Journal of the American Society of Nephrology

Background Acute kidney injury (AKI) is a major contributor to morbidity, mortality, and healthcare utilization among hospitalized adults. Long-standing racial and ethnic inequities in U.S. healthcare--including unequal access to care, neighborhood disadvantage, and other structural factors--are known to influence kidney health, yet national data describing how these inequities manifest in AKI remain limited. Methods We conducted a retrospective, cross-sectional analysis of the 2022 National Inpatient Sample. AKI was identified using ICD-10-CM codes N17.x, and race/ethnicity followed HCUP categories. Descriptive analyses compared characteristics across groups. Survey-weighted logistic regression estimated adjusted odds of developing AKI, in-hospital mortality among AKI patients, and dialysis use, adjusting for demographics, payer, and comorbidities. Age-specific predicted AKI probabilities were derived from the adjusted model. Results AKI prevalence ranged from 15% to 23% across racial and ethnic groups. After adjustment, Black (OR 1.34), Native American (OR 1.08), and Other patients (OR 1.07) had higher odds of AKI, whereas Asian/Pacific Islander (OR 0.94) and Hispanic (OR 0.98) had slightly lower or similar odds. Among AKI hospitalizations, mortality was modestly lower for Black and Hispanic patients relative to White patients and higher for Asian/Pacific Islander and Native American patients. All non-White groups had higher odds of dialysis use. Age-specific curves showed persistent risk differences across adulthood. Conclusions Substantial racial disparities in AKI incidence, mortality, and dialysis use persisted after adjustment, reflecting broader structural inequities. Addressing these gaps will require both targeted clinical strategies and policy interventions focused on upstream determinants.

BackgroundPatients with kidney failure undergoing maintenance hemodialysis suffer high rates of major adverse cardiovascular events(MACE) that are not accurately predicted by traditional cardiovascular risk models. There is an urgent need to identify novel, modifiable cardiovascular risk factors for these patients. MethodsWe analyzed associations of 6287 circulating proteins with MACE among 1048 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort(CRIC) (14-year follow-up) with validation in the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease study(PACE) (7-year follow-up). In both cohorts, proteins were measured shortly after dialysis initiation and one year later. We compared protein-based risk models derived by elastic net regression to the Pooled Cohort Equations(PCE) optimized for these cohorts(Refit PCE), and to an Expanded Refit PCE that included Troponin T and N-terminal pro-B-type natriuretic peptide. ResultsIn CRIC, 149 proteins were associated with MACE at false discovery rate<0.05. Among 22 proteins significant at Bonferroni p<8x10-6, proteins that validated in PACE included Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), Complement component C7, R-spondin 4, Tenascin, Fibulin-3 and Fibulin-5. Complement pathways were prominent in network analyses. SVEP1 surpassed other markers by statistical significance, with CRIC HR per log2 1.8 (p=2.1x10-12) and HR per annual doubling 1.6 (p=6.8x10-6). For 2-year MACE, AUC(95%CI) for SVEP1 alone was 0.72(0.59, 0.84) in CRIC, and 0.73(0.63, 0.81) in PACE. SVEP1 surpassed the Expanded Refit PCE in CRIC (0.61 (0.48, 0.73)) (p=0.038). In the pooled CRIC + PACE cohort, SVEP1 AUC(95%CI) (0.79(0.70, 0.88)) surpassed Refit PCE (0.61(0.51, 0.72)) (p=0.004). ConclusionsSVEP1, a 390 kDa protein unlikely to be renally cleared, surpassed over 6000 other proteins and by itself outperformed traditional clinical risk models in predicting MACE in two populations of patients undergoing maintenance hemodialysis. Future studies should provide mechanistic insights behind these findings. Key PointsO_LIPatients with kidney failure undergoing hemodialysis have 20-fold higher cardiovascular mortality compared to the general population, and conventional risk factors have low prognostic utility for these patients. C_LIO_LIBy applying large-scale circulating proteomics in two independent hemodialysis cohorts, we have discovered >20 novel proteins that predict major adverse cardiovascular events(MACE). C_LIO_LISushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1) surpassed >6000 individual proteins and clinical factors for predicting MACE. C_LI

Secondary hyperparathyroidism persists in the majority of kidney transplant recipients and is associated with adverse graft and cardiovascular outcomes. The immunosuppressive drug class used post-transplant may modulate parathyroid hormone (PTH) levels through distinct mechanisms: calcineurin inhibitors (CNI) stabilize PTH mRNA, while mTOR inhibitors (mTORi) suppress parathyroid cell proliferation in experimental models. We report supporting evidence from two independent analyses. In a multinational real-world database analysis (TriNetX Global Collaborative Network), kidney transplant recipients with documented mTORi use and eGFR in the target range had lower PTH than those on CNI across eGFR strata examined (15-30, 30-45, 45-60, 60-75, >75 mL/min/1.73 m2), with risk ratios for PTH >130 pg/mL ranging from 0.47 to 0.67 in propensity-matched analyses (all p < 0.05). The known confounders - calcium (higher in CNI) and phosphate (higher in mTORi) - both act to oppose this pattern, strengthening the possibility of a drug effect. In a longitudinal single-center cohort (n = 118; 796 PTH measurements), a linear mixed-effects model with time-varying mTORi exposure confirmed a 42% lower PTH during on-mTORi periods after adjustment for eGFR, transplant vintage, diabetes, age, and sex (fold-change 0.58 [95% CI 0.50-0.68]; p < 0.0001). These findings suggest a direct PTH-lowering effect of mTORi. Immunosuppression choice may be considered in the management of post-transplant hyperparathyroidism in selected patients.

