorescence signals, supporting the use of this probe for imaging-based monitoring of renal injury progression and treatment response. These results establish PB-PB-B(OH)2 as a mitochondria-targeted dual-parameter molecular imaging tool for visualizing redox-biophysical remodeling in LPS-induced AKI, rather than as a clinically validated replacement for established AKI biomarkers.

The sequential monitoring of two pathological processes has clinical significance for early detection of drug-induced acute kidney injury (AKI), but remains challenging due to the lack of spatiotemporal probes. Here, we developed a hydrogen peroxide (H2O2) and myeloperoxidase (MPO) programmable responsive magnetic resonance imaging (MRI) probe (PAH-Gd) for spatiotemporal monitoring of renal oxidative stress and inflammation. Upon exposure to H2O2, PAH-Gd transformed into a kidney-targeting moiety, H-Gd, which selectively accumulated in kidneys and moderately enhanced renal T1-weighted imaging (T1 WI) signal. Subsequently, the H-Gd could be oxidized by MPO to form dimers or adducts with nearby proteins, further enhancing renal T1 WI signal. We found that PAH-Gd could perform spatiotemporal monitoring of renal oxidative stress and inflammation at 12 h and 24 h post-Cisplatin (DDP) administration, enabling early detection of DDP-induced AKI at least 60 h earlier than that of standard clinical assays and permitting dynamic monitoring of renal injury progression. The spatiotemporal T1 WI overcame the limitations in detecting diverse pathological processes with a single MRI probe, accurately reporting the drug-induced AKI in the early stage and contributing to AKI prevention and treatment in the clinic.

Wang et al. showcase a green mamba-derived compound, MQ232, which interferes with cyst growth in a mouse model of autosomal dominant polycystic kidney disease, similar to the only approved drug for autosomal dominant polycystic kidney disease treatment, tolvaptan. However, the authors reveal cyclic adenosine monophosphate-dependent and -independent components in MQ232's mode of action and gender differences in efficacy. Therefore, MQ232 may pave the way to novel treatment options for autosomal dominant polycystic kidney disease.

Tolvaptan, a vasopressin V2 receptor (V2R) inverse agonist, is the only treatment specifically approved for autosomal dominant polycystic kidney disease (ADPKD). In addition to inhibiting cAMP synthesis, it has other effects on V2R signaling. Our goal was to mechanistically characterize the effects of MQ232, an optimized peptide of the green mamba snake and a new V2R inverse agonist, in Pkd1RC/RC mice. Pkd1RC/RC mice were treated with MQ232 (0.5, 2, 4, or 8 nmols/kg/hour via minipump), tolvaptan (0.2% in chow), or vehicle from four to 16 weeks of age. MRI measurements of kidney volume were used for randomization and endpoint, urine was collected at 12 and 16 weeks, and mice were sacrificed at 16 weeks for blood and tissue collections. MQ232 and tolvaptan equally attenuated PKD. In male mice, increasing doses of MQ232 were associated with greater reductions in kidney cAMP, aquaporin-2 expression and phosphorylation, and with higher urine outputs, but equally ameliorated PKD; there was no correlation between kidney cAMP or urine output with disease attenuation. Phosphorylated/total ratios for Src, ERK, CRAF, Akt, RPS6, and Stat3 were, in general, lower in the treated mice, but this was less or reversed with increasing MQ232 doses. Analysis of previous studies with tolvaptan showed similar dose-dependent effects. This is consistent with these compounds being dual efficacy V2R ligands with inverse agonistic activity on Gαs/cAMP and, at high doses, activating β-arrestin-dependent or -independent Src and ERK signaling. Both compounds downregulated PAPPA. MQ232 inhibited IGF1Rβ phosphorylation, whereas tolvaptan at the dose/schedule used in the study did not. Vasopressin binding to V2R activates many cystogenic pathways: Gαs/cAMP, β-arrestin-Src and β-arrestin-ERK, and PAPPA and IGF1R signaling. Activation of cAMP-independent signaling may limit the benefit from MQ232 and tolvaptan when administered at high doses, questioning the rationale of titrating these compounds to maximally tolerated doses to treat ADPKD. Improved understanding of V2R signaling in ADPKD will lead to better therapies.

To examine whether IgG N-glycosylation patterns are prospectively associated with incident diabetic nephropathy and neuropathy. We analyzed IgG N-glycosylation profiles in four cohorts: EPIC-Potsdam, DiaGene, GenoDiabMar, and Hoorn DCS. Among 3,263 individuals with and without type 2 diabetes at profiling, 674 incident neuropathy and 639 incident nephropathy cases occurred after diabetes diagnosis. Associations of IgG N-glycan peaks (IgG-GPs) and traits with incident outcomes were examined using Cox models and meta-analyzed across cohorts. Agalactosylated, asialylated, and bisected IgG-GPs were associated with higher nephropathy risk (IgG-GP3: hazard ratio [HR] 1.13 [95% CI 1.04-1.24]; IgG-GP4: HR 1.15 [95% CI 1.05-1.26]), while galactosylated and sialylated IgG-GPs were associated with lower risk (IgG-GP14: HR 0.86 [95% CI 0.78-0.94]; IgG-GP18: HR 0.85 [95% CI 0.77-0.94]) (all false discovery rate <0.05). Associations of IgG-GPs with incident neuropathy were rendered nonsignificant after multiple testing correction. IgG N-glycosylation may reflect immune-related mechanisms relevant to diabetic nephropathy; but the evidence between IgG-GPs and diabetic neuropathy remains inconclusive.

