肾内科领域文献阅读汇编

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

The Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) randomised trial found that a restrictive intravenous fluid regimen increased the risk of acute kidney injury (AKI) after major abdominal surgery. We examined whether AKI after restrictive fluid therapy increased the risk for chronic kidney disease (CKD). We conducted long-term follow-up between 90 days and 48 months after surgery in RELIEF participants randomly assigned to a restrictive vs liberal fluid regimen, from May 2013 through September 2016. The primary outcome was incident or progressive CKD (stage ≥3), including worsening by ≥1 CKD stage in participants with preoperative CKD stage ≥3. Secondary outcomes included lowest recorded estimated glomerular filtration rate (eGFR) and maximal change in eGFR from baseline. Long-term follow-up data were obtained for 1670/2983 participants (mean age 69 (range: 58-75)yr; 47% females) included in the modified intention-to-treat analysis of the original RELIEF trial. The primary analysis was performed for 754 (49.6%) assigned to a restrictive fluid regimen and 766 (50.4%) assigned to a liberal fluid regimen. The incidence of new or worse CKD ≥ stage 3 did not differ between 422/754 (56%) participants assigned to restrictive fluid therapy, compared with 409/766 (53.4%) participants who received liberal fluid therapy (adjusted odds ratio 1.13 [95% CI 0.91-1.41]). These findings remained unaltered in sensitivity analyses. There were also no differences for eGFR secondary outcomes. Within the limits of this post hoc analysis, no difference was found in the incidence of new or progressive CKD was not related to a restrictive perioperative fluid regimen. ClinicalTrials.gov (NCT01424150).

This study aimed to evaluate whether achieving a minimum of 15% weight loss early after type 2 diabetes diagnosis was associated with subsequent lower risks of developing macrovascular and microvascular complications. Using U.K. primary care data from Clinical Practice Research Datalink Aurum linked to hospital and mortality data, we conducted a cohort study (2000-2024) of adults with obesity and type 2 diabetes. Individuals with ≥15% weight loss within 2 years of type 2 diabetes diagnosis were propensity score matched 1:4 to control subjects maintaining a stable weight (<2% weight change). Cumulative incidence rates were determined, and time to first macrovascular (myocardial infarction, stroke, angina, peripheral arterial disease) and microvascular (chronic kidney disease, retinopathy, neuropathy) events was analyzed using Cox proportional hazards regression. The matched cohort included 14,496 individuals with ≥15% weight loss and 57,984 control subjects. Compared with control subjects, the weight loss group had significantly lower risk of first macrovascular (hazard ratio 0.86, 95% CI 0.81-0.91) and microvascular (hazard ratio 0.90, 95% CI 0.86-0.94) events. Individually, significantly lower risks were observed for myocardial infarction, angina, chronic kidney disease, and retinopathy. The weight loss group also demonstrated better glycemic and blood pressure levels, despite fewer medications. Achieving ≥15% weight loss early in type 2 diabetes was associated with clinically meaningful lower risks for macro- and microvascular complications and better glycemic control compared with stable weight. These real-world findings support prioritizing early, substantial weight reduction as a core therapeutic strategy to improve glycemic control and prevent end-organ damage.

To evaluate whether the efficacy and safety of finerenone varied by baseline hemoglobin A1c (HbA1c) level, a proxy of glycemic control, and diabetes duration in people with type 1 diabetes and chronic kidney disease (CKD). Adults with type 1 diabetes, urinary albumin-to-creatinine ratio (UACR) 200 to <5,000 mg/g, and estimated glomerular filtration rate (eGFR) 25 to <90 mL/min/1.73 m2 were randomly assigned (one to one) to finerenone or placebo. UACR change from baseline over 6 months by baseline HbA1c and diabetes duration was analyzed. Baseline HbA1c was available for 240 of 242 participants; mean (SD) HbA1c, diabetes duration, and eGFR were 7.6% (1.1%; 60 [12] mmol/mol), 32.0 (14.2) years, and 58.9 (19.2) mL/min/1.73 m2, respectively. At 6 months, HbA1c (95% CI) remained unchanged (finerenone +0.03% [-0.14%, 0.20%]; placebo 0.00% [-0.12%, 0.11%]; between-group difference +0.04% [-0.17%, 0.24%]; P = 0.74). Over 6 months, median UACR decreased from 574.6 to 373.5 mg/g with finerenone and from 506.4 to 475.6 mg/g with placebo, corresponding to a -25% placebo-corrected change (95% CI -35%, -13%; P = 0.0001). Treatment effects were consistent across HbA1c tertiles (<7.1%, ≥7.1% to ≤8.1%, and >8.1%), with placebo-corrected UACR changes (95% CIs) of -17% (-40%, 13%), -18% (-39%, 10%), and -37% (-55%, -13%), respectively (P interaction = 0.41). Effects were similarly consistent across diabetes duration tertiles (P interaction = 0.70). Overall safety and incidence of hyperkalemia were similar across HbA1c tertiles. In adults with type 1 diabetes and CKD, finerenone reduced UACR and was well tolerated irrespective of HbA1c level or diabetes duration.

Data on sex-specific risk factors for type 1 diabetes microvascular complications are limited. We assessed sex-specific associations of longitudinal clinical risk factors and 30-year retinopathy and kidney end point incidence in the Pittsburgh Epidemiology of Diabetes Complications type 1 diabetes cohort. The cohort (n = 325 women and 333 men; mean baseline age 27 years; diabetes duration 19 years) was followed from 1986-1988 to 2016-2018 for the following: incident proliferative diabetic retinopathy (PDR) (Early Treatment of Diabetic Retinopathy Study grade ≥60 or laser photocoagulation); severely increased albuminuria (SIA) (albumin excretion rate ≥200 µg/min); and estimated glomerular filtration rate < 60 mL/min/1.73 m2 (chronic kidney disease [CKD] G3). Associations between longitudinal risk factors and time to each event were assessed by sex in multivariable joint models in those who were complication free at baseline. PDR incidence was similar by sex (57% in women vs. 59% in men; P = 0.54). SIA incidence was lower in women (18% vs. 25% in men; P = 0.10); and CKD G3 was higher in women (28% vs. 21% in men; P = 0.11). In both sexes, independent risk factors for PDR included HbA1c and blood pressure (BP) (women's systolic BP: hazard ratio [HR] 1.27 [95% CI 1.12, 1.45]; men's diastolic BP: HR 1.40 [95% CI 1.15, 1.70]). For SIA, HbA1c was associated in both sexes, but other factors differed, including triglyceride levels (HR 1.38 per log1.2; 95% CI 1.06, 1.78) and BMI (HR 0.87; 95% CI 0.76, 1.00) in women and smoking (HR 3.46; 95% CI 1.07, 11.24) in men. For CKD G3, HbA1c was a risk factor in both sexes; smoking was also associated in men. Although HbA1c and BP are important risk factors for retinopathy regardless of sex, sex-specific clinical targets warrant further research to optimize kidney protection in type 1 diabetes.

Belimumab, approved for systemic lupus erythematosus (SLE) and lupus nephritis (LN) treatment, is a B-cell-modulating monoclonal antibody that selectively inhibits B-lymphocyte stimulator (BLyS) and downregulates autoreactive B-cells. Comparing belimumab's results from BLISS-LN (phase 3, ClinicalTrials.gov Identifier: NCT01639339) with other LN trial outcomes pose challenges because, unlike other trials, BLISS-LN included patients with pure class V LN (membranous) and patients receiving cyclophosphamide as standard therapy (ST). This post hoc analysis of BLISS-LN investigated kidney outcomes in patients with proliferative (class III or IV) or proliferative plus membranous LN (class III or IV with/without class V) treated with mycophenolate mofetil (MMF)-based ST to more closely align with those of other phase 3 LN trials and current practice. Only patients with active class III or IV LN with/without class V who received MMF ST in BLISS-LN were included. Kidney responses (complete renal response [CRR]; primary efficacy renal response [PERR]), urine protein to creatinine ratio (uPCR) under 0.5 g/g responders, estimated glomerular filtration rate (eGFR) slope, and changes from baseline in uPCR, eGFR, and biomarkers were assessed up to Week 104. Safety outcomes were assessed through Week 104. The MMF subgroup comprised 271 patients (60.5% of overall BLISS-LN population; with 135 receiving belimumab; 136 receiving placebo). Baseline demographics and characteristics were balanced. CRR treatment differences between belimumab and placebo were higher in the MMF subgroup (14.9%) versus the overall BLISS-LN population (10.3%). Treatment differences were greater for PERR, uPCR under 0.5 responders and eGFR slope with belimumab versus placebo in the MMF subgroup, and versus the overall population. Other endpoints showed a similar trend. Safety outcomes were consistent with belimumab's known safety profile. Fewer serious adverse events were reported for belimumab vs placebo in the MMF subgroup. The improvements in kidney outcomes with belimumab in patients with LN receiving MMF highlight the benefit of belimumab in a population more closely aligned with recent phase 3 LN trials and underlines kidney function preservation.

