Wu Z, Sun M, Hu M
… +4 more, Yu Q, Wang P, Luo L, Ma M
J Am Soc Nephrol
· 2026 Jun · PMID 42333604
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BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, which encode the ciliary proteins polycystin-1 and polycystin-2, respectively. Genetic ablation of primary cilia or...BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, which encode the ciliary proteins polycystin-1 and polycystin-2, respectively. Genetic ablation of primary cilia or disruption of ciliary membrane protein trafficking markedly suppresses cyst formation in adult-onset ADPKD models, indicating that cilia harbor membrane-associated signaling pathways that promote cyst progression. However, the specific ciliary receptors mediating these extracellular cyst promoting signals remain poorly defined. METHODS: We performed RiboTag-based translational profiling of early cystic kidneys in genetic mouse models of ADPKD to identify differentially expressed genes, with a focus on transmembrane protein-coding candidates. The localization and function of parathyroid hormone receptor 1 (Pth1r) were examined using immunofluorescence, genetic inactivation in developmental and adult-onset ADPKD models, and in vitro studies of renal epithelial cells. Downstream signaling was assessed by cAMP measurements and CREB phosphorylation analysis. Therapeutic relevance was evaluated using the calcimimetic cinacalcet. RESULTS: RiboTag profiling identified upregulation of Pth1r in early cystic kidneys. Pth1r localized to primary cilia across nephron segments, and its genetic inactivation significantly attenuated cyst growth in both developmental and adult-onset ADPKD models. In vitro, parathyroid hormone (PTH) promoted Pth1r trafficking to cilia through a conserved VxP motif independently of polycystins. PTH stimulation increased intracellular cAMP levels in renal epithelial cells, with efficient downstream activation requiring intact primary cilia. In vivo, CREB phosphorylation was increased during cyst progression in Pkd1 mutant kidneys and was partially reduced by Pth1r inactivation. Cinacalcet treatment reduced cystic burden and normalized circulating PTH levels. CONCLUSIONS: These findings support a role for Pth1r as a ciliary GPCR linking systemic PTH signaling to cyst-promoting pathways in ADPKD.
Tian L, Wang Y, Li LX
… +4 more, Agborbesong E, Zhou JX, Mou S, Li X
J Am Soc Nephrol
· 2026 Jun · PMID 42329029
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BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by metabolic reprogramming with enhanced glycolysis and lactate accumulation. However, the enzy...BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by metabolic reprogramming with enhanced glycolysis and lactate accumulation. However, the enzyme that senses lactate and uses it as a substrate for protein lactylation in ADPKD remains unknown. Alanyl-tRNA synthetase 1 (AARS1) is a lactate-responsive enzyme with lactyltransferase activity, while its role and mechanisms in ADPKD have not been defined. METHODS: To investigate the role of AARS1, we generated Pkd1 and Aars1 double conditional knockout Pkd1fl/fl:Aars1fl/fl:Ksp-Cre mice and evaluated the effect of AARS1 inhibitor, β-alanine, in two ADPKD mouse models. Coimmunoprecipitation and CUT&Tag analyses were performed to identify novel AARS1 substrates and downstream target genes involved in cystogenesis. RESULTS: AARS1 was elevated in Pkd1 mutant renal epithelial cells and kidneys, and genetic deletion of Aars1 significantly delayed cyst growth, preserved kidney function, and reduced renal lactylation in Pkd1 mutant mice. Mechanistically, AARS1 promoted lactylation-dependent activation of STAT3 and NF-κB (p65), specifically at STAT3 K140 and p65 K310, thereby amplifying pro-proliferative and pro-inflammatory transcriptional programs. AARS1 also associated with promoter regions and mediated histone H3K14 lactylation, thereby repressing the transcription of Atg5 to impair autophagy and suppressing the transcription of Dusp4 to sustain phosphorylation of cAMP response element-binding protein (CREB) and retinoblastoma protein (Rb). Cytokine signaling via IL-6 and TNF-α further reinforced AARS1 expression through STAT3- and NF-κB-dependent feed-forward loops. Importantly, inhibition of AARS1 with β-alanine markedly slowed cyst progression in Pkd1 mutant mouse models. CONCLUSIONS: Our study identified AARS1 as a central metabolic sensor linking lactate-driven lysine lactylation to transcriptional, epigenetic, and signaling pathways that drive ADPKD progression.