BackgroundDysregulation of phosphate homeostasis contributes to reduced longevity and vascular complications in chronic kidney disease and aging. This study investigates the role of TMEM174, a proximal tubule-specific protein, in regulating the phosphate co-transporter NPT2A and its subsequent impact on lifespan and vascular health. MethodsTMEM174 knockout (KO) mice (C57BL6/J and DBA/2J) were fed diets with varying phosphate concentrations (0.6% vs. 1.2%). In OKP cells, TIRF and FRET microscopy, alongside immunoprecipitation, were used to identify the TMEM174 protein regions essential for NPT2A binding and endocytosis. ResultsTMEM174 KO mice exhibited significantly shorter lifespans than wild-type controls. High phosphate diets exacerbated vascular calcification, stiffness, and mortality, while low phosphate diets rescued these phenotypes. In vitro, TMEM174 siRNA blocked PTH-induced NPT2A endocytosis, increasing its apical membrane retention. FRET and biochemical assays revealed that the C-terminal region of TMEM174 is essential for its association with NPT2A. While intact TMEM174 and N-terminal mutants (TMEM174{Delta}N) facilitated NPT2A degradation, C-terminal deletions (TMEM174{Delta}C) failed to associate with or degrade NPT2A. ConclusionsTMEM174 is a critical regulator of phosphate homeostasis and longevity. The C-terminal region of TMEM174 is specifically required for NPT2A endocytosis and degradation, identifying it as a potential therapeutic target for managing phosphate-related vascular complications.

BackgroundPersistent neurohormonal activation is a key driver of maladaptive remodeling and disease progression in heart failure (HF). Sodium-glucose cotransporter 2 inhibitors (SGLT2is) confer robust renoprotective effects in HF; however, the extent to which these benefits involve modulation of renal neurohormonal activity remains unclear. We hypothesized that SGLT2i-mediated renoprotection in HF is associated with attenuation of excessive renal neurohormonal activation. MethodsMale rats with myocardial infarction-induced HF and sham controls were fed standard chow or chow containing empagliflozin (EMPA, 300 mg/kg) for four weeks, followed by assessment of renal inflammatory and neurohormonal markers. Parallel in vitro studies in THP-1 macrophages and HK-2 proximal tubule cells evaluated the direct effects of EMPA on norepinephrine (NE)-dependent tubular inflammatory signaling. ResultsHF rats displayed higher renal cortical renin gene expression and angiotensin II concentrations, which remained unaffected by EMPA. Conversely, EMPA normalized the elevated urinary NE excretion and renal cortical NE content observed in HF rats. Given the inflammatory role of sympathetic hyperactivity, we assessed renal macrophage polarization. EMPA-treated HF rats showed reduced expression of pro-inflammatory markers (Tnf, Ccr2, Nos2, Il-6) and increased expression of markers associated with a reparative macrophage profile (Arg1, Mrc1, CD163), supported by higher CD206 macrophages in kidney sections. While EMPA did not directly alter THP-1 macrophage activation in vitro, it significantly reduced NE-induced SGLT2 expression and interleukin-6 (IL-6) release by HK-2 human proximal tubule epithelial cells. ConclusionThese findings support a model in which SGLT2 inhibitors confer renoprotection in HF by suppressing renal sympathetic hyperactivity, independently of the intrarenal renin-angiotensin system, thereby disrupting a maladaptive renal neuro-epithelial-immune axis and promoting a reparative macrophage phenotype. CLINICAL PERSPECTIVE Whats new?O_LIThis study identifies a renal neuro-epithelial-immune axis underlying empagliflozin-mediated renoprotection in heart failure. C_LIO_LIEmpagliflozin reduces renal cortical and urinary norepinephrine levels in heart failure without altering intrarenal renin-angiotensin system activity, revealing a distinct neurohumoral target of SGLT2 inhibition. C_LIO_LIThis sympatholytic effect is associated with a shift in renal macrophages toward a reparative (M2) phenotype, without changes in total macrophage abundance. C_LIO_LIEmpagliflozin blocks norepinephrine-induced SGLT2 upregulation, limiting proximal tubular glucose reabsorption and IL-6 production, and linking sympathetic signaling to renal inflammation. C_LI What are the clinical implications?O_LIOur findings provide a mechanistic basis for the additive cardiorenal benefits of SGLT2 inhibitors in heart failure, beyond conventional RAS-directed therapies. C_LIO_LITargeting renal sympathetic-driven inflammation may help preserve kidney function and attenuate the progression of cardiorenal syndrome. C_LIO_LISuppression of a renal neuroinflammatory pathway may help explain the early and sustained benefits of SGLT2 inhibitors across heart failure phenotypes, including nondiabetic patients. C_LI