Lupus nephritis (LN) remains a major cause of morbidity and progression to chronic kidney disease in systemic lupus erythematosus. Beyond immunosuppression, emerging evidence highlights the critical role of nephron-protective therapies in mitigating chronic damage and preserving renal function. This narrative review included a structured literature search in PubMed, EMBASE, and Web of Science for new cardio-renoprotective therapies in LN. Agents targeting metabolic, hemodynamic, and inflammatory pathways, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs), have shown renal and cardiovascular benefits in proteinuric and diabetic populations, and recent data suggest potential efficacy in LN. These therapies reduce intraglomerular pressure, proteinuria, oxidative stress, and tubular inflammation, complementing the immunomodulatory effects of standard regimens. In addition, endothelin receptor antagonists and novel anti-fibrotic or metabolic modulators are under investigation for synergistic cardiorenal protection. Early integration of these agents may delay progression to end-stage kidney disease, improve systemic vascular health, and reduce long-term treatment burden. Future randomized trials specifically designed in LN cohorts are warranted to define optimal timing, combinations, and safety in the context of immunosuppression. Nephron-protective therapy represents a paradigm shift in LN management, from solely controlling autoimmunity toward preserving long-term renal structure and function through multi-system, cardio-renal protection.

Chronic kidney disease (CKD) complicates insulin dosing and increases glycaemic instability in diabetes. We aimed to compare feasibility, safety and efficacy of automated insulin delivery (AID) with usual care in people with diabetes and advanced CKD. We conducted a prospective, open-label, randomised crossover trial at five tertiary hospitals in Australia and one tertiary centre in Denmark. Adults aged ≥18 years with type 1 diabetes or insulin-treated type 2 diabetes and advanced CKD (stage 3b or higher, including dialysis) were eligible. Participants were randomly assigned in a 1:1 sequence to receive either AID followed by usual care with real-time continuous glucose monitoring (CGM), or the reverse sequence, each for 8 weeks. Allocation was generated centrally using computerised randomisation. Due to the nature of the intervention, participants and clinicians were aware of treatment assignment. The primary outcome was percentage time in range (3.9-10.0 mmol/l) during the final 3 weeks of each treatment period. Forty participants (24 type 1 diabetes, 16 type 2 diabetes; median [IQR] age 60 [55, 69] years; HbA1c 64 [54, 73] mmol/mol [8.0% (7.1%, 8.8%)]; eGFR 30 [18, 37] ml/min per 1.73 m2) were enrolled: 33 not on dialysis, four on peritoneal dialysis and three on haemodialysis. AID significantly improved all hyperglycaemic CGM metrics compared with usual care. Time in range (3.9-10.0 mmol/l) improved from 60% (51%, 66%) at the end of usual care to 73% (65%, 78%) at the end of AID (p<0.001). Hypoglycaemia rates were unchanged. Participants were predominantly pre-frail at baseline and remained stable on-trial. No serious adverse events were attributed to the study devices. Nonetheless, 25% of participants experienced hospital admissions during the trial period for medical issues unrelated to device use. AID is feasible and safe and compared with usual care provides superior glucose management in predominantly pre-frail people with diabetes complicated by advanced CKD. Australian New Zealand Clinical Trials Registry ACTRN12622000889752; ClinicalTrials.gov NCT06330194 FUNDING: This trial was funded by the Australian Centre for Advancing Diabetes Innovations (ACADI), St Vincent's Hospital Melbourne and Diabetes Australia.

To examine the associations between cardiovascular-kidney-metabolic syndrome (CKM) stages and the risk of cardiovascular disease (CVD), including atherosclerotic CVD (ASCVD), and all-cause mortality (ACM), stratified by sex. Using a population-based cohort, CoLaus|PsyCoLaus, we categorized participants into CKM stages: 0 (no CKM factors), 1 (excess/dysfunctional adiposity), 2 (metabolic risk factors and/moderate- to high-risk CKD), 3 (very high predicted CVD risk per SCORE2/very high-risk CKD), and 4 (clinical CVD). Associations were assessed using generalized ordered logistic regression, Cox proportional hazards models, and population attributable fractions (PAFs). Among 5,752 participants (53.2% women; mean age: women 53.1 ± 10.7, men 52.3 ± 10.7 years), 580 CVD events (381 ASCVD), and 723 deaths occurred over 14.3 years. CKM stage distribution differed by sex (men vs women): 0 (9.9 vs 26.1%), 1 (13.3 vs 13.7%), 2 (62.6 vs 56.8%), 3 (9.4 vs 1.7%), 4 (4.8 vs 1.7%). Risk of CVD and ASCVD rose with higher CKM stage (vs stage 0), with HRs of 5.16 (95% CI, 2.61-10.19) and 3.82 (1.76-8.27) for stage 3 in men, compared with 1.92 (0.91-4.04) and 1.95 (0.79-4.81) in women. For all-cause mortality, risk peaked at stage 3 in women (3.43 [1.92-6.10]) and at stage 4 in men (2.42 [1.27-4.64]). Incremental PAFs peaked at stage 2. CKM stages were associated with a stepwise increase in risk of CVD and all-cause mortality, with important sex-specific differences observed particularly for all-cause mortality. These findings support the relevance of CKM staging for cardiovascular risk stratification and prevention in the general population.

Target-dose angiotensin-converting enzyme inhibitors (ACEIs), compared with below-target doses, have been associated with lower risks of death and kidney failure (KF) in patients with heart failure with reduced ejection fraction (HFrEF). We examined these associations in heart failure with preserved ejection fraction (HFpEF). Among 96,473 Veterans with HFpEF (EF ≥ 50%) newly initiated on ACEIs (2000-2018), 32,728 received target doses recommended for HFrEF. Propensity scores for receiving target-dose ACEIs were used to assemble an outcome-blinded matched cohort of 61,160 patients (target-dose, n=30,580), balanced on 76 baseline characteristics. Outcomes were 5-year all-cause mortality, incident KF, and HF hospitalization. Compared with below-target-dose ACEIs, target-dose ACEIs were associated with a lower KF risk (HR, 0.89; 95% CI, 0.83-0.97), no mortality difference (HR, 0.99; 95% CI, 0.97-1.02), and a higher risk of HF hospitalization (HR, 1.08; 95% CI, 1.04-1.12). Among 16,735 patients with chronic kidney disease (CKD; eGFR 15-59 mL/min/1.73 m2), target-dose ACEIs were associated with a lower risk of KF (HR, 0.82; 95% CI, 0.75-0.90) and mortality (HR, 0.93; 95% CI, 0.89-0.96) without a higher HF hospitalization risk (HR, 0.95; 95% CI, 0.90-1.01). Each association differed significantly from those in patients with eGFR ≥ 60 mL/min/1.73 m2 (interaction p<0.001). In HFpEF, target-dose ACEIs were associated with a lower risk of KF, a higher risk of HF hospitalization, and no association with mortality. These associations were consistently more favorable in the subgroup with CKD. These findings underscore the importance of evaluating treatment strategies within biologically coherent HFpEF phenotypes.

Recent clinical trials have shown that dual GLP-1R/GCGR agonists, including mazdutide and cotadutide, provide kidney benefits in patients with type 2 diabetes and CKD, suggesting a potential contribution of GCGR activation to these renal effects. However, whether GCGR directly confers renoprotection and the underlying mechanisms remain unclear. Here, using tubule-specific GCGR loss- and gain-of-function mouse models and human kidney samples, we show that tubular GCGR signaling exerts an important renoprotective role in DKD. Tubular GCGR expression is reduced in humans and mice with DKD and correlates with worse kidney function and increased renal injury. Genetic ablation of tubular GCGR markedly exacerbates DKD and induces pronounced phospholipid accumulation within enlarged lysosomes. Mechanistically, GCGR loss disrupts its association with the V-ATPase V1A subunit ATP6V1A, compromises V1-V0 assembly, and thereby impairs lysosomal acidification. This defect leads to impaired phospholipid hydrolysis and protease maturation, blockade of autophagic flux, and ultimately tubular cell injury. In vivo, ATP6V1A overexpression markedly reverses GCGR deficiency-induced lysosomal dysfunction and DKD progression. Consistently, re-expression of tubular GCGR via AAV9 restores lysosomal function, reduces phospholipid accumulation, and mitigates renal injury in DKD. Together, these findings provide genetic evidence for the renoprotective role of tubular GCGR in DKD, delineate a kidney-intrinsic GCGR-ATP6V1A-lysosome axis that protects tubular integrity, and extend prior GCGR-in-kidney observations into a more concrete GCGR-lysosome mechanism.

Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays critical regulatory roles in multiple signaling pathways by preventing the ubiquitin-mediated degradation of its substrates. Dysregulated expression of USP7 is implicated in tumor progression; however, its role in renal fibrosis remains unclear. In the present study, USP7 was observed to be significantly upregulated in the kidneys of patients with chronic kidney disease (CKD), which correlated with fibrotic lesions and renal dysfunction. Both genetic depletion and pharmacological blockade of USP7 significantly attenuated fibroblast activation and extracellular matrix deposition in two mouse models of kidney fibrosis-unilateral ureteral obstruction and unilateral renal ischemia-reperfusion injury models, indicating a pro-fibrotic function of USP7. Mechanistically, intergrated proteomic sequencing and phosphoproteomic sequencing revealed that USP7 modulated the tuberous sclerosis complex 1 (TSC1)-mTOR pathway. USP7 knockdown restored TSC1 expression and inhibited mTOR activation. However, USP7 did not directly interact with TSC1; instead, it deubiquitinated and stabilized lysine-specific demethylase 5B (KDM5B), which subsequently reduced histone H3K4me3 modification at the Tsc1 promoter to repress its transcription. Conversely, the inhibition of USP7 promoted KDM5B degradation, thereby restoring TSC1 expression and suppressing mTOR-driven fibrogenesis. Thus, these findings identify USP7 as a critical promoter of renal fibrosis, acting at least in part through the KDM5B-TSC1-mTOR axis. This highlights USP7 as a potential therapeutic target for CKD.