Donnelly CB, Patel SS, Husain SA
… +10 more, Gentry SE, Patzer RE, Lonze BE, Bae S, Axelrod D, Orandi BJ, McAdams-DeMarco MA, Segev DL, Massie AB, Mankowski MA
J Am Soc Nephrol
· 2026 Jun · PMID 42322663
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KEY POINTS: In this cohort study of 720,348 adults referred for kidney transplantation from 2014 to 2025, only 48% were evaluated and 19% were waitlisted. Progression from referral to evaluation, waitlisting and kidney t...KEY POINTS: In this cohort study of 720,348 adults referred for kidney transplantation from 2014 to 2025, only 48% were evaluated and 19% were waitlisted. Progression from referral to evaluation, waitlisting and kidney transplantation was limited by individual, center-level, and geographic factors. Some centers evaluated and waitlisted patients at rates far below the national average, and low-volume centers had lower rates of transplantation. BACKGROUND: Kidney transplantation is a cost-effective, lifesaving treatment of kidney failure, compared with dialysis. Unfortunately, most patients with kidney failure never undergo transplantation. METHODS: Using Epic Cosmos electronic health record data on all patients referred for kidney transplantation from 2014 to 2025, we assessed the stage-specific progression and attrition in the process of evaluation, waitlisting, and kidney transplantation. Center-level and individual (socioeconomic, geographic, and insurance status) factors associated with access to evaluation, waitlisting, and kidney transplantation were characterized using modified Poisson regression. RESULTS: Among 720,348 referred candidates, the median age was 55 years (interquartile range [IQR], 42-64); 47% of patients were White, 52% were male, and 87% were English speaking. Eighty-five percent of patients lived in urban areas. Of the referred candidates, 48% initiated evaluation, 19% were waitlisted, and 10% ultimately underwent transplantation. Among the referred patients who initiated evaluation, the median (IQR) time to evaluation initiation was two (1-4) months after referral; among the patients who were waitlisted, the median (IQR) time to waitlisting was four (2-9) months after evaluation initiation. Patients who were never married (0.94; 95% confidence interval [CI], 0.93 to 0.94), had severe obesity (0.70; 95% CI, 0.69 to 0.72), or were from rural zip codes (relative risk, 0.98; 95% CI, 0.97 to 1.00) were less likely to initiate evaluation. Low-volume centers had lower relative rates of transplantation (0.92; 95% CI, 0.88 to 0.96). In centers with documentation for nonprogression to evaluation, reasons for removal included not meeting criteria/not a candidate (18%), patient decision (13%), unable to contact (12%), death (4%), and financial/insurance complications (7%). CONCLUSIONS: Our study shows substantial attrition before kidney transplant waitlisting.
