KEY POINTS:Lipocalin-2 upregulation paralleled intracellular uromodulin aggregates in mouse and cellular models of autosomal dominant tubulointerstitial kidney disease because of pathogenic uromodulin. The induction of lipocalin-2 was triggered by mutant uromodulin accumulation and endoplasmic reticulum stress in tubular cells. Genetic loss of lipocalin-2 reduced iron deposits in the kidney but did not affect kidney damage, indicating that lipocalin-2 was not driving disease progression. BACKGROUND:Autosomal dominant tubulointerstitial kidney disease due to pathogenic UMOD variants (ADTKD- UMOD ) is a toxic proteinopathy caused by intracellular accumulation of mutant uromodulin (UMOD) and endoplasmic reticulum (ER) stress. Lipocalin-2 (LCN2) is an acute phase protein induced by ER stress with context-dependent roles in kidney injury. METHODS:To examine the role of LCN2 in ADTKD- UMOD , we used Umod knock-in mouse models (C171Y, R186S, C125R), urine samples from affected patients, and mIMCD3 cells expressing wild-type or mutant UMOD. LCN2 expression was assessed by immunoblotting, immunostaining, and ELISA. Autophagy was stimulated with Torin1 to evaluate effects on LCN2 induction. UmodR186S/+ mice were crossed with Lcn2-/- mice to determine the impact of LCN2 deficiency on disease progression. RESULTS:Robust LCN2 induction was observed in kidneys and urine of UmodR186S/+ , UmodC125R/+ , and UmodC171Y/+ mice, correlating with UMOD aggregates and ER stress severity in thick ascending limb cells. In patients, specific UMOD variants were associated with elevated urinary LCN2. In mIMCD3 cells expressing mutant UMOD (C170Y, R185S), treatment with Torin1 reduced aggregates and attenuated LCN2 induction. Genetic deletion of Lcn2 in UmodR186S/+ mice decreased interstitial iron deposition but did not alter UMOD accumulation, interstitial inflammation, or fibrosis. CONCLUSIONS:LCN2 was induced by intracellular UMOD aggregates and ER stress in various models of ADTKD- UMOD . Although it influenced iron handling, LCN2 did not drive fibrosis or inflammation, supporting a role as a biomarker of toxic proteinopathy rather than a therapeutic target.

KEY POINTS:The causal relationship between serum osmolality and kidney outcome remained unclear in patients with autosomal dominant polycystic kidney disease. Serum osmolality may be a possible surrogate marker for the clinical monitoring of autosomal dominant polycystic kidney disease patients, especially when access to copeptin level is limited. High serum osmolality conveys possible detrimental effect on the kidney outcomes. BACKGROUND:Current treatment of autosomal dominant polycystic kidney disease (ADPKD) is mainly focused on inhibiting cystogenesis through arginine vasopressin suppression, and there has been interest in achieving similar vasopressin suppression by reduction of osmolality with increased water intake. However, the causal relationship between serum osmolality (sOSM) and kidney outcome remained unclear in patients with ADPKD. We aim to evaluate the relationship of sOSM and its effect on kidney outcome in patients with ADPKD. METHODS:Three hundred and eleven tolvaptan treatment-naïve patients with ADPKD were recruited prospectively from the CysticHK cohort, a territory-wide ADPKD registry across 12 tertiary hospitals in Hong Kong. Beside clinical data, serial measurement of serum, and urinary osmolality were obtained every 6 months over 5 years. All participants were treated according to the standard of clinical care. The primary outcome was the 40% decline from baseline eGFR. RESULTS:Patients with a high sOSM have a worse kidney outcome, as shown by the Kaplan-Meier plots (log-rank P ≤ 0.001) and the Cox regression model that showed a 5.91 times higher risk of reaching 40% eGFR decline compared with the top with bottom quartiles of osmolality ( P = 0.018). By contrast, there is an inverse relationship for urine osmolality. A receiver-operating characteristic analysis to assess the predictive efficacy of osmolality for identifying those at high risk of kidney decline also showed a good performance for sOSM (area under the curve, 0.81; 95% confidence interval, 0.73 to 0.89; P < 0.001). The urinary osmolality did not show a clinical meaningful predictive efficacy (area under the curve, 0.35; 95% confidence interval, 0.28 to 0.43; P = 0.003). CONCLUSIONS:sOSM may be a possible surrogate marker for the clinical monitoring of patients with ADPKD, especially when access to copeptin level is limited; and high sOSM conveys possible detrimental effect on the kidney outcomes.