Monocyte-derived macrophages are central drivers of chronic renal inflammation and fibrosis, yet the regulatory mechanisms that restrain their profibrotic differentiation remain poorly defined. Here, we identified serine/threonine kinase 40 (STK40) as a suppressor of profibrotic macrophage differentiation and renal fibrosis progression. Myeloid-specific Stk40 deletion exacerbated renal fibrosis in multiple mouse models. Single-cell RNA sequencing revealed expansion of Arg1⁺ macrophages in STK40-deficient kidneys. In vitro, STK40 restrained the differentiation of profibrotic Arg1⁺ macrophages in a constitutive photomorphogenic protein 1 (COP1)-dependent manner. Functionally, Arg1⁺ macrophages were potent extracellular matrix (ECM)-producing cells and promoted renal fibrosis both directly, through cell-intrinsic macrophage-to-myofibroblast transition (MMT), and indirectly, by inducing epithelial-mesenchymal transition (EMT). STK40 loss led to aberrant STAT3 activation, whereas pharmacological inhibition of STAT3 attenuated excessive profibrotic differentiation of STK40-deficient bone marrow-derived macrophages (BMDMs). Mechanistically, STK40 functioned as an adaptor linking COP1 and STAT3, thereby promoting STAT3 poly-ubiquitination. Finally, oral administration of an Arg1-targeted small-molecule inhibitor rescued renal fibrosis exacerbated by myeloid Stk40 deficiency. These findings define an STK40-COP1-STAT3 axis that restrains profibrotic Arg1⁺ macrophage differentiation and identify Arg1⁺ macrophages as a potential therapeutic target for chronic kidney disease with progressive renal fibrosis.

1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) benzene (EDPrB), a highly polluting fluorinated liquid-crystal monomers (FLCMs), accumulates in the kidneys over the long term. First, our study demonstrates that exposure to EDPrB can induce inflammatory responses and fibrosis in human renal cortical proximal tubule epithelial cells (HK-2), posing a risk of nephrotoxicity. Next, our study investigates the renal injury induced by EDPrB in male Kunming mice after 70-day exposure at 13, 130, and 1300 μg/kg bw/day, using an adverse outcome pathway (AOP) framework. Histopathological observations demonstrate that EDPrB corresponds to an elevated probability of developing chronic kidney disease (CKD). Proteomics and Western blot analysis revealed that mTOR signaling may be the mechanism by which EDPrB induces CKD in mice and causes damage to HK-2 cells. Finally, by treating EDPrB-exposed mice with RAPA, we demonstrated that activation of the mTOR signaling is the molecular initiating event driving EDPrB-induced CKD in mice. This study proposes an AOP framework focused on EDPrB-induced CKD. The molecular initiating event is identified as mTOR activation, followed by autophagy inhibition leading to inflammation and fibrosis as key events, ultimately resulting in CKD as an adverse outcome. This highlights the renal risks of FLCMs and supports stricter environmental release regulations.

Diabetic nephropathy is a leading cause of end-stage renal disease, with podocyte loss being a critical event in its progression. However, the dominant molecular mechanism driving podocyte loss remains elusive, hindering targeted therapy. We aimed to identify the key pathways of podocyte failure in human diabetic nephropathy and investigate metformin's therapeutic potential. We employed an integrative multi-omics approach, including single-nucleus RNA-seq (snRNA-seq) of 156,043 human kidney nuclei from individuals with diabetic nephropathy and healthy control individuals, db/db mouse models of diabetic nephropathy, spatial metabolomics, in vitro podocyte cultures, and targeted urinary metabolomics in individuals with diabetic nephropathy and healthy control individuals. snRNA-seq identified ferroptosis and fatty acid metabolic dysregulation as the most enriched pathways within podocytes, mechanistically linked to the MAPK14-solute carrier family 7 member 11 (SLC7A11)-glutathione peroxidase 4 (GPX4) axis. In murine diabetic nephropathy models and in vitro, metformin directly inhibited this MAPK14-SLC7A11-GPX4 axis, suppressed podocyte ferroptosis (including restoration of GPX4 and SLC7A11 expression and reduction of p-p38 and lipid peroxidation) and restored compartment-specific renal lipid accumulation as shown by spatial metabolomics. Clinically, we identified and validated a urinary fatty acid signature, with palmitoylcarnitine as a key biomarker (AUC 0.974, calculated from receiver operating characteristic curves), correlating with disease indices including blood glucose, eGFR, serum creatinine and blood urea nitrogen. Our study reveals podocyte ferroptosis to be a central pathogenic event in human diabetic nephropathy, repositioning metformin as a direct ferroptosis inhibitor that preserves podocyte integrity via the MAPK14-SLC7A11-GPX4 axis. Furthermore, we provide a high-performance urinary biomarker, offering a direct translational link toward targeted anti-ferroptosis therapies and non-invasive diagnostics for diabetic nephropathy.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome encompassing hypertensive left ventricular remodelling with diastolic dysfunction and systemic inflammation-driven endothelial dysfunction, with possible contributions from visceral adipose tissue-associated metabolic and proinflammatory alterations. However, conventional key risk factors for HFpEF, including advanced age, female sex, obesity, diabetes, and chronic kidney disease, are closely associated with mineralocorticoid receptor (MR) overactivation through several under-recognized mechanisms, i.e. renin-independent aldosterone excess, cortisol dysregulation, and ligand-independent activation. MR overactivation promotes myocardial hypertrophy and fibrosis, vascular remodelling, and systemic inflammation, all of which are hallmark features of HFpEF. Among patients with HFpEF, the steroidal MR antagonist (MRA) spironolactone has been suggested to reduce the risk of HF-related events, while the non-steroidal MRA finerenone has significantly reduced the primary composite of total worsening HF events and cardiovascular death. Across subgroups suggestive of MR overactivation, MRA therapy has shown generally consistent efficacy and safety, although greater adiposity may be associated with greater MRA efficacy. Given the continuum of MR activation across HF stages, early therapeutic intervention targeting MR overactivation may mitigate the risk of HFpEF development and progression. Furthermore, aldosterone synthase inhibitors and MR modulators, which also attenuate MR overactivation, are being evaluated for HFpEF prevention and treatment. This paper presents the mechanistic pathways linking MR overactivation to HFpEF and highlights the potential benefits of mitigating MR activation for its prevention and treatment, calling for renewed consideration of treatment strategies in clinical practice and trial design.

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major unmet clinical challenge. Increasing evidence supports the view of HFpEF as a systemic inflammatory syndrome driven by aging and cardiometabolic comorbidities, including obesity, hypertension, and chronic kidney disease. Within this framework, regulatory T cells (Tregs), which are essential for maintaining immune tolerance and limiting excessive inflammation, have emerged as important modulators of disease progression. However, the mechanisms underlying Treg dysfunction in HFpEF have remained poorly understood. In this issue, Srinivas et al. identify stromal interaction molecule 1 (STIM1)-dependent calcium signaling as a critical regulator of Treg instability in HFpEF. The authors show that patients with HFpEF exhibit reduced circulating Treg numbers, increased STIM1 expression, and activation of endoplasmic reticulum stress, apoptotic, and inflammatory pathways. Using a cardiometabolic murine model and Treg-specific STIM1 knockout mice, they establish a causal role for Treg-intrinsic STIM1 signaling in disease development. These findings position STIM1 as a molecular link between cardiometabolic stress, immune dysregulation, and cardiac remodeling. They further support the concept that immune-cell plasticity is a major determinant of HFpEF pathogenesis and suggest that preserving Treg stability may represent a novel therapeutic strategy. Although important questions remain regarding disease timing, clinical translation, and sex-specific effects, this work advances our understanding of HFpEF as an immune-mediated disorder and identifies STIM1-dependent calcium signaling as a promising therapeutic target.

Cellular calcium homeostasis is essential for maintaining kidney function. Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), the primary calcium pump responsible for transporting cytosolic calcium ions back into the endoplasmic reticulum, is a key regulator of endoplasmic reticulum stress and intracellular calcium balance. However, its specific role in acute kidney injury (AKI) and the underlying regulatory mechanisms remain poorly understood. SERCA2 expression was measured in biopsies of patients with AKI, animal models, and cellular assays. AKI models were established using SERCA2 conditional knockdown and overexpression mice, HK-2 cells and primary kidney tubular epithelial cells in vitro. To investigate the underlying mechanisms, we integrated approaches including RNA-sequencing, transmission electron microscopy, immunofluorescence, and Seahorse analyses. Transcriptomic and histopathological analyses revealed reduced SERCA2 expression in proximal tubules of both patient AKI biopsies and murine models. Proximal tubule-specific SERCA2 knockdown exacerbated kidney dysfunction and tubular injury in murine AKI, while SERCA2 allosteric activation with CDN1163 or its overexpression attenuated these injuries. Mechanistically, SERCA2 deficiency disrupted endoplasmic reticulum calcium homeostasis, leading to endoplasmic reticulum stress and promoting voltage dependent anion channel 1 (VDAC1) oligomerization through impaired mitochondria-associated endoplasmic reticulum membranes. These changes led to mitochondrial permeability transition pore opening, mitochondrial calcium overload, oxidative stress, and ferroptosis. Importantly, stopping VDAC1 oligomerization with small molecule inhibitor VBIT-4 or blocking ferroptosis with ferrostatin-1 restored mitochondrial function and mitigated ferroptosis in SERCA2-deficient models. Our study identifies the SERCA2-VDAC1 axis as a critical regulator of endoplasmic reticulum-mitochondrial calcium homeostasis in AKI. Both SERCA2 activation and inhibition of VDAC1 oligomerization conferred substantial renoprotection, highlighting this pathway as a promising therapeutic target for attenuating tubular damage in AKI.

