Glioneuronal tumor in an autosomal-dominant polycystic kidney disease patient: a case report and literature review.

Introduction: The association between primary brain tumors, such as glioneuronal tumors, with autosomal-dominant polycystic kidney disease (ADPKD) remains poorly understood, with only two cases reported excluding this one. This case of an ADPKD patient diagnosed with a rosette-forming glioneuronal tumor highlights an exceptionally rare potential association warranting further investigation. Case presentation: A 28-year-old male with ADPKD presented with progressive ataxia, dizziness, and headache. MRI revealed a cerebellar mass and obstructive hydrocephalus. Surgical resection and histopathological examination confirmed the diagnosis of a rosette-forming glioneuronal tumor. Postoperatively, the patient showed significant symptom improvement. Discussion: The interplay between genetics and glioneuronal development is complex and underexplored. While most glioneuronal arise sporadically, rare genetic syndromes may predispose individuals to these tumors. Additionally, although more than 70 cases of ADPKD with concurrent tumors were reported, the literature on this specific association remains limited. Conclusion: This case underscores the need for heightened awareness of potential associations between ADPKD and tumors such as glioneuronal tumors. With limited literature on this subject, further research is imperative to understand the underlying mechanisms and clinical implications. Enhancing our knowledge in this area can improve patient outcomes and management strategies.

Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis.

Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.

Disease-associated missense mutations in the pore loop of polycystin-2 alter its ion channel function in a heterologous expression system.

Polycystin-2 (PC2) is mutated in ∼15% of patients with autosomal dominant polycystic kidney disease (ADPKD). PC2 belongs to the family of transient receptor potential (TRP) channels and can function as homotetramer. We investigated whether three disease-associated mutations (F629S, C632R or R638C) localized in the channel's pore loop alter ion channel properties of human PC2 expressed in Xenopus laevis oocytes. Expression of wildtype (WT) PC2 typically resulted in small but measurable Na+ inward currents in the absence of extracellular divalent cations. These currents were no longer observed, when individual pore mutations were introduced in WT PC2. Similarly, Na+ inward currents mediated by the F604P gain-of-function (GOF) PC2 construct (PC2 F604P) were abolished by each of the three pore mutations. In contrast, when the mutations were introduced in another GOF construct, PC2 L677A N681A, only C632R had a complete loss-of-function effect, whereas significant residual Na+ inward currents were observed with F629S (∼15 %) and R638C (∼30 %). Importantly, the R638C mutation also abolished the Ca2+ permeability of PC2 L677A N681A and altered its monovalent cation selectivity. To elucidate the molecular mechanisms by which the R638C mutation affects channel function, molecular dynamics (MD) simulations were used in combination with functional experiments and site-directed mutagenesis. Our findings suggest that R638C stabilizes ionic interactions between Na+ ions and the selectivity filter residue D643. This probably explains the reduced monovalent cation conductance of the mutant channel. In summary, our data support the concept that altered ion channel properties of PC2 contribute to the pathogenesis of ADPKD.

Changes in tubular biomarkers with dietary intervention and metformin in patients with autosomal dominant polycystic kidney disease: a post-hoc analysis of two clinical trials.

BACKGROUND: Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury. METHODS: 66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m2 who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression. RESULTS: Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m2, and baseline BMI was 30.5 ± 5.9 kg/m2. None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics. CONCLUSIONS: Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.

Cross-Species Insights into Autosomal Dominant Polycystic Kidney Disease: Provide an Alternative View on Research Advancement.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent hereditary disorder that affects the kidneys, characterized by the development of an excessive number of fluid-filled cysts of varying sizes in both kidneys. Along with the progression of ADPKD, these enlarged cysts displace normal kidney tissue, often accompanied by interstitial fibrosis and inflammation, and significantly impair renal function, leading to end-stage renal disease. Currently, the precise mechanisms underlying ADPKD remain elusive, and a definitive cure has yet to be discovered. This review delineates the epidemiology, pathological features, and clinical diagnostics of ADPKD or ADPKD-like disease across human populations, as well as companion animals and other domesticated species. A light has been shed on pivotal genes and biological pathways essential for preventing and managing ADPKD, which underscores the importance of cross-species research in addressing this complex condition. Treatment options are currently limited to Tolvaptan, dialysis, or surgical excision of large cysts. However, comparative studies of ADPKD across different species hold promise for unveiling novel insights and therapeutic strategies to combat this disease.