Gabapentin and pregabalin are renally cleared gabapentinoids with markedly different pharmacokinetic profiles in chronic kidney disease: gabapentin half-life extends from 5-7 hours to 52-132 hours in advanced chronic kidney disease, while pregabalin accumulation is more predictable. In an active comparator new-user cohort of 33,791 adults aged [&ge;]40 years with hypertension initiating gabapentinoids (2018-2024) from the Rutgers Clinical Research Data Warehouse, chronic kidney disease substantially amplified gabapentin-associated dementia risk (hazard ratio 7.39, 95% confidence interval 3.43 to 15.92, P<0.001), whereas patients without chronic kidney disease showed near-null effect (hazard ratio 1.09, 95% confidence interval 0.89 to 1.34; P=0.41; interaction P<0.001). This effect was independent of prescribed dose: within the low-dose stratum, chronic kidney disease patients showed hazard ratio 5.06 versus 1.27 in patients without chronic kidney disease. Pre-existing chronic kidney disease conferred significantly elevated risk (hazard ratio 1.78; P=0.001), while incident chronic kidney disease showed a nonsignificant trend (hazard ratio 1.32; P=0.16), consistent with cumulative pharmacokinetic burden. Independent replication in the NIH All of Us Research Program Controlled Tier (N=47,079; hazard ratio 1.593, 95% confidence interval 1.349 to 1.882; P<0.001) confirmed the overall gabapentin-pregabalin signal; eGFR-staged analysis showed the expected pharmacokinetic pattern (mild CKD [eGFR [&ge;]45]: hazard ratio 1.15, not significant; severe CKD [eGFR <45]: hazard ratio 1.77, directionally elevated but underpowered with 51 events). Food and Drug Administration Adverse Event Reporting System data corroborated the renal mechanism (odds ratio 1.642 for renal events in elderly co-exposed patients). These converging findings suggest that chronic kidney disease is a clinically important modifier of gabapentin-associated cognitive risk, and that gabapentinoid selection in chronic kidney disease patients should integrate renal function status into prescribing decisions. Significance StatementGabapentin is the most prescribed gabapentinoid in the United States, with approximately 59 million annual prescriptions, and is entirely dependent on renal clearance. In this active comparator cohort study of 33,791 gabapentinoid initiators, chronic kidney disease amplified gabapentin-associated dementia risk nearly 7-fold compared with pregabalin, an effect that was independent of prescribed dose and persisted even among patients receiving low-dose gabapentin. External replication in the NIH All of Us Research Program and FDA pharmacovigilance data corroborated the signal. These findings suggest that current dose-adjustment guidelines for gabapentin in CKD may be insufficient to prevent cognitive harm, and that renal function status should be incorporated into gabapentinoid selection decisions.

Background.Renoprotective therapies - SGLT2 inhibitors, finerenone, and renin-angiotensin system inhibitors (RASi) - remain underutilisedin chronic kidney disease (CKD). Large language models (LLMs) may detect therapy omissions, but their performance acrossCKD severity strata and at clinical decision boundaries has not been evaluated.Methods.We constructed 100 synthetic CKD vignettes (G3a-G5D; 75 with prespecified omissions, 25 decoys) and queried four LLMsthree times each at temperature 0 (1,200 calls). Omission criteria were adapted from KDIGO 2024, including an investigator-defined gray-zone RASi initiation criterion at eGFR<15. Two nephrologists independently classified a stratified 20-casesubset.Results.For SGLT2 inhibitor and finerenone omissions, all models achieved near-ceiling sensitivity (97-100%). For RASi, performancediverged at the eGFR<15 boundary: Grok 4.1 Fast 85% versus GPT-5.4 55%, Gemini 10%, DeepSeek 10%. Gap-detectioninter-rater agreement was perfect (kappa = 1.000). Clinically incorrect reasoning rates ranged from 0% (GPT-5.4) to 27%(DeepSeek R1); of 52 instances, 31 were factual pharmacology errors and 21 reflected conservative boundary-discordantreasoning. Reproducibility (Jaccard) ranged from 0.74 to 0.93.Conclusions.This boundary-aware synthetic benchmark showed that aggregate sensitivity can conceal clinically important operational-rulediscordance. Rule-based SGLT2 inhibitor and finerenone omissions were detected with near-ceiling sensitivity, whereas aninvestigator-defined gray-zone RASi criterion at eGFR<15 exposed model-specific boundary behaviour. Evaluation of LLM-based CKD decision support should report boundary-specific performance, reproducibility, and clinically incorrect reasoningalongside aggregate metrics.

