Anemia is less prevalent in autosomal dominant polycystic kidney disease (ADPKD) owing to preserved erythropoietin production. However, its impact on kidney prognosis remains unclear. Given sex-related differences in hemoglobin (Hb) levels, we hypothesized that the prognostic relevance of anemia may vary by sex and age. Therefore, we aimed to identify subgroup-specific risk patterns using an attribute-based cross-classification approach to support individualized anemia management in ADPKD. We analyzed 552 Japanese patients with ADPKD from a single-center cohort. The primary outcome was a ≥ 30% decline in the estimated glomerular filtration rate (eGFR) or initiation of renal replacement therapy. Cox regression analysis was used to assess the association between Hb and kidney outcomes. Subgroup analyses were performed using cross-classification by sex and age (< 50 or ≥ 50years). Anemia was defined using multiple Hb thresholds (< 11, < 12, and < 13g/dL). Lower Hb levels were independently associated with worse renal outcomes (hazard ratio [HR] per 1g/dL increase: 0.83). Cross-classified analyses revealed distinct risk patterns. Anemia (Hb level < 13.0g/dL) significantly increased the risk in young (HR: 2.92) and old men (HR: 3.84). In women, anemia defined as a Hb level < 12.0g/dL was associated with adverse outcomes in both age groups (HR: 1.98 in < 50years; HR: 2.08 in ≥ 50years). Anemia is a significant prognostic marker for kidney disease progression in ADPKD. Its prognostic impact differs by sex and age, suggesting the need for attribute-based, individualized hemoglobin thresholds rather than uniform cutoffs, to optimize risk stratification and clinical assessment.

ACR Appropriateness Criteria® Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of kidney failure, results from loss-of-function mutations in PKD1, encoding polycystin-1 (PC1). PC1 localizes to the primary cilium. In the absence of PC1, adverse signaling from the primary cilium orchestrates cyst formation, but the biomechanical underpinnings of this cilia-dependent cyst activation (CDCA) remain unclear. Combining tubule-specific orthologous mouse models with a tubule-on-chip platform, we show that PC1 and cilia govern the composition, mechanical properties and shape of the tubular basement membrane (TBM), the principal rigid determinant of tubule geometry. PC1 loss triggers TBM thinning, heparan sulfate enrichment and deformation, leading to distension, preferentially of the distal nephron. These changes are driven by a cilia-dependent transcriptional program, with GLIS2 - a key CDCA effector - participating as a downstream mediator. Reduction of TBM stiffness amplifies Pkd1-/- tubule-on-chip dilation and increases cyst formation in vivo. Conversely, increasing luminal pressure through ureteral obstruction induces disproportionate distension of Pkd1-deficient tubules and triggers an irreversible cystogenic program. Together, these findings establish a TBM-centered biomechanical model of ADPKD in which tubule deformation is governed by both basolateral and luminal mechanical factors, and identify the cilium-TBM axis, operating in part through GLIS2, as a central driver of cystogenesis.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth, kidney enlargement, and decline in renal function. Increasing evidence suggests that inflammatory processes may contribute to disease progression. This study aimed to evaluate the association between tolvaptan use, systemic inflammatory markers, and total kidney volume (TKV) progression in patients with ADPKD. This retrospective study included 67 patients with ADPKD, including 40 receiving tolvaptan and 27 untreated controls. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), estimated glomerular filtration rate (eGFR), and TKV were evaluated at baseline and after 24 months. Longitudinal changes were assessed using Wilcoxon signed-rank tests and linear mixed-effects models. Patients receiving tolvaptan were younger and had higher baseline TKV values than untreated patients. During follow-up, NLR, PLR, and SII decreased in the tolvaptan group, whereas these markers increased in untreated patients. eGFR declined in both groups but appeared less pronounced in patients receiving tolvaptan. TKV increased in both groups; however, the percentage increase in TKV was lower among patients receiving tolvaptan. Significant time × treatment interactions were observed for NLR, PLR, SII, and TKV. In the non-tolvaptan group, NLR at 24 months showed a significant positive association with TKV. Tolvaptan use was associated with differences in longitudinal changes in systemic inflammatory markers and kidney volume progression in ADPKD. Further prospective studies are needed to clarify the clinical relevance of these associations.