Characterizing the Impact of the Covid-19 Pandemic on Adults with Autosomal Dominant Polycystic Kidney Disease: A Cross-Sectional Study.

Background: The Covid-19 pandemic greatly affected those with chronic diseases, impacting healthcare access and healthcare seeking behaviors. The impact of the pandemic on adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD) has not been investigated. Methods: Participants were recruited from a cohort of 239 ADPKD patients enrolled in a longitudinal study at the University of Maryland. Patients on renal replacement therapy were excluded. N = 66 patients participated in a phone questionnaire from June 2022-December 2022 about ADPKD-related complications, concern about contracting Covid-19, healthcare-seeking behaviors, and telehealth utilization before and after March 2020. Results: N = 34 (51.5%) of participants reported a positive Covid-19 test result and N = 29 (44%) expressed high concern of contracting Covid-19. Those who avoided medical care at least once (N = 17, 25.8%) had similar demographics and ADPKD severity to those who did not, but reported greater telehealth utilization (88.2% vs. 42.9%, p = 0.002), greater use of non-prescribed medication for Covid-19 treatment or prevention (35.3% vs. 8.2%, p = 0.01), and were more likely to contract Covid-19 (76.5% vs. 42.9%, p = 0.02). Among the N = 53 who reported very good or excellent ADPKD disease management pre-pandemic, N = 47(89%) reported no significant change during the pandemic. Conclusions: In this highly educated, high-income cohort with a mean age of 46.1 years, most people reported well-managed ADPKD prior to the pandemic. This may explain why less than half of participants expressed high concern for contracting Covid-19. Overall, there was no significant pandemic-related decline in self-reported ADPKD management, like due to excellent access to, and uptake of, telehealth services. Notably, 1 in 4 participants reported healthcare avoidant behavior, the effect of which may only be seen years from now. Future studies should investigate potential impacts of avoidant behaviors, as well as expand investigation to a more diverse cohort whose care may not have been as easily transitioned to telehealth.

Pain and Health-Related Quality of Life in Autosomal Dominant Polycystic Kidney Disease: Results from a National Patient-Powered Registry.

Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) affects health-related quality of life (HRQoL) including pain, discomfort, fatigue, emotional distress, and impaired mobility. Stakeholders prioritized kidney cyst-related pain as an important core outcome domain in clinical trials, leading to the development of disease-specific assessment tools. Study Design: The ADPKD Registry is hosted online with multiple disease-specific patient-reported outcomes modules to characterize the patient experience in the United States. Setting & Participants: The ADPKD Registry allows consented participants access to a Core Questionnaire that includes demographics, comorbid conditions, current symptoms, and kidney function. Participants complete subsequent modules on a 3-month schedule, including 2 validated HRQoL tools, the ADPKD-Pain and Discomfort Scale (ADPKD-PDS), the ADPKD Impact Scale (ADPKD-IS) and a Healthcare Access and Utilization module. Exposures: Patient-reported latest estimated glomerular filtration rate or creatinine used to calculate stage of chronic kidney disease. Outcomes: Health-related quality of life, measured using validated ADPKD-specific tools; access to polycystic kidney disease-specific health care. Analytical Approach: For the 2 HRQoL tools, scores were calculated for physical, emotional, and fatigue domains; pain severity; and pain interference (based on the licensed user manuals). Associations to health care access were also assessed. Results: By July 2022, 1,086 individuals with ADPKD completed at least 1 of the HRQoL modules, and 319 completed 4 over a year. Participants were an average age of 53. In total, 71% were women, and 91% were White, with all chronic kidney disease (CKD) stages represented. In total, 2.5% reported being treated with dialysis, and 23% had a kidney transplant. CKD stage 4/5 participants reported the most dull kidney pain, whereas sharp kidney pain was evenly distributed across early CKD stages. Dull kidney pain had an impact on sleep regardless of CKD stage. There was a strong positive correlation between the ADPKD-PDS and ADPKD-IS. Patients with a neutral or positive HRQoL were less likely to have been denied access to imaging or other care. Limitations: Currently, all the information collected is patient reported without health record validation of clinical variables. Conclusions: Use of the HRQoL tools in the ADPKD Registry provided a broad cross-sectional assessment in the United States and provided granular information on the burden of pain across the CKD spectrum in ADPKD. The ADPKD Registry allowed assessment of ADPKD impact in a community that experiences decline in health and kidney function over decades.