Background and hypothesis: Sodium-glucose cotransporter-2 inhibitors (SGLT2-inhibitors) slow chronic kidney disease progression, but evidence in non-diabetic kidney transplant recipients is limited. We evaluated associations between SGLT2-inhibitor use and major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), and all-cause mortality. Methods: In this retrospective cohort study using the TriNetX federated research network, adult non-diabetic kidney transplant recipients transplanted between January 2015 and January 2022 were identified. SGLT2-inhibitor users initiating therapy [&ge;]1000 days post-transplant were compared with non-users after 1:1 propensity score matching. The primary outcome was MAKE, defined as dialysis initiation or death. Secondary outcomes included all-cause mortality and MACE. Results: Propensity score matching yielded 867 pairs of SGLT2-inhibitor users and non-users. SGLT2-inhibitor use was associated with lower risks of MAKE (adjusted hazard ratio [aHR] 0.64, 95% CI 0.45-0.91) and all-cause mortality (aHR 0.55, 95% CI 0.36-0.85). No significant association was observed for MACE (aHR 0.86, 95% CI 0.64-1.17). No increased risk of urinary tract infections was observed among SGLT2-inhibitor users. Conclusion: SGLT2-inhibitor use was associated with lower risks of MAKE and all-cause mortality in non-diabetic kidney transplant recipients.

Abstract Background Alport Syndrome (AS), caused by pathogenic variants in type IV collagen genes COL4A3/4/5, is a leading monogenic cause of Kidney Failure (KF). Clinical course varies widely, and disease specific predictors of progression relevant to clinical care and trial design remain incompletely defined. Methods In this retrospective cohort study of individuals with AS in the UK National Registry of Rare Kidney Diseases, patients were classified as having AS or heterozygous genotypes and followed to assess proteinuria progression, eGFR slope and kidney survival. Proteinuria and eGFR trajectories were analysed using mixed effects regression models; kidney survival using Kaplan Meier analysis. Results Among 1032 participants (median follow up 11.6 years; 47% female), 475 (46%) had AS genotypes (Male XLAS or autosomal recessive AS). eGFR decline accelerated with advancing CKD stage across all genotypes (p<0.001). Proteinuria increased as eGFR declined and occurred earlier in AS genotypes. After reaching proteinuria thresholds of more than 1.0 and 3.0g/g, kidney survival over the subsequent 5 years did not differ significantly between genotypes (logrank p=0.14, p=0.17, respectively), although modest differences emerged over longer follow-up. Across eGFR thresholds (90, 60, and 45mL/min/1.73m2), higher proteinuria was associated with shorter time to KF; for example, at eGFR 45mL/min/1.73m2, median time to KF was 3.0 years (IQR, 1.6-5.4) for above-median vs 6.5 years (5.1-not estimable) for below-median proteinuria (p<0.0001). Almost all patients who reached KF had developed proteinuria of more than 0.3g/g. Conclusion In this national cohort, eGFR decline accelerated with CKD stage and proteinuria was strongly associated with progression to KF across genotypes. The non linearity of eGFR decline may inform its interpretation in clinical practice and use as a trial endpoint. Once comparable proteinuria levels were reached, differences in outcomes by genotype were attenuated, supporting proteinuria as a key prognostic marker and strengthening rationale for its use as a surrogate endpoint in AS clinical trials

Rationale & ObjectivePeriodontal disease(PD), a chronic inflammatory condition, may contribute to chronic kidney disease(CKD) through systemic inflammation, but its impact on CKD outcomes and the potential protective effects of periodontal treatment and routine dental prophylaxis remain uncertain. This study evaluated associations between PD, dental interventions, and kidney outcomes in a large U.S. veteran cohort. Study DesignRetrospective cohort study. Setting & ParticipantsUsing Veterans Health Administration data(2009-2019), we identified 86,376 adults eligible for comprehensive dental care with baseline eGFR >60 mL/min/1.73m{superscript 2} and followed them from their initial dental examination. ExposurePatients with PD (Cohort-A) were divided into those who received periodontal treatment (PD-Treated), those who did not receive treatment but had [&ge;]1 dental prophylaxis visit/year (PD-Prophylaxis), and those who received neither (PD-Untreated). Those without PD (Cohort-B) were grouped by presence or absence of regular dental prophylaxis ([&ge;]1 visit/year). OutcomeIncident CKD (eGFR <60 mL/min/1.73 m{superscript 2} and >25% decline from baseline), [&ge;]40% eGFR reduction, and incident albuminuria (>30 mg/g), each confirmed with repeat labs [&ge;]90 days apart. Analytical ApproachMultivariable logistic regression model ResultsOf 86,376 veterans (mean age 57.17{+/-}12.59 years; 91.4% male), 37.6% had PD. Adjusted model showed significantly lower odds of incident CKD, [&ge;]40% eGFR decline, and incident albuminuria noted in both PD-Treated [OR(95%CI): 0.80(0.70-0.91), 0.69(0.56-0.84), 0.88 (0.79-0.99)] and PD-Prophylaxis groups [OR(95%CI): 0.81(0.66-0.98), 0.60(0.43-0.82), 0.79(0.67-0.94)] compared to the PD-Untreated. Similarly, among patients without PD, regular dental prophylaxis was associated with reduced odds of Incident CKD, [&ge;]40% eGFR decline, and incident albuminuria [OR(95%CI): 0.87(0.78-0.96), 0.76(0.65-0.90), 0.85(0.78-0.93)]. LimitationsRetrospective design, unmeasured confounders, and reliance on electronic health records. ConclusionsPD is associated with increased risks of incident CKD, accelerated eGFR decline, and new-onset albuminuria. Periodontal treatment and routine dental prophylaxis mitigate these risks. Even in individuals without PD, regular dental prophylaxis appears protective against CKD development and progression.