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. 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. 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. These findings support a role for Pth1r as a ciliary GPCR linking systemic PTH signaling to cyst-promoting pathways in ADPKD.

Purpose To develop and systematically evaluate an iterative training approach, termed the expert-guided annotation loop, for efficient reference standard medical image segmentation, including assessment of two sample-selection strategies and real-world clinical implementation. Materials and Methods This retrospective study included ten datasets comprising 1948 CT or MRI examinations from autosomal dominant polycystic kidney disease, prostate cancer, uveal melanoma, thyroid eye disease, and non-small cell lung cancer patients. nnU-Net segmentation models were iteratively trained using an expert-guided annotation loop with random or active learning-based sample selection. In each iteration, additional samples were added to the training set, and model-generated presegmentations were corrected by expert radiologists to create reference standard annotations. Expert time required for manual segmentation versus presegmentations correction was measured. Model performance and efficiency were assessed using nonparametric tests, and cost savings were estimated for kidney and tumor segmentation using probabilistic sensitivity analysis. Feasibility of end-to-end no-code implementation was evaluated. Results Fifty-seven segmentation models were trained and evaluated. Final model Dice scores ranged from 0.67-0.97 for organ segmentation and from 0.64-0.69 for lung tumor segmentation across internal and external test sets. Maximum expert time savings were 90.3% for kidney and 48.2% for tumor segmentation (P < .001 and P = .003), corresponding to estimated per-examination cost savings of $14.30[95% CI: $5.94, $26.87] and $5.63[95% CI: $-7.26, $26.09], respectively. No-code execution of the expert-guided annotation loop was feasible. Conclusion The expert-guided annotation loop reduced expert annotation time and enabled estimated cost savings while producing high-quality reference standard CT and MRI segmentations. The no-code workflow was implemented in a clinical environment. © RSNA, 2026.

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. 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. 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. Our study identified AARS1 as a central metabolic sensor linking lactate-driven lysine lactylation to transcriptional, epigenetic, and signaling pathways that drive ADPKD progression.

SGLT2 inhibitors have demonstrated robust cardiorenal benefits across diverse chronic kidney disease populations but remain underutilized in autosomal dominant polycystic kidney disease (ADPKD) due to lack of disease-specific data and theoretical safety concerns. We report a 58-year-old man with genetically confirmed PKD2-associated ADPKD who developed progressive proteinuria (0.8g/24h increasing to 2.0g/24h over three years) despite optimal ACE inhibition. Clinical findings suggested concomitant IgA nephropathy, but biopsy was contraindicated. Empagliflozin 10mg/day was initiated off-label. Proteinuria decreased progressively to 0.9g/24h at one month, 0.645g/24h at three months, 0.4g/24h at six months, and stabilized between 0.3 and 0.4g/24h through 18 months (82-85% reduction sustained to date). Renal function remained stable (eGFR 33-35 mL/min/1.73m²). No infections or adverse events occurred. This case supports safety and antiproteinuric efficacy of empagliflozin in ADPKD with superimposed glomerular disease and provides context for broader therapeutic potential of SGLT2i in this systemic cardiorenal-metabolic disorder.

Autosomal dominant polycystic kidney disease (ADPKD), primarily driven by PKD1 or PKD2 mutations, is a prevalent hereditary nephropathy for which large-animal models capturing human renal anatomy and disease tempo remain urgently needed. This study aimed to establish a site-specific human PKD2 (hPKD2) transgenic porcine model as a versatile platform capable of supporting two temporally distinct applications: longitudinal evaluation of whether sustained PKD2 overexpression is sufficient to induce renal pathology, and-should overexpression prove phenotypically silent-future crossbreeding-based functional rescue of PKD2-knockout lines. A CRISPR/Cas9-mediated, homology-recombination-independent strategy was employed to target full-length hPKD2 cDNA into the porcine pH11 safe harbor locus. Somatic cell nuclear transfer yielded five F0 transgenic founders, and natural mating of two founders with wild-type sows produced four F1 transgenic offspring, confirming stable germline transmission. Quantitative real-time PCR and whole-genome sequencing validated single-copy, site-specific transgene integration at the designated locus. Robust hPKD2 mRNA and FLAG-tagged polycystin-2 (PC-2) expression were detected in renal and other tissues across both generations. During the initial 12-month monitoring period, serum blood urea nitrogen and creatinine levels remained within normal ranges and no gross histological abnormalities were evident. However, given that these biomarkers are insensitive to early-stage renal impairment, extended observation with more comprehensive phenotyping is required before definitive conclusions regarding renal function can be drawn. A transgenic porcine model with stable, single-copy hPKD2 integration at the pH11 safe harbor locus was successfully generated and shown to permit germline transmission. This platform provides a foundation for long-term investigation of PKD2 overexpression pathophysiology and, alternatively, for functional complementation of PKD2-deficient models, thereby advancing both mechanistic and translational ADPKD research.

