53 results on '"Ong ACM"'
Search Results
2. Chronic kidney disease and the global public health agenda: an international consensus.
- Author
-
Francis A, Harhay MN, Ong ACM, Tummalapalli SL, Ortiz A, Fogo AB, Fliser D, Roy-Chaudhury P, Fontana M, Nangaku M, Wanner C, Malik C, Hradsky A, Adu D, Bavanandan S, Cusumano A, Sola L, Ulasi I, and Jha V
- Subjects
- Humans, Consensus, Risk Factors, Global Health, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic therapy, Public Health
- Abstract
Early detection is a key strategy to prevent kidney disease, its progression and related complications, but numerous studies show that awareness of kidney disease at the population level is low. Therefore, increasing knowledge and implementing sustainable solutions for early detection of kidney disease are public health priorities. Economic and epidemiological data underscore why kidney disease should be placed on the global public health agenda - kidney disease prevalence is increasing globally and it is now the seventh leading risk factor for mortality worldwide. Moreover, demographic trends, the obesity epidemic and the sequelae of climate change are all likely to increase kidney disease prevalence further, with serious implications for survival, quality of life and health care spending worldwide. Importantly, the burden of kidney disease is highest among historically disadvantaged populations that often have limited access to optimal kidney disease therapies, which greatly contributes to current socioeconomic disparities in health outcomes. This joint statement from the International Society of Nephrology, European Renal Association and American Society of Nephrology, supported by three other regional nephrology societies, advocates for the inclusion of kidney disease in the current WHO statement on major non-communicable disease drivers of premature mortality., (© 2024. Springer Nature Limited.)
- Published
- 2024
- Full Text
- View/download PDF
3. Combining genotype with height-adjusted kidney length predicts rapid progression of ADPKD.
- Author
-
Chen EWC, Chong J, Valluru MK, Durkie M, Simms RJ, Harris PC, and Ong ACM
- Subjects
- Humans, Male, Female, Cross-Sectional Studies, Adult, Middle Aged, Prognosis, Follow-Up Studies, Body Height genetics, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant pathology, Disease Progression, Genotype, Kidney pathology, Kidney diagnostic imaging, Glomerular Filtration Rate, TRPP Cation Channels genetics
- Abstract
Introduction: Our main objective was to identify baseline prognostic factors predictive of rapid disease progression in a large unselected clinical autosomal dominant polycystic kidney disease (ADPKD) cohort., Methods: A cross-sectional analysis was performed in 618 consecutive ADPKD patients assessed and followed-up for over a decade. A total of 123 patients (19.9%) had reached kidney failure by the study date. Data were available for the following: baseline eGFR (n = 501), genotype (n = 549), baseline ultrasound mean kidney length (MKL, n = 424) and height-adjusted baseline MKL (HtMKL, n = 377). Rapid disease progression was defined as an annualized eGFR decline (∆eGFR) of >2.5 mL/min/year by linear regression over 5 years (n = 158). Patients were further divided into slow, rapid and very rapid ∆eGFR classes for analysis. Genotyped patients were classified into several categories: PKD1 (T, truncating; or NT, non-truncating), PKD2, other genes (non-PKD1 or -PKD2), no mutation detected or variants of uncertain significance., Results: A PKD1-T genotype had the strongest influence on the probability of reduced baseline kidney function by age. A multivariate logistic regression model identified PKD1-T genotype and HtMKL (>9.5 cm/m) as independent predictors for rapid disease progression. The combination of both factors increased the positive predictive value for rapid disease progression over age 40 years and of reaching kidney failure by age 60 years to 100%. Exploratory analysis in a subgroup with available total kidney volumes showed higher positive predictive value (100% vs 80%) and negative predictive value (42% vs 33%) in predicting rapid disease progression compared with the Mayo Imaging Classification (1C-E)., Conclusion: Real-world longitudinal data confirm the importance of genotype and kidney length as independent variables determining ∆eGFR. Individuals with the highest risk of rapid disease progression can be positively selected for treatment based on this combination., (© Crown copyright 2024.)
- Published
- 2024
- Full Text
- View/download PDF
4. Clinical Characteristics and Kidney Outcomes in Chinese Patients with Autosomal Dominant Polycystic Kidney Disease.
- Author
-
Fung WW, Szeto CC, Chow KM, Cheng PM, Kwong VW, Lau SL, Pang WF, Chu WC, Ong ACM, Devuyst O, and Li PK
- Subjects
- Humans, Female, Male, Adult, China epidemiology, Middle Aged, Asian People, Glomerular Filtration Rate, Kidney pathology, East Asian People, Polycystic Kidney, Autosomal Dominant genetics
- Published
- 2024
- Full Text
- View/download PDF
5. Corrigendum to "An Artificial Intelligence Generated Automated Algorithm to Measure Total Kidney Volume in ADPKD" [ Kidney International Reports Volume 9, Issue 2, February 2024, Pages 249-256].
- Author
-
Taylor J, Thomas R, Metherall P, van Gastel M, Cornec-Le Gall E, Caroli A, Furlano M, Demoulin N, Devuyst O, Winterbottom J, Torra R, Perico N, Le Meur Y, Schoenherr S, Forer L, Gansevoort RT, Simms RJ, and Ong ACM
- Abstract
[This corrects the article DOI: 10.1016/j.ekir.2023.10.029.]., (Crown Copyright © 2024 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)
- Published
- 2024
- Full Text
- View/download PDF
6. HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial.
- Author
-
Bais T, Meijer E, Kramers BJ, Vart P, Vervloet M, Salih M, Bammens B, Demoulin N, Todorova P, Müller RU, Halbritter J, Paliege A, Gall EC, Knebelmann B, Torra R, Ong ACM, Karet Frankl FE, and Gansevoort RT
- Subjects
- Humans, Tolvaptan adverse effects, Hydrochlorothiazide adverse effects, Quality of Life, Glomerular Filtration Rate, Antidiuretic Hormone Receptor Antagonists adverse effects, Kidney, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant drug therapy
- Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD., Methods: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m
2 , and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care., Outcomes: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume., Conclusion: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
