Kidney International

BackgroundImmune checkpoint inhibitor (ICI)-associated acute interstitial nephritis (ICI-AIN) has emerged as a common cause of acute kidney injury (AKI). However, acute tubular necrosis (ATN) may present with similar clinical features yet requires fundamentally different management. Robust data on the prevalence of ATN among patients with suspected ICI-AIN are limited. The aim of this study was to determine the prevalence of ATN in patients with suspected ICI-AIN and to estimate the risk of diagnostic error associated with empirical corticosteroid therapy in the absence of kidney biopsy. MethodsWe conducted a retrospective multicenter study including ICI-treated patients who developed AKI and underwent kidney biopsy. Patients with glomerular presentations were excluded. Based on histopathological findings, patients were classified into two groups: ICI-AIN and isolated ATN. The primary outcome was the prevalence of ATN among patients with suspected ICI-AIN. Secondary outcomes included the description of clinical characteristics, concomitant medications, and laboratory findings, as well as the identification of factors potentially distinguishing ATN from ICI-AIN. ResultsA total of 132 patients were included. ICI-AIN was diagnosed in 76 patients (58%), while isolated ATN was identified in 56 patients (42%). Among subgroups with known risk factors for ICI-AIN, isolated ATN was observed in 20% (7/35) of patients exposed to proton pump inhibitors (PPIs), 23% (3/13) receiving combination ICI therapy, 31% (5/16) with pre-existing chronic kidney disease (CKD), and 34% (10/34) with concomitant extrarenal immune-related adverse events (irAEs). ATN was also present in 23% (6/26) of patients treated with ICI monotherapy. Patients with AIN had more severe renal impairment, with a higher median serum creatinine level at presentation (200 {micro}mol/L vs. 141 {micro}mol/L, p < 0.001). Leukocyturia and hematuria were significantly more frequent in the AIN group (p = 0.007 and p = 0.009, respectively). PPI use was significantly more common in patients with AIN than in those with ATN (40% vs. 19%, p = 0.027), whereas exposure to platinum-based chemotherapy was more frequent in the ATN group (78% vs. 59%, p = 0.027). ConclusionAlthough certain clinical features are associated with ICI-AIN, they are insufficient to reliably differentiate it from ATN without histological confirmation. An empirical management strategy involving corticosteroid therapy without kidney biopsy carries a diagnostic error risk of approximately 40%, underscoring the importance of kidney biopsy as the diagnostic gold standard.

IntroductionThere remains considerable debate as to the cause of the epidemic of Mesoamerican Nephropathy (MeN). We have previously reported early loss of estimated glomerular filtration rate (eGFR) as a surrogate for disease onset in a population-representative cohort study of young-adults at risk of disease from Northwest Nicaragua. Using a nested case-control approach we analysed urine and serum proteins surrounding this timepoint with the aim of gaining insight into the primary disease aetiology. MethodsWe conducted label-free ultra high-performance liquid chromatography mass-spectrometry based proteomics using urine samples collected at the study visit before, and at, first observed eGFR loss amongst cases and compared results to matched controls. We then performed direct protein measurements in a discovery cohort followed by quantification of serum total immunoglobulin E (stIgE) at multiple timepoints in a replication cohort. ResultsProteomic analysis demonstrated no differences in the levels of any single protein between cases and controls (n=25 each), at either timepoint, after correction for multiple comparisons. However, functional enrichment analysis demonstrated upregulation of adaptive immune pathways amongst cases. Direct measurements in the discovery cohort using high-sensitivity PCR-based immunoassay (n=21 controls, 19 cases) demonstrated higher stIgE in cases at the study visit immediately prior to first observed eGFR loss (mean difference 810kU/L, 95% confidence interval (CI): 162-1457kU/L). In the replication cohort (n=22 cases, 21 controls) an stIgE level >500kU/L measured by electrochemiluminescence in study samples from any timepoint in the 3 years prior to the first observed loss of eGFR was independently associated with case status when compared to samples from controls at matched visits (adjusted Odds Ratio: 8.1, 95% CI: 1.4-47.8). DiscussionA high level of stIgE precedes loss of eGFR in those at risk of MeN. Understanding what leads to this rise is likely to be key to understanding the cause of the MeN epidemic. Lay SummaryMesoamerican nephropathy describes an epidemic-level chronic kidney disease impacting rural working age adults in Central America. Although a number of exposures, including occupational heat exposure, have been proposed the cause of the epidemic, there remains much debate as to the primary aetiology of the disease. In this study we interrogated urine and blood samples from individuals from affected communities at risk of disease both before and after they develop kidney dysfunction. Using two different approaches, analysis of both urine and blood samples provide evidence of upregulation of immunoglobulin-E (IgE) related pathways in the 2-3 years before individuals develop evidence of kidney disease. Infections (particularly those involving parasites) and allergic reactions, but not heat exposure, have been reported to increase IgE levels. Going forwards, understanding the cause of this increase in IgE in individuals at risk of disease is likely to provide insight into the cause of Mesoamerican Nephropathy epidemics.

