Autosomal Dominant Polycystic Kidney Disease Research Articles

Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants.

Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2, at least 8 others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100kGP (100kGP), UK Biobank (UKBB), and Mayo Clinic Biobank (MCBB)), were screened for ALG8/ALG9 pathogenic variants. Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families; frequencies that were ∼10x and ∼24x greater than non-polycystic kidney disease (PKD) controls. Analysis of individuals with PKD phenotypes in 100kGP, UKBB, and MCBB identified 9 ALG8 (0.39%) and 9 ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (56%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%) with enlarged livers (>2L) found in 11/62 patients although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys but enlarged livers were rare; for both genes chronic kidney disease or kidney failure were rare. ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the first KDIGO guideline on this subject. Its scope includes nomenclature, diagnosis, prognosis, and prevalence; kidney manifestations; chronic kidney disease (CKD) management and progression, kidney failure, and kidney replacement therapy; therapies to delay progression of kidney disease; polycystic liver disease; intracranial aneurysms and other extrarenal manifestations; lifestyle and psychosocial aspects; pregnancy and reproductive issues; pediatric issues; and approaches to the management of people with ADPKD. The guideline has been developed with patient partners, clinicians, and researchers around the world, with the goal to generate a useful resource for healthcare providers and patients by providing actionable recommendations. The development of this guideline followed an explicit process of evidence review and appraisal, based on a rigorous, formal systematic literature review. The strength of recommendations follows the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The guideline also provides practice points serving to direct clinical care or activities relating to areas for which a systematic review was not conducted. Limitations of the evidence are discussed. Research recommendations to address gaps in knowledge, and implications for policy and payment, are provided. The guideline targets a broad audience of healthcare providers, people living with ADPKD, and stakeholders involved in the various aspects of ADPKD care.

Characteristics of patients with autosomal polycystic kidney disease reaching kidney failure by age 40.

Autosomal dominant polycystic kidney disease (ADPKD) demonstrates broad genetic and phenotypic variability, with kidney failure (KF) occurring across a wide age spectrum. Despite several predictor tools, there remains a need to identify factors associated with rapid disease progression. This study describes the phenotypic characteristics of a multicentric cohort experiencing early-onset KF by age 40. This retrospective, multicenter cohort study analyzed longitudinal data of rapidly progressive ADPKD patients (n = 199). The prevalence of established risk factors was compared to nine existing ADPKD cohorts (ntotal = 6782) with KF after 40years of age. We examined the longitudinal impact of early hypertension and urological events on the risk of developing KF. The median age at ADPKD diagnosis was 22.3years (IQR, 16.5-28.6) and median age of KF was 35.6years (31.7-38.0). Hypertension was observed in 68.1% of cases, with early-onset hypertension being more common among those with accelerated progression towards KF. Urological events were present in 60.1% of cases, with a high burden of gross hematuria (30.4%). Existing ADPKD cohorts had a mean age of 45.5years, with weighted prevalences of hypertension (71.1%), kidney stones (22.4%), hematuria (22.9%), and urinary tract infections (22.8%). Extrarenal manifestations were less prevalent compared to other ADPKD cohorts. This study outlines a cohort of ADPKD patients with accelerated disease progression, reaching KF before age 40. Hypertension and urological events were highly prevalent at a young age, emphasizing the importance of early and regular blood pressure monitoring.

Intestinal barrier function declines during polycystic kidney disease progression.