7. Global analysis of urinary extracellular vesicle small RNAs in autosomal dominant polycystic kidney disease.
- Author
-
Ali H, Malik MZ, Abu-Farha M, Abubaker J, Cherian P, Nizam R, Jacob S, Bahbahani Y, Naim M, Ahmad S, Al-Sayegh M, Thanaraj TA, Ong ACM, Harris PC, and Al-Mulla F
- Subjects
- Humans, Cross-Sectional Studies, Biomarkers, Formins, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant pathology, MicroRNAs genetics, MicroRNAs metabolism, Extracellular Vesicles genetics, Extracellular Vesicles metabolism
- Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease progressing to end-stage renal disease. There is a pressing need for the identification of early ADPKD biomarkers to enable timely intervention and the development of effective therapeutic approaches. Here, we profiled human urinary extracellular vesicles small RNAs by small RNA sequencing in patients with ADPKD and compared their differential expression considering healthy control individuals to identify dysregulated small RNAs and analyze downstream interaction to gain insight about molecular pathophysiology., Methods: This is a cross-sectional study where urine samples were collected from a total of 23 PKD1-ADPKD patients and 28 healthy individuals. Urinary extracellular vesicles were purified, and small RNA was isolated and sequenced. Differentially expressed Small RNA were identified and functional enrichment analysis of the critical miRNAs was performed to identify driver genes and affected pathways., Results: miR-320b, miR-320c, miR-146a-5p, miR-199b-3p, miR-671-5p, miR-1246, miR-8485, miR-3656, has_piR_020497, has_piR_020496 and has_piR_016271 were significantly upregulated in ADPKD patient urine extracellular vesicles and miRNA-29c was significantly downregulated. Five 'driver' target genes (FBRS, EDC3, FMNL3, CTNNBIP1 and KMT2A) were identified., Conclusions: The findings of the present study make significant contributions to the understanding of ADPKD pathogenesis and to the identification of novel biomarkers and potential drug targets aimed at slowing disease progression in ADPKD., (© 2024 The Authors. The Journal of Gene Medicine published by John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF
8. Macrophage subpopulation identity in Drosophila is modulated by apoptotic cell clearance and related signalling pathways.
- Author
-
Brooks EC, Zeidler MP, Ong ACM, and Evans IR
- Subjects
- Animals, Drosophila melanogaster genetics, Efferocytosis, Macrophages metabolism, Drosophila metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism
- Abstract
In Drosophila blood, plasmatocytes of the haemocyte lineage represent the functional equivalent of vertebrate macrophages and have become an established in vivo model with which to study macrophage function and behaviour. However, the use of plasmatocytes as a macrophage model has been limited by a historical perspective that plasmatocytes represent a homogenous population of cells, in contrast to the high levels of heterogeneity of vertebrate macrophages. Recently, a number of groups have reported transcriptomic approaches which suggest the existence of plasmatocyte heterogeneity, while we identified enhancer elements that identify subpopulations of plasmatocytes which exhibit potentially pro-inflammatory behaviours, suggesting conservation of plasmatocyte heterogeneity in Drosophila . These plasmatocyte subpopulations exhibit enhanced responses to wounds and decreased rates of efferocytosis when compared to the overall plasmatocyte population. Interestingly, increasing the phagocytic requirement placed upon plasmatocytes is sufficient to decrease the size of these plasmatocyte subpopulations in the embryo. However, the mechanistic basis for this response was unclear. Here, we examine how plasmatocyte subpopulations are modulated by apoptotic cell clearance (efferocytosis) demands and associated signalling pathways. We show that loss of the phosphatidylserine receptor Simu prevents an increased phagocytic burden from modulating specific subpopulation cells, while blocking other apoptotic cell receptors revealed no such rescue. This suggests that Simu-dependent efferocytosis is specifically involved in determining fate of particular subpopulations. Supportive of our original finding, mutations in amo (the Drosophila homolog of PKD2 ), a calcium-permeable channel which operates downstream of Simu, phenocopy simu mutants. Furthermore, we show that Amo is involved in the acidification of the apoptotic cell-containing phagosomes, suggesting that this reduction in pH may be associated with macrophage reprogramming. Additionally, our results also identify Ecdysone receptor signalling, a pathway related to control of cell death during developmental transitions, as a controller of plasmatocyte subpopulation identity. Overall, these results identify fundamental pathways involved in the specification of plasmatocyte subpopulations and so further validate Drosophila plasmatocytes as a heterogeneous population of macrophage-like cells within this important developmental and immune model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Brooks, Zeidler, Ong and Evans.)
- Published
- 2024
- Full Text
- View/download PDF
9. Liver transplant recipients with polycystic liver disease have longer waiting times but better long-term clinical outcomes than those with liver disease due to other causes: A retrospective cross-sectional study.
- Author
-
Gittus M, Moore J, and Ong ACM
- Subjects
- Humans, Cross-Sectional Studies, Retrospective Studies, Waiting Lists, Liver Transplantation, Liver Diseases surgery
- Abstract
Introduction: Liver transplantation is the only curative option for patients with polycystic liver disease (PLD). In the United Kingdom, these patients are listed on the variant syndrome list due to their preserved liver function reflected in the United Kingdom End-stage Liver Disease (UKELD) score. The transplantation and survival rates for this patient group in the UK have not been previously reported., Methods: A retrospective cross-sectional analysis of patients receiving liver transplantation between 2010 and 2017 was performed using the NHS blood and transplantation database. This database contains the demographic, clinical parameters, indication for transplantation and follow-up of all patients in UK-based transplant centres. Basic statistics was performed using SPSS version 27., Results: 5412 recipients received elective liver allografts in the study period. 1.6% (100) of recipients had PLD as their primary indication for transplantation with 60 receiving liver only allografts and 40 receiving combined liver-kidney allografts. PLD patients had a >3-fold longer mean waiting time for transplantation compared to non-PLD patients, 508 days v 154 days respectively. PLD patients receiving combined liver-kidney allografts had a longer waiting time than those receiving a liver only allograft, 610 days v 438 days respectively. There were comparable patient survival rates for people with PLD and non-PLD primary indications at 30 days (94.0% vs 97.6%) and 1 year (92.0% vs 93.2%) but improved survival rates at 5 years (81.3% vs 76.5%). There were also comparable allograft survival rates for people with PLD and non-PLD primary indications at 30 days (93.9% vs 95.3%) and 1 year (91.9% vs 91.2%) but improved survival rates at 5 years (82.5% vs 77.3%). Transplant centre-level analysis identified variation in the proportion of liver transplantations for people with PLD as their primary listed indication., Conclusions: Patients with PLD wait significantly longer for liver transplantation compared to other indications. However, transplanted PLD patients demonstrate better longer-term patient and liver allograft survival rates compared to transplanted non-PLD patients. The unexpected variation between individual UK centres transplanting for PLD deserves further study., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gittus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2024