BackgroundProgression into more severe stages of chronic kidney disease (CKD) based on estimated glomerular filtration rate (eGFR) and albuminuria are associated with increased risk of end-stage renal failure, cardiovascular diseases, and mortality. Vesicles in the urine are cell-derived particles containing constituents of the cells of origin. Little is known about the prognostic capacity of urinary vesicles for CKD progression. PurposeTo evaluate the association between components of urinary vesicles and incident CKD. MethodsIn the AugUR study, a prospective population-based cohort study in individuals aged 70-95 years at baseline, we isolated and characterized urinary vesicles from 580 participants at two timepoints. In cross-sectional data, influences of age, sex and established kidney biomarkers on vesicular albumin and podocalyxin were characterised. Longitudinal data were used to test associations of vesicular albumin and podocalyxin with incident eGFR-based CKD and albuminuria. ResultsCross-sectionally, urinary vesicle albumin and urinary vesicle-bound podocalyxin were moderately correlated with each other and with urinary albumin and alpha1-microglobulin, but not with eGFR. Vesicular albumin concentrations were influenced by sex, whereas age showed an effect on podocalyxin. After adjusting for age and sex, higher vesicular albumin was associated with higher urinary albumin and lower eGFR. Higher vesicular podocalyxin concentrations were associated with higher urinary albumin but not with eGFR. Both markers showed identical associations with urinary alpha1-microglobulin. In longitudinal analyses, baseline vesicular albumin showed association with incident CKD based on eGFR. This association was no longer present after adjustment for baseline eGFR. In contrast, higher baseline podocalyxin concentrations were predictive for decreased risk of incident albuminuria after adjustment for baseline free urinary albumin. Baseline-adjusted change in urinary vesicle albumin and urinary vesicle-bound podocalyxin were both associated with incident albuminuria, independent of free urinary albumin and other kidney biomarkers. Here, increase in follow-up versus baseline values were associated with higher risk for incident albuminuria, with higher effect sizes for vesicular albumin. ConclusionThis study indicates that higher vesicular podocalyxin at baseline might be a potential predictor for lower risk for albuminuria over three years in an old-aged cohort. In contrast, longitudinal increase in urinary vesicle biomarkers, especially vesicular albumin, might be diagnostic markers for incident albuminuria in the elderly. KEY MessagesWhat is known O_LIAccording to a previous study in animals, accumulation of albumin in the subpodocyte space leads to subsequent endocytosis by the podocytes. C_LIO_LIPodocyte-produced vesicles contain potential biomarkers of the deterioration of kidney function in humans. C_LI What is new O_LIBiomarkers from urinary vesicles can be quantified from biobanked human samples. C_LIO_LIHigher vesicular podocalyxin at baseline might be a potential predictor for lower risk for albuminuria over three years in an old-aged cohort. C_LIO_LIChanges in urinary vesicle biomarkers over time, especially vesicular albumin, are associated with incident albuminuria independent of eGFR and free urinary albumin. C_LI

BackgroundThe Kidney Precision Medicine Project (KPMP) consortium aims to redefine chronic kidney disease (CKD) by integrating clinical, pathological, and molecular tissue data from kidney biopsies. Here, we demonstrate how biopsy data in CKD can clarify disease etiology and contribute to understandings of disease pathophysiology and clinical prognosis. MethodsThe KPMP is obtaining research kidney biopsies from individuals with CKD (defined as an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2 and/or albuminuria [&ge;]30 mg/g creatinine) and diabetes (enrolled as diabetes and CKD or DKD) or hypertension (enrolled as hypertension and CKD or HCKD). A team of kidney pathologists and nephrologists adjudicated the primary clinico-pathological diagnosis for 258 participants with CKD. We compared pathological features and kidney transcriptional signatures between participants with a primary adjudicated diagnosis of diabetic nephropathy and those with other causes of CKD. We developed a model using clinical and biomarker data that predicted the probability of diabetic nephropathy and tested associations of the signature with CKD progression among Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (n=229). ResultsAmong 183 participants enrolled as DKD, 102 (56%) had a primary adjudicated clinico-pathologic diagnosis of diabetic nephropathy. Among 75 participants enrolled as HCKD, 42 (56%) had a primary diagnosis of hypertension-associated kidney disease. Those with diabetic nephropathy, compared with other diagnoses, had more severe interstitial fibrosis, tubular atrophy, tubular injury, segmental sclerosis, and severe arteriolar hyalinosis, and single-nucleus and single-cell transcriptional analyses revealed upregulation of immune and inflammatory pathways and downregulation of oxidative phosphorylation. A combination of age, hemoglobin A1c, urine albumin-creatinine ratio, and serum KIM-1 and sTNFR1 predicted a clinico-pathologic diagnosis of diabetic nephropathy in the KPMP (AUC 0.82, 95% CI 0.75-0.89) and was associated with an increased risk of CKD progression among patients with diabetes enrolled in CRIC (HR 1.48 [95% CI 1.27-1.73] per 10% higher predicted probability of diabetic nephropathy). ConclusionIn common presentations of CKD, kidney biopsies may alter a priori impressions, reveal a diversity of diagnosis, structure, and function that is associated with clinical outcomes and can impact therapeutic decisions.