Most patients with autosomal dominant polycystic kidney disease (ADPKD) develop kidney cysts due to germline PKD1 mutations. In the kidney, Pkd1 loss impairs epithelial cell integrity and increases macrophage infiltration, contributing to cyst growth. Despite its role as the body's largest inflammatory cell reservoir, it has yet to be elucidated whether a similar phenotype presents in the intestines. We hypothesize that loss of Pkd1 leads to a leaky intestinal epithelial barrier and increased inflammation, before rapid cystogenesis. Control and inducible, global Pkd1 knockout (Pkd1KO) mice were euthanized at 3 and 6 mo of age (early and late stage) to evaluate kidney disease progression, small and large intestinal integrity, and inflammation. Early-stage Pkd1KO mice displayed mild cystic kidneys and tubular injury with preserved kidney function. Intestinal epithelial barrier was tighter in KO mice, which was associated with higher expression of cell-cell epithelial integrity markers. However, there was no evidence of local or systemic inflammation in either genotype. Late-stage Pkd1KO mice had severely cystic, impaired kidneys with increased expression of integrity markers, tubular injury, and inflammation. Intestinal epithelial barrier was leakier in late-stage Pkd1KO mice, accompanied by gene reduction of integrity markers, increased inflammation, and elevated water and sodium channel expression. Gut motility and fecal water excretion were increased in Pkd1KO compared with flox mice irrespective of age. Overall, kidney injury appears to precede intestinal injury in ADPKD, whereby the intestinal barrier becomes leaky as cystogenesis progresses.NEW & NOTEWORTHY Though autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder, this is the first study to explore a kidney-gut contribution to disease progression. We identified a tightened intestinal epithelial barrier in early PKD, which becomes leaky as kidneys become more cystic, accompanied by a sustained loss of fecal water. Given the only approved ADPKD therapeutic yields adverse aquaretic events, this study emphasizes the need to evaluate extrarenal water loss in patients before prescribing.

Kidney growth progression patterns in autosomal dominant polycystic kidney disease

BackgroundPrognosis for autosomal dominant polycystic kidney disease (ADPKD), the main inherited cause of kidney failure, relies on estimating cystic growth using linear formulas derived from height-adjusted total kidney volume (Ht-TKV). However, nonlinear renal growth patterns may occur in typical ADPKD. AimsTo determine kidney outcomes of subjects diagnosed with typical ADPKD exhibiting nonlinear, and unpredictable cystic growth during follow-up. MethodsRetrospective cohort study. We categorized TKV changes in individuals with typical ADPKD according to observed kidney growth trajectories. Ht-TKV was calculated from consecutive CT or MRI using the ellipsoid method. We compared estimated glomerular filtration rate (eGFR) trajectories with linear mixed models. ResultsWe included 83 individuals with ADPKD (67% women; age 47 ± 12 years; follow-up 5.2 years [IQR 2.8–9.0]). Three kidney growth patterns were observed: slow progression (24%, <3%/year linear increase), fast progression (39%, ≥3%/year linear increase), and atypical progression (37%, nonlinear growth). Adjusted ht-TKV change in mL/m/year was +1.4 (IQR –4.5 to +10.0), +40.3 (+16.9 to +89.3), and +32.8 (+15.9 to +85.9) for slow, fast, and atypical progressors, respectively (p <0.001). Atypical progressors exhibited a significantly greater decline in eGFR in mL/min/m²/year (–7.9, 95% CI –6.5, –3.9) compared to slow (–0.5, 95% CI –3.1 to +0.5) and fast progressors (–3.4, 95% CI –7.9, –2.0; between-group p <0.001). Atypical progressors had a higher proportion of acute complications, including hemorrhages, infections, and urolithiasis (84%), compared to slow (20%) and fast progressors (31%) (p <0.001). ConclusionIn typical ADPKD, nonlinear, abrupt, and unpredictable cyst growth occurs frequently, leading to a higher risk of acute complications and kidney function decline.

WCN25-3652 Uncommon Novel Genetic Mutations in Autosomal Dominant Polycystic Kidney Disease: Implications for Early Onset and Severe Phenotypes

WCN25-3652 Uncommon Novel Genetic Mutations in Autosomal Dominant Polycystic Kidney Disease: Implications for Early Onset and Severe Phenotypes

KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).

KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).