Quinn RR, Oliver MJ, Wald R
… +22 more, Hiremath S, Pauly RP, Miller L, Barrett B, Nesrallah G, Gallagher M, Kotwal S, Gray NA, Hassan HC, Talaulikar GS, Thorpe K, Graham J, Clarke A, Bian J, MacRae J, Santana M, Bohm C, Mamdani M, Nagpal S, Yilmaz S, Moist L, Ravani P
J Am Soc Nephrol
· 2026 Jun · PMID 42319856
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BACKGROUND: Fistulas are the preferred form of vascular access and historically, have been recommended by guidelines because they were associated with improved clinical outcomes and costs. However, there has never been a...BACKGROUND: Fistulas are the preferred form of vascular access and historically, have been recommended by guidelines because they were associated with improved clinical outcomes and costs. However, there has never been a randomized comparison of catheters to fistulas and the evidence on which recommendations were based is observational with potential for bias. METHODS: A pilot randomized controlled trial was conducted in 12 hemodialysis centers in Canada and Australia. Individuals aged 55 years and older who started hemodialysis using a tunneled or non-tunneled central venous catheter for vascular access were randomized to an attempt at fistula creation or continued use of a tunneled, central venous hemodialysis catheter. The primary outcome was feasibility, as measured by the proportion of eligible patients who consented to randomization and the proportion of patients randomized to the fistula group who underwent fistula placement within 90 days. Secondary outcomes included invasive access-related procedures, hospitalizations, access-related infections, tissue plasminogen activator usage, and death. RESULTS: A total of 1287 patients were screened and 67 patients underwent randomization. A total of 25% of eligible patients agreed to randomization and 71% randomized to the fistula arm underwent fistula placement within 90 days. The most common reason patients declined to participate in the trial was that they preferred to continue to dialyze with their catheter. Patients randomized to fistulas had nominally more access-related interventions, hospitalizations, and bacteremia (the majority of which were catheter-related), while the catheter group experienced greater reliance on thrombolytic therapy. CONCLUSIONS: Findings from this trial suggest that conducting a definitive randomized trial of fistulas versus catheters is not feasible in the current climate. There was no signal of harm associated with randomization to the catheter strategy and most outcomes favored the catheter group. Patients exhibited strong preferences regarding choice of vascular access.
Jin Y, Xie Y, Davis S
… +4 more, Flores AM, Wang XL, Guzman RJ, Cai Y
J Am Soc Nephrol
· 2026 Jun · PMID 42308131
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BACKGROUND: Medial artery calcification is highly prevalent in patients with CKD and peripheral artery disease. It is strongly associated with higher cardiovascular morbidity and mortality. The second messengers cyclic n...BACKGROUND: Medial artery calcification is highly prevalent in patients with CKD and peripheral artery disease. It is strongly associated with higher cardiovascular morbidity and mortality. The second messengers cyclic nucleotides cAMP and cGMP play important regulatory roles in a variety of human diseases, which are controlled by distinct phosphodiesterase (PDE) isozymes. PDEs have proven to be highly effective drug targets for the treatment of various conditions. Their function and regulation in medial artery calcification, however, remain unknown. METHODS: To investigate the role of PDE10A in medial artery calcification, we utilized calcified human tibial arteries from peripheral artery disease patients, calcified arteries from in vivo models, and calcifying vascular smooth muscle cells in vitro. Functional studies were conducted using PDE10A knockdown, overexpression, global deletion, and smooth muscle cell-specific deficiency models. Furthermore, we employed an ex vivo aortic ring culture model. The therapeutic potential of the pharmacological PDE10A inhibitor, TAK-063, was evaluated in two distinct in vivo calcification models: vitamin D3 injection and the 5/6 nephrectomy CKD model. RESULTS: We observed that PDE10A was increased in calcifying vascular smooth muscle cells in vitro, calcified arteries in vivo, and calcified human tibial arteries. Knockdown and inhibition of PDE10A markedly attenuated phosphate-induced smooth muscle cell osteogenic transformation and calcification, whereas overexpression of PDE10A enhanced smooth muscle cell calcification. Consistently, both global and smooth muscle cell-specific PDE10A deficiency significantly reduced medial artery calcification in vivo, and deletion of PDE10A alleviated calcification in the aortic ring model. Mechanistically, PDE10A promoted medial artery calcification through activation of the p38 MAPK-MMP-3 signaling axis. Additionally, the inhibitor TAK-063 significantly reduced medial artery calcification in both the vitamin D3 and 5/6 nephrectomy models. CONCLUSIONS: PDE10A was a critical mediator of medial artery calcification, and pharmacological inhibition effectively reduced medial artery calcification in vivo.