A significant proportion of patients present with chronic kidney disease of unexplained cause (CKDx) despite standard-of-care diagnostic workup. Data from Australian, European and United States cohorts show that some are due to monogenic etiology. The diagnostic yield and clinical utility of genetic testing in Chinese patients remains unclear. We prospectively recruited adult CKDx patients following up at Queen Mary Hospital nephrology unit from 1 Oct 2022 to 1 June 2024. After genetic counselling, patients underwent whole genome sequencing focused on kidney disease genes(637 genes). Variants classification was performed according to the American College of Medical Genetics guidelines. Among 131 CKDx patients, 92% self-identified as Chinese and 21% presented with kidney failure. Mean age at clinical presentation was 35 years. 36% had positive family history of CKD. We identified Pathogenic/Likely pathogenic variants in 13 patients, giving a diagnostic yield of 10%. 33% of variants identified were novel. Variants in type IV collagen genes(COL4A3, COL4A5, COL4A4) were the most frequent, followed by ALG9, CEP290 and IFT140. Alport-spectrum disorders were the leading genetic diagnoses, representing 77% of all genetically positive cases. A significantly higher proportion of patients with positive genetic findings had positive family history of CKD or CKDx, compared to those with negative genetic findings (CKD: 85% versus 31%, p<0.001; CKDx: 77% versus 19%, p<0.001). Monogenic etiology could be established in 10% of adult CKDx patients in Hong Kong. Alport-spectrum disorders were the leading genetic diagnoses, followed by atypical Autosomal Dominant Polycystic Kidney Disease and nephronophthisis. Genetic testing in CKDx population is clinically useful since a significant proportion could reach a diagnosis and permit disease specific management.

A three-year randomized, double-blind, placebo-controlled study of lanreotide in stage 2/3 autosomal dominant polycystic kidney disease.

MicroRNAs (miRNAs) are short RNA molecules that bind to target mRNAs, resulting in translational repression and gene silencing. Overexpression of microRNA-21 (miR-21) is associated with various human diseases, including autosomal dominant polycystic kidney disease (ADPKD) and pulmonary fibrosis. In this study, a previously described heterobifunctional molecule, TGP-21-RiboTAC, that degrades the miR-21 precursor (pre-miR-21) in triple-negative breast cancer cells was investigated in polycystic kidney cell lines and a lung fibroblast cell line. In the former, TGP-21-RiboTAC degraded pre-miR-21 and derepressed miR-21's downstream targets, programmed cell death 4 (PDCD4) and peroxisome proliferator-activated receptor alpha (PPARα), known drivers of ADPKD. The heterobifunctional molecule also inhibited cyst growth and rescued the metabolic alterations that occur in ADPKD. In the lung fibroblast cell line, MRC-5, TGP-21-RiboTAC also reduced pre- and mature miR-21 levels, rescued transforming growth factor β (TGF-β)-induced repression of SMAD family member 7 (SMAD7), and inhibited cell invasion. Collectively, these studies demonstrate the potential of targeted RNA degradation as therapeutic agents that retard the development of organ fibrosis.