- Full Text
- View/download PDF
10. An Artificial Intelligence Generated Automated Algorithm to Measure Total Kidney Volume in ADPKD.
- Author
-
Taylor J, Thomas R, Metherall P, van Gastel M, Cornec-Le Gall E, Caroli A, Furlano M, Demoulin N, Devuyst O, Winterbottom J, Torra R, Perico N, Le Meur Y, Schoenherr S, Forer L, Gansevoort RT, Simms RJ, and Ong ACM
- Abstract
Introduction: Accurate tools to inform individual prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD) are lacking. Here, we report an artificial intelligence (AI)-generated method for routinely measuring total kidney volume (TKV)., Methods: An ensemble U-net algorithm was created using the nnUNet approach. The training and internal cross-validation cohort consisted of all 1.5T magnetic resonance imaging (MRI) data acquired using 5 different MRI scanners (454 kidneys, 227 scans) in the CYSTic consortium, which was first manually segmented by a single human operator. As an independent validation cohort, we utilized 48 sequential clinical MRI scans with reference results of manual segmentation acquired by 6 individual analysts at a single center. The tool was then implemented for clinical use and its performance analyzed., Results: The training or internal validation cohort was younger (mean age 44.0 vs. 51.5 years) and the female-to-male ratio higher (1.2 vs. 0.94) compared to the clinical validation cohort. The majority of CYSTic patients had PKD1 mutations (79%) and typical disease (Mayo Imaging class 1, 86%). The median DICE score on the clinical validation data set between the algorithm and human analysts was 0.96 for left and right kidneys with a median TKV error of -1.8%. The time taken to manually segment kidneys in the CYSTic data set was 56 (±28) minutes, whereas manual corrections of the algorithm output took 8.5 (±9.2) minutes per scan., Conclusion: Our AI-based algorithm demonstrates performance comparable to manual segmentation. Its rapidity and precision in real-world clinical cases demonstrate its suitability for clinical application., (Crown Copyright © 2023 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)
- Published
- 2023
- Full Text
- View/download PDF
11. The association of urinary epidermal growth factors with ADPKD disease severity and progression.
- Author
-
Harskamp LR, Perez-Gomez MV, Heida JE, Engels GE, van Goor H, van den Heuvel MC, Streets AJ, Ong ACM, Ortiz A, and Gansevoort RT
- Subjects
- Humans, Heparin-binding EGF-like Growth Factor, Epidermal Growth Factor, Disease Progression, Kidney, Glomerular Filtration Rate, Patient Acuity, Polycystic Kidney, Autosomal Dominant complications
- Abstract
Background: The epidermal growth factor receptor (EGFR) pathway is involved in kidney tissue repair and growth. Preclinical interventional data and scarce human data have suggested a role for this pathway in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD), while other data have suggested that its activation is causally linked to repair of damaged kidney tissue. We hypothesize that urinary EGFR ligands, as a reflection of EGFR activity, are associated with kidney function decline in ADPKD in the context of tissue repair following injury, and as the disease progresses as a sign of insufficient repair., Methods: In the present study, we measured the EGFR ligands, EGF and heparin binding-EGF (HB-EGF), in 24-h urine samples of 301 ADPKD patients and 72 age- and sex-matched living kidney donors to dissect the role of the EGFR pathway in ADPKD. During a median follow-up of 2.5 years, the association of urinary EGFR ligand excretion with annual change in estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume in ADPKD patients was analyzed using mixed-models methods, and the expression of three closely related EGFR family receptors in ADPKD kidney tissue was investigated by immunohistochemistry. Additionally, the effect of reducing renal mass (after kidney donation), was assessed to investigate whether urinary EGF matches this reduction and thus reflects the amount of remaining healthy kidney tissue., Results: At baseline, urinary HB-EGF did not differ between ADPKD patients and healthy controls (P = .6), whereas a lower urinary EGF excretion was observed in ADPKD patients [18.6 (11.8-27.8)] compared with healthy controls [51.0 (34.9-65.4) μg/24 h, P < .001]. Urinary EGF was positively associated with baseline eGFR (R = 0.54, P < .001) and a lower EGF was strongly associated with a more rapid GFR decline, even when adjusted for ADPKD severity markers (β = 1.96, P < .001), whereas HB-EGF was not. Expression of the EGFR, but not other EGFR-related receptors, was observed in renal cysts but was absent in non-ADPKD kidney tissue. Finally, unilateral nephrectomy resulted in a decrease of 46.4 (-63.3 to -17.6) % in urinary EGF excretion, alongside a decrease of 35.2 ± 7.2% in eGFR and 36.8 ± 6.9% in measured GFR (mGFR), whereas maximal mGFR (measured after dopamine induced hyperperfusion) decreased by 46.1 ± 7.8% (all P < .001)., Conclusions: Our data suggest that lower urinary EGF excretion may be a valuable novel predictor for kidney function decline in patients with ADPKD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2023