Gong W, Yang S, Wang Y
… +5 more, Zhang M, Guan N, Lu L, Hao C, Guan Y
J Am Soc Nephrol
· 2026 Jun · PMID 42307263
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BACKGROUND: Biological sex is recognized as a modulator of acute kidney injury (AKI), whereas the underlying molecular mechanisms remain incompletely understood. METHODS: An ischemia-reperfusion injury-induced AKI model...BACKGROUND: Biological sex is recognized as a modulator of acute kidney injury (AKI), whereas the underlying molecular mechanisms remain incompletely understood. METHODS: An ischemia-reperfusion injury-induced AKI model was established on adult male and female wild-type and female kynureninase (Kynu) knockout (Kynu-/-) mice. Prepubertal wild-type mice were gonadectomized and euthanized 5 weeks later. 13C-tryptophan was administered via tail vein injection and renal levels of nicotinamide adenine dinucleotide (NAD+) and metabolites in the de novo pathway was examined using high-performance liquid chromatography (HPLC). Quinolinic acid (QA) and nicotinamide mononucleotide (NMN) were administered via oral gavage or intraperitoneal injection. RESULTS: Male mice were more susceptible to ischemic kidney injury, accompanied by a more pronounced decrease in NAD+ levels compared to female mice. Further experiments demonstrated that the expression of KYNU, a central enzyme in the de novo NAD+ biosynthetic pathway, was significantly downregulated in male kidneys. HPLC analysis revealed that male mice exhibited significantly lower renal QA (a downstream metabolite of KYNU) and reduced tryptophan-derived NAD+ after ischemia-reperfusion injury compared to females, reflecting impaired NAD+de novo biosynthesis. Notably, QA supplementation effectively alleviated the exacerbated kidney injury observed in male mice. In addition, castration markedly elevated renal Kynu expression to levels comparable to those in females, which decreased again after testosterone supplementation. Furthermore, genetic ablation of Kynu replicated the decreased renal QA and NAD+ levels observed in male mice, accompanied by exacerbated kidney damage. Supplementation with NMN, an NAD+ precursor, significantly alleviated AKI in Kynu-/- mice. CONCLUSIONS: Androgen-dependent KYNU downregulation was found in the adult mouse kidney. Disrupted NAD+de novo biosynthesis caused by Kynu deficiency mediated the sex-biased susceptibility to AKI.
Jeon HJ, Jang HM, Park YS
… +11 more, Kim SM, Kim BJ, Kim HW, Jeong JC, Park S, Park BG, Kim MS, Park HY, Kim YJ, Yang J, Korean Organ Transplantation Registry (KOTRY) Study Group
J Am Soc Nephrol
· 2026 Jun · PMID 42302843
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BACKGROUND: Kidney failure represents the final, irreversible stage of chronic kidney disease (CKD), yet its genetic architecture remains incompletely defined compared to CKD. While prior studies largely focused on kidne...BACKGROUND: Kidney failure represents the final, irreversible stage of chronic kidney disease (CKD), yet its genetic architecture remains incompletely defined compared to CKD. While prior studies largely focused on kidney function traits, the genetic determinants of kidney failure itself and its etiologic subtypes are poorly understood. Therefore, this study aimed to identify genetic loci associated with kidney failure and its subtypes and to evaluate the predictive performance of multiple polygenic risk scores (PRSs) for stratifying kidney failure risk. METHODS: We performed a large-scale genome-wide association study (GWAS) using a dataset of 2,355 kidney failure patients across three subtypes defined by primary disease, along with 152,131 controls. PRSs for type 2 diabetes, hypertension, estimated glomerular filtration rate (eGFR), and CKD were calculated, and a multi-PRS model was derived. RESULTS: The GWAS identified multiple kidney failure-associated loci, including HLA-DRB1 for all kidney failure and glomerulonephritis as the primary disease, and COL24A1 for hypertensive kidney failure at genome-wide significance (P<5x10-8), implicating distinct immune and hypertension-related pathways in kidney failure pathogenesis. PRS analysis revealed that genetically distinct components of type 2 diabetes, hypertension, CKD, and eGFR were significantly linked to kidney failure risk across subtypes (OR=1.1-2.5). A combined multi-PRS model demonstrated superior predictive performance (OR=1.5-2.5). Comparison with CKD cohorts, predominantly influenced by eGFR-related genetics, uncovered unique kidney failure-specific genetic signatures, highlighting kidney failure as a genetically heterogeneous and multifactorial disease beyond CKD. CONCLUSIONS: This study identified subtype-specific genetic loci and demonstrated that multi-PRS models improve kidney failure risk prediction beyond basic available clinical factors.