The impact of a secondary, rare, non-pathogenic PKD1 variant on disease progression in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is caused primarily by pathogenic variants in the PKD1 and PKD2 genes. Although the type of ADPKD variant can influence disease severity, rare, hypomorphic PKD1 variants have also been reported to modify disease severity or cause biallelic ADPKD. This study examines whether rare, additional, potentially protein-altering, non-pathogenic PKD1 variants contribute to ADPKD phenotypic outcomes. We investigated the prevalence of rare, additional, potentially protein-altering PKD1 variants in patients with PKD1-associated ADPKD. The association between rare, additional, potentially protein-altering variants and phenotypic outcomes, including progression to kidney failure, age at onset of hypertension and urological events, height-adjusted total kidney volume, and predicting renal outcomes in PKD (PROPKD) score, were examined. Rare, additional, potentially protein-altering variants were detected in 6% of the 932 ADPKD patients in the study. The presence of rare, additional, potentially protein-altering variants was associated with 4years earlier progression to kidney failure (hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.18-2.34; P = 0.003), with in-trans rare, additional, potentially protein-altering variants (n = 13/894) showing a greater risk of kidney failure (HR: 1.83; 95% CI 1.00-3.33; P = 0.049). We did not detect statistically significant differences between rare, additional, potentially protein-altering variants and other phenotypic outcomes compared to those without rare, additional, potentially protein-altering variants. In patients with PKD1-associated ADPKD, our findings suggest that rare, additional, potentially protein-altering variants in PKD1 may influence disease severity. These findings have potential clinical implications in counselling and treating patients with rare, additional, potentially protein-altering variants, but further investigation of such variants in larger, longitudinal cohorts with detailed, standardised phenotype data is required.

Phenotypic outcomes of PKD1 compared with non-PKD1 genetically confirmed autosomal dominant polycystic kidney disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the most common monogenic cause of kidney failure. While identifying genetic variants predicts disease progression, characterization of recently describedADPKD-like variants is limited. We explored disease progression and genetic spectrum of genetically-confirmed ADPKD families with PKD1 and non-PKD1 variants. In this observational study, we evaluated the clinical (ADPKD-related complications, estimated glomerular filtration rate (eGFR) decline, and progression to kidney failure), radiological (height-adjusted total kidney volume (ht-TKV)), and genetic characteristics of ADPKD families referred to the Irish Kidney Gene Project. Logistic regression and Kaplan-Meier analysesexamined relationships between genetic variants and disease progression. Genomic sequencing was performed on 261 ADPKD families, and 75.8% (198/261 families, comprising 391 individuals) were identified to harbor pathogenic/likely pathogenic variants; 74.2% (147/198) PKD1 families and 23.2% (46/198) non-PKD1 families, which include PKD2 (n = 29 families), IFT140 variants (n = 4), ALG5, DNAJB11 and NEK8 (n = 3 each), ALG8 and ALG9 variants (n = 2 each). The remaining 2.6% (5/198) accounted for non-ADPKD variants. Compared to PKD1, non-PKD1 families were characterized by a milder phenotype; milder eGFR decline (-1.4mL/min/1.73m2/year vs. -3.2; p < 0.001), smaller ht-TKV (449.7mL/m vs. 1769; p 0.002) and a delayed progression towards kidney failure (73 vs. 52years; HR: 0.12, p < 0.001 [95% CI: 0.07-0.19]). ADPKD-NEK8 heterozygotes demonstrated earlier progression to kidney failure (average age 8 vs. 49years for PKD1; Bonferroni-corrected p 0.017). Non-PKD1 variants have heterogeneous phenotypic and genotypic attributes resulting in milder disease, although ADPKD-NEK8 is an important exception with early progression.

Elucidating the Molecular Landscape of Cystic Kidney Disease: Old Friends, New Friends and Some Surprises.