- Full Text
- View/download PDF
12. Identification of renal cyst cells of type I Nephronophthisis by single-nucleus RNA sequencing.
- Author
-
Wang Q, Zou B, Wei X, Lin H, Pang C, Wang L, Zhong J, Chen H, Gao X, Li M, Ong ACM, Yue Z, and Sun L
- Abstract
Background: Nephronophthisis (NPH) is the most common genetic cause of end-stage renal disease (ESRD) in childhood, and NPHP1 is the major pathogenic gene. Cyst formation at the corticomedullary junction is a pathological feature of NPH, but the mechanism underlying cystogenesis is not well understood. The isolation and identification of cystic cell subpopulation could help to identify their origins and provide vital clues to the mechanisms underlying cystogenesis in NPH. Methods: Single-nucleus RNA sequencing (snRNA-seq) was performed to produce an atlas of NPHP1 renal cells. Kidney samples were collected from WT ( Nphp1
+/+ ) mice and NPHP1 ( Nphp1del2-20/del2-20 ) model mice. Results: A comprehensive atlas of the renal cellular landscape in NPHP1 was generated, consisting of 14 basic renal cell types as well as a subpopulation of DCT cells that was overrepresented in NPHP1 kidneys compared to WT kidneys. GO analysis revealed significant downregulation of genes associated with tubular development and kidney morphogenesis in this subpopulation. Furthermore, the reconstruction of differentiation trajectories of individual cells within this subpopulation confirmed that a specific group of cells in NPHP1 mice become arrested at an early stage of differentiation and proliferate to form cysts. We demonstrate that Niban1 is a specific molecular marker of cystic cells in both mice and human NPHP1. Conclusion: In summary, we report a novel subpopulation of DCT cells, marked by Niban1, that are classified as cystic cells in the NPHP1 mice kidney. These results offer fresh insights into the cellular and molecular basis of cystogenesis in NPH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Zou, Wei, Lin, Pang, Wang, Zhong, Chen, Gao, Li, Ong, Yue and Sun.)- Published
- 2023
- Full Text
- View/download PDF
13. Barriers and facilitators to the implementation of guidelines in rare diseases: a systematic review.
- Author
-
Gittus M, Chong J, Sutton A, Ong ACM, and Fotheringham J
- Subjects
- Humans, Rare Diseases, Health Personnel
- Abstract
Background: Rare diseases present a challenge to guideline implementation due to a low prevalence in the general population and the unfamiliarity of healthcare professionals. Existing literature in more common diseases references barriers and facilitators to guideline implementation. This systematic review aims to identify these barriers and facilitators in rare diseases from existing literature., Methods: A multi-stage strategy included searching MEDLINE PubMed, EMBASE Ovid, Web of Science and Cochrane library from the earliest date available to April 2021, Orphanet journal hand-search, a pearl-growing strategy from a primary source and reference/citation search was performed. The Integrated Checklist of Determinants of Practice which comprises of twelve checklists and taxonomies, informed by 57 potential determinants was selected as a screening tool to identify determinants that warrant further in-depth investigation to inform design of future implementation strategies., Results: Forty-four studies were included, most of which were conducted in the United States (54.5%). There were 168 barriers across 36 determinants (37 studies) and 52 facilitators across 22 determinants (22 studies). Fifteen diseases were included across eight WHO ICD-11 disease categories. Together individual health professional factors and guideline factors formed the majority of the reported determinants (59.5% of barriers and 53.8% of facilitators). Overall, the three most reported individual barriers were the awareness/familiarity with the recommendation, domain knowledge and feasibility. The three most reported individual facilitators were awareness/familiarity with the recommendation, agreement with the recommendation and ability to readily access the guidelines. Resource barriers to implementation included technology costs, ancillary staff costs and more cost-effective alternatives. There was a paucity of studies reporting influential people, patient advocacy groups or opinion leaders, or organisational factors influencing implementation., Conclusions: Key barriers and facilitators to the implementation of clinical practice guidelines in the setting of rare diseases were at the individual health professional and guideline level. Influential people and organisational factors were relatively under-reported and warrant exploration, as does increasing the ability to access the guidelines as a potential intervention., (© 2023. Crown.)
- Published
- 2023
- Full Text
- View/download PDF
14. Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial.
- Author
-
Gansevoort RT, Hariri A, Minini P, Ahn C, Chapman AB, Horie S, Knebelmann B, Mrug M, Ong ACM, Pei YPC, Torres VE, Modur V, Antonshchuk I, and Perrone RD
- Subjects
- Adult, Humans, Kidney, Glomerular Filtration Rate, Disease Progression, Polycystic Kidney, Autosomal Dominant complications, Renal Insufficiency complications
- Abstract
Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD., Study Design: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m
2 ., Setting & Participants: Enrollment included 236 and 242 patients in stages 1 and 2, respectively., Interventions: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo., Outcomes: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2)., Results: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early., Limitations: The short follow-up period after the end of treatment and limited generalizability of the findings., Conclusions: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels., Funding: This study was funded by Sanofi., Trial Registration: Registered at ClinicalTrials.gov with study number NCT03523728., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
15. A founder UMOD variant is a common cause of hereditary nephropathy in the British population.
- Author
-
Valluru MK, Chung NK, Gilchrist M, Butland L, Cook J, Takou A, Dixit A, Weedon MN, and Ong ACM
- Subjects
- Humans, Uromodulin genetics, Base Sequence, Haplotypes genetics, Kidney Diseases genetics, Renal Insufficiency genetics
- Abstract
Background: Monogenic disorders are estimated to account for 10%-12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin (UMOD) variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant., Methods: Probands from 12 apparently unrelated pedigrees with a family history of kidney failure within a geographically contiguous UK region were shown to be heterozygous for a pathogenic variant of UMOD c.278_289delTCTGCCCCGAAG insCCGCCTCCT., Results: A total of 88 clinically affected individuals were identified, all born in the UK and of white British ethnicity. 20 other individuals with the variant were identified in the UK 100,000 Genomes (100K) Project and 9 from UK Biobank (UKBB). A common extended haplotype was present in 5 of the UKBB individuals who underwent genome sequencing which was only present in <1 in 5000 of UKBB controls. Significantly, rare variants (<1 in 250 general population) identified within 1 Mb of the UMOD variant by genome sequencing were detected in all of the 100K individuals, indicative of an extended shared haplotype., Conclusion: Our data confirm a likely founder UMOD variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