Background: Clinical LLM benchmarks rarely test whether algorithmic rankings agree with expert clinical judgment. We developed a trap-embedded peritoneal dialysis (PD) benchmark comparing multiple scoring constructs with blinded nephrologist ratings. Methods: We generated 125 synthetic PD cases containing 13 ISPD-aligned trap types. Five LLMs (Claude Sonnet 4.5, GPT-5.4, Gemini 3.1 Pro, DeepSeek-R1, Grok 4.1 Fast) evaluated each case three times at temperature 0 (1,875 calls). Primary outcome was must-identify TDR_must, analyzed with GEE and case-clustered bootstrap. Secondary analyses included a verbosity-sensitive alarm-burden proxy, WCS, relaxed-match scoring, WCS sensitivity analyses, and a 25-output blinded expert adequacy substudy. Must-identify kappa was 0.89 in Stage 1 and 0.92 in Stage 2. Results: Rankings were discordant. Recall ranked Claude (0.977) and GPT-5.4 (0.955) above the other models (0.86-0.90, p<0.0001). The alarm-burden proxy favored concise models (Grok 0.689; 21.6 vs 2.4 issues/case), while WCS produced a third ordering. In the expert substudy, inter-rater concordance was strong (rho 0.977), but WCS did not show a positive association with expert adequacy (rho -0.17, p=0.41). Conclusion: Clinical LLM rankings in PD prescription review depend strongly on scoring construct. Algorithmic metrics should be reported alongside blinded expert adequacy ratings and should not alone determine deployment.

Importance: Recently, proteinuria has been accepted as a surrogate end point for clinical trials in focal segmental glomerulosclerosis (FSGS) ang IgA nephropathy. However, proteinuria has not been evaluated in Apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD). Methods: Real world data (RWD) analysis of 128 patients of African ancestry with APOL1 high risk genotypes, without diabetes, enrolled in the Million Veteran Program (MVP; n=109) or the biorepository at Vanderbilt University (BioVU; n=19), who had urine albumin-creatinine ratio (UACR) >= 420 mg/g (PCR~0.9 g/g) with a concurrent GFR value. The main predictor was change in the log-UACR at 12 months. The primary outcome was annual GFR slope over 24 months. Secondary outcomes included a kidney composite of a sustained 30% GFR decline, end stage kidney disease (ESKD) or death and ESKD as a single outcome. Linear regression and Cox proportional hazards models were used to assess the effect of changes in UACR and the outcomes. Results: In the pooled analysis the mean age was 56.8 (SD 15.5) y, 116 were male (90.6%) and three patients had diagnosis of FSGS at baseline. Mean baseline eGFR was 46.8 (SD 16.1) mL/min/1.73m2, mean baseline UACR was 1240.8 (1107.7) mg/g, mean eGFR slope was -4.67[-6.00, -3.33] mL/min/1.73m2/year and the geometric mean percentage changes in the UACR at 12 months were -57.5% [-65.0%, -48.4%]. For every 1 unit of log (UACR) increment at 12 months, the annual eGFR slope decreased by -1.80 [-2.56, -1.03] mL/min/1.73m2 in the pooled analysis. For every 1 unit of log (UACR) increment at 12 months, the Cox regression showed a 61% increase in the risk of a kidney composite (p=0.002) and a 98% increase in the risk of ESKD (p<0.001). It was estimated that a 50% reduction of UACR at 12 months was associated with a 28% reduction in the kidney composite endpoint (adjusted hazard ratio [aHR]=0.72; 95% confidence interval [CI]:0.59-0.88; p=0.002), and a 38% reduction in the risk of ESKD (aHR=0.62; 95% CI:0.49-0.80; p<0.001). Conclusions and relevance: Changes in UACR at 12 months significantly modify the rate of decline of GFR over 24 months and clinically meaningful endpoints, supporting the use of UACR changes as surrogate endpoint in AMKD.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder marked by numerous renal cysts that impair kidney function, with about half of affected individuals progressing to kidney failure by midlife. Patients exhibit reduced circulating apelin, a ligand of the apelin receptor, known to regulate cardiovascular function including hypertension. We tested whether diminished apelin signaling contributes to cystogenesis and if exogenous apelin receptor activation can improve disease outcomes. MethodsPlasma samples from age- and sex-matched healthy controls and ADPKD participants were analyzed for circulating apelin peptides. To assess direct cystic effects, primary ADPKD renal epithelial cells were grown as 3D collagen-embedded cysts and treated with apelin agonists. Male and female Pkd1RC/RC; Pkd2+/- (PKD) mice were treated for 27 days with apelin agonists, vehicle, or the standard of care drug, Mozavaptan. Kidney and heart weight ratios, BUN, renal cAMP, and kidney transcriptional profiles were evaluated. ResultsCirculating apelin peptides were significantly reduced in ADPKD patients despite normal kidney function (eGFR, BUN, and creatinine). In vitro, both apelin and the small molecule apelin receptor agonist Azelaprag inhibited cyst growth. Apelin and Mozavaptan reduced kidney weight, cystic index, blood urea nitrogen and renal cAMP in PKD mice, whereas Azelaprag did not. Apelin downregulated expression of genes associated with cyst progression, including Lcn2 (Ngal), Postn, and Havcr1 (Kim-1). Mozavaptan, but not apelin, induced diuresis and reduced urinary concentration. ConclusionApelin receptor activation by exogenous apelin inhibited cAMP synthesis and cyst growth and improved kidney function in an orthologous mouse model of ADPKD. We propose that the apelin receptor may be a potential therapeutic target in ADPKD.