Cystic kidney diseases (CyKD) are a diverse group of disorders affecting more than 1 in 1000 individuals. Over 120 genes are implicated, primarily encoding components of the primary cilium, transcription factors, and morphogens. Prognosis varies greatly by molecular diagnosis. Causal variants are not identified in 10%-60% of individuals due to our limited understanding of CyKD. To elucidate the molecular landscape of CyKD, we queried the CAG Biobank using the ICD10 codes N28.1, Q61.1, Q61.11, Q61.19, Q61.2, Q61.3, and Q61.8 to identify individuals with CyKD. One hundred eight individuals met clinical criteria for CyKD and underwent proband-only exome sequencing. Causal variants were identified in 86/108 (80%) individuals. The most common molecular diagnoses were PKD1-related autosomal dominant polycystic kidney disease (32/108; 30%) and autosomal recessive polycystic kidney disease (21/108; 19%). Other common molecular diagnoses were ciliopathy syndromes (7/108; 6.5%) and Tuberous Sclerosis (6/108; 5.6%). Seven individuals had variants in genes not previously associated with CyKD (7/108; 6.5%). Candidate genes were identified in five individuals (5/108; 4.5%). Discordance between molecular and clinical diagnosis was present in two individuals. We demonstrate a high molecular diagnosis rate in individuals with CyKD that can result in diagnostic reclassification, supporting a role for genetic testing in CyKD.

Impact of Race on Transplantation in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end-stage kidney disease (ESKD) and occurs without racial predilection. In general, non-White ESKD patients have less access to transplantation, especially living donor transplantation. We examined long-term outcomes of ADPKD-ESKD patients by self-reported race, with attention to the trajectory of Estimated Post-Transplant Survival (EPTS) scores over time. United Network for Organ Sharing Standard Transplant Analysis and Research files were used to identify 32,611 ADPKD transplant recipients between 1/2000-12/2022. EPTS scores were calculated from the date of waitlisting until transplantation occurred. Cumulative incidences of living and deceased transplantation were calculated and plotted. Cox models were made for graft failure and death, and a sub-distribution hazards model for graft failure accounted for death as a competing outcome, with adjustment for patient, donor, and transplant factors. Compared to White ADPKD patients, all other groups had more dialysis years, more delayed graft function, and fewer living and pre-emptive transplants; mean EPTS scores were lower in African American (AA) and Hispanic patients at each timepoint on the waitlist. However, EPTS scores at the time of transplant was less likely to be <20% in AA and Hispanic patients, due to longer waiting time. AA patients had a significantly higher risk of graft failure with death as competing risk compared to White patients. Asian and Hispanic patients had similar graft survivals but better patient survival compared to White patients. Waitlist experience, allograft quality, and post-transplant outcomes of patients with ADPKD are influenced by patient race.

Understanding the Support Needs of People with Autosomal Dominant Polycystic Kidney Disease: A Qualitative Phenomenological Descriptive Study.

Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary kidney disease and the fourth most common cause of kidney failure. Patients may be aware of their condition from an early age or discover it unexpectedly, with varying levels of familial knowledge about the disease. This chronic condition presents significant challenges for healthcare professionals. The study aimed to investigate how people with ADPKD experience their participation in a dedicated ADPKD clinic and to investigate their support needs in managing their disease in everyday life. A qualitative phenomenological descriptive study was conducted, involving semi-structured telephone interviews with patients who attended a newly established dedicated ADPKD clinic between March and April 2023. The data were analyzed using Malterud's principles of systematic text condensation. In total, 18 out of 22 patients agreed to participate in the interviews. Six themes emerged from the interviews. Participants expressed feelings of uncertainty about their future and highlighted the necessity for personalized care tailored to their individual circumstances. They reported challenges in coping with emotions associated with the disease and sought assistance in making difficult decisions. Maintaining control over their health and illness was a significant theme, alongside a desire for increased knowledge about their condition. Our study supports existing knowledge in this area. In this study, the participants experienced satisfaction with the dedicated ADPKD clinic, feeling well informed, listened to, and more at ease after the check-up. Investing in a dedicated ADPKD clinic could help alleviate the uncertainty that many people with ADPKD experience.