16. Hypertension in young adults with autosomal dominant polycystic kidney disease: a case for early screening?
- Author
-
Cadnapaphornchai MA and Ong ACM
- Abstract
ADPKD is the most common hereditary kidney disease and a major cause of kidney failure world-wide. Significant kidney enlargement occurs decades preceding loss of kidney function. However, the earliest clinical manifestations of disease have been less well characterized in young adults, a typically healthy population who do not often seek routine medical care. In this study, Martinez and colleagues report a high prevalence of hypertension among young adults (18-30 years) enrolled in the Spanish ADPKD registry REPQRAD. Their findings confirm previous studies in children and young adults with ADPKD and make a strong case for earlier screening and intervention within this age group., Competing Interests: M.A.C. reports having received consultancy fees and serving on the paediatric research steering committee for Otsuka Pharmaceuticals, Inc., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2023
- Full Text
- View/download PDF
17. OVERTURE: A Worldwide, Prospective, Observational Study of Disease Characteristics in Patients With ADPKD.
- Author
-
Perrone RD, Oberdhan D, Ouyang J, Bichet DG, Budde K, Chapman AB, Gitomer BY, Horie S, Ong ACM, Torres VE, Turner AN, and Krasa H
- Abstract
Introduction: The course of autosomal dominant polycystic kidney disease (ADPKD) varies greatly among affected individuals, necessitating natural history studies to characterize the determinants and effects of disease progression. Therefore, we conducted an observational, longitudinal study (OVERTURE; NCT01430494) of patients with ADPKD., Methods: This prospective study enrolled a large international population ( N = 3409) encompassing a broad spectrum of ages (12-78 years), chronic kidney disease (CKD) stages (G1-G5), and Mayo imaging classifications (1A-1E). Outcomes included kidney function, complications, quality of life, health care resource utilization, and work productivity., Results: Most subjects (84.4%) completed ≥12 months of follow-up. Consistent with earlier findings, each additional l/m of height-adjusted total kidney volume (htTKV) on magnetic resonance imaging (MRI) was associated with worse outcomes, including lower estimated glomerular filtration rate (eGFR) (regression coefficient 17.02, 95% confidence interval [CI] 15.94-18.11) and greater likelihood of hypertension (odds ratio [OR] 1.25, 95% CI 1.17-1.34), kidney pain (OR 1.22, 95% CI 1.11-1.33), and hematuria (OR 1.35, 95% CI 1.21-1.51). Greater baseline htTKV was also associated with worse patient-reported health-related quality of life (e.g., ADPKD Impact Scale physical score, regression coefficient 1.02, 95% CI 0.65-1.39), decreased work productivity (e.g., work days missed, regression coefficient 0.55, 95% CI 0.18-0.92), and increased health care resource utilization (e.g., hospitalizations, OR 1.48, 95% CI 1.33-1.64) during follow-up., Conclusion: Although limited by a maximum 3-year duration of follow-up, this observational study characterized the burden of ADPKD in a broad population and indicated the predictive value of kidney volume for outcomes other than kidney function., (© 2023 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)
- Published
- 2023
- Full Text
- View/download PDF
18. The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD.
- Author
-
Perrone RD, Hariri A, Minini P, Ahn C, Chapman AB, Horie S, Knebelmann B, Mrug M, Ong ACM, Pei YPC, Torres VE, Modur V, and Gansevoort RT
- Abstract
Rationale & Objective: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials., Study Design: STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m
2 at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies., Setting & Participants: Target enrollment in stages 1 and 2 was 240 and 320 patients, respectively., Interventions: Stage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data., Outcomes: Primary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2)., Limitations: If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects., Conclusions: Modeling allows the design and powering of a 2-stage combined study to assess venglustat's impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration., Funding: This study was funded by Sanofi., Trial Registration: STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728., (© 2022 The Authors.)- Published
- 2022
- Full Text
- View/download PDF
19. Regional variation in tolvaptan prescribing across England: national data and retrospective evaluation from an expert centre.
- Author
-
Chong J, Harris T, and Ong ACM
- Abstract
Background: Tolvaptan, a vasopressin V2 receptor antagonist, was approved in 2015 by the UK National Institute for Health and Care Excellence for use in patients with autosomal dominant polycystic kidney disease (ADPKD) and rapid disease progression. Simultaneous guidance was issued by the UK Kidney Association (UKKA) to facilitate national implementation., Methods: Data on tolvaptan prescribing in England was obtained through the National Health Service (NHS) Digital, a national survey of all 77 adult kidney units, and the implementation of UKKA guidance was evaluated at an expert PKD centre., Results: A regional variation of up to 4-fold for tolvaptan prescribing in England was found. Despite most kidney units following UKKA guidance, centre-based estimates of eligible or treated patient numbers were highly variable. Retrospective evaluation at an expert PKD centre revealed that in a cohort demonstrating rapid estimated glomerular filtration rate (eGFR) decline, 14% would not be eligible for tolvaptan by Mayo imaging classification and more than half (57%) would not be eligible by Predicting Renal Outcome in Polycystic Kidney Disease score. The 3-year discontinuation rate was higher than expected (56%), the majority (70%) due to aquaretic symptoms. In patients taking tolvaptan for at least 2 years, 81% showed a reduction in the rate of eGFR decline compared with baseline, with earlier disease associated with positive treatment response., Conclusion: Real-world data have revealed a much higher regional variation in tolvaptan prescribing for ADPKD in England than expected. We propose further investigation into the factors responsible for this variation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2022
- Full Text
- View/download PDF
20. Flank pain has a significant adverse impact on quality of life in ADPKD: the CYSTic-QoL study.
- Author
-
Winterbottom J, Simms RJ, Caroli A, Gall EC, Demoulin N, Furlano M, Meijer E, Devuyst O, Gansevoort RT, Le-Meur Y, Perico N, Torra R, and Ong ACM
- Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of kidney failure worldwide. However, its impact on quality-of-life has not been systematically explored., Methods: The CYSTic-QoL study was an observational study designed to study quality-of-life in adult European ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m
2 . A total of 465 patients were recruited from six expert European centres with baseline data recorded, including health-related quality-of-life (HRQoL), incorporating a Kidney Disease QoL short form questionnaire (KDQoL-SF, version 1.3), magnetic resonance imaging (MRI) for total kidney volume (TKV) measurements and DNA for genotyping. The cohort was stratified by baseline eGFR, TKV or genotype and correlated with HRQoL scores. Bivariate and multivariate analyses were applied to examine the relationship between HRQoL and variables of interest. KDQoL-SF scores were calculated using an online tool provided by the RAND organization. For 36-item short form values, mean centre scores were normalized to their native populations., Results: The mean age of participants was 43 years and 55% were female, with a mean eGFR of 77 mL/min/1.73 m2 and height-adjusted TKV (ht-TKV) of 849 mL/min; 66% had PKD1 pathogenic variants. ADPKD patients uniformly reported decreased general health and less energy, with the majority also experiencing poorer physical, mental or emotional health and limitations in social functioning. A total of 32.5% of participants experienced flank pain, which was significantly and negatively correlated with the majority of KDQoL-SF subscales by multivariate analysis. Higher ht-TKV and lower eGFR were negatively associated with decreased energy and poorer physical health, respectively, although not with flank pain., Conclusion: ADPKD patients suffer from significantly decreased QoL in multiple domains, exacerbated particularly by chronic pain., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)- Published
- 2022
- Full Text
- View/download PDF
21. Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.