Fibroblast growth factor 23 (FGF23) contributes to left ventricular hypertrophy (LVH) and mortality in chronic kidney disease (CKD). Males have a higher risk of cardiovascular events than females. The protective effects of estrogen on the heart are well established, but it remains unclear if cardiac FGF23 signaling is modified in females with CKD. We studied mineral metabolism, kidney and heart phenotypes of age-matched wild-type (WT) and Col4a3 knockout (Col4a3KO) mice during CKD progression and used transcriptomics to identify proximal targets of FGF23 involved in CKD-associated LVH. Additionally, we tested the effects of FGF23 and estradiol (E2) in vivo and on cultured neonatal mouse cardiomyocytes (NMCMs). All results were separated by sex. Compared to WT, CKD males showed progressive increases in blood urea nitrogen (BUN) and FGF23 levels, overt LVH at 20 weeks, and premature death at 22 weeks. In contrast, CKD females showed earlier increases in BUN and FGF23 levels but did not develop LVH and lived longer than males. RNA sequencing analyses revealed that the proximal targets of FGF23 identified in males with CKD are established downstream targets of estrogen signaling. In vitro, FGF23 induced the hypertrophic growth of NMCMs isolated from male and female mice and E2 co-treatment prevented this effect. Finally, E2 prevented FGF23-induced calcineurin activity in the heart of male mice, whereas ovariectomy triggered the development of LVH in female mice with CKD. We identified common molecular targets of FGF23 and E2 signaling in the heart and show that estrogen antagonizes the hypertrophic effects of FGF23, supporting female-specific cardioprotective mechanisms in CKD.

Renal fibrosis is a common pathological hallmark of chronic kidney disease (CKD), and ultimately leads to end-stage renal disease. ER-stress and TGF-β signaling pathway activation play critical roles in renal fibrosis, but the precise mechanisms underlying the intricate interplay between ER-stress and TGF-β signaling pathway remain ambiguous. Our previous study has demonstrated that EVA1A responds to ER-stress to regulate hematopoietic stem cell regeneration; However, the function of EVA1A in renal fibrosis remains unexplored. To elucidate the role of EVA1A in TGF-β signaling regulation and renal fibrosis. We characterized EVA1A expression changes in chronic kidney disease through single-cell RNA-seq data analysis, immunohistochemical staining and Western blot analysis. Eva1a conditional knockout mouse subjected to unilateral-ischemia-reperfusion-injury (UIRI) and unilateral-ureteral-obstruction (UUO), two well-established and widely used fibrosis-related CKD mouse models, were used to investigate the role of EVA1A in renal fibrosis. Subsequently, we characterized the interaction of EVA1A and TGF-β receptor type Ⅱ (TGFBR2) by co-immunoprecipitation and bimolecular-fluorescence-complementation (BiFC) assays to clarify the regulatory mechanism of EVA1A in TGF-β signaling. We found that EVA1A was significantly upregulated in fibrotic kidneys from CKD patients and mice with UUO or UIRI treatment. Deletion of Eva1a significantly attenuated kidney fibrosis and damage in mice with UUO or UIRI treatment. Overexpression of EVA1A enhanced fibrosis levels in mice with UUO treatment and upregulated the expression of fibrosis-related proteins in cultured renal epithelial cells. Mechanistically, we found that ER stress upregulates EVA1A expression via CHOP in CKD mouse model. Subsequently, EVA1A interacted with BIP to stabilize and facilitate the secretion of TGFBR2 from ER to plasma membrane, thereby promoting TGF-β signaling activation and renal fibrosis. During the progression of CKD, EVA1A serves as a sensor for ER stress and regulates renal fibrosis by promoting TGF-β signaling pathway activity.

Diabetic nephropathy (DN) is a major public health concern. Our previous study found that annexin A1 (ANXA1) alleviated DN by improving mitochondrial homeostasis. However, the underlying mechanism is not fully clear yet. This study aimed to explore mechanisms by which ANXA1 improves mitochondrial homeostasis and identify novel therapeutic targets for DN. Diabetic Anxa1-/-/uncoupling protein 1 (Ucp1)-/- mice and renal Ucp1/cardiolipin synthase 1 (Crls1)-overexpressing mice were constructed. Diabetes was established using high-fat diet (HFD) plus streptozotocin (STZ). CL316243 was used to upregulate UCP1 in db/db mice. Knockdown and overexpression in proximal tubular epithelial cells (PTECs) were constructed. Metabolomics and lipidomics were applied. Transcriptomics revealed that Ucp1 was the most significantly downregulated mitochondria-associated gene in kidneys of diabetic Anxa1-KO mice. Functional validation demonstrated that local overexpression of Ucp1 in kidneys alleviated urine albumin-to-creatine ratio (uACR), kidney injuries in histopathology and mitochondrial fission in Anxa1-KO diabetic mice. In vitro, UCP1 silencing abolished the improvements of human recombinant ANXA1 on high glucose (HG)-induced inflammation, fibrosis and mitochondrial dysfunction in PTECs. Silencing/overexpression of ANXA1 reduced/increased the stability of transcription factor GATA binding protein 3 (GATA3) in HK-2 cells under HG conditions, respectively. GATA3 could bind to the proximal promoter region of UCP1, thereby enhancing its transcriptional activity. UCP1 was significantly upregulated in kidneys of DN patients and mice. UCP1 deficiency reduced renal cardiolipin and exacerbated diabetes-induced kidney injury, including aggravated uACR, interstitial inflammation and fibrosis, and enhanced mitochondrial fission. Mechanistically, UCP1 upregulated CRLS1 by modulating aristaless-related homeobox (ARX), thereby promoting cardiolipin biosynthesis and reducing mitochondrial fission. Therapeutically, pharmacological upregulation of UCP1 by CL316243 attenuated established DN in db/db mice. ANXA1 stabilized GATA3 to upregulate UCP1, which promoted cardiolipin biosynthesis through the ARX/CRLS1 axis, inhibited mitochondrial fission, thereby alleviated DN. This study highlighted the therapeutic potential of targeting UCP1 in DN.

This Matters Arising comments on Yoon et al.'s multitask gradient boosting model for predicting acute kidney injury, postoperative respiratory failure and in-hospital mortality after non-cardiac surgery. We ask for clarification on the clinical decision context and threshold ranges in the decision curve analyses, the absolute impact of the model for rare outcomes, and calibration and potential recalibration in external cohorts to support implementation.

We thank Wo and Zhang for their comments on our multitask prediction model for postoperative complications, including postoperative acute kidney injury, respiratory failure, and in-hospital mortality. Here, we responded by mapping specific threshold probabilities to specific clinical actions in the decision curve analyses, quantifying the net benefit to express clinical gains as the number of additional true events detected per 1000 patients, and providing detailed calibration metrics with recalibration guidance.

Biomarkers have been identified to predict, diagnose and prognosticate acute kidney injury (AKI) but existing studies are heterogenous and contradictory. To compare diagnostic performance of AKI biomarkers, evaluate the quality of AKI biomarker studies and to develop standards for reporting studies of diagnostic test accuracy (DTA) of AKI biomarkers. A systematic literature review was conducted to identify studies focusing on the diagnostic performance of AKI biomarkers published before February 2025. Retrieved DTA studies were assessed for methodological quality and completeness using the QUADAS-2 and Standards for Reporting Diagnostic Accuracy (STARD) 2015 checklists. An international 17 member expert panel was convened to agree consensus standards for AKI biomarker studies (STARDaki) via a modified Delphi process. 122 DTA studies for AKI biomarkers were identified, but 15 were insufficiently reported. Of the remaining 107 studies, only 19 reported on diagnosis of AKI within 48 h of sampling. Of these studies, only 16 were considered high-quality based on the QUADAS-2 criteria. The compliance level with the STARD checklist was too low to permit meta-analysis. The expert panel agreed criteria for patient selection, reference standards, and reporting of test-retest reliability to supplement the STARD guidance for AKI biomarker studies. Most studies examining AKI biomarker performance fail to conform to the STARD standards for reporting, leading to poor diagnostic accuracy estimates and reduced clinical applicability and generalizability. An expert panel proposed STARDaki criteria to advance the development and clinical use of AKI biomarkers ( www.stardaki.icu ).