BackgroundPolycystic kidney disease (PKD) is the leading genetic cause of renal failure, resulting in the accumulation of fluid filled cysts and gross enlargement of the kidney. Mutations in PKD1 or PKD2, which encode ciliary polycystin proteins, are the most common cause of PKD. These proteins function in a cilia-dependent cyst activation (CDCA) pathway-one that requires cilia for its pro-cystic function-yet the molecular driver(s) of this pathway are unknown. ARL13B is a regulatory GTPase enriched in cilia and links to renal cystogenesis. ARL13B possesses guanine nucleotide exchange factor (GEF) activity for ARL3, another ARL with links to cilia. MethodsWe used two distinct Arl13b mouse alleles to investigate whether ARL13B is a component of the CDCA pathway: Arl13bV358Aencodes for enzymatically normal ARL13B that is undetectable in cilia, and Arl13bR79Qencodes for cilia-localized ARL13B lacking a residue critical for its ARL3 GEF activity. We used these alleles in a Pkd1-deficient adult mouse model and investigated renal morphology (H&E and cystic index analysis), physiology (blood urea nitrogen measurements), renal fibrosis (picrosirius staining and -smooth muscle actin levels), renal injury (SOX9 immunofluorescent staining and quantification), and Wnt signaling ({beta}-catenin and cyclin D1 protein levels). ResultsWe found that loss of ciliary ARL13B or mutation of a single residue critical for its ARL3 GEF activity suppressed Pkd1-dependent cysts. We observed reductions in kidney size, cystic index, and blood urea nitrogen. We also observed suppression of renal fibrosis, renal injury, and {beta}-catenin and cyclin D1 protein levels. ConclusionsOur results identified a subcellular location and mechanism driving Pkd1-dependent renal cystogenesis. We demonstrated that expression of a critical residue for ARL13Bs GEF activity specifically in cilia is a key mechanism of the CDCA pathway driving renal cystogenesis. Key PointsO_LILoss of ciliary ARL13B suppressed renal cystogenesis in an adult mouse model of polycystic kidney disease (PKD) without ablating cilia C_LIO_LILoss of ciliary ARL13B or mutation of the residue critical for its GEF activity did not affect renal morphology or physiology in a PKD mouse model C_LIO_LIMutation of a residue critical for ARL13B activation of ARL3 suppressed cystic phenotypes in Pkd1-dependent cysts C_LI

Background and objectiveKidney stone disease (KSD) is common and distinct monogenic forms with well-defined treatment pathways exist. However, it is unclear which patients should undergo genetic testing and the significance of monoallelic variants in SLC34A1, SLC34A3, CYP24A1, SLC7A9, and SLC3A1. We aimed to define monogenic KSD inheritance patterns, determine the diagnostic yield of genetic testing in selected and unselected cohorts, and establish the utility of standard serum biochemistry in highlighting those at risk of monogenic KSD. MethodsWe compared genetic and phenotypic data from individuals with and without KSD in the UK Biobank to determine inheritance patterns. We established the "number needed to test" (NNTT) to identify monogenic KSD in the UK Biobank and a specialist adult kidney stone nephrology clinic where patients had genetic testing based on age, recurrence, and family history. We examined the utility of standard serum biochemistry in identifying monogenic KSD in both settings. Key findings and limitationsMonogenic KSD associated with SLC34A3, SLC7A9, and SLC3A1 is inherited in an autosomal dominant manner and monogenic KSD associated with SLC34A1 and CYP24A1 in an autosomal recessive manner. A monogenic diagnosis was made in [~]1% of KSD in the UK Biobank (NNTT[~]90) and 15% of KSD in a specialist nephrology clinic (NNTT[~]7). In both settings, standard serum biochemistry failed to identify individuals at risk of monogenic KSD. Conclusions and clinical implicationsGenetic testing for monogenic KSD has utility in specialist settings where there is clinical suspicion of an inherited disorder even in the absence of biochemical abnormalities.