PC1 (polycystin-1), traditionally viewed through the lens of renal pathophysiology in autosomal dominant polycystic kidney disease, has emerged as a central regulator of cardiovascular mechanobiology. Recent structural elucidation of the PC1/PC2 (polycystin-2) complex provides a molecular framework emphasizing its mechanically sensitive ectodomain, regulated proteolytic cleavage, and functional coupling with PC2, framing PC1 as a versatile integrator of biomechanical cues, extracellular matrix interactions, and Ca2+ signaling across cardiovascular cell types. This review synthesizes evidence demonstrating that PC1 plays a direct and primary role in the cardiovascular system, independent of renal decline, regulating vascular homeostasis, endothelial shear stress responsiveness, smooth muscle phenotype, and myocardial mechanotransduction. We describe the molecular mechanisms whereby PC1 dysfunction perturbs nitric oxide signaling, cytoskeletal remodeling, excitation-contraction coupling, and hypertrophic transcriptional programs, and highlight tissue-specific roles in cardiac morphogenesis and adult myocardial integrity. By integrating structural biology with cardiovascular physiology, this review provides a unified framework for understanding PC1 as a master mechanosensor linking biomechanical forces to pathological remodeling. Critical knowledge gaps, emerging therapeutic opportunities, and the potential role of artificial intelligence in PC1-targeted drug discovery are also discussed.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth, inflammation, fibrosis, and renal failure. Klotho is a renoprotective protein with anti-proliferative, anti-inflammatory, and antioxidant properties, but its mechanistic role in ADPKD remains poorly defined. Klotho expression was analyzed in human ADPKD kidneys, public bulk and single-cell RNA-seq datasets, Pkd1 mutant renal epithelial cells, and Pkd1 mouse models. The therapeutic effects of recombinant Klotho were evaluated in late-onset Pkd1fl/fl: tamoxifen-Cre mice. Molecular mechanisms were investigated using cell viability assays, Western blotting, RT-qPCR, immunohistochemistry, ferroptosis assays, DNA methylation analysis, chromatin immunoprecipitation assay. Klotho expression was markedly reduced in human ADPKD kidneys and Pkd1-deficient cells and mice, particularly in distal nephron segments. Recombinant Klotho treatment significantly reduced cyst burden, kidney enlargement, and blood urea nitrogen levels, while decreasing epithelial proliferation and increasing apoptosis in cyst-lining cells. Mechanistically, Klotho suppressed PKD-associated signaling pathways, including AKT, STAT3, and Rb, reduced NF-κB-mediated inflammation via downregulation of Smyd2, and attenuated TGF-β-Smad-dependent renal fibrosis. Klotho also inhibited ferroptosis by upregulating GPX-4 and reducing lipid peroxidation. Epigenetic analyses revealed DNMT1-mediated hypermethylation of the Klotho promoter and gene body in ADPKD kidneys, contributing to Klotho silencing. Inhibition of DNMT1 restored Klotho expression, and recombinant Klotho reduced DNMT1 levels, suggesting a negative feedback loop. Klotho is epigenetically repressed in ADPKD and functions as a central regulator of cyst growth, inflammation, fibrosis, and ferroptosis. Restoration of Klotho signaling markedly attenuates disease progression in Pkd1 mutant mice, identifying the Klotho-DNMT1 axis as a promising therapeutic target for ADPKD.

Autosomal dominant polycystic kidney disease: Current perspectives in 2026.

A hidden nonfunctioning kidney in autosomal dominant polycystic kidney disease.

A pilot study of magnetic resonance fingerprinting and radiomics analysis in autosomal dominant polycystic kidney disease.