The optimal mean arterial pressure (MAP) target in high-risk hypertensive patients undergoing major abdominal surgery remains unclear. The HISTAP trial evaluated whether targeting an intraoperative MAP ≥ 80 compared with ≥ 65 mmHg reduces postoperative organ dysfunction and 30-day mortality, in this population. HISTAP was a multicenter, randomized trial conducted at 18 Italian centers between March 2023 and April 2025. The study included patients aged ≥ 60 years with chronic hypertension requiring home therapy, undergoing elective major abdominal surgery and having at least one additional high-risk criterion. The intraoperative MAP was targeted to ≥ 80 mmHg (Treatment group) or ≥ 65 mmHg (Control group). The primary outcome was a composite endpoint including postoperative mortality and at least one major organ dysfunction. Of 636 randomized patients, 6 were excluded since surgery was canceled after randomization, 630 completed the trial and were included in the intention-to-treat analysis (median age, 74 years [IQR, 69-79]). Mean intraoperative MAP was 77 ± 7 mmHg in the Control group and 88 ± 9 mmHg in the Treatment group. The primary composite outcome occurred in 48.9% of patients in the Control group versus 38.1% of patients in the Treatment group (relative risk, 0.78; 95% CI 0.65-0.93; P = 0.006). Acute kidney injury was significantly less frequent in the Treatment group (23.5 vs. 33.7%; P = 0.005). Among hypertensive patients receiving continuous hemodynamic monitoring and protocolized fluid therapy at increased postoperative risk undergoing major abdominal surgery, targeting an intraoperative MAP ≥ 80 mmHg, compared with ≥ 65 mmHg, reduced major organ dysfunction, primarily due to fewer mild-to-moderate acute kidney injuries. The HISTAP trial has been registered at ClinicalTrials.gov, NCT05637606 (Date of registration: 24 November 2022).

Preoperative anaemia is associated with adverse surgical outcomes, yet it is unclear whether anaemia-outcome relationships are consistent for women and men. This observational cohort study was conducted between August 1, 2012 and July 31, 2022 in adults undergoing surgery requiring postoperative hospitalisation at a large academic medical centre in the USA. Anaemia was defined as haemoglobin <12 g dl-1 in women or <13 g dl-1 in men. Multivariable regression models assessed associations between preoperative anaemia severity and postoperative outcomes, including a primary outcome of postoperative acute kidney injury (AKI), with interactions evaluated by gender. Of 228 341 procedures (49.4% among women) included, AKI occurred in 13.2% overall, with a lower rate in women (7.6% in women vs 18.8% in men). Preoperative anaemia was present in 70 968 (31.1%) patients, including 30.8% of women and 31.4% of men. In adjusted analyses, increasing severity of preoperative anaemia was associated with worse outcomes. When comparing severe preoperative anaemia to no anaemia, the adjusted odds ratio (OR) for AKI was 2.91 (95% confidence interval: 2.47, 3.44) in women vs 1.43 (1.22, 1.68) in men. Corresponding ORs were 2.48 (2.14, 2.88) vs 1.62 (1.40, 1.86) for ischaemic events, and 4.78 (3.94, 5.80) vs 2.62 (2.13, 3.23) for surgical site infection. Interaction testing confirmed stronger associations in women for AKI, ischaemic events, and surgical site infection (all interaction P<0.001). Preoperative anaemia is associated with adverse outcomes in both women and men, though the associations with acute kidney injury, ischaemic events and surgical site infection are stronger in women.

Acute kidney injury (AKI) occurs in approximately one-third of babies treated in a neonatal intensive care unit. The establishment of consensus standardized definitions has improved clinical recognition and research into neonatal AKI. Neonatal AKI is now recognized for its independent associations with increased morbidity and neonatal intensive care unit mortality. Current definitions use increasing serum creatinine and/or decreasing urine output to diagnose AKI; however, these biomarkers reflect organ dysfunction long after injury has begun. Furthermore, they are impractical and insensitive metrics of kidney function in neonates, particularly in preterm neonates or the first weeks of life, when the risk is greatest. Given the lack of symptoms and limitations of current criteria, risk recognition and stratification are imperative to focus AKI stewardship. Urinary biomarkers (such as neutrophil gelatinase-associated lipocalin), which have demonstrated some challenges in adult studies, appear more promising in their capacity to reliably detect early pediatric and neonatal AKI. Even without novel biomarkers, numerous multidisciplinary AKI education and stewardship programs have demonstrated capacity to substantially reduce risk and incidence of AKI, particularly those focusing on the risk represented by nephrotoxic medication exposure. This narrative review reflects on the evolution of neonatal AKI definitions and how the improved epidemiologic understanding of the condition has been leveraged to drive quality improvement initiatives, development of risk stratification tools, improved diagnostics, and potential preventative therapies. Future integration of this burgeoning body of collaborative research will expedite accurate neonatal AKI diagnosis, while scaffolding kidney health surveillance into follow-up for the improvement of short- and long-term outcomes for these most vulnerable patients.

Intraoperative norepinephrine is associated with postoperative acute kidney injury (AKI), but bedside-readable dose anchors remain undefined. We investigated the dose-response relationship between intraoperative norepinephrine and AKI, and its interaction with intraoperative hypotension. We analysed 27 874 surgical cases from the Medical Informatics Operating Room Vitals and Events Repository. The primary exposure was intraoperative norepinephrine dose, expressed as norepinephrine base (μg kg-1 min-1). The primary outcome was AKI within 7 postoperative days. The maximum dose, time-weighted intensity, duration, and area under the curve (AUC) were evaluated using restricted cubic splines and tensor-product generalised additive models, with multivariable mixed-effects logistic regression with a directed acyclic graph-derived adjustment set. Norepinephrine was administered in 1232 patients (4.4%), and AKI occurred in 4448 (16.0%). Restricted cubic spline analyses showed significant nonlinearity for unit-rate metrics (maximum dose P=0.008; time-weighted intensity P=0.022), whereas time-integrated metrics were linear (AUC P=0.10; duration P=0.50). Two bedside-readable anchors for maximum norepinephrine dose were identified at 0.029 and 0.064 μg kg-1 min-1. Dose-duration (P=0.286) and dose-hypotension interactions (P=0.298) were non-significant, supporting additive effects. A maximum norepinephrine dose of >0.029 μg kg-1 min-1 remained independently associated with AKI (odds ratio [OR] 1.76; 95% confidence interval [CI] 1.41-2.20; P<0.001); adjustment for intraoperative hypotension minimally attenuated this association (5.1%; adjusted OR 1.71; 95% CI 1.36-2.15). Intraoperative norepinephrine exposure was independently associated with postoperative AKI, with nonlinear behaviour for unit-rate metrics and linear behaviour for time-integrated metrics, largely independent of intraoperative hypotension. The two anchors define a two-tier vigilance framework.

Organelle communication through endoplasmic reticulum-mitochondrial crosstalk is essential for maintaining cellular homeostasis and is tightly regulated by tethering proteins within mitochondria-associated endoplasmic reticulum membranes. In a recent study published in Kidney International, He et al. identified sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 as a key regulator of endoplasmic reticulum-mitochondrial calcium homeostasis in proximal tubules and demonstrated that loss of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 drives voltage-dependent anion channel 1 oligomerization, mitochondrial DNA release, stimulator of interferon genes activation, and ferroptosis in acute kidney injury. This study establishes the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2-voltage-dependent anion channel 1 axis as a mechanistic link between mitochondrial calcium dysregulation and ferroptotic tubular injury.

Recent basic research suggests that the neuroimmune axis plays an important role in the pathogenesis of acute kidney injury. Although it is established that the kidney is innervated by both afferent and efferent nerves, there are few studies on the role of renal sensory nerves. Zhang et al. postulated that renal sensory nerves activate a high IL4Rα expression macrophage subset, resulting in the amelioration of kidney injury. This finding highlights a potential neuroimmune pathway that may represent a novel therapeutic target for acute kidney injury.

Transient receptor potential cation channel subfamily V member 1+ (TRPV1+) sensory nerves, usually involved in transmitting pain and itch signals, densely innervate the kidney. Because the kidney is not a classic pain-sensitive organ, the roles of these sensory nerves beyond pain perception remain unknown. Here, we reveal a neuroimmune axis wherein TRPV1+ nociceptive sensory neurons protect against kidney ischemia-reperfusion (I/R) injury by inducing an anti-inflammatory macrophage subset. We used reporter mice to visualize TRPV1+ nociceptive sensory nerves and used retrograde neuronal tracing to identify the activation of kidney-innervating TRPV1+ neurons during kidney ischemia/reperfusion injury. To examine their function, we applied multiple nociceptor ablation strategies (genetic and chemical) and activation approaches. Macrophage responses were analyzed using flow cytometry and RNA sequencing, whereas molecular signaling pathways were investigated with pharmacological inhibitors and in vitro stimulation assays. Urinary calcitonin gene-related peptide (CGRP) levels and macrophage profiles were also assessed in postnephrectomy patients to validate clinical relevance. Nociceptive sensory nerves are activated by inflammation during kidney ischemia/reperfusion injury and initiate protective anti-inflammatory programs by releasing CGRP, which signals through receptor activity-modifying protein 1 (RAMP1) receptors on macrophages to induce a unique interleukin-4 receptor alpha (IL4Rαhi) population via the cAMP PKA-CREB-dependent pathway. CGRP synergizes with IL-4 to promote the anti-inflammatory and prohealing function of macrophages. Elevated urinary CGRP levels correlated with reduced kidney injury markers (KIM-1 and NGAL) and higher proportions of anti-inflammatory macrophages in postnephrectomy patients. Our findings redefine nociceptors as active regulators of kidney inflammation and homeostasis, leveraging CGRP to convert macrophages into anti-inflammatory phenotypes to protect against kidney injury, offering new therapeutic opportunities for AKI.