Kidney transplantation (KT) remains the optimal treatment for kidney failure, improving survival and quality of life. However, long-term graft outcomes have plateaued, largely due to transplant CKD and cardiovascular disease; agents such as mineralocorticoid receptor antagonists (MRAs) may help mitigate these risks. Mineralocorticoid receptor (MR) overactivation contributes to oxidative stress, inflammation, and fibrosis in both the heart and kidneys, suggesting a potential role for mineralocorticoid receptor antagonists (MRAs) in improving long-term patient and graft outcomes. Although evidence in KT is limited, MR blockade may offer clinical benefits by targeting aldosterone-mediated pathways. Proteinuria promotes sodium reabsorption in the aldosterone-sensitive distal nephron via epithelial sodium channels (ENaC), contributing to hypertension and volume overload. MRAs have been shown to reduce albuminuria and blood pressure in patients with diabetic nephropathy, even on background renin-angiotensin-aldosterone system (RAAS) blockade. The use of MRAs post-KT should be individualized, considering patient comorbidities and concomitant immunosuppressive therapy. While MRAs may provide cardiovascular and antiproteinuric benefits, the risk of hyperkalemia-though reduced with non-steroidal MRAs-must be carefully managed. PLAIN LANGUAGE SUMMARY: When the kidneys no longer work properly, receiving healthy kidney is the best way of treatment, called transplantation. After kidney transplantation (KT), the patient should receive several medicines to keep the new kidney healthy and protect it from rejection and failure. These medicines may help with immunity against the transplanted kidney or protect the kidney in general. One way the medicines may work is to decrease the effect of the hormone aldosterone, which helps control water and salt balance in the kidney by hanging on to sodium while releasing potassium from the body. By blocking aldosterone receptors, the body reduces protein leaking in the urine, controls blood pressure, minimizes kidney scarring, and protects against the hazardous effects of diabetes on the kidneys. Most evidence for these benefits comes from people who have not received a transplant, and transplant-specific studies are still small. In transplant recipients, these medicines may interact with anti-rejection therapy and can raise potassium. Care therefore requires careful patient selection, review of other medicines, and close monitoring of potassium, kidney function, and anti-rejection drug levels.

Simultaneous pancreas-kidney transplantation (SPKTx) and kidney transplantation alone (KTx) are common treatment modalities for individuals with type 1 diabetes with end-stage kidney disease. This study compared metabolic and macrovascular disease outcomes between SPKTx and KTx in recipients with type 1 diabetes. We conducted a systematic search of the Embase, MEDLINE and Scopus databases (last searched 23 February 2025). We included retrospective and case-control studies, owing to a lack of randomised controlled trials in English, with adult patients. We excluded studies reporting on a return to dialysis post transplant, islet-kidney transplantation or separate pancreas-kidney transplants. Bias and study quality were assessed via the Newcastle-Ottawa scale for cohort studies. Demographic and outcome data were synthesised as both categorical and continuous data, with pooled means and summary statistics computed where applicable. Meta-analysis was performed on post-transplant outcomes in studies evaluating total cholesterol (TC), triglyceride (TG) level, HDL, LDL, blood pressure, HbA1c and renal function. Macrovascular outcomes included the frequency of new or adverse events associated with coronary artery disease (CAD), cerebrovascular disease (CeVD) and peripheral vascular disease (PVD). A total of 15 studies (n=564 SPKTx, 419 KTx) were included. Meta-analysis demonstrated lower post-transplant TC (mean difference -0.41 mmol/l [95% CI -0.60, -0.22], p<0.01, I2=37%), TG level (mean difference -0.76 mmol/l [95% CI -1.02, -0.49], p<0.01, I2=86%), LDL (mean difference -0.28 mmol/l [95% CI -0.42, -0.14], p<0.01, I2=15%), HbA1c (mean difference -28.79 mmol/mol [95% CI -35.75, -21.82], p<0.01, I2=98%; mean difference -2.61% [95% CI -3.05, -2.16], p<0.01) and creatinine levels (mean difference -21.54 μmol/l [95% CI -39.23, -3.85], p=0.02, I2=90%) following SPKTx compared with KTx. Mean antihypertensive agent use per participant decreased post SPKTx (1.0 vs 2.5 pre transplant; p<0.01), but was not significantly different from post-KTx groups. HbA1c increased following KTx (69 mmol/mol [8.5%]) compared with pre KTx (53 mmol/mol [7.0%], p<0.01). Progression of CAD, CeVD and PVD occurred across both groups post transplant. PVD showed more than a twofold increase in amputations and revascularisations post transplant. No difference was observed in the post-transplant frequency of CAD, CeVD or PVD between SPKTx and KTx. Evidence from this study was limited by a lack of subgroup data for analysis, a lack of randomised studies and a paucity of reported lifestyle factors influencing outcomes. SPKTx demonstrates a superior metabolic profile post transplant to that in KTx in recipients with type 1 diabetes. However, this does not translate into differences in the risk of CAD or PVD post transplant, with PVD accounting for the greatest burden of macrovascular disease. This protocol has been registered a priori on PROSPERO (CRD42024622408).