The Autosomal Dominant Polycystic Kidney Disease Registry is a longitudinal, patient-powered research tool created with the goal to better understand the impacts of ADPKD on affected individuals in the United States. Here, we analyze pain and other health-related quality of life outcomes in 1,086 individuals using validated tools and comment on the utility of these tools for future use in clinical trials and observational studies. We found that sharp pain, dull pain, fullness discomfort, and other related impacts affected individuals across the disease spectrum, although some participants reported more dull pain in later stages (CKD stages 4 and 5). Future analysis of these trends over time will be valuable in understanding how to assess and address the burden of pain in autosomal dominant polycystic kidney disease.

Protocol for the nationwide registry of patients with polycystic kidney disease: japanese national registry of PKD (JRP).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP). METHODS: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618). RESULTS: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD. CONCLUSIONS: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice.

An Electronic Health Record-Integrated Application for Standardizing Care and Monitoring Patients With Autosomal Dominant Polycystic Kidney Disease Enrolled in a Tolvaptan Clinic: Design and Implementation Study.

Background: Tolvaptan is the only US Food and Drug Administration-approved drug to slow the progression of autosomal dominant polycystic kidney disease (ADPKD), but it requires strict clinical monitoring due to potential serious adverse events. Objective: We aimed to share our experience in developing and implementing an electronic health record (EHR)-based application to monitor patients with ADPKD who were initiated on tolvaptan. Methods: The application was developed in collaboration with clinical informatics professionals based on our clinical protocol with frequent laboratory test monitoring to detect early drug-related toxicity. The application streamlined the clinical workflow and enabled our nursing team to take appropriate actions in real time to prevent drug-related serious adverse events. We retrospectively analyzed the characteristics of the enrolled patients. Results: As of September 2022, a total of 214 patients were enrolled in the tolvaptan program across all Mayo Clinic sites. Of these, 126 were enrolled in the Tolvaptan Monitoring Registry application and 88 in the Past Tolvaptan Patients application. The mean age at enrollment was 43.1 (SD 9.9) years. A total of 20 (9.3%) patients developed liver toxicity, but only 5 (2.3%) had to discontinue the drug. The 2 EHR-based applications allowed consolidation of all necessary patient information and real-time data management at the individual or population level. This approach facilitated efficient staff workflow, monitoring of drug-related adverse events, and timely prescription renewal. Conclusions: Our study highlights the feasibility of integrating digital applications into the EHR workflow to facilitate efficient and safe care delivery for patients enrolled in a tolvaptan program. This workflow needs further validation but could be extended to other health care systems managing chronic diseases requiring drug monitoring.

Autosomal dominant polycystic kidney disease (ADPKD) with multiple complications: Management challenges.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary polycystic kidney disease characterized by renal enlargement, resulting in renal failure. In Indonesia, the exact prevalence of ADPKD is unknown due to limited reports on the disease. The aim of this study was to report a case of a patient with ADPKD with multiple complications. A 54-year-old male presented to the emergency room of Dr. Soetomo Academic General Hospital, Surabaya, Indonesia, with a chief complaint of dark-red-colored urine for one week. There was a progressive abdominal enlargement over the past five years, which had become more tense and rigid for the past one month. The patient had a history of fatigue and hypertension with routine follow-up. Physical examination on admission showed normal vital signs, and the abdominal assessment revealed a palpable hard mass approximately 4 cm in size in the right upper abdomen. Laboratory test indicated anemia, leukocytosis, lymphopenia, proteinuria, hematuria, leukocyturia, and elevated serum creatinine and urea levels. Abdominal imaging using ultrasonography, computed tomography (CT) scan, and magnetic resonance imaging (MRI) revealed bilateral kidney and liver enlargement containing multiple cysts, suggesting polycystic kidney and liver disease. There was a ruptured cyst in the middle of the left kidney pole with minimal ascites found in the CT scan. The MRI exhibited the presence of multiple cysts in both kidneys, partially filled with blood. The patient was diagnosed with ADPKD, gross hematuria, acute or chronic kidney disease (CKD), urinary tract infection (UTI), normochromic-normocytic anemia, and metabolic acidosis. Dietary control with high-calorie, high-protein, and low-salt diet; fluid balance; and other symptomatic medications were initiated. It is critical to be aware of risk factors associated with the rapid progression of ADPKD in order to be able to provide a favorable impact on the disease prevention and management.