- Author
-
Chang MY, Tsai CY, Chou LF, Hsu SH, Yang HY, Hung CC, Tian YC, Ong ACM, and Yang CW
- Subjects
- Animals, Disease Models, Animal, Female, Kidney metabolism, Lactic Acid metabolism, Male, Mice, Mice, Transgenic, Polycystic Kidney Diseases, TRPP Cation Channels genetics, TRPP Cation Channels metabolism, Cysts metabolism, Metformin metabolism, Metformin pharmacology, Polycystic Kidney, Autosomal Dominant drug therapy, Polycystic Kidney, Autosomal Dominant genetics, Polycystic Kidney, Autosomal Dominant metabolism
- Abstract
Metabolic reprogramming is a potential treatment strategy for autosomal dominant polycystic kidney disease (ADPKD). Metformin has been shown to inhibit the early stages of cyst formation in animal models. However, metformin can lead to lactic acidosis in diabetic patients with advanced chronic kidney disease, and its efficacy in ADPKD is still not fully understood. Here, we investigated the effect of metformin in an established hypomorphic mouse model of PKD that presents stable and heritable knockdown of Pkd1. The Pkd1 miRNA transgenic mice of both genders were randomized to receive metformin or saline injections. Metformin was administrated through daily intraperitoneal injection from postnatal day 35 for 4 weeks. Unexpectedly, metformin treatment at a concentration of 150 mg/kg increased disease severity, including kidney-to-body weight ratio, cystic index and plasma BUN levels, and was associated with increased renal tubular cell proliferation and plasma lactate levels. Functional enrichment analysis for cDNA microarrays from kidney samples revealed significant enrichment of several pro-proliferative pathways including β-catenin, hypoxia-inducible factor-1α, protein kinase Cα and Notch signaling pathways in the metformin-treated mutant mice. The plasma metformin concentrations were still within the recommended therapeutic range for type 2 diabetic patients. Short-term metformin treatment in a second Pkd1 hypomorphic model (Pkd1RC/RC) was however neutral. These results demonstrate that metformin may exacerbate late-stage cyst growth associated with the activation of lactate-related signaling pathways in Pkd1 deficiency. Our findings indicate that using metformin in the later stage of ADPKD might accelerate disease progression and call for the cautious use of metformin in these patients., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
22. An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International.
- Author
-
Müller RU, Messchendorp AL, Birn H, Capasso G, Cornec-Le Gall E, Devuyst O, van Eerde A, Guirchoun P, Harris T, Hoorn EJ, Knoers NVAM, Korst U, Mekahli D, Le Meur Y, Nijenhuis T, Ong ACM, Sayer JA, Schaefer F, Servais A, Tesar V, Torra R, Walsh SB, and Gansevoort RT
- Subjects
- Antidiuretic Hormone Receptor Antagonists pharmacology, Antidiuretic Hormone Receptor Antagonists therapeutic use, Female, Humans, Kidney, Male, Patient Selection, Tolvaptan therapeutic use, Polycystic Kidney, Autosomal Dominant drug therapy
- Abstract
Approval of the vasopressin V2 receptor antagonist tolvaptan-based on the landmark TEMPO 3:4 trial-marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2022
- Full Text
- View/download PDF
23. Can ketogenic dietary interventions slow disease progression in ADPKD: what we know and what we don't.
- Author
-
Ong ACM and Torra R
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease leading to kidney failure. To date, there is no cure for the disease although there is one approved disease-modifying therapy: tolvaptan. In this context, a common question that ADPKD patients ask in clinical practice is whether there is anything they can do to slow their disease by modifying their diet or lifestyle. Recent evidence from experimental PKD models has shown the potential benefits of caloric restriction, high water intake and especially ketogenic diets in preserving kidney function. Whether these benefits are translatable to humans remains unknown. In this issue of CKJ , Strubl et al. report results of a self-enrolled survey of autosomal dominant polycystic kidney disease (ADPKD) patients who have self-administered a ketogenic diet [1]. These results provide interesting insights into the tolerability, potential benefits and harms of such an intervention that could inform a future clinical trial., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2022
- Full Text
- View/download PDF
24. Individualized everolimus treatment for tuberous sclerosis-related angiomyolipoma promotes treatment adherence and response.
- Author
-
Chung NKX, Metherall P, McCormick JA, Simms RJ, and Ong ACM
- Abstract
Background: Everolimus is a potential alternative to embolization and nephrectomy for managing tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML). In 2016, National Health Service England approved its use through regional centres for renal AML ≥30 mm showing interval growth. Evidence of lesion stabilization or reduction after 6 months is mandated for continuation of long-term treatment., Methods: From November 2016 to June 2021, all potentially eligible adult TSC patients with AML across Yorkshire and Humber were referred for assessment and monitoring. Eligible patients underwent baseline renal magnetic resonance imaging (MRI) assessment and a follow-up MRI scan after 6 months on everolimus. Dose titration was guided by trough levels and lesion responsiveness using a new 3D MRI volumetric protocol., Results: Of 28 patients commencing treatment, 19 tolerated everolimus for >3 months. Overall, 11 patients (40%) discontinued treatment, mostly due to recurrent infections (42%) and allergic reactions (25%). Sixty-eight percent required dose adjustments from the initiating dose (10 mg) due to sub-optimal trough levels (38%), minimal AML response (15%) or adverse events (47%). 3D volumetric assessment confirmed a reduction in AML volume of a pre-selected index lesion in all treatment-naïve cases ( n = 14), showing superiority over 2D measurements of lesion diameter., Conclusion: In this cohort, everolimus promoted AML regression in all patients who tolerated the drug for >6 months with stabilization observed over 3 years. Trough levels enabled individual dose titration to maximize responsiveness and minimize side effects. The use of 3D MRI assessment of lesion volume was superior to 2D measurements of lesion diameter in monitoring treatment response., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2022
- Full Text
- View/download PDF
25. Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype.