IntroductionPatients with type 2 diabetes mellitus (T2DM) are at increased risk of coronary artery disease and frequently undergo coronary angiography or percutaneous coronary intervention. Although risk factors for post-contrast acute kidney injury (PC-AKI) are well defined, effective preventive strategies remain limited. MethodsThis multicenter observational cohort study included 975 patients aged 18-75 years who underwent coronary angiography and/or percutaneous coronary intervention with iodinated contrast between June 2023 and June 2024. All patients received standardized intravenous hydration. Participants were grouped according to chronic sodium-glucose co-transporter-2 (SGLT2) inhibitor use ([&ge;]3 months). PC-AKI was defined as a [&ge;]25% or [&ge;]0.5 mg/dL increase in serum creatinine within 48-72 hours after contrast exposure. ResultsThe mean age was 59.2 {+/-} 11.7 years, and 70.8% were male; 16.9% were using SGLT2 inhibitors. PC-AKI occurred in 7.3% of patients, and 0.7% required renal replacement therapy. In univariate analysis, advanced age, diabetes, hypertension, heart failure, diuretic use, and elevated urea, creatinine, potassium, and uric acid levels were associated with PC-AKI. Higher eGFR, albumin, sodium levels, and SGLT2 inhibitor use were inversely associated. In multivariate analysis, age [&ge;]65.5 years (OR 4.53), diabetes (OR 2.49), and uric acid >6.75 mg/dL (OR 2.34) remained independent risk factors, while eGFR >81.5 mL/min/1.73 m2 (OR 0.38), sodium >137.5 mmol/L (OR 0.36), and SGLT2 inhibitor use (OR 0.09) were independently protective. ConclusionBeyond established cardioprotective and renoprotective effects, SGLT2 inhibitors may reduce the risk of PC-AKI in patients with T2DM, potentially through decreased renal oxygen consumption and attenuation of contrast-induced hypoxic injury.

Background and objectivesDiagnostic disclosure practices for autosomal dominant polycystic kidney disease (ADPKD) vary and may influence patient experience and linkage to nephrology care. We characterized patient-reported diagnostic pathways, perceived timing, and disclosure experiences in the PK-DIAG survey. Design, setting, participants, and measurementsCross-sectional web-based survey in France (February 2019-August 2024) among adults with self-reported ADPKD, disseminated via patient organizations. Primary outcomes were poor tact (tact score 0-1 on a 0-5 scale) and very negative diagnostic disclosure experience (overall score 0-1 on a 0-5 scale). Multivariable logistic regression used complete-case analyses. ResultsAmong 1,021 respondents, diagnosis was commonly disclosed outside nephrology care; 49% reported disclosure by a radiologist. Poor tact was reported by 25% and was associated with radiologist (vs nephrologist) disclosure (adjusted odds ratio 2.50; 95% confidence interval 1.57-3.98). Very negative experience was reported by 29% and was associated with poor tact (adjusted odds ratio 4.55; 95% confidence interval 2.90-7.12) and information perceived as insufficient/unclear/inaccurate (adjusted odds ratio 2.52; 95% confidence interval 1.53-4.15). Most participants perceived diagnosis as timely (67%), while 18% perceived it as too early and 15% as too late. Distress (36%) or unmet psychological needs (40%) in the immediate post-disclosure period was common. ConclusionsADPKD diagnostic disclosure often occurred outside dedicated nephrology consultations and was frequently associated with poor tact and inadequate information. These findings support structured, guideline-aligned disclosure pathways incorporating timely counseling, psychosocial support, and rapid linkage to nephrology care. Key PointsO_LIIn PK-DIAG, initial disclosure of ADPKD frequently occurred outside nephrology care, most often by radiologists in radiology settings. C_LIO_LIAbout one quarter of respondents reported poor tact and 29% reported a very negative overall diagnostic disclosure experience. C_LIO_LIPoor tact and information perceived as insufficient/unclear/inaccurate were strongly associated with a very negative diagnostic experience. C_LI