Abstract Uromodulin is a kidney‐specific protein that is excreted in the normal urine. Factors regulating its excretion are unknown. Conflicting studies suggest that water balance may influence uromodulin excretion which, in turn, may cooperate with vasopressin to increase water reabsorption in the distal nephron. We analyzed the interplay between uromodulin excretion and water balance in a healthy adult population. Participants were recruited in a population‐based study in Switzerland. The urine uromodulin excretion rate (UUER) (mg/24 h) was measured (ELISA) in parallel with urine osmolality and serum copeptin (pmol/L) (immune‐luminometric assay) as a surrogate for vasopressin. Mixed multi‐variate linear regression models were used. We included 937 participants with 497 (53.0%) women, median age 47.7 years (32.4–61.6) and 27 (2.8%) with eGFR <60 mL/min/1.73m2. In univariate analysis, UUER was positively associated with urine volume (p < 0.001) and negatively with serum copeptin concentration (p < 0.001). In fully adjusted analysis, UUER remained positively associated with urine volume (p = 0.004) but not with serum copeptin concentration (p = 0.224). In univariate analysis, urine osmolality was negatively associated with UUER (p = 0.016). In fully adjusted analysis, namely accounting for serum copeptin and urine volume, urine osmolality was positively associated with UUER (p = 0.001). These results indicate that, in a healthy population, urine uromodulin excretion strongly associates with urine volume and, once accounting for confounding factors, influences urine osmolality in addition to vasopressin/copeptin levels. These data substantiate the role of urine flow in regulating uromodulin excretion and suggest an additive effect of uromodulin on urine concentration, alongside vasopressin.

While ultra-rare missense variants in UMOD cause highly penetrant autosomal dominant tubulointerstitial kidney disease, a more frequent UMOD T62P variant conveys intermediate risk with variable penetrance. To determine whether age or polygenic risk contributes to the variable penetrance of T62P, we combined genotype and phenotype data from 882,306 individuals across the UK Biobank (discovery cohort) and the All of Us and MyCode biobanks (validation cohorts). We also analyzed the impact of aging on uromodulin processing and cellular stress in stably transfected kidney tubular cells expressing wild-type or mutant UMOD. We compared the effects of the GPS on risk of CKD between T62P carriers and non-carriers and tested for the GPS-by-T62P interaction. The UMOD T62P variant was reproducibly associated with increased risk of CKD in an age-dependent manner. Compared to wild-type, clones of T62P-expressing cells exhibited a defective uromodulin maturation profile, causing endoplasmic reticulum retention and stress. We also observed significant T62P-by-GPS interaction, with T62P carriers in the top quintile of the GPS having over 5-fold higher risk of CKD compared to population average (OR 5.17, 95%CI: 2.94-9.08, P=1.0E-08). In summary, we demonstrate that the penetrance of kidney disease in T62P carriers is strongly modified by both age and polygenic risk.

An efficient endolysosomal pathway is crucial to mediate the reabsorption and processing of ultrafiltered solutes including low-molecular-weight (LMW) proteins by epithelial cells lining the proximal tubule (PT) of the kidney. The zebrafish pronephros is used as a model system for congenital or acquired disorders that impair endolysosomal processing in PT cells, causing inappropriate loss of solutes and LMW proteins in urine. Here, we describe a new reporter ½vdbp-NanoLuc zebrafish line, in which vitamin D-binding protein is coupled to NanoLuc luciferase for detection of PT dysfunction and LMW proteinuria. We demonstrate the reliability and value of the ½vdbp-NanoLuc biosensor in fish models of monogenic endolysosomal diseases, gentamicin and cisplatin-induced nephrotoxicity, and metal contamination. This novel reporter system yields mechanistic insights into cadmium- and copper-induced PT dysfunction and provides a platform for drug screening.