- Author
-
Senum SR, Li YSM, Benson KA, Joli G, Olinger E, Lavu S, Madsen CD, Gregory AV, Neatu R, Kline TL, Audrézet MP, Outeda P, Nau CB, Meijer E, Ali H, Steinman TI, Mrug M, Phelan PJ, Watnick TJ, Peters DJM, Ong ACM, Conlon PJ, Perrone RD, Cornec-Le Gall E, Hogan MC, Torres VE, Sayer JA, and Harris PC
- Subjects
- Adult, Aged, Amino Acid Substitution, Biological Specimen Banks, Cilia pathology, DNA Copy Number Variations, Female, Genetic Association Studies, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Kidney Function Tests, Male, Middle Aged, Pedigree, Phenotype, Polycystic Kidney, Autosomal Dominant diagnosis, Sequence Analysis, DNA, United Kingdom, Exome Sequencing, Alleles, Carrier Proteins, Genetic Predisposition to Disease, Mutation, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum., Competing Interests: Declaration of interests M.M. reports grants and consulting fees outside the submitted work from Otsuka Pharmaceuticals, Sanofi, Chinook, Goldilocks, Natera, and Palladio. R.D.P. reports clinical trial support from Reata, Kadmon, Sanofi-Genzyme, US Department of Defense; consultant/advisory fees from Otsuka and Sanofi-Genzyme; and is section editor Renal Cystic Disease: UpToDate. J.A.S. has received honorarium from consulting positions from Otsuka Pharmaceuticals, Sanofi, and Takeda. V.E.T. reports grants and/or other fees from Mironid, Blueprint Medicines, Otsuka Pharmaceuticals, Palladio Biosciences, Sanofi Genzyme, Reata, and Regulus Therapeutics, all outside the submitted work., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
26. An Nphp1 knockout mouse model targeting exon 2-20 demonstrates characteristic phenotypes of human nephronophthisis.
- Author
-
Li D, Hu M, Chen H, Wu X, Wei X, Lin H, Gao X, Wang H, Li M, Ong ACM, Yue Z, and Sun L
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Cytoskeletal Proteins genetics, Exons genetics, Humans, Male, Membrane Proteins genetics, Mice, Mice, Knockout, Phenotype, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic pathology, Polycystic Kidney Diseases genetics
- Abstract
Nephronophthisis (NPH) is the most prevalent monogenetic disorder leading to end-stage renal failure (ESRD) in childhood. Mutations in Nphp1, encoding a cilia-localized protein, account for the majority of NPH cases. Despite its identification many years ago, Nphp1 deletions targeting exon 4 or exon 20 have not reproduced the histological features of human NPH in murine models. In this study, we deleted exon 2-20 of Nphp1 by CRISPR/Cas9 gene editing to create a near-total knockout (KO) mouse model (Nphp1del2-20/del2-20). Nphp1del2-20/del2-20 mice faithfully reproduced the renal and extrarenal phenotypes associated with human NPH, including renal cyst development, tubular basement membrane thickening, retinal degeneration and abnormal spermatogenesis. Importantly, Nphp1 re-expression using an adenoviral-associated-virus-9 vector could partially rescue both renal and retinal phenotypes in Nphp1del2-20/del2-20 mice. Our results reported the first relevant Nphp1 mouse model with renal phenotypes for human disease. It will be a valuable model for future studies of Nphp1 function and to develop novel treatments for this common childhood disease., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
- View/download PDF
27. TAMEing ADPKD with metformin: safe and effective?
- Author
-
Ong ACM and Gansevoort RT
- Subjects
- Humans, Hypoglycemic Agents adverse effects, Research Design, Diabetes Mellitus, Type 2 drug therapy, Metformin adverse effects, Polycystic Kidney, Autosomal Dominant drug therapy
- Abstract
The biguanide metformin has been safely and widely used in the treatment of type 2 diabetes mellitus for decades. Preclinical studies have suggested that it may have a role in slowing disease progression in autosomal dominant polycystic kidney disease. In this issue, Perrone et al. report results from the Trial of Administration of Metformin in PKD (TAME PKD) study, a phase 2 randomized controlled trial investigating the safety and tolerability of metformin in patients in the early stages of autosomal dominant polycystic kidney disease. We discuss the implications of these findings and how they relate to a major phase 3 trial in autosomal dominant polycystic kidney disease that will start later in 2021., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
28. Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.
- Author
-
Durkie M, Chong J, Valluru MK, Harris PC, and Ong ACM
- Subjects
- Child, Humans, Infant, Mutation, TRPP Cation Channels genetics, Exome Sequencing, Heredity, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant epidemiology, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Purpose: To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010-2020)., Methods: All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing., Results: Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%)., Conclusion: We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.
- Published
- 2021
- Full Text
- View/download PDF
29. Drug repurposing in autosomal dominant polycystic kidney disease: back to the future with pioglitazone.
- Author
-
Mao Z, Valluru MK, and Ong ACM
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney failure. At present, only one drug, tolvaptan, has been approved for use to slow disease progression, but its use is limited by reduced tolerability and idiosyncratic liver toxicity. Thiazolidinediones were first developed as insulin-sensitizers but also regulate gene transcription in multiple tissues, leading to systemic effects on metabolism, inflammation and vascular reactivity. In this issue, Blazer-Yost et al. report the results of a single-centre Phase 1b double-blind placebo-controlled crossover study of the peroxisome proliferator-activated receptor γ (PPAR-γ) agonist pioglitazone in 18 ADPKD patients. Encouragingly, there were no major safety signals, although evidence of efficacy could not be demonstrated due to the small sample size. We review the preclinical evidence for the use of PPAR-γ agonists in ADPKD and speculate on the likely beneficial and adverse clinical effects of this interesting class of compounds in a future trial., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)
- Published
- 2021
- Full Text
- View/download PDF
30. Establishing a Core Outcome Set for Autosomal Dominant Polycystic Kidney Disease: Report of the Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Consensus Workshop.