Kidney Measurement and Glomerular Filtration Rate Evolution in Children with Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal tubular cystic dilatations. The cysts can develop anywhere along the nephron, and over time the cystic dilatation leads to kidney enlargement. On the other hand, the cysts begin to reduce the number of functional nephrons as a consequence of cystic expansion that further contributes to the decline in renal function over the years. The pressure exerted by the dilated cysts leads to compensatory mechanisms that further contribute to the decline in renal function. These structural changes are responsible of glomerular hyperfiltration states, albuminuria, proteinuria, and hematuria. However, the presentation of ADPKD varies in children, from a completely asymptomatic child with incidental ultrasound detection of cysts to a rapidly progressive disease. There have been reports of early onset ADPKD in children younger than 2 years that showed a more rapid decline in renal function. ADPKD is caused by a mutation in PKD1 and PKD2 genes. Today, the PKD1 gene mutation seems to account for up to 85% of the cases worldwide, and it is associated with worse renal outcomes. Individuals with PKD2 gene mutation seem to present a milder form of the disease, with a more delayed onset of end-stage kidney disease. The cardinal sign of ADPKD is the presence of renal cysts during renal ultrasound. The current guidelines provide clinicians the recommendations for genetic testing in children with a positive family history. Given that the vast majority of children with ADPKD present with normal or supra-normal kidney function, we explored the glomerular filtration rates dynamics and the renal ultrasound-adjusted percentiles. In total, 14 out of 16 patients had kidney percentiles over 90%. The gene mutations were equally distributed among our cohort. In addition, we compared the modified Schwartz formula to the quadratic equation after adjusting the serum creatinine measurements. It seems that even though children with ADPKD have enlarged kidneys, the renal function is more likely normal or near normal when the quadratic estimation of glomerular filtration rate is used (qGFR tended to be lower, 111.95 ± 12.43 mL/min/1.73 m2 when compared to Schwartz eGFR 126.28 ± 33.07 mL/min/1.73 m2, p = 0.14). Also, when the quadratic equation was employed, not even a single patient reached the glomerular hyperfiltration threshold. The quadratic formula showed that glomerular filtration rates are linear or slightly decreasing after 1 year of follow-up (quadratic ΔeGFR = -0.32 ± 5.78 mL/min/1.73 m2), as opposed to the Schwartz formula that can falsely classify children in a hyperfiltration state (ΔeGFR = 7.51 ± 19.46 mL/min/1.73 m2), p = 0.019.

Semi-simultaneous hand-assisted laparoscopic (HAL) bilateral nephrectomy and kidney transplantation from the same incision in ADPKD, first case report in Saudi Arabia.

This case report discusses the management of a 46-year-old male patient with autosomal dominant polycystic kidney disease and a high body mass index, who underwent a semi-simultaneous procedure involving hand-assisted laparoscopic bilateral nephrectomy to alleviate severe abdominal symptoms and prepare for a kidney transplantation, all using the same incision. This is the first reported occurrence of such a procedure in Saudi Arabia. Post-operatively, the patient made a successful recovery with excellent kidney function and no complications.

Empyema Resulting From a Nephro-Pleural Fistula in an Adult With Polycystic Kidney Disease With Obstructive Uropathy.

Nephropleural fistula, a rare complication of percutaneous nephrolithotomy (PCNL), occurred in a 45-year-old male with adult autosomal dominant polycystic kidney disease (ADPKD). The patient had undergone right PCNL in 2021 and 2023 and presented to the emergency department with symptoms of fever, breathlessness, and cough lasting one week. Imaging studies, including chest radiograph and contrast-enhanced computed tomography (CECT) of the abdomen and pelvis, revealed gross right pleural effusion, right perinephric abscess, multiple renal cysts, right renal calculi and right ureteric calculi causing severe right hydronephrosis and proximal hydroureter. The imaging also confirmed a nephropleural fistula, with the right kidney's perinephric abscess communicating with the right pleura via the right subhepatic space. Subsequent thoracic ultrasound showed a large effusion of 1500ml with underlying lung collapse. Diagnostic thoracocentesis confirmed empyema, necessitating immediate tube thoracostomy. CT intravenous urography confirmed a non-functioning right kidney. The perinephric abscess was drained with a PCNL tube and meanwhile, pleural fluid and perinephric abscess isolated Klebsiella pneumonia on cultures. The patient received parenteral antibiotics and intravenous fluids and had an intercostal drain and PCNL tube in place for drainage. A right nephrectomy was recommended due to the non-functioning right kidney and the patient is awaiting the procedure.

Aortic Dilatation in Children and Young People With ADPKD.