Poor outcomes in proteinuric kidney diseases are challenging to successfully manage therapeutically due to the heterogeneity of underlying disease pathogenesis and associated risk for progression. The role of cytoskeleton-associated proteins, including the scaffolding protein Anillin (ANLN), are of specific interest in kidney disease given the importance of actin dynamics in the kidneys specialized epithelial cell types. In this study, we identify the prevalence of genetic variants in ANLN, the gene encoding ANLN, in a cohort of deeply phenotyped individuals with non-diabetic proteinuric kidney disease. Thirty-one individuals (of 864 genotyped) harbor heterozygously expressed variants in ANLN; 7 unrelated individuals shared the same variant (I1109V) in the C-terminal pleckstrin homology (PH) domain, a region necessary for interaction with the plasma membrane. Kidney organoids generated from I1109V induced pluripotent stem cells from 1 of these individuals showed increased epithelial cell mitogen-activated protein kinase 8 network activity and apoptosis, which was enhanced by tumor necrosis factor alpha (TNF-) and phenocopied by actin polymerization inhibition. TNF--treated I1109V organoids also exhibited tubular lumen expansion. Knockdown and re-expression of the analogous ANLN variant in Xenopus laevis embryonic epithelia resulted in defects in cell-cell junction dynamics including wavy cell membranes exhibiting increased transverse movements as well as abnormal junctional F-actin remodeling in response to mechanical stress and leaky barrier function. Taken together, these results indicate that enhanced tubular epithelial cell death, perturbed cell-cell contacts and barrier function defects are associated with a novel ANLN variant discovered in individuals with non-diabetic proteinuric kidney disease. ONE SENTENCE SUMMARYEnhanced tubular epithelial cell death and perturbed cell-cell junction integrity and barrier function are associated with a novel Anillin coding variant discovered in a cohort of individuals with proteinuric kidney disease.

Background and hypothesis Autosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide including an estimated 30,000-70,000 in the United Kingdom (UK). Tolvaptan is the only disease-modifying therapy approved for rapidly progressing disease. Despite national guidance, prescribing rates were hypothesised to vary by kidney centre. Treatment may not always align with guidelines: some patients eligible for tolvaptan may not be initiated, while other patients initiated on tolvaptan may not meet eligibility criteria. This may have important consequences for healthcare costs and health-related quality of life. Methods The National Registry of Rare Kidney Diseases (RaDaR) collects longitudinal data from UK NHS kidney centres. This retrospective cohort study used routinely collected data (2016-2023) to examine tolvaptan prescribing across kidney centres. Kidney centre-level initiation patterns were described, assessed using mixed-effects logistic regression and visualised with funnel plots. Cost-effectiveness analyses combined observed prescribing practices under likely negotiated commercial discounts to estimate costs and quality-adjusted life year (QALY) consequences of prescribing at the national level. Results Our study included 3,609 people with ADPKD from 72 kidney centres. Patients eligible for tolvaptan who were not initiated accounted for 34.8% (292/839). Across centres, five (6.9%) initiated tolvaptan significantly more than expected among eligible participants, while one centre (1.4%) initiated significantly less. Nationally, this could result in up to {pound}53.7 million in lost savings (assuming a 60% medication price reduction) and result in up to 1,245 lost QALYs. Patients initiated on tolvaptan who were not eligible accounted for 26.1% (103/395). Only one centre had significantly fewer eligible patients than expected among initiated patients. Nationally, this could cost up to {pound}15.9 million (assuming a 60% medication price reduction). Conclusions There is evidence of variation in tolvaptan prescribing in the UK. A substantial proportion of patients eligible for tolvaptan were not initiated at the cohort-level, with evidence of variation between centres suggesting differences in treatment decision-making. A substantial proportion of patients initiated on tolvaptan were not eligible at the cohort-level, but there was limited evidence of variation between centres. Together, these findings raise questions regarding the potential consistency of clinical decision-making, equitable access to a sole disease-modifying therapy in a rare disease, alignment with national guidance, and effective use of healthcare resources.