Klein JA, Taber D, Wojciechowski D
… +51 more, Mandelbrot DA, Glehn-Ponsirenas R, Olaitan O, Jain P, Lu J, McGrath MM, Narayanan M, Patel AM, Merzkani M, Permpalung N, Choudhury RA, Josephson MA, Anand S, Vaitla P, Langewisch E, Ajaimy M, Kumar D, Burke GW, Pesavento TE, Langone AJ, Huang Y, Leeser D, Fischbach B, Costa N, Sureshkumar K, Qannus AA, Fan CS, Zaky Z, Shihab F, Kulkarni S, Maw TT, Tanriover B, Akalin E, Cooper M, Tawhari I, Weir MR, Alhamad T, Brennan DC, Leca N, Bunnapradist S, Shen L, Woodward RN, Chuang P, Anand P, Poggio ED, Guerra G, Wiseman A, Paramesh A, Cibrik D, Bromberg J, KOAR Study Investigators
J Am Soc Nephrol
· 2026 Jun · PMID 42302101
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KEY POINTS: We assessed whether an initial donor-derived cell-free DNA elevation during routine surveillance was associated with allograft dysfunction and loss in kidney transplant recipients. Intermediate and high donor...KEY POINTS: We assessed whether an initial donor-derived cell-free DNA elevation during routine surveillance was associated with allograft dysfunction and loss in kidney transplant recipients. Intermediate and high donor-derived cell-free DNA states were independently associated with 3.7-fold and 6.4-fold higher risks of allograft loss, respectively. Persistently low donor-derived cell-free DNA levels were associated with low rates of rejection and allograft loss, identifying a low-risk population. BACKGROUND: Although donor-derived cell-free DNA (dd-cfDNA) correlates with histologic rejection and injury severity, its association with long-term graft outcomes has yet to be well established in kidney transplant recipients. We hypothesize that among patients monitored with dd-cfDNA, an initial elevation may be associated with subsequent allograft dysfunction and loss. METHODS: The Kidney Allograft Outcomes AlloSure Registry is a prospective, multicenter cohort of 1743 adult kidney transplant recipients from 56 US centers; this analysis included 1258 patients who initiated dd-cfDNA surveillance 15-60 days post-transplant with up to 3-year follow-up. A multistate model was applied to characterize transitions from a low dd-cfDNA state (no elevations) to intermediate (0.5%-1.0% with ≥61% relative change value) or high (≥1.0%) dd-cfDNA states, and their unadjusted and covariate-adjusted associations with allograft loss or all-cause death were quantified using hazard regression models. RESULTS: Within 3 years, 36% of patients transitioned to an elevated dd-cfDNA state (intermediate n=216; high n=233). Allograft dysfunction by 36 months occurred significantly more often in patients with dd-cfDNA elevations despite preserved allograft function at the time of elevation (eGFR ≥60 ml/min per 1.73 m2 in 42% of intermediate and 33% of high), consistent with subclinical injury. Transitions from low to elevated dd-cfDNA states were strongly associated with subsequent allograft loss (adjusted hazard ratios, 3.70 [95% confidence interval [CI], 1.38 to 9.90] for intermediate; 6.36 [95% CI, 2.80 to 14.42] for high) while mortality did not differ by dd-cfDNA state. CONCLUSIONS: Initial dd-cfDNA elevations exceeding established thresholds were independently associated with higher risks of allograft dysfunction and loss across both elevation categories, whereas patients who remained in the low dd-cfDNA state experienced favorable outcomes.