Autosomal Dominant Polycystic Kidney Disease Inflammation Biomarkers in the Tolvaptan Era

With the approval of tolvaptan as the first specific medicine for the treatment of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD), biomarker discovery has gained renewed interest as it is widely recognized that these will be crucial in clinical decision-making, serving as either prognostic or predictive tools. Since the marketing authorization was first issued in 2015 for ADPKD, tolvaptan has remained the sole pharmacological compound specifically targeting the disease. For ADPKD patients it is an invaluable medicine for retarding disease progression. Although the field of overall biomarker discovery and validation has been detailed in several publications, the role of inflammation remains largely overlooked in ADPKD. The current work aims to provide the reader with an updated review of inflammation biomarkers research in ADPKD, highlighting the role of urinary MCP-1 (monocyte chemoattractant protein-1) as the most promising tool.

Nephrectomy in Autosomal Dominant Polycystic Kidney Disease: A consensus statement of the ERA Genes & Kidney Working Group.

A substantial number of patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) undergo a nephrectomy, especially in work-up for a kidney transplantation. Currently, there is no evidence-based algorithm to guide clinicians which patients should undergo nephrectomy, the optimal timing of this procedure, or the preferred surgical technique. This systematic review-based consensus statement aimed to answer important questions regarding nephrectomy in ADPKD. A literature review was performed and extended to a meta-analysis when possible. For this purpose, PubMed and EMBASE were searched up to May 2024. Fifty-four publications, describing a total of 2391 procedures, were included. In addition, an exploratory questionnaire was sent to urologists, nephrologists, and transplant-surgeons. These sources were used to develop practice points about indications, complications, mortality, timing, and technique of nephrectomy. In addition, data on renal embolization as a potential alternative to nephrectomy was explored and summarized. To reach consensus, practice points were defined and improved in three Delphi survey rounds by experts of the European Renal Association Working Group Genes & Kidney and the European Association of Urology Section of Transplantation Urology. A total of 23 practice points/statements were developed, all of which reached consensus. Among others, it was deemed that nephrectomy can be performed successfully for various indications and is an intermediate risk procedure with acceptable mortality and minimal impact on kidney graft function when performed before, in the same session or after transplantation. The complication rate seems to increase when the procedure is performed as an emergency. During the work-up for transplantation, patient complaints should be assessed routinely by questionnaires to indicate symptom burden. Deciding on the need for nephrectomy and exploring potential alternatives such as kidney embolization should be a process of shared decision making, preferably after multidisciplinary consultation.

Segmentation of ADPKD Computed Tomography Images with Deep Learning Approach for Predicting Total Kidney Volume

Background: Total Kidney Volume (TKV) is widely used globally to predict the progressive loss of renal function in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Typically, TKV is calculated using Computed Tomography (CT) images by manually locating, delineating, and segmenting the ADPKD kidneys. However, manual localization and segmentation are tedious, time-consuming tasks and are prone to human error. Specifically, there is a lack of studies that focus on CT modality variation. Methods: In contrast, our work develops a step-by-step framework, which robustly handles both Non-enhanced Computed Tomography (NCCT) and Contrast-enhanced Computed Tomography (CCT) images, ensuring balanced sample utilization and consistent performance across modalities. To achieve this, Artificial Intelligence (AI)-enabled localization and segmentation models are proposed for estimating TKV, which is designed to work robustly on both NCCT and Contrast-Computed Tomography (CCT) images. These AI-based models incorporate various image preprocessing techniques, including dilation and global thresholding, combined with Deep Learning (DL) approaches such as the adapted Single Shot Detector (SSD), Inception V2, and DeepLab V3+. Results: The experimental results demonstrate that the proposed AI-based models outperform other DL architectures, achieving a mean Average Precision (mAP) of 95% for automatic localization, a mean Intersection over Union (mIoU) of 92% for segmentation, and a mean R2 score of 97% for TKV estimation. Conclusions: These results clearly indicate that the proposed AI-based models can robustly localize and segment ADPKD kidneys and estimate TKV using both NCCT and CCT images.