Acute kidney injury (AKI) is a clinically significant syndrome characterized by a rapid decline in renal function, affecting over 50% of patients in intensive care units. Ferroptosis, a recently identified form of regulated cell death, is driven by iron-dependent lipid peroxidation and has been implicated in AKI pathogenesis. Emerging evidence suggests that lipophagy - a selective autophagic degradation of lipid droplets - potentiates ferroptosis, though the upstream regulatory mechanisms remain poorly understood. ESRRA (estrogen related receptor, alpha), a key transcriptional regulator of fatty acid metabolism and macroautophagy/autophagy, may play a critical role in this process. In this study, we identified ESRRA as a pivotal transcription factor in proximal tubular epithelial cells using single-cell transcriptomic analysis. To investigate its functional role, we employed wild-type mice and tubular epithelial cell-specific Esrra deficient mice to establish AKI models. Our findings demonstrated that ESRRA exerted a protective effect by modulating the RAB7-dependent lipophagy-ferroptosis axis. Furthermore, integrating chromatin Immunoprecipitation (ChIP)-seq and JASPAR database analyses, we predicted PIK3CA as a direct transcriptional target of ESRRA. Mechanistically, ESRRA bind to a specific promoter region within Pik3ca, enhancing its expression and subsequently activating the AKT-MTOR signaling pathway, which is required for the suppression of RAB7 mediated lipophagy in renal tubular epithelial cells, thereby attenuating AKI progression.Abbreviations: ACSL4: acyl-CoA synthetase long-chain family member 4; AKI: acute kidney injury; AKT/PKB: Akt serine/threonine kinase; ChIP: chromatin Immunoprecipitation; Cis-AKI: cisplatin-induced acute kidney injury; CI-AKI: contrast-induced acute kidney injury; ER: endoplasmic reticulum; ESRRA: estrogen related receptor, alpha; FFAs: free fatty acids; FA-AKI: folic acids-induced acute kidney injury; GPX4: glutathione peroxidase 4; GSH: glutathione; HK-2 cells: human renal proximal tubular epithelial cells; LDs: lipid droplets; LV: lentivirus; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PPARGC1A/PGC1-α: PPARG coactivator 1 alpha; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PLIN2: perilipin 2; PNPLA2/ATGL: patatin-like phospholipase domain containing 2; PT: proximal tubular epithelial cells; PUFA: polyunsaturated fatty acid; RAB7: RAB7, member RAS oncogene family; ROS: reactive oxygen species; SQSTM1: sequestosome 1.

Acute kidney injury (AKI) requires rapid and reliable biomarker quantification, yet early assessment is hindered by delayed biomarker kinetics and signal fluctuation under decentralized testing conditions. Here, we developed a pump-free microfluidic aptamer-ratiometric surface-enhanced Raman scattering (SERS) platform for simultaneous quantification of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (Cys C). The assay uses a Y-shaped aptamer architecture to convert target binding into programmed structural disassembly and controlled release of Au@Ag SERS tags. A substrate-embedded internal standard enables self-calibrated readout through the I1617/I2228 ratio, thereby improving signal robustness against substrate heterogeneity and environmental interference. Integrated into a capillary-driven microfluidic chip, the platform completed dual-biomarker analysis within 15 min. It achieved detection limits of 1 pg/mL for NGAL and 34 pg/mL for Cys C, with excellent linearity (R2 > 0.99). In a cisplatin-induced AKI rat model, both biomarkers increased significantly at 4-6 h after injury, preceding oxidative stress imaging and histopathological changes. Analysis of clinical serum samples showed good agreement with enzyme-linked immunosorbent assay and recovery rates above 99%. These results demonstrate a rapid and reliable strategy for early AKI assessment and quantitative point-of-care biomarker analysis.

Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), are associated with changes in the composition and function of gut microbiota. Available evidence has delineated that both AKI and CKD were associated with microbial dysbiosis that led to impairment of the intestinal epithelial cell barrier, decreasing the abundance of beneficial bacteria (Lactobacillus reuteri and Bifidobacterium animalis), and increasing the abundance of pathogenic bacteria (Eggerthella lenta and Fusobacterium nucleatum). This was accompanied by the alteration in microbial-derived metabolites, including reducing short-chain fatty acid production and accumulating uremic toxins, such as indoxyl sulphate, indole-3-acetic acid (IAA), and trimethylamine-N-oxide (TMAO), thereby exacerbating renal inflammation and fibrosis. However, supplementation with probiotics, such as Parabacteroides goldsteinii, Lactobacillus johnsonii, Bacteroides ovatus and Bacteroides fragilis, attenuated renal fibrosis by the regulation of nuclear factor κB, NLR family pyrin domain containing 3 inflammasome, aryl hydrocarbon receptor, sodium-glucose transport 2, farnesoid X receptor, glucagon-like peptide-1 receptor, and nuclear factor erythroid 2-related factor 2 signalling pathways via microbial-derived metabolites, such as IAA, TMAO, indole-3-aldehyde, hyodeoxycholic acid and 1,5-anhydroglucitol. This review elaborates on the microbial dysbiosis-related renal pathogenesis and discusses therapeutic potential and targets of renal fibrosis. Further, targeting modulation of gut microbiota by several cardinal approaches, such as probiotics, natural products (neohesperidin, madecassoside, and polysaccharides), and fecal microbiota transplant, are also highlighted. However, these therapeutic approaches need to be further evaluated by large controlled trials. These findings expand the understanding of microbial dysbiosis-associated underlying molecular mechanisms of renal fibrosis in the host and elucidate a clear pathophysiological rationale for the intervention of renal fibrosis.

Mitochondrial dysfunction is recognized as a pivotal event in the pathogenesis of acute kidney injury (AKI). Selenoprotein (SelH), a mammalian selenoprotein, is extensively involved in regulating of diseases associated with mitochondrial dysfunction. However, its regulatory role in mitochondrial quality control during AKI remains unclear. This study aims to explore the impact of SelH on AKI and potential regulatory mechanisms of SelH in AKI. In vivo, a cisplatin (CP)-induced AKI model was established using SelH knockout mice to evaluate renal injury. Additionally, co-immunoprecipitation (Co-IP). combined with mass spectrometry, Co-IP assays, laser confocal microscopy, and molecular docking were employed to identify proteins interacting with SelH. In vitro, SelH/mitochondrial carrier homolog 2 (MTCH2) knockdown and overexpression models were constructed in HEK293t cells. Indicators related to oxidative stress, mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and apoptosis were analyzed. MTCH2 was identified as a potential interacting partner of SelH. Deficiency of renal SelH directly triggered oxidative stress, impaired mitochondrial biogenesis, disrupted mitochondrial dynamics, enhanced mitophagy, and promoted apoptosis. In HEK293t cells, SelH targeted MTCH2 to regulate mitofusin 2 (MFN2), thereby promoting mitochondrial fusion, alleviating mitochondrial dysfunction, maintaining mitochondrial quality control (MQC) homeostasis, and reducing renal oxidative damage and apoptosis. The results showed that SelH targets the MTCH2/MFN2 aixs to maintain MQC balance, alleviate oxidative stress and cell apoptosis induced by AKI. This study not only supplements kidney specific regulatory targets for the field of mitochondrial medicine but also suggests that SelH could serve as a potential molecule for proactive medicine intervention in AKI, providing experimental evidence for the early intervention of AKI.

Peritoneal dialysis is a widely used treatment for kidney failure; however, peritoneal dialysis-related infections (exit-site, tunnel infection, peritonitis) occur frequently. The effect of standardised nurse and patient training on peritoneal dialysis infections is uncertain. The aim of this study was to determine whether implementing an international guideline-based standardised training curriculum for nurse trainers and new peritoneal dialysis patients reduces the risk of peritoneal dialysis-related infections compared with existing local training practices. Targeted Education ApproaCH to improve Peritoneal Dialysis (TEACH-PD) was a pragmatic, investigator-initiated, cluster-randomised controlled trial conducted in Australia and New Zealand. Adult patients 18 years of age or older with kidney failure who required training for incident peritoneal dialysis treatment and who were able to provide written informed consent were eligible. Clusters were randomised 1:1 to either the standardised training curriculum or usual care. Participant data and infection outcomes were routinely collected in national patient registries. The primary outcome was time to first peritoneal dialysis-related infection (exit site infection, tunnel infection, or peritonitis). Secondary outcomes were the first of each individual infection type in the primary composite outcome, catheter removal, haemodialysis transfer, all-cause death and quality of life. This trial was registered with ClinicalTrials.gov, number NCT03816111. Between 22 July 2019 and 29 September 2023, 42 clusters were randomised: 21 to the standardised training group and 21 to the usual care group. Overall, 1462 incident peritoneal dialysis patients were included; 667 were assigned to the standardised training group and 795 to the usual care group. A peritoneal dialysis-related infection occurred in 296 of 667 patients in the standardised training group and 297 of 795 patients in the usual care group (sub-hazard ratio 1.230, 95% confidence interval [CI] 1.004-1.507, p = 0.0457). Secondary outcomes were similar in the two groups. Among patients commencing peritoneal dialysis, the use of a standardised training curriculum for nurses and patients based on the International Society for Peritoneal Dialysis guidelines increased peritoneal dialysis-related infection. Implementation-focused research is needed to identify which elements of training require standardisation and where individualisation is most beneficial to support safe, sustainable and patient-centred peritoneal dialysis care. The TEACH-PD trial is funded by MRFF Clinical Trials Activity: Rare Cancers, Rare Diseases and Unmet Need Grant Opportunity; National Health & Medical Research Council BEAT-CKD Program Grant; Health Research Council of New Zealand grant; Metro South Health Research Support Scheme Research Fund-Health System and Health Economics Project Grant; Queensland Health; South Western Sydney Research Small Grant Scheme; International Society for Peritoneal Dialysis; Translational Research Institute Australia; Amgen and Baxter Healthcare (Vantive).