Introduction: Aortic root dilatation is a reported cardiovascular sequela seen in children and young people (CYP) with chronic kidney disease (CKD) but has yet to be described in those with autosomal dominant polycystic kidney disease (ADPKD). Methods: Single center, cross-sectional study in a dedicated ADPKD clinic. Echocardiograms were evaluated for the presence of dilatation (defined by a z-score ≥2 [≥99th percentile] SDs from the mean) at 4 standardized locations, namely the aortic valve annulus, sinuses of Valsalva (SoV), sinotubular junction (STJ), and the ascending aorta. Measurements were compared with a control group to assess prevalence, severity, and determinants of aortic dilatation. Results: Ninety-seven children, median age (interquartile range) of 9.3 (6.1, 13.6) years were compared with 19 controls without ADPKD or other CKD. The prevalence of dilatation ranged from 5.2% to 17% in ADPKD, depending on anatomical location with no aortic dilatation identified in the control group. In multivariable regression, aortic root dilatation was significantly associated with cyst burden at the aortic valve annulus and SoV (ß = 0.42 and ß = 0.39, both P < 0.001), with age at SoV (ß = -0.26, P = 0.02), systolic blood pressure (SBP) z-score at SoV (ß = -0.20, P = 0.04) and left ventricular mass index (LVMI) at SoV and STJ (ß = 0.24, P = 0.02 and ß = 0.25, P = 0.03, respectively) following adjustment for age, sex (male or female), body mass index (BMI) z-score, estimated glomerular filtration rate (eGFR), SBP z-score, and LVMI. Conclusion: Our data suggests increased prevalence of aortic root and ascending aortic dilatation in CYP with ADPKD compared with controls. Further studies are needed to understand the pathogenesis and its contribution to the high cardiovascular morbidity in ADPKD.

How Does ADPKD Severity Differ Between Family Members?

Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity. This narrative review explores contributors to within-family discordance in ADPKD severity. Cases of biallelic and digenic inheritance, where 2 rare pathogenic variants in cystogenic genes are coexistent in one family, account for a small proportion of within-family discordance. Genetic background, including cis and trans factors and the polygenic propensity for comorbid disease, also plays a role but has not yet been exhaustively quantified. Environmental exposures, including diet; smoking; alcohol, salt, and protein intake, and comorbid diseases, including obesity, diabetes, hypertension, kidney stones, dyslipidemia, and additional coexistent kidney diseases all contribute to ADPKD phenotypic variability among family members. Given that many of the factors contributing to phenotype variability are preventable, modifiable, or treatable, health care providers and patients need to be aware of these factors and address them in the treatment of ADPKD.

Revisiting the gene mutations and protein profile of WT 9-12: An autosomal dominant polycystic kidney disease cell line.

WT 9-12 is one of the cell lines commonly used for autosomal dominant polycystic kidney disease (ADPKD) studies. Previous studies had described the PKD gene mutations and polycystin expression in WT 9-12. Nonetheless, the mutations occurring in other ADPKD-associated genes have not been investigated. This study aims to revisit these mutations and protein profile of WT 9-12. Whole genome sequencing verified the presence of truncation mutation at amino acid 2556 (Q2556X) in PKD1 gene of WT 9-12. Besides, those variations with high impacts included single nucleotide polymorphisms (rs8054182, rs117006360, and rs12925771) and insertions and deletions (InDels) (rs145602984 and rs55980345) in PKD1L2; InDel (rs1296698195) in PKD1L3; and copy number variations in GANAB. Protein profiles generated from the total proteins of WT 9-12 and HK-2 cells were compared using isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Polycystin-1 was absent in WT 9-12. The gene ontology enrichment and reactome pathway analyses revealed that the upregulated and downregulated proteins of WT 9-12 relative to HK-2 cell line leaded to signaling pathways related to immune response and amino acid metabolism, respectively. The ADPKD-related mutations and signaling pathways associated with differentially expressed proteins in WT 9-12 may help researchers in cell line selection for their studies.

DNA methyltransferase 1 (DNMT1) promotes cyst growth and epigenetic age acceleration in autosomal dominant polycystic kidney disease.