IntroductionGenome-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. MethodsWe performed a GWA meta-analysis for creatinine clearance (CrCl), a muscle mass-independent kidney function phenotype, in 58,976 individuals of European descent from the Lifelines Cohort Study. ResultsWe 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 x 10-9) and rs117014836, located near the AGPAT4 gene (EAF = 0.02, P = 5.42 x 10-9). Both SNPs were also associated with eGFRcrea in Lifelines (rs146465192: P = 1.34 x 10-8; rs117014836: P = 3.64 x 10-7), but not in previously published eGFR GWASs. In silico follow-up analyses revealed that rs146465192 was associated with plasma IGF2R ({beta} = -0.519, P = 1.40 x 10-6), while rs117014836 was associated with blood expression levels of AGPAT4 (eQTL P = 6.54 x 10-6). Furthermore, we identified two female-specific CrCl loci (t-statistic P < 0.004): rs8002366 (GPC6) and rs12908437 (IGF1R), associated with GPC6 expression in kidney (eQTL P = 8.38 x 10-10) and IGF1R expression in blood (eQTL P = 2.62 x 10-6), respectively. ConclusionThis first large-scale GWAS of CrCl revealed two new genetic variants among both sexes and two female-specific variants influencing kidney function. Lay summaryKidney function is a complex phenotype influenced by many different factors, including genetics. Earlier genetic studies often used the creatinine-based estimated glomerular filtration rate (eGFRcrea) as the measure of kidney function. However, eGFRcrea is influenced not just by kidney function but also by an individuals muscle mass, which may distort the results. Therefore, in this study we used creatinine clearance (CrCl), a measure of kidney function independent of muscle mass, to look for genes in a European-ancestry population. We identified 16 genetic regions; two of which had not been found before. We also found two additional regions that were only related to CrCl in females. This shows the added value of investigating CrCl and suggests sex-based differences in how genetics affect kidney function.

The long-term impact of SARS-CoV-2 infection on kidney allograft survival remains incompletely understood, particularly regarding the influence of vaccination, acute kidney injury (AKI), and post-infection immunosuppression. We conducted a retrospective analysis of 129 kidney transplant recipients with confirmed SARS-CoV-2 infection between March 2020 and March 2022 with a median follow-up of 50 months. Among 129 recipients, 106 (82%) received vaccination at any time before or after SARS-CoV-2 infection (82%) while 23 (18%) remained unvaccinated. Unvaccinated patients experienced significantly lower long-term graft survival (52% vs. 85%; p = 0.0004) and patient survival (83% vs. 99%; p = 0.0003) compared with vaccinated recipients. AKI occurred in 15% of recipients and independently predicted graft failure (aHR 2.88; p = 0.0341). Post-SARS-CoV-2 serum creatinine and albuminuria were strong prognostic markers of graft loss. Unvaccinated status independently predicted graft failure in both transplantation-anchored (aHR 2.80; p = 0.0342) and SARS-CoV-2-anchored models (aHR 5.31; p = 0.0004). Continuation of mycophenolate mofetil at post-infection assessment was associated with reduced graft-failure risk (aHR 0.99; p = 0.0193). These findings underscore the importance of sustained vaccination in preserving long-term allograft function.