A miRNA-Based Approach in Autosomal Dominant Polycystic Kidney Disease: Challenges and Insights from Adult to Pediatric Evidence.

Autosomal dominant polycystic kidney disease (ADPKD) represents the most common inherited kidney disorder leading to kidney failure in a significant percentage of patients over time. Although previously considered as an adult disease, robust evidence demonstrated that clinical manifestations might occur during childhood and adolescence. Therefore, early identification and treatment of the disease are of cardinal importance for pediatricians to ensure the best long-term outcomes. To date, licensed treatment options are limited but promising potential therapeutic targets are emerging. Among these, an intriguing pathophysiological role for microRNAs as small molecules with a critical role in regulating gene expression has been considered possible in ADPKD. Indeed, numerous circulating microRNAs have been found to be dysregulated in ADPKD, suggesting their potential role as biomarkers and therapeutic targets. Basedon this background, further detailed insights into the mechanisms of miRNAs contributing to ADPKD development might pave the way for their effective application as a targeted treatment in young patients with ADPKD. We aimed to summarize the most recent evidence in this fascinating research area, providing a comprehensive overview of the current landscape of specific microRNAs in ADPKD as a potential innovative therapeutic strategy for these young patients.

Defining the Polycystin Pharmacophore Through HTS & Computational Biophysics.

Polycystins (PKD2, PKD2L1) are voltage-gated and Ca2+-modulated members of the transient receptor potential (TRP) family of ion channels. Loss of PKD2L1 expression results in seizure-susceptibility and autism-like features in mice, whereas variants in PKD2 cause autosomal dominant polycystic kidney disease. Despite decades of evidence clearly linking their dysfunction to human disease and demonstrating their physiological importance in the brain and kidneys, the polycystin pharmacophore remains undefined. Contributing to this knowledge gap is their resistance to drug screening campaigns, which are hindered by these channels' unique subcellular trafficking to organelles such as the primary cilium. PKD2L1 is the only member of the polycystin family to form constitutively active ion channels on the plasma membrane when overexpressed. HEK293 cells stably expressing PKD2L1 F514A were pharmacologically screened via high-throughput electrophysiology to identify potent polycystin channel modulators. In-silico docking analysis and mutagenesis were used to define the receptor sites of screen hits. Inhibition by membrane-impermeable QX-314 was used to evaluate PKD2L1's binding site accessibility. Screen results identify potent PKD2L1 antagonists with divergent chemical core structures and highlight striking similarities between the molecular pharmacology of PKD2L1 and voltage-gated sodium channels. Docking analysis, channel mutagenesis, and physiological recordings identify an open-state accessible lateral fenestration receptor within the pore, and a mechanism of inhibition that stabilizes the PKD2L1 inactivated state. Outcomes establish the suitability of our approach to expand our chemical knowledge of polycystins and delineates novel receptor moieties for the development of channel-specific antagonists in TRP channel research.

Gut microbiota and kidney function in autosomal dominant polycystic kidney disease participants in Cameroon: a cross-sectional study