The Affordable Care Act (ACA) provided continued Medicaid coverage to US children transitioning into young adulthood, but whether expansion averted deaths among younger adults with kidney failure remains unclear. To examine the association of Medicaid expansion with 1-year mortality among young adults with kidney failure initiating dialysis. This cohort study using a quasi-experimental difference-in-differences design compared changes in outcomes before and after Medicaid expansion between patients aged 19 to 23 years (affected by expansion) and patients aged 14 to 18 years (comparison group with unchanged eligibility). The study period extended from January 1, 2010, to December 31, 2019. Data analysis was performed from January 2023 to February 2025. Medicaid expansion under the ACA. The primary outcome was 1-year mortality from the date of dialysis initiation. Secondary outcomes were Medicaid coverage, uninsurance, predialysis nephrology care, prescribed hemodialysis duration, modality of dialysis, and catheter use at hemodialysis initiation. Among 7139 patients in expansion states, 2348 were 14 to 18 years old (1280 male [54.5%]; 1068 female [45.5%]), and 4791 were 19 to 23 years old (2717 male [56.7%]; 2074 female [43.3%]. One-year mortality for 19- to 23-year-olds declined from 3.6% (95% CI, 2.4% to 4.9%) in the pre-expansion period to 2.1% (95% CI, 1.2% to 3.0%) after expansion (change, -1.5 percentage points; 95% CI, -2.5 to -0.6), while for 14- to 18-year-olds, the concurrent mortality rate was 0.7% (95% CI, 0.3% to 1.0%) pre-expansion and 1.1% (95% CI, 0.5% to 1.7%) postexpansion (change, 0.4 percentage points; 95% CI, -0.3 to 1.1). The adjusted difference-in-difference estimate was -1.8 percentage points (95% CI, -2.9 to -0.7). Medicaid coverage for 19- to 23-year-olds increased from 37.1% to 48.5% and uninsurance rates declined from 19.4% to 7.8%. After accounting for concurrent changes among 14- to 18-year-olds, the adjusted difference-in-difference estimates were 8.4 percentage points (95% CI, 4.8 to 12.0) for Medicaid and -9.1 percentage points (95% CI, -12.4 to -5.8) for uninsurance. Medicaid expansion was associated with higher rates of predialysis nephrology care, prescribed hemodialysis sessions of 4 or more hours, and use of peritoneal dialysis, but not associated with use of catheters for hemodialysis or kidney transplant rates. This study found that Medicaid expansion was associated with reductions in 1-year mortality among young adults with kidney failure initiating dialysis. Policy changes to health insurance programs may affect survival for young adults with this highly morbid condition.

Space missions require liquid drug formulations that remain physically stable and exhibit predictable release under launch, microgravity, and handling stresses. This study examined melatonin‑loaded nanoemulsions flown on the MAPHEUS‑15 sounding rocket, comparing an uncoated nanoemulsion (MN) with a chitosan‑coated nanoemulsion (CCN). Droplet size, polydispersity index (PDI), and zeta potential were measured at Day 0 and after spaceflight, ground vibration testing, matched ground controls, and laboratory storage. Melatonin release was quantified by dynamic dialysis and interpreted using a compartmental mass-transfer model. Melatonin‑loaded nanoemulsion (MN) showed a modest, systematic increase in droplet size under all post‑experiment conditions, with unchanged PDI and zeta potential, consistent with time‑dependent coalescence and Ostwald ripening rather than a specific microgravity effect. CCN maintained essentially unchanged droplet size, PDI, and zeta potential, indicating interfacial steric stabilization by chitosan. For MN, ageing and sounding‑rocket exposure increased the apparent fraction of melatonin available to the aqueous phase, but normalized release profiles overlapped when scaled to the fitted maximum releasable fraction, suggesting unchanged intrinsic release kinetics. In CCN, both the accessible fraction and the release profile were preserved. Overall, chitosan coating enhanced dimensional and release stability, supporting interfacial polymer coatings as a strategy for robust liquid pharmaceutical formulations for future space medicine.

Chromium electroplating is widely used in manufacturing but generates large volumes of highly toxic Cr(VI)-contaminated aging solutions, posing significant environmental and energy challenges. Current treatment methods mainly rely on end-of-pipe processes that consume large amounts of chemicals, generate secondary waste, and fail to recover resources. Here, we report a materials-enabled strategy for sustainable management of electroplating aging solutions through an integrated system for online separation and in situ reuse. A sulfonyl-functionalized resin was engineered to achieve exceptional oxidative stability under strongly acidic, Cr(VI)-rich conditions. Sulfonyl-induced electronic modulation, together with a rigid framework, effectively suppresses polymer backbone degradation while maintaining stable ion-exchange performance. Coupling ion exchange with diffusion dialysis and electro-oxidation enables simultaneous impurity removal, sulfuric acid recovery, and chromium regeneration, establishing a closed-loop resource recovery pathway. Industrial-scale trials demonstrate that the regenerated electrolyte can be directly reused for electroplating, delivering coating performance comparable to fresh baths while reducing energy consumption by 35% and improving corrosion resistance by 28.4% relative to untreated solutions. Life-cycle and techno-economic analyses further confirm substantial environmental and economic benefits, reducing operating costs to 2.1% of conventional treatment. These findings provide a scalable pathway for transforming hazardous electroplating wastes into recyclable resources, advancing circular manufacturing and zero-liquid-discharge electroplating.

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.

The study by Caza et al. is the largest study to date to examine the prevalence of nondiabetic kidney disease in clinically indicated kidney biopsies obtained from patients with diabetes. Nondiabetic kidney disease was identified in patients both with and without concurrent diabetic nephropathy and encompassed a wide spectrum of kidney diseases. Clinical data available at biopsy had limitations for predicting nondiabetic kidney disease and distinguishing affected patients from those with diabetic nephropathy only.

The number of kidney biopsies performed in patients with diabetes has increased rapidly over the last two decades. However, the overall value of the biopsy has been questioned because any coexisting non-diabetic kidney disease (NDKD) is not identified in many patients. Here, we quantify the frequency of identifying NDKD and examine clinical indications, demographic factors, and histologic parameters that increase the odds of finding NDKD and the impact on developing end stage kidney disease. A retrospective analysis of clinical and pathologic parameters of 49,075 biopsied patients with diabetes with and without diabetic nephropathy (DN) from 2001-2024 was performed. Data from the United States Renal Data Service were examined to determine the impact of a NDKD on disease progression to end stage kidney disease. NDKD was found in 58.8% of patients with diabetes who underwent kidney biopsy, including 35.9% without concurrent DN and 22.9% as a second diagnosis in DN. Acute kidney injury and acute nephritic syndrome had greater odds of a NDKD diagnosis in patients with DN. The youngest (under 30 years) and oldest (60 years and older) patients had a higher prevalence of NDKD. Higher chronicity on biopsy was associated with a lower prevalence of NDKD diagnosis. Patients with NDKD were 2.56-fold less likely to develop end stage kidney disease compared to patients with DN alone. This is the largest analysis examining prevalence of a NDKD in patients with diabetes and the impact of biopsy indication on finding a second diagnosis in biopsy-proven DN. The objective is to provide nephrologists with guidance in when to perform a biopsy based on the odds of finding a NDKD related to the patient's clinical indication. Given the high prevalence of NDKD, our study shows that kidney biopsy remains a critical tool in the care of diabetic patients.

Cardiovascular diseases (CVDs) involve complex, interrelated pathologies such as oxidative stress, inflammation, endothelial dysfunction, platelet aggregation, and dyslipidemia, for which single-target drugs remain constrained. As a multicomponent herbal medicine, Ginkgo biloba L. (G. biloba) contains diverse bioactive constituents, primarily flavonoids (e.g., quercetin, kaempferol, isorhamnetin, ginkgetin, and isoginkgetin) and ginkgolides (e.g., ginkgolide A, B, C, and J), which are proposed to exert synergistic effects against the multifaceted pathology of CVDs. This review systematically summarizes the pharmacokinetic characteristics and pharmacodynamic mechanisms of the major bioactive components in G. biloba, highlighting distinct mechanistic axes of Nrf2-mediated antioxidant defense, platelet-activating factor (PAF) receptor antagonism, and inflammasome inhibition. These preclinical findings collectively suggest the therapeutic potential of G. biloba extracts (GbE) for atherosclerosis, stable and unstable angina, myocardial infarction, heart failure, obesity-related and diabetic cardiomyopathy, as well as diabetic nephropathy, retinopathy, and non-alcoholic fatty liver disease. However, the clinical evidence remains limited and inconsistent, and G. biloba has not been established as a standard therapy for CVDs. This review evaluates the current clinical evidence and combination therapeutic strategies, aiming to provide a reference for the design of future clinical trials.