IntroductionGenomic testing is reshaping nephrology practice, yet the structure, outcomes, and implementation of kidney genetics services remain poorly characterized. MethodsWe conducted a two-part scoping study comprising (i) a literature review (JBI methodology, PRISMA-ScR compliant; OSF registration doi.org/10.17605/OSF.IO/N32VA) of English-language publications (2000-2025) describing kidney genetics services and outcomes, and (ii) an international stakeholder consultation of clinic leads to capture real-world service and implementation experiences. ResultsSixty studies were included, predominantly from North America (n=23), followed by United Kingdom/Ireland (n=5), Europe (n=17), Australia/New Zealand (n=10), and Asia (n=5). Among the 25 studies describing clinic models, four types were identified: multidisciplinary integrated (n=12), nephrologist-led (n=9), mainstreaming (n=2), and traditional genetics referral (n=2). Clinic structure varied by region. Outcome reporting focused on diagnostic yield (92%), with limited data on timeliness (16%), patient-reported outcomes (12%), or implementation outcomes (4%). Test penetration was high across regions and models, while diagnostic yield varied. Nephrologist-led clinics demonstrated comparable performance to multidisciplinary models when adequately supported. International stakeholder consultation data (n=48) revealed diversification of clinic models across regions. In Australia/New Zealand, multidisciplinary clinics predominated, supported by public funding and in-house or hybrid laboratory. United Kingdom/Ireland clinics used public funding and a national laboratory. North American clinics show greater heterogeneity, with higher prevalence of nephrologist-led models, reliance on commercial laboratories, and mixed or private funding. Asian clinics reported nephrologist-led models, with resource constraints, and hybrid testing and funding arrangements. Comprehensive sequencing with virtual panels predominated in Australia/New Zealand, United Kingdom, and Europe; phenotype-driven panels {+/-} reflex testing were more common in North America. ConclusionsKidney genetics care is expanding but remains unevenly implemented. Nephrologist-led and multidisciplinary models can be effective with appropriate support. Patient selection may influence diagnostic yield more than testing modality. Standardized outcome reporting and theory-driven implementation evaluation are essential for delivering equitable, sustainable genomic services. Lay SummaryThis study examined how kidney genetics services are delivered across the globe. We reviewed 60 studies (2000-2025) and consulted 48 clinic leaders globally. Four service models were identified--multidisciplinary integrated, nephrologist-led, mainstreaming, and traditional genetics referral--and mapped variation in care teams, test strategies, test laboratories, and funding. Most studies reported diagnostic yield, but few assessed patient experience or how well services were implemented. European programs showed the highest performance, attributed to clear referral criteria, deep phenotyping, detailed family histories, multidisciplinary review, and strong public funding. Clinics led by nephrologists performed comparably to multidisciplinary teams when adequately supported. Across all settings, patient selection was more important than the specific type of genetic test used in determining diagnostic success. Kidney genetics services are expanding but remain uneven. This study highlights the need for context-specific, theory-informed, and determinants-targeted strategies to support scalable, equitable, and sustainable genomic care worldwide.

The pivotal role of Kir5.1 (KCNJ16) in maintaining electrolyte and acid-base homeostasis was demonstrated by animal studies and highlighted by the identification of disease-causing mutations in KCNJ16 resulting in a complex tubulopathy with variable severity. Although the underlying molecular mechanisms remain elusive, the modus operandi of Kir5.1 is rooted in its heteromeric association with Kir4.1 (KCNJ10) and Kir4.2 (KCNJ15). The ubiquitous expression of KCNJ16 and the heterogenous clinical picture point towards the importance of protein-protein interactions and membrane trafficking of the heteromeric channels involving Kir5.1. Alongside a retrospective report on the R137C variant, we describe a divergent clinical phenotype in a patient compound heterozygous for I132R and R176*. Moreover, we characterize a novel variant (homozygous for K48* and Y57*) whose clinical presentation coincides with the phenotype of the Kcnj16-/- mouse model (lack of deafness). Functional studies, buttressed by biomolecular studies (imaging and Co-IPs) in mammalian cells emphasize that the type and location of the KCNJ16 mutations may determine their interaction, membrane localization, and consequently, channel function and the resulting clinical phenotype. Our study highlights the need for molecular understanding of the KCNJ16 variants to promote correct diagnosis and personalized therapies, especially those involving channel modulators.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are two interconnected clinical conditions, both defined by degree of functional impairment, but with heterogeneous clinical trajectories. Using new transcriptomic technologies, recent studies have described the cellular diversity in the healthy and injured kidney at the single cell level. Here, we used single nucleus transcriptomics to investigate the molecular diversity and commonalities in kidney biopsies from over 150 participants with AKI and CKD enrolled within the Kidney Precision Medicine Project (KPMP), and did so at the patient participant level. Using an unsupervised approach, we identified two multi-cellular programs associated with clinical and histopathological features of acute injury and chronic damage, respectively. We found that these programs are expressed across patients with AKI and CKD, supporting shared, rather than distinct, underlying molecular mechanisms. These programs capture tissue-level compositional changes towards adaptive and failed-repair states in tubular epithelial cells, as well as intra-cellular molecular changes characteristic of stress in all cell types. We identified subunits of the NFkB and AP-1 complexes, as well as members of the STAT family, as putative upstream regulators of the acute and chronic programs. We were able to link these continuous molecular measures of acute injury and chronic damage with urine and plasma protein profiles obtained at time of biopsy. These non-invasive protein signatures were predictive of renal outcomes in an independent cohort of 44 thousand participants from the UK biobank. In summary, unbiased identification of cellular programs in kidney disease biopsies defined molecular programs of injury cutting across conventional disease categorisation and established a non-invasive molecular link to long term patient outcomes.