Background and hypothesisGut dysbiosis characterized by an imbalance in pathobionts (Enterobacter, Escherichia and Salmonella) and symbionts (Bifidobacterium, Lactobacillus and Prevotella) can occur during chronic kidney disease (CKD) progression. We evaluated the associations between representative symbionts (Bifidobacterium and Lactobacillus) and pathobionts (Enterobacteriaceae) with kidney function in persons with autosomal dominant polycystic kidney disease (ADPKD).MethodsIn this cross-sectional study, 29 ADPKD patients were matched to 15 controls at a 2:1 ratio. Clinical data and biological samples were collected. The estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine concentration using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Microbial DNA extracted from stool specimens and amplified by qPCR was used to quantify Enterobacteriaceae, Bifidobacterium and Lactobacillus abundance. Differences between ADPKD subgroups and controls were assessed using nonparametric tests.ResultsThe mean age (SD) of the 44 participants was 40.65 (± 11.9) years. Among the participants with ADPKD, 62.1% experienced flank pain, and 48.3% had hypertension. Their median eGFR [IQR] was 74.4 [51.2–94.6] ml/min/1.73m2. All stool samples had Enterobacteriaceae. Lactobacillus abundance was lower in ADPKD participants with more pronounced kidney function decline (CKD G3-5: 0.58 ng/μL) than in those with milder damage and controls (G1-2: 0.64 ng/μL, p = 0.047; controls: 0.71 ng/μL, p = 0.043), while Enterobacteriaceae abundance was greater in ADPKD patients with lower kidney function (CKD G3-5: 78.6 ng/μL) than in those in the other two groups (G1-2: 71.6 ng/μL, p = 0.048; controls: 70.5 ng/μL, p = 0.045).ConclusionDecreased kidney function was associated with decreased symbiont and increased pathobiont abundance in ADPKD patients, suggesting a potential role for the microbiota in disease progression and possible targets for further research.

Change in kidney volume growth rate and renal outcomes of tolvaptan treatment in autosomal dominant polycystic kidney disease: post-hoc analysis of TEMPO 3:4 trial

Abstract Background Despite of long-lasting tolvaptan treatment, individual renal outcomes are unclear in autosomal dominant polycystic kidney disease (ADPKD). This post-hoc analysis of the TEMPO 3:4 trial aimed to evaluate the predictability of estimated height-adjusted total kidney volume growth rate (eHTKV-α) on renal outcomes. Methods In TEMPO 3:4, 1445 patients with ADPKD were randomised to tolvaptan or placebo for 3 years. The present analysis included patients with total kidney volume (TKV) data available at baseline and month 12 (tolvaptan, n = 812; placebo, n = 453); tolvaptan-assigned patients were grouped into quartiles based on percent change in eHTKV-α from baseline at 1 year. Clinical parameters were compared between quartiles, and regression analyses evaluated the predictive value of 1-year percent change in eHTKV-α and other factors on annual changes in TKV and estimated GFR (eGFR) over 3 years. Results Trend tests identified significant differences between quartiles for several baseline parameters. Multivariate regression models confirmed that 1-year percent change in eHTKV-α was a significant predictor of annual changes in both TKV and eGFR over 3 years. Other significant predictors of annual changes in TKV and eGFR over 3 years were sex, age and body mass index, and first-year change in eGFR, race and baseline eGFR, respectively. Predicting factors using urine osmolality and plasma copeptin levels were not significant by backward stepwise selection analysis. Conclusions 1-year percent change in eHTKV-α is useful biomarker to identify treatment good responders and may be utilized for early estimate of trial outcomes of new drugs in ADPKD.

G-quadruplex stabilization provokes DNA breaks in human PKD1, revealing a second hit mechanism for ADPKD

The “secondhit” pathway is responsible for biallelic inactivation of many tumor suppressors, where a pathogenic germline allele is joined by somatic mutation of the remaining functional allele. The mechanisms are unresolved, but the human PKD1 tumor suppressor is a good experimental model for identifying the molecular determinants. Inactivation of PKD1 results in autosomal dominant polycystic kidney disease, a very common disorder characterized by the accumulation of fluid-filled cysts and end-stage renal disease. Since human PKD1 follows second hit and mouse Pkd1 heterozygotes do not, we reasoned that there is likely a molecular difference that explains the elevated mutagenesis of the human gene. Here we demonstrate that guanine quadruplex DNA structures are abundant throughout human, but not mouse, PKD1 where they activate the DNA damage response. Our results suggest that guanine quadruplex DNAs provoke DNA breaks in PKD1, providing a potential mechanism for cystogenesis in autosomal dominant polycystic kidney disease specifically and for the inactivation of guanine quadruplex-rich tumor suppressors generally.