IgA nephropathy is the most common primary glomerulonephritis worldwide, characterized by IgA deposition and a high risk of progression to kidney failure. While emerging therapies target IgA production or downstream inflammation, strategies to directly clear established IgA deposits from the kidney remain underexplored. Here, we evaluate a novel therapeutic IgA protease for its ability to clear glomerular IgA deposits and restore normal histology. The recombinant IgA protease was derived from Thomasclavelia ramosa (strain AK183), a human commensal bacterium presumed to have evolved for mutual tolerance within the microbiome with the host. The enzyme was PEGylated to reduce immunogenicity and prolong its half-life, producing the drug product PEG-AK183. We characterized its ex vivo potency and pharmacokinetic-pharmacodynamic profile in mice and then assessed therapeutic efficacy over eight weeks. In vitro, a single molecule of PEG-AK183 cleaved between 500 and 1000 hIgA1 molecules in 60 minutes, demonstrating high catalytic efficiency. A single injection into human IgA1 (hIgA1) transgenic mice induced complete clearance of serum hIgA1 for up to eight days. Following eight-week weekly treatments, PEG-AK183 reduced circulating IgA and immune complex levels by approximately 80% and completely cleared glomerular IgA and associated complement C3 deposits. This was accompanied by a 45.5% reduction in proteinuria and significant improvements in histopathological indices, including mesangial proliferation and endocapillary hypercellularity. No treatment-related adverse effects were observed, including abnormalities in intestinal plasma B cells, hepatotoxicity, or the anti-drug antibody development, supporting a favorable safety profile for long-term, repeated administration. Our preclinical study demonstrated that the engineered IgA degrader PEGAK183 is a potent, effective, and safe therapeutic in a humanized IgA nephropathy mouse model. By achieving sustained clearance of pathogenic IgA from both circulation and glomerular deposits, this IgA-protease-based therapy represents a promising candidate for the future treatment of IgA nephropathy.

Anti-glomerular basement membrane (GBM) disease is the most severe form of autoimmune glomerulonephritis following assaults on kidney and alveolar basement membranes by pathogenic anti-GBM antibodies. Typically, anti-GBM disease is characterized by rapidly progressive glomerulonephritis and an increased risk of lung hemorrhage, with kidney biopsy revealing ominous crescent formation. Although patient survival has improved with standard of care including plasma exchange and intensive immunosuppression in the recent decade, kidney survival still remains poor because of delayed recognition and tardy initiation of standard therapy. With the increasing understanding of the disease in clinical practice, several variant forms have been recognized. We here propose to group these forms into 4 categories according to their immunologic properties and clinical presentations: overlapping autoimmune syndromes (anti-GBM disease with combined antineutrophil cytoplasmic antibody, concurrent membranous nephropathy, or IgA nephropathy), immunologic distinct forms (Alport post-transplant anti-GBM disease and seronegative anti-GBM disease), clinical phenotypic variant forms (recurrent anti-GBM disease in native kidney, anti-GBM disease in elderly individuals, or with normal kidney function), and medication-associated anti-GBM disease. These patients have different features in terms of clinical manifestations, pathologic findings, or prognosis compared with patients with classical anti-GBM disease. In this review, we discuss these variant forms with emphasis on their phenotypes and underlying mechanisms. An enhanced understanding of pathophysiology of anti-GBM disease variant forms can pave the way for personalized therapies tailored to patients with different presentations of the disease.

The gut microbiome plays a crucial role in regulating systemic immunity and has been implicated in several chronic inflammatory diseases. Intestinal expansions of Ruminococcus gnavus (RG), a dominant gut commensal, correlate with disease flares in lupus nephritis (LN), but the underlying mechanism remains unknown. In a Pilot cohort of patients with biopsy-proven LN, subsetted by gut microbiota community, immune status was characterised using bulk-blood RNA sequencing libraries, serum levels of representative host proteins, and levels of immunoglobulin (Ig)G antibodies to the novel lipoglycan (LG) produced by pathogenic RG strains. A Validation LN cohort was evaluated for blood transcriptomic profiles and levels of anti-LG antibodies. In murine models, mechanistic hypotheses were tested after RG gut colonisation or after intraperitoneal injection with an LG preparation, with outcomes determined by transcriptomic analyses, platelet functional readouts, and tissue histology. In a Pilot cohort of patients with LN, RG gut expansions were associated with high-level platelet, neutrophil, and monocyte activation. Serum levels of platelet factor 4 and release of neutrophil extracellular traps (NETs) were significantly higher in patients with high serum IgG antibody against the novel RG-specific LG, a marker of in vivo immune exposure. An LN Validation cohort confirmed these correlates and showed that anti-LG antibodies serve as a surrogate for thromboinflammatory profile in this LN-associated endotype. In mice, gut colonisation with LG-producing RG strains or a single LG injection caused megakaryocytosis and platelet activation; RG colonisation with LG-producing strains induced tubulointerstitial injury with NETosis. In vivo responses to LG toxin were Toll-like receptor 2-dependent. Gut expansions of the RG pathobiont may contribute to autoimmune pathogenesis through the LG toxin and cause LN flares through thromboinflammatory mechanisms in this previously unrecognised LN endotype.

Antigen delisting has emerged as a strategy to expand kidney transplant opportunities for highly sensitized candidates, but its clinical safety limits remain uncertain. Since October 2019, eight elite French kidney transplant centers have applied automated delisting, allowing systematic and adjustment of unacceptable HLA antigens. We retrospectively reviewed all delisting decisions applied to 2418 candidates enrolled until March 2025. Two approaches were used: time-dependent delisting, restricting unacceptable antigens to those detected within a defined look-back period, and mean fluorescent intensity-dependent delisting, reintroducing weak antigens by raising the mean fluorescence intensity threshold for unacceptable ones. Post-transplant outcomes were assessed in 804 recipients with available follow-up. Delisting significantly improved transplant probability only for candidates with a baseline calculated panel-reactive antibody (cPRA) 96.6% or more. A two-fold increase in donor offers was sufficient at 99% or more, while a three-fold increase was required at 98% or more. Among the transplanted recipients, the risk of graft loss or death was significantly higher when donor-specific antibodies persisted at above 2000 mean fluorescence intensity at transplant (24.4% vs 10.7%). Patients with historical antibodies that had fallen below 2000 mean fluorescence intensity before transplant showed an early post-transplant donor-specific antibody rebound but had outcomes comparable to antibody-negative recipients. Automated delisting primarily benefited extremely sensitized patients. Time-dependent strategies that required antibody clearance before transplant appeared safer than approaches accepting persistent donor-specific antibodies. A conservative three-year time threshold with a 2000 mean fluorescence intensity offered a balanced approach for candidates with baseline cPRA 98% or more.

Tubulointerstitial diseases represent a heterogeneous group of kidney diseases with diverse causes and overlapping histopathologic and immunophenotypic patterns. Unlike glomerular disease, tubulointerstitial diseases have lacked specificity and standardized classification, but greater diagnostic precision is now possible and is necessary as nephrology enters an era of personalized medicine. This review provides an updated etiologic and attributive framework for tubulointerstitial nephritis/nephropathy (TIN) and tubular injury with 8 categories: drug effect, autoimmune/immune-mediated, infection-associated, hereditary/genetic, toxic/metabolic, monoclonal protein-associated, mimics of TIN, and idiopathic/other, recognizing overlap between these forms. This review highlights recently described or elucidated tubulointerstitial diseases such as immune checkpoint inhibitor-associated TIN, IgG4-related TIN, IgM plasma cell TIN, and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. The milestones of IgG4-related TIN exemplify how a TIN disease entity evolves and can serve as a model for the recognition of new TIN entities. Looking forward, new biopsy-based technologies, digital pathology, and artificial intelligence can refine classification, enable precision diagnostics, and help to discover new entities. Continued collaborative efforts will be required to translate these advances into clinical practice and improved outcomes.

Recent awareness that metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver condition in individuals with type 2 diabetes and carries a significant risk of cirrhosis and extrahepatic disease has called for an examination of its relationship with diabetes-related complications. MASLD, especially at-risk steatohepatitis (metabolic dysfunction-associated steatohepatitis [MASH]) with significant fibrosis ≥F2, shares many metabolic abnormalities with type 2 diabetes, including insulin resistance, gluco- and lipotoxicity, chronic subclinical inflammation and mitochondrial impairment. In addition, many cross-sectional and longitudinal observational studies suggest an association between MASLD and micro- and macrovascular complications of type 1 and type 2 diabetes. However, a causal pathogenic relationship has been difficult to confirm given the overlap of cardiometabolic risk factors (CMRFs) in MASLD and type 2 diabetes. Complicating matters further, most of the available evidence has significant limitations. These include shortcomings in participant selection, heterogeneity in study design, use of diagnostic tools with low sensitivity for liver disease and diabetes-related complications, inadequate control for alcohol consumption or CMRFs, and lack of repeat measurements during longitudinal studies. Nevertheless, current evidence suggests that MASLD is a 'risk enhancer' for both micro- and macrovascular disease in diabetes, rather than an independent risk factor. Here, we review the underlying mechanistic pathways and clinical evidence that appear to link both conditions and identify knowledge gaps in need of future research. Until more robust evidence emerges, we hope that a greater awareness about the link between MASLD and diabetes-related micro- and macrovascular complications will prompt clinicians to educate their patients and peers on the potentially heightened health risks of MASLD and encourage clinicians to take a more proactive approach to risk stratification and intervention.