Icodextrin enhances ultrafiltration (UF) in patients on peritoneal dialysis (PD) but is restricted to 1 bag/d, according to regulatory authorities. The Double-Icodextrin Dose (DIDo) study is a prospective randomized trial investigating the superiority and safety of using 2 bags/d versus 1 bag/d of icodextrin to extend incremental (3 bags/d) continuous ambulatory PD (CAPD) duration in older incident patients. After a 2-month "run-in" period, the patients were randomized to 2 icodextrin ("double dose") + 1 glucose or 1 icodextrin ("single dose") + 2 glucose dialysates daily. The primary end point was a composite of excessive use of hypertonic dialysates, transfer to another dialysis modality (automated PD [APD], nonincremental CAPD, or hemodialysis) or death at month 9. Secondary end points included mortality, daily UF, technique survival, rates of peritonitis and hospitalizations, and safety at month 18. Forty-one patients were randomized to double dose and 42 to single-dose icodextrin. Baseline characteristics were well-balanced between groups. At month 9, the proportion of patients who discontinued 3 exchanges/d was similar between those receiving the double and the single icodextrin dose (16 [39%] vs. 21 [50%]; HR: 0.69; 95% confidence interval: 0.35-1.33). The results were similar at month 18. Patients in the double dose icodextrin had higher net UF and less hypertonic dialysates use. Rates of peritonitis, hospitalizations, residual urine output decline and serious adverse events (SAEs) were similar between both groups. In older patients on incremental CAPD, the double icodextrin dose did not reduce the primary outcome incidence compared with the single icodextrin dose. Significantly enhanced UF was observed in the double icodextrin dose group and no safety issue was identified.

Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat C. albicans infections, the underlying mechanisms remain unclear. Using global and conditional Il1r1 knockouts in mice, here we show that IL-1R signaling in non-hematopoietic cells in the kidney and brain is crucial for a protective response. In the kidney, endothelial IL-1R contributes to fungal clearance independent of neutrophil recruitment, while IL-1R in hematopoietic cells is dispensable. IL-1R signaling indirectly recruits neutrophils and monocytes in the brain by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing data implicates excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of Il1r1-deficient mice within a few hours upon infection, with associated, localized hypoxia at infection foci. Lastly, we find that hypoxia promotes fungal growth and pathogenicity. In summary, our results show that IL-1R-signaling in non-hematopoietic cells is required to prevent fatal candidiasis by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia.

Data on the presentation of Autosomal Dominant Polycystic Kidney Disease (ADPKD) in children have been based on small/regional cohorts and practices regarding both asymptomatic screening in minors and genetic testing differ greatly between countries. To provide a global perspective, we analyzed over 2100 children and adolescents with ADPKD from 32 countries in six World Health Organization regions: 1060 children from the multi-national ADPedKD registry were compared to 269 pediatric patients from the United Kingdom (RaDaR) and 825 from the European Rare Kidney Disease Registry (ERKReg). Asymptomatic family screening was a common mode of presentation (48% in ADPedKD, 62% in ERKReg) with broad international variability (19%-75%), but fairly stable temporal trends in both registries with no correlation to genetic testing. The national rates of genetic testing varied and correlated significantly with healthcare expenditure (odds ratio 1.030 per 100 United States Dollars/capita/year, in the ERKReg cohort), with little variation over time. Diagnosis due to prenatal abnormalities was more common than anticipated at 14% increasing steadily from 2000 onward in both registries. Realistically, a high proportion of children were diagnosed with ADPKD by active screening, underlining that families affected by ADPKD have a high need for counselling on the complex issues around presymptomatic diagnosis. Regional variations in rate of genetic testing appeared to be driven by economic factors. However, large differences in rate of active screening were not correlated to healthcare spending and probably reflect the influence of different of cultural, legal and ethical frameworks on families and clinicians in different healthcare systems.

[This corrects the article DOI: 10.1016/j.ekir.2025.05.036.].