BackgroundThe extent to which achieving multiple metabolic treatment targets confers sustained cardiorenal protection across all stages of cardiovascular - kidney - metabolic (CKM) syndrome remains uncertain. MethodsThis multicenter retrospective cohort study used data from the China Renal Data System (CRDS). Participants were classified into CKM stages 1-4. Metabolic target achievement was defined as simultaneous control of blood pressure (BP<130/80 mmHg), fasting blood glucose (FBG<5.6 mmol/L), and low-density lipoprotein cholesterol (LDL-C<1.8 mmol/L). A metabolic score (0-3) reflected the number of targets met. Outcomes included a composite cardiovascular-renal endpoint and all-cause mortality. Cox and restricted cubic spline regression models were used to assess associations between metabolic control and outcomes in CKM patients. ResultsThe proportion of patients meeting all three metabolic targets decreased markedly with advancing CKM stage. Kaplan-Meier curves showed increasing risks of cardiovascular-renal events and mortality across higher stages (P<0.001). After adjustment, higher metabolic scores were linked to lower risks: for cardiovascular-renal outcomes, HR 0.82 (95% CI 0.77-0.87) for score 1, 0.72 (0.68-0.77) for score 2, and 0.65 (0.57-0.73) for score 3; for mortality, HR 0.73 (0.62-0.87) for score 1 and 0.68 (0.47-1.00) for score 2 (both P<0.05). However, achieving all three targets did not reduce mortality risk (HR 1.04, 95% CI 0.64-1.68). Stratified analysis showed significant risk reduction in early CKM stages but not in advanced stages. Restricted cubic spline models indicated nonlinear associations between LDL-C and both outcomes, and between FBG, systolic BP, and mortality, after full adjustment (all P<0.05). ConclusionWhile multifactorial metabolic target attainment shows strong protective associations with cardiovascular-renal outcomes in early CKM stages, this relationship diminishes in advanced disease. These findings highlight the need for stage-specific management strategies in CKM syndrome.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of pediatric kidney failure, but predicting individual progression remains challenging. This multicenter study developed and validated POCC, a machine learning model for predicting kidney failure risk at 1, 3, and 5 years post-diagnosis in CAKUT patients. Two versions were created using data from 2,249 children. The general model achieved internal AUCs of 0.93-0.99 and external AUCs of 0.90-0.98 and 0.81- 0.90 in two independent validations at pediatric and general hospitals, respectively. The specialized model, integrating congenital-hereditary features, achieved internal AUCs of 0.93-0.99 and external AUCs of 0.91-0.96 in pediatric hospitals. Deployed online, POCC demonstrated 90.7% accuracy in real-world validation, with the specialized model reaching 100% sensitivity and specificity for 5-year predictions. As the first tool for multi-timepoint risk prediction across diverse CAKUT subphenotypes per patient, POCC has strong potential to support personalized management.

BackgroundThe effects of Banff histological diagnoses on kidney transplant outcome have been well characterized. However, repeated observation of such histological injury across multiple biopsies in kidney transplant recipients remains insufficiently explored. MethodsIn an observational cohort (N=1819 transplantations with 5736 post-transplant biopsies, recurrent event survival models quantified transitions between diagnoses of T-cell mediated rejection (TCMR), antibody-mediated rejection (AMR), DSA-negative C4d-negative microvascular inflammation (MVIDSA-/C4d-), BK polyomavirus nephropathy (BKPyVAN), borderline TCMR (bTCMR), and probable AMR (pAMR), revealing patterns in the disease trajectories. In two observational cohorts (N=1818 transplantations with 5732 biopsies, N=853 transplantations with 975 biopsies), time-dependent cumulative covariates were constructed for TCMR, AMR, MVIDSA-/C4d- and BKPyVAN, enabling estimation of associations of repeated diagnoses with graft failure using multivariable cause-specific Cox models. ResultsThe incidence rate of a diagnosis was most strongly associated with earlier diagnosis of the same type, but associations between different types of diagnoses also occurred. The hazard of kidney graft failure was significantly increased by repeated observation of TCMR in multiple biopsies (HR 7.97, 95% CI 4.94 - 12.86), as well as by repeated AMR (HR 6.19, 95% CI 3.15 - 12.17), repeated MVIDSA-/C4d- (HR 4.53, 95% CI 2.15-9.54) and repeated BKPyVAN (HR 10.90, 95% CI 5.83 - 20.35). The hazard of graft failure was increased more after repeated diagnoses in transplants than after first diagnoses. The effects of repeated TCMR and repeated AMR remained significant even when observed in protocol biopsies in the absence of graft dysfunction. Repeated observation of BKPyVAN was the most detrimental of all diagnoses when observed in indication biopsies, but it was the least harmful when observed in protocol biopsies. ConclusionIncidence of Banff histological diagnoses appears to be affected by earlier diagnoses, especially those of the same type. These repeated observations of a specific diagnosis have an additional effect on the hazard of graft failure, underscoring a critical unmet need for adequate treatment strategies for these recurrent or persistent injury processes. Lay summaryIn two observational cohorts of 1819 and 750 kidney transplant recipients, kidney transplant biopsies were taken at multiple time points after transplantation. Based on the Banff classification for transplant pathology, various post-transplant diseases were diagnosed, often at more than one time point during follow-up. We assessed patterns in the occurrence of diagnoses over time, and related these diagnoses to survival of the kidney grafts using survival models with time-dependent cumulative diagnoses. We found that repeated observation of the same diagnosis was much more common than consecutive observations of different diagnoses. Repeated diagnoses of tissue injury also decreased kidney graft survival more compared to single diagnoses. This indicates that treatment options for patients with repeated or persistent diagnoses are currently inadequate and novel strategies are needed.