Adebayo OC, Dallali I, Kerselaers S
… +12 more, Gimeno-Rocafort S, Van Aerschot S, Janssens A, Bondue T, Cresens C, Asouzu NJ, Corthout N, Gijsbers R, Levtchenko EN, van den Heuvel L, Vriens J, Labarque V
J Am Soc Nephrol
· 2026 Jun · PMID 42295851
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BACKGROUND: The mechanisms by which apolipoprotein L1 (APOL1) risk variants, G1 and G2, induce kidney disease in individuals of African ancestry remain contentious. METHODS: In this study, we utilized a heterologous expr...BACKGROUND: The mechanisms by which apolipoprotein L1 (APOL1) risk variants, G1 and G2, induce kidney disease in individuals of African ancestry remain contentious. METHODS: In this study, we utilized a heterologous expression system of HEK-293 cells and human podocytes to investigate APOL1-mediated cytotoxicity using genetic, electrophysiological, and microscopy-based approaches. RESULTS: APOL1 variants showed dynamic transport in vesicle-like structures towards the plasma membrane via actin filaments. At the plasma membrane, the non-risk APOL1 G0 and risk variants formed non-selective cation-permeable pores for Na+ and Ca2+, exhibiting functional activity under basal conditions. Extracellular Ca2+ was identified as the primary source of Ca2+ influx through APOL1, leading to cytotoxicity. APOL1 risk variants exhibited increased basal channel activity compared to non-risk APOL1 G0, resulting in haplotype-dependent cytotoxicity. Furthermore, we observed that both the M1 (N264K) variant and APOL1 inhibitor, VX-147, exerted protective effects on cell viability by blocking the APOL1-dependent intracellular Ca2+ influx. CONCLUSIONS: This study demonstrated APOL1 to be a membrane protein involved in the influx of Ca2+ from the extracellular medium. Increased activity of APOL1 led to markedly increased cytotoxicity, which supports the gain-of-function theory. This effect was prevented by the presence of N264K variant or treatment with the APOL1 inhibitor VX-147.
Chen J, Keswich JE, Chiazza F
… +10 more, Moyes AJ, Gobbetti T, Purvis GSD, Salvatori DCF, Patel NSA, Perretti M, Hobbs AJ, Collino M, Yaqoob MM, Thiemermann C
J Am Soc Nephrol
· 2026 Jun · PMID 42295849
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J Am Soc Nephrol
· 2026 Jun · PMID 42262862
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BACKGROUND: In CKD trials, the eGFR slope has emerged as a surrogate endpoint for earlier assessment of treatment effects. However, the influence of key design parameters-slope difference, trial duration, measurement fre...BACKGROUND: In CKD trials, the eGFR slope has emerged as a surrogate endpoint for earlier assessment of treatment effects. However, the influence of key design parameters-slope difference, trial duration, measurement frequency, and dropout patterns-on the required sample size remains unclear. We aimed to derive a sample size formula that incorporated these factors and develop a practical tool for efficient calculation across diverse trial scenarios. METHODS: A sample size formula for comparing eGFR slopes in early-stage CKD trials was derived using a linear mixed-effects model and validated against a simulation-based method. Guided by National Kidney Foundation, US Food and Drug Administration, and European Medicines Agency workshop reports, the formula was applied to systematically examine the effects of these design parameters on sample size. RESULTS: The derived formula yielded three key insights for early-stage CKD trials. First, frequent measurements allowed for a lower sample size in short-term trials but had a limited effect in longer ones (e.g., shortening the interval from 2 months to 1 month allowed for a smaller sample size by approximately 230 participants in a 12-month trial versus approximately 30 participants in a 36-month trial). Second, long-term trials were preferable for small expected slope differences, whereas short-term trials required a sufficiently large slope difference for feasibility. Third, compared with a simple inflation approach, incorporating dropout patterns into the target sample size calculation reduced overestimation. CONCLUSIONS: The derived formula quantified interactions among key trial design parameters. The effect of frequent measurements on required sample size was greater in short-term trials, whereas small expected slope differences required longer trial durations.