Background and ObjectiveSurgical complexity for renal tumors has traditionally been assessed using manual nephrometry scores, which require unreimbursed physician effort and are subject to interobserver variability. This study introduces an objective, fully automated alternative derived from decades of experience at a large academic center. MethodsWe trained a CT classification model to predict whether a patient would ultimately undergo Partial or Radical Nephrectomy (PN or RN). We hypothesized that the models confidence in RN (termed the CLARITY score) would serve as a surrogate for the difficulty of nephron-sparing approaches and thus for tumor complexity. This hypothesis was tested using multivariate logistic regression for failure to achieve trifecta, estimated blood loss (EBL) [&ge;] 500 mL, and length of stay [&ge;] 3 d. CLARITY was compared with tumor size and R.E.N.A.L. score. External validation in a geographically distinct cohort was performed. Key Findings and LimitationsFor predicting RN, CLARITY achieved an AUROC of 0.899 internally and 0.898 externally. In the external PN subgroup, it outperformed tumor size and R.E.N.A.L. score in predicting failure to achieve trifecta (AUROC 0.613), EBL [&ge;] 500 mL (0.727), and length of stay [&ge;] 3 d (0.673). In multivariable analysis, CLARITY remained associated with each outcome, whereas R.E.N.A.L. and size were not. This study is limited by its retrospective design. Conclusions and Clinical ImplicationsCLARITY is an automated CT-derived marker that quantifies renal tumor complexity more effectively than tumor size and R.E.N.A.L. score and may support scalable, objective preoperative complexity assessment. To support reproducibility and external validation, we have released a public inference pipeline and web-based DICOM upload portal for research use.

Acute kidney injury (AKI) is a sudden episode of kidney failure linked to a wide range of health conditions. High mortality in AKI highlights the need to identify new therapeutic approaches. Homeostasis in multicellular organisms is exquisitely regulated by phagocytosis of apoptotic cells, also known as efferocytosis. Apoptotic cells are frequently observed at sites of inflammation, including in AKI. Engulfment and cell motility protein-1 (ELMO1) is a regulator of the actin cytoskeleton that promotes apoptotic cell removal by phagocytes during efferocytosis. Mutations in the human ELMO1 gene are linked with diabetic nephropathy and, in animal models of this disease, high ELMO1 levels promote renal dysfunction. However, the role of ELMO1 in AKI was not known. Here, we describe the links between ELMO1 and kidney pathology and test global and tissue-specific ELMO1-deficient mice in models of AKI. While global loss of Elmo1 expression did not impact the immediate loss of renal function after ischemia-reperfusion elicited AKI, ELMO1 deficiency resulted in increased tissue injury in AKI caused by cisplatin injection. Cisplatin induced robust renal cell apoptosis that was significantly elevated in mice with the global loss of ELMO1, but not in mice with the macrophage-specific Elmo1 deletion. Using primary cell culture and immunofluorescence approaches, we highlight the role of ELMO1 in efferocytosis by several renal cell types, suggesting possible additive effects during nephrotoxic injury.

BackgroundMicrovascular dysfunction is a key contributor to the development and progression of chronic kidney disease (CKD), yet direct and reproducible assessment of microvascular function in clinical CKD populations remains limited. Laser Doppler flowmetry (LDF) provides a noninvasive, dynamic assessment of skin microvascular blood flow and may serve as a surrogate measure of systemic microvascular health. However, the extent to which LDF-derived measures relate to kidney function, proteinuria, and kidney histopathology in CKD remains unclear. MethodsWe assessed cutaneous microvascular function in 150 participants with CKD (estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m{superscript 2}) using a standardized forearm LDF protocol. Baseline perfusion was recorded at [~]30{degrees}C, followed by local heating to 44 {degrees}C to induce hyperemia. The percentage change in perfusion unit (PU) was calculated and used to define microvascular functional reserve. Associations between LDF-derived measures with eGFR and urine protein-to-creatinine ratio (uPCR) were assessed using multivariable linear regression adjusted for demographic and clinical covariates. Unsupervised k-means clustering was performed to identify microvascular phenotypes based on resting PU and microvascular function reserve. Associations of LDF measures with glomerulosclerosis (GS) and interstitial fibrosis and tubular atrophy (IFTA) were evaluated in a subset of participants (n = 20) who underwent clinically indicated kidney biopsies. ResultsAmong 150 CKD participants, the mean (SD) age was 64 (14) years, 46% were female, 38% had diabetes, and 83% had hypertension. The mean eGFR was 42 (21) mL/min/1.73 m{superscript 2} and median uPCR was 0.21 (interquartile range (IQR) 0.11 to 1.20) mg/mg. Higher baseline PU ({beta} = -12; 95% CI, -24 to -1) and reduced percentage change in PU ({beta} = 7; 95% CI, 2 to 13) was associated with lower eGFR, independent of covariates. Baseline PU or percentage change in PU were not associated with uPCR. Unsupervised clustering identified four distinct microvascular phenotypes characterized by graded differences in resting perfusion and microvascular function reserve. Among participants with biopsy data, higher baseline PU and lower percentage change in PU were associated with greater severity of GS and IFTA. ConclusionIn persons with CKD, elevated resting perfusion and impaired microvascular functional reserve were associated with lower eGFR. These findings suggest that LDF-derived measures capture clinically relevant alterations in systemic microvascular function and may serve as a noninvasive biomarker of kidney function and underlying histopathologic injury in CKD.