BackgroundKidney disease refers to a broad range of disorders that impair renal structure and function. Among these, chronic kidney disease (CKD) is the most prevalent worldwide, affecting approximately 10% of the global adult population. While large-scale omics studies have identified numerous molecular associations with kidney function and disease, these insights often remain isolated within individual data layers, hindering a systems-level understanding of the functional interplay between genes, proteins, metabolites and clinical phenotypes. MethodsWe developed the Kidney Disease Atlas (KD Atlas) using an extended QTL-based integration strategy combined with a composite network approach. For this purpose, we leveraged results from omics studies in population-based and kidney disease-specific cohorts from the CKDGen Consortium and other large-scale initiatives and integrated them with data from knowledge databases, inferring a comprehensive network of relationships between metabolites, proteins, genes, and kidney disease-related traits. ResultsWe present the KD Atlas, an online resource (https://metabolomics.helmholtz-munich.de/kdatlas) integrating over 25 large studies providing disease-relevant information on 20,456 protein-coding genes, 1,962 proteins, 1,375 metabolites and 40 kidney disease phenotypes connected by more than 1.2 million relationships. Through an interactive web interface, researchers can dynamically construct context-specific molecular subnetworks and perform integrated analyses without requiring specialized bioinformatics expertise. Application showcases demonstrate the resources utility for providing the molecular context of KD-associated genes or metabolites and for generating novel mechanistic hypotheses. ConclusionThe KD Atlas provides a global, multi-omics network view of kidney pathophysiology through an intuitive interface, empowering researchers to formulate mechanistic hypotheses and prioritize candidate targets for subsequent experimental validation.

BackgroundSnakebite is a neglected tropical disease with a high burden in South Asia, particularly India. Acute kidney injury (AKI) is one of the most serious complications of snake envenomation, which has significant morbidity, mortality and risk of chronic kidney disease (CKD). The present study aimed to evaluate the incidence, predictors, and outcomes of snakebite-associated AKI (SBE-AKI) in a tertiary care centre. MethodsWe retrospectively analysed 325 patients with snakebite envenomation, admitted to our institution. Demographic, clinical, laboratory, and treatment variables were compared between patients with and without AKI. AKI was staged according to KDIGO criteria. Renal biopsy was performed in selected patients. Outcomes assessed included recovery, Progression to CKD, and mortality. ResultsOf the 325 patients, 79 (32.1%) developed AKI. Patients with AKI were significantly younger (mean age 34 vs. 45 years, p = 0.001). Delay in anti-snake venom (ASV) administration (18 vs. 6 hrs, p = 0.001), need for inotropes (41.8% vs. 14.2%, p = 0.001), and mechanical ventilation (36.7% vs. 6.9%, p = 0.001) were strong predictors. Proteinuria was more frequent in AKI (80% vs. 32.5%). Among AKI patients, 57% had stage 3 AKI; 39.2% required dialysis. Biopsy (n=8) showed acute tubular necrosis in 37.5% and cortical necrosis in 25%. Outcomes included 77.2% recovery, 6.3% progression to CKD, and 16.5% mortality. ConclusionSBE-AKI is a common and serious complication of snakebite. Delay in ASV administration, hemodynamic instability, proteinuria, advanced AKI stage and cortical necrosis predict poor outcomes. Early ASV, timely dialysis, and long-term nephrology follow-up are essential to improve survival and reduce CKD progression.

IntroductionThe global prevalence of chronic kidney disease (CKD) is rising and initial studies suggest that diets predominantly based on greater inclusion of plant foods may be associated with lower CKD risk. As population-based studies are lacking, we investigated the association between habitual plant-based diets and CKD in the UK Biobank cohort. MethodsThe UK Biobank is a large prospective cohort study of participants aged 40-69 years. Habitual diet was assessed using a baseline food frequency questionnaire, and participants were classified into five dietary groups: high meat eaters, low meat eaters, poultry eaters, pescatarians, and vegetarians. To assess the risk of CKD across these groups, we conducted multivariable Cox proportional hazard regression analyses. ResultsDuring follow up of 12.9 years 23,084 out of 416,584 developed CKD. Compared to high meat eaters, only vegetarians had a statistically significant lower risk of CKD [HR = 0.81, 95% CI: 0.71- 0.93]. ConclusionThis is the first population-based study on plant-based diet types and CKD risk. Our findings suggest that vegetarian diets are associated with a lower risk of CKD. Future research is needed to assess the feasibility and acceptability of plant-based diets for the prevention of CKD and other chronic diseases.