Alteration of DNA methylation leads to diverse diseases, and the dynamic changes of DNA methylation (DNAm) on sets of CpG dinucleotides in mammalian genomes are termed "DNAm age" and "epigenetic clocks" that can predict chronological age. However, whether and how dysregulation of DNA methylation promotes cyst progression and epigenetic age acceleration in autosomal dominant polycystic kidney disease (ADPKD) remains elusive. Here, we show that DNA methyltransferase 1 (DNMT1) is upregulated in cystic kidney epithelial cells and tissues and that knockout of Dnmt1 and targeting DNMT1 with hydralazine, a safe demethylating agent, delays cyst growth in Pkd1 mutant kidneys and extends life span of Pkd1 conditional knockout mice. With methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), DNMT1 chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing analysis, we identified two novel DNMT1 targets, PTPRM and PTPN22 (members of the protein tyrosine phosphatase family). PTPRM and PTPN22 function as mediators of DNMT1 and the phosphorylation and activation of PKD-associated signaling pathways, including ERK, mTOR and STAT3. With whole-genome bisulfide sequencing in kidneys of patients with ADPKD versus normal individuals, we found that the methylation of epigenetic clock-associated genes was dysregulated, supporting that epigenetic age is accelerated in the kidneys of patients with ADPKD. Furthermore, five epigenetic clock-associated genes, including Hsd17b14, Itpkb, Mbnl1, Rassf5 and Plk2, were identified. Thus, the diverse biological roles of these five genes suggest that their methylation status may not only predict epigenetic age acceleration but also contribute to disease progression in ADPKD.

Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review.

INTRODUCTION: Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes. AIM: A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period. METHODS AND MATERIALS: Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes. RESULTS: During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet-Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0-31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0-141.0) months. The median follow-up duration in the cohort was 3.0 (1.0-7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation. CONCLUSION: This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.

Treatment for patients with autosomal dominant polycystic kidney disease in the chronic kidney disease without kidney replacement therapy in real-world clinical practice: a descriptive retrospective cohort study.

BACKGROUND: In real-world clinical practice, treatments selected for patients with autosomal dominant polycystic kidney disease (ADPKD) in the chronic kidney disease (CKD) without kidney replacement therapy (KRT) have not been reported. This study investigated the oral treatments used in these patients and the changes in their use in recent years. Additionally, we studied the factors affecting tolvaptan dose reduction or discontinuation. METHODS: This retrospective cohort study was conducted using the medical records of 160 hospitals in Japan. Patients with ADPKD or polycystic kidney disease registered on the database between January 2014 and December 2020 were selected. Changes in prescription proportions over time were assessed using the Cochran-Armitage test. We focused on patients prescribed with >15 mg of tolvaptan daily to identify the factors related to its dose reduction or discontinuation and used Multivariate Cox regression analysis to evaluate them. RESULTS: Tolvaptan use in patients with ADPKD in the CKD without KRT stage has increased. As of 2020, 25% of patients were treated with tolvaptan. Overall, 3639 patients with ADPKD were enrolled in the database, of whom 156 were treated with tolvaptan. Of these, 64 patients (41%) reduced or discontinued tolvaptan during the observation period. The presence of an estimated glomerular filtration rate <60 mL/min/1.73 m2 at the beginning of the treatment was associated with a higher risk of tolvaptan dose reduction or discontinuation. CONCLUSION: The proportion of patients with ADPKD treated with high-dose tolvaptan is increasing. However, patients with late-stage CKD tended to reduce or discontinue tolvaptan.

Polycystin-2 Mediated Calcium Signalling in the Dictyostelium Model for Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) occurs when the proteins Polycystin-1 (PC1, PKD1) and Polycystin-2 (PC2, PKD2) contain mutations. PC1 is a large membrane receptor that can interact and form a complex with the calcium-permeable cation channel PC2. This complex localizes to the plasma membrane, primary cilia and ER. Dysregulated calcium signalling and consequential alterations in downstream signalling pathways in ADPKD are linked to cyst formation and expansion; however, it is not completely understood how PC1 and PC2 regulate calcium signalling. We have studied Polycystin-2 mediated calcium signalling in the model organism Dictyostelium discoideum by overexpressing and knocking down the expression of the endogenous Polycystin-2 homologue, Polycystin-2. Chemoattractant-stimulated cytosolic calcium response magnitudes increased and decreased in overexpression and knockdown strains, respectively, and analysis of the response kinetics indicates that Polycystin-2 is a significant contributor to the control of Ca2+ responses. Furthermore, basal cytosolic calcium levels were reduced in Polycystin-2 knockdown transformants. These alterations in Ca2+ signalling also impacted other downstream Ca2+-sensitive processes including growth rates, endocytosis, stalk cell differentiation and spore viability, indicating that Dictyostelium is a useful model to study Polycystin-2 mediated calcium signalling.