OBJECTIVE: This study explores how Swiss citizens prioritise healthcare resource allocation for rare diseases, considering variables such as disease rarity, treatment cost, patient age and treatment outcomes. METHODS: We conducted an exploratory survey using visual discrete-choice vignettes embedded in scenario cards. Each card depicted a fictional patient case based on real-world disease attributes. A total of 157 unique real-world scenarios were designed by combining variables such as rarity, age group, cost and impact on quality of life. Participants were asked whether they would recommend treatment funding for each scenario. RESULTS: A total of 375 participant responses were analysed. Our findings reveal that the probability of a positive decision to treat was influenced more by treatment effectiveness and quality-of-life outcomes than by disease rarity or cost. CONCLUSION: The results suggest that while high treatment costs do pose challenges, they are often secondary to the perceived benefits of treatment; Swiss citizens prioritise treatment effectiveness and quality-of-life improvements over rarity or treatment cost when considering funding decisions

Mutations in the CLCN5 gene encoding the chloride-hydrogen exchanger ClC-5 cause Dent disease, a genetic disorder of the endolysosomal pathway in the proximal tubules of the kidneys. Many patients also develop glomerular lesions, but the underlying mechanism is unclear. We have established an in vivo model for Dent disease using Drosophila nephrocytes that share similarities with podocytes and proximal tubular cells. Upon depletion of ClC-c, the fly homologue of CLCN5, the endocytic receptor Cubilin was lost from the cortex of nephrocytes, which led to a strong decrease in albumin uptake and slit diaphragm (SD) turnover. Moreover, the actin and microtubular cytoskeleton as well as Rab11-marked recycling endosomes showed a strong cortical accumulation, whereas cholesterol-enriched autophagic compartments emerged in the perinuclear area. Cubilin exhibited a mild mislocalization to cortical early and late endosomal compartments and, in addition, strongly accumulated in the endoplasmic reticulum (ER). This was accompanied by a fragmentation of the ER morphology and an increase in ER exit sites and associated Golgi stacks. These secretory pathway phenotypes were also observed upon silencing of a subunit of the vacuolar H+-ATPase (V-ATPase) suggesting that they depend on acidification. Therefore, we speculate that ClC-c and the V-ATPase together acidify the Golgi to allow proper glycosylation and surface trafficking of Cubilin (or its binding partner Amnionless). Interestingly, ER retention of Cubilin was confirmed in ClC-5 knockout mice, underscoring the relevance of this pathomechanism for Dent disease. ### Competing Interest Statement The authors have declared no competing interest.

Dent disease is a rare X-linked tubulopathy that is characterized by low-molecular-weight proteinuria associated with hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and kidney failure between the third and fifth decades of life in 30%-80% of affected males. The disease is most often associated with various manifestations of proximal tubular dysfunction. Affected individuals may present nephrotic-range proteinuria which may be misinterpreted and cause diagnostic delay. Due to its rarity, there is limited evidence to guide diagnosis and management. These clinical practice recommendations summarize the current knowledge on Dent disease and provide guidance for diagnosis and management. The recommendations are based on a systematic search of the literature and were endorsed by a Delphi procedure among stakeholders in the field as well as the respective ERA and ESPN working groups.

Homeostasis in the kidney proximal tubule (PT) requires coordination between metabolism and differentiation, yet the mechanisms governing this balance remain elusive. Here, we integrate model organisms, multiomics profiling, and human genetics to identify the autophagy regulator ATG7 as a key determinant of cell-fate decisions, sustaining PT specialization in health and contributing to dysfunction in disease. In mice, PT-specific deletion of ATG7 reprograms differentiated cells into anabolic, proliferative states, impairing their specialized function and causing kidney tubulopathy. Mechanistically, loss of ATG7-dependent autophagy hinders lipid droplet clearance and restricts fatty-acid oxidation (FAO), leading to energy depletion and functional decline. In zebrafish pronephros, re-expression of wild-type ATG7 restores homeostasis in atg7 mutants, while pharmacological FAO inhibition triggers dysfunction. In humans, ATG7 variants associate with cardio-renal-metabolic traits and increased disease risk, whereas low ATG7 expression correlates with transcriptional signatures of metabolic reprogramming, loss of epithelial markers, and poor prognosis in renal cell carcinoma. These findings establish a conserved genetic paradigm that links autophagy to kidney epithelial cell-fate specialization, with implications for disease, cancer, and metabolic health.