IntroductionChronic kidney disease imposes a high clinical and economic burden on the Brazilian Unified Health System, and kidney transplantation offers the best prognosis. ObjectiveTo describe trends in living kidney (LD) donation in Brazil (2010-2023), analyzing the donor-recipient relationship and the operational stock-to-annual production ratio on the waiting list, and to compare hospital indicators and estimated patient and graft survival between LD and deceased-donor (DD) kidney transplants. MethodsDescriptive ecological time-series study using aggregated, publicly available data. ResultsThe waiting list increased by 15% (from 33,253 to 38,258), and the total number of transplants rose by 29% (from 4,656 to 6,047). Data showed an increase in deceased-donor transplants (from 3,001 to 5,189) and a decrease in LD transplants (from 1,655 to 858), with the LD share declining from 35.55% to 14.19% and the per-million-population rate falling from 8.8 to 4.2. Among LD, there was a relative decrease in related donors (from 82.80% to 71.21%), a relative increase in unrelated spouse donors (from 10.57% to 18.65%), and in other unrelated donors (from 6.63% to 10.14%). Comparatively, LD showed better descriptive performance on survival indicators and lower in-hospital mortality, length of stay, and mean Hospital Admission Authorization value. ConclusionThe findings indicate a need for strategies to sustain DD procurement and LD donation.

BackgroundIn lung transplantation, de novo immunodominant donor-specific anti-HLA antibodies recognizing HLA-DQ antigens (dn-iDSA-DQ) are predominant and can induce chronic lung allograft dysfunction (CLAD). We previously developed a method to measure the active concentration of dn-iDSA-DQ. We aimed to determine whether this new quantitative biomarker is associated with transplantation outcomes. MethodsThis retrospective multicentre cohort study included 90 lung transplant recipients (LTRs) developing dn-iDSA-DQ, evidenced through single antigen flow beads (SAFB) follow-up. We measured the active concentration of dn-iDSA-DQ at the time of their first detection (T0) for all LTRs, and within the 2 years after DSA detection, whenever possible. SAFB dn-iDSA-DQ characteristics and clinical data were retrieved up to 5 years after DSA detection. ResultsWe tested 184 sera with SPR (n=90 at T0, n=94 within the 2 years after DSA detection), among which 63 (34.4%) had a quantifiable concentration of the dn-iDSA-DQ ([&ge;]0.3 nM). The median SAFB mean fluorescence intensity (MFI) of the dn-iDSA-DQ with a concentration [&ge;]0.3 nM was higher (p<0.0001), yet the correlation between SAFB MFI and active concentration was low (r=0.758, p<0.0001). In multivariate analysis, a concentration of the dn-iDSA-DQ [&ge;]0.3 nM at T0 was independently associated with a lower 2-year CLAD-free survival (HR 2.06, p=0.02). A concentration of the dn-iDSA-DQ [&ge;]0.3 nM within the 2 years from DSA detection was associated with a lower graft survival in univariate analysis. ConclusionsActive concentration of dn-iDSA-DQ appears as a valuable biomarker to identify pathogenic DSA at their first detection because of its association with CLAD.

The integration of regenerative medicine into dynamic organ preservation may mitigate ischemia-reperfusion injury in kidney transplantation. This systematic review and meta-analysis evaluated the therapeutic potential of stem cell-based interventions during machine perfusion. Following PRISMA guidelines, PubMed, Embase, and Scopus were searched for experimental studies using stem cells or extracellular vesicles (EVs) during hypothermic or normothermic machine perfusion in animal or discarded human kidneys. Outcomes included renal function, injury biomarkers, inflammation, and histology. Nine studies were included, seven in meta-analysis. Despite heterogeneity in models and protocols, several reported reductions in inflammatory cytokines (e.g., IL-6, IL-1{beta}) and biomarkers (e.g., NGAL) following stem cell or EVs administration. However, meta-analysis showed no significant effects on creatinine clearance (Standardized Means (SMD): 0.00; 95% CI: -0.54 to 0.55), urine output (SMD: 0.54; 95% CI: -0.46 to 1.55), or NGAL (SMD: -1.68; 95% CI: -5.60 to 2.25). Histological protection varied, and stem cell retention was limited. Only one study assessed post-transplant function. While stem cell therapies during perfusion may have immunomodulatory and cytoprotective effects, consistent functional benefits were not observed. Further standardized studies, including transplant models and long-term outcomes, are needed to clarify therapeutic potential and optimize delivery strategies.