Abdominal arterial calcification is a well-established predictor of cardiovascular events and mortality in kidney failure. Autosomal dominant polycystic kidney disease (ADPKD), a common genetic cause of kidney failure, presents with a distinct vascular profile. However, the burden of abdominal arterial calcification in ADPKD remains inadequately characterized. Clarifying these differences may improve cardiovascular risk stratification and transplant timing. We conducted a retrospective cohort study of 4088 adult patients listed for kidney transplant at three Mayo Clinic sites (2005-2024). Patients were categorized by kidney failure cause: ADPKD vs. non-ADPKD. Abdominal arterial calcification was quantified on non-contrast computed tomography (CT) scans using a modified Agatston scoring method. Propensity score matching (1:1) adjusted for age, sex, race, lipid levels, left ventricular ejection fraction, dialysis exposure, coronary artery disease, neurovascular disease, and smoking history, was performed. Abdominal arterial calcification scores were compared between matched groups, and subgroup analyses evaluated abdominal arterial calcification severity across dialysis durations in ADPKD patients. After matching, 309 patients with ADPKD were compared with 309 non-ADPKD chronic kidney disease (CKD) controls. Abdominal arterial calcification scores were significantly lower in the ADPKD group (median: 425.3; IQR: 0.0-2033.5) than in the non-ADPKD group (median: 1256.8; IQR: 96.5-5033.8). Among ADPKD patients, abdominal arterial calcification scores increased with dialysis duration (P < .001). ADPKD patients exhibit lower abdominal arterial calcification scores than their non-ADPKD counterparts after adjusting for clinical variables. Abdominal arterial calcification progression with dialysis highlights the importance of early transplant evaluation. This study introduces a novel adaptation of coronary calcium scoring software for quantifying abdominal calcification, offering a standardized approach to vascular risk assessment in kidney transplant candidates.

Diet is a priority to the kidney community, with increasing interest in whether a ketogenic diet can slow autosomal dominant polycystic kidney disease (ADPKD) progression. People with ADPKD have unique nutritional requirements that need to be considered when designing a ketogenic diet for this population. The nutritional adequacy of an ADPKD ketogenic diet needs to be evaluated prior to testing in a clinical trial. The current paper describes the (i) development of an ADPKD-Keto meal plan, in addition to modified PKD-Keto diets targeting the risk of nephrolithiasis and hyperkalemia, (ii) nutritional adequacy of these diets compared to a reference chronic kidney disease (CKD) diet, and (iii) cost-analysis of PKD-Keto meal plans and CKD reference meal plans. Dietary guidelines for ADPKD, CKD and general healthy eating were used to develop ketogenic meal plans for people living with ADPKD. All meal plans were analyzed for energy, macronutrient and micronutrient content, and results were compared to dietary intake targets. Caloric and macronutrient targets were achieved, with total carbohydrate, total fat and protein meeting 10%, 75% and 15% of total caloric intake, respectively across PKD-Keto meal plans. Micronutrients were mostly adequate in all meal plans except for iodine in the PKD-Keto meal plans; iron for females aged 19-50; and zinc for males. PKD-Keto diet meal plans were slightly higher in cost, however there was no difference based on socioeconomic area. A well-planned ketogenic diet tailored for ADPKD can be nutritionally adequate with supplementation of iodine, iron and zinc to be considered if the diet is to be used for an extended period.

Renal water reabsorption is classically regulated by vasopressin V2 receptor (V2R) signaling through cyclic AMP and protein kinase A, driving apical accumulation of aquaporin-2 (AQP2). However, collecting duct water handling is also modulated by vasopressin-independent mechanisms. Here, we examined intracellular soluble urate as a vasopressin-independent regulator of AQP2 trafficking. Intracellular urate accumulation in collecting duct cells was mediated by enhanced apical urate uptake via GLUT9b and reduced apical urate efflux through ABCG2, triggering phosphodiesterase-4 activation, reduced cAMP, and downstream AMP-activated protein kinase (AMPK) activation. The resulting AQP2 accumulation at the apical membrane was independent of V2R signaling, required ongoing endocytosis and was associated with features of post-endocytic apical trafficking of internalized AQP2. In vivo ABCG2 inhibition with probenecid increased apical AQP2 abundance and markedly attenuated tolvaptan-induced polyuria in both wild-type and Pkd1RC/RC autosomal dominant polycystic kidney disease (ADPKD) mice in a uricase-independent manner, while preserving tolvaptan's ADPKD-modifying efficacy. In a Phase 2 trial with tolvaptan-treated ADPKD patients, probenecid reduced urine volume and nocturia frequency. Together, these findings support a vasopressin-independent urate-AMPK-AQP2 pathway that regulates renal water handling and, in a preclinical ADPKD model, can uncouple cyst growth attenuation from the dose-limiting aquaretic effects of V2R antagonism.