- Author
-
Cho Y, Tong A, Craig JC, Mustafa RA, Chapman A, Perrone RD, Ahn C, Fowler K, Torres V, Gansevoort RT, Ong ACM, Coolican H, Tze-Wah Kao J, Harris T, Gutman T, Shen JI, Viecelli AK, Johnson DW, Au E, El-Damanawi R, Logeman C, Ju A, Manera KE, Chonchol M, Odland D, Baron D, Pei Y, Sautenet B, Rastogi A, Sharma A, and Rangan G
- Subjects
- Activities of Daily Living, Administrative Personnel, Cardiovascular Diseases etiology, Caregivers, Delphi Technique, Disease Progression, Humans, Nephrologists, Outcome Assessment, Health Care, Pain etiology, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant therapy, Renal Insufficiency etiology, Stakeholder Participation, Cardiovascular Diseases physiopathology, Mortality, Pain physiopathology, Polycystic Kidney, Autosomal Dominant physiopathology, Renal Insufficiency physiopathology
- Abstract
The omission of outcomes that are of relevance to patients, clinicians, and regulators across trials in autosomal dominant polycystic kidney disease (ADPKD) limits shared decision making. The Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Initiative convened an international consensus workshop on October 25, 2018, to discuss the identification and implementation of a potential core outcome set for all ADPKD trials. This article summarizes the discussion from the workshops and the SONG-PKD core outcome set. Key stakeholders including 11 patients/caregivers and 47 health professionals (nephrologists, policy makers, industry, and researchers) attended the workshop. Four themes emerged: "Relevance of trajectory and impact of kidney function" included concerns about a patient's prognosis and uncertainty of when they may need to commence kidney replacement therapy and the lack of an early prognostic marker to inform long-term decisions; "Discerning and defining pain specific to ADPKD" highlighted the challenges in determining the origin of pain, adapting to the chronicity and repeated episodes of pain, the need to place emphasis on pain management, and to have a validated measure for pain; "Highlighting ADPKD consequences" encompassed cyst-related complications and reflected patient's knowledge because of family history and the hereditary nature of ADPKD; and "Risk for life-threatening but rare consequences" such as cerebral aneurysm meant considering both frequency and severity of the outcome. Kidney function, mortality, cardiovascular disease, and pain were established as the core outcomes for ADPKD., (Copyright © 2020 National Kidney Foundation, Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
31. An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.
- Author
-
Živná M, Kidd K, Zaidan M, Vyleťal P, Barešová V, Hodaňová K, Sovová J, Hartmannová H, Votruba M, Trešlová H, Jedličková I, Sikora J, Hůlková H, Robins V, Hnízda A, Živný J, Papagregoriou G, Mesnard L, Beck BB, Wenzel A, Tory K, Häeffner K, Wolf MTF, Bleyer ME, Sayer JA, Ong ACM, Balogh L, Jakubowska A, Łaszkiewicz A, Clissold R, Shaw-Smith C, Munshi R, Haws RM, Izzi C, Capelli I, Santostefano M, Graziano C, Scolari F, Sussman A, Trachtman H, Decramer S, Matignon M, Grimbert P, Shoemaker LR, Stavrou C, Abdelwahed M, Belghith N, Sinclair M, Claes K, Kopel T, Moe S, Deltas C, Knebelmann B, Rampoldi L, Kmoch S, and Bleyer AJ
- Subjects
- Adult, Child, Cohort Studies, Female, Humans, Male, Mutation, Renin genetics, Young Adult, Anemia, Polycystic Kidney Diseases genetics
- Abstract
There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
32. The Controversial Role of Fibrosis in Autosomal Dominant Polycystic Kidney Disease.
- Author
-
Fragiadaki M, Macleod FM, and Ong ACM
- Subjects
- Disease Progression, Fibrosis complications, Fibrosis pathology, Humans, Inflammation complications, Inflammation genetics, Inflammation pathology, Kidney pathology, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant pathology, STAT Transcription Factors, Fibrosis genetics, Janus Kinases genetics, MicroRNAs genetics, Polycystic Kidney, Autosomal Dominant genetics, Transforming Growth Factor beta genetics
- Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the 'chronic hypoxia hypothesis', persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided., Competing Interests: The authors declare no conflict of interest.
- Published
- 2020
- Full Text
- View/download PDF
33. Coronavirus-associated kidney outcomes in COVID-19, SARS, and MERS: a meta-analysis and systematic review.
- Author
-
Zhou S, Xu J, Xue C, Yang B, Mao Z, and Ong ACM
- Subjects
- Coronavirus, Humans, Incidence, Pandemics statistics & numerical data, Renal Replacement Therapy statistics & numerical data, Risk Factors, Acute Kidney Injury epidemiology, Acute Kidney Injury therapy, Acute Kidney Injury virology, COVID-19 mortality, COVID-19 physiopathology, Coronavirus Infections mortality, Coronavirus Infections physiopathology, Kidney Failure, Chronic epidemiology, Kidney Failure, Chronic therapy, Kidney Failure, Chronic virology, Severe Acute Respiratory Syndrome mortality, Severe Acute Respiratory Syndrome physiopathology
- Abstract
Objectives: A meta-analysis and systematic review was conducted on kidney-related outcomes of three recent pandemics: SARS, MERS, and COVID-19, which were associated with potentially fatal acute respiratory distress syndrome (ARDS)., Methods: A search of all published studies until 16 June 2020 was performed. The incidence/prevalence and mortality risk of acute and chronic renal events were evaluated, virus prevalence, and mortality in preexisting hemodialysis patients was investigated., Results: A total of 58 eligible studies involving 13452 hospitalized patients with three types of coronavirus infection were included. The reported incidence of new-onset acute kidney injury (AKI) was 12.5% (95% CI: 7.6%-18.3%). AKI significantly increased the mortality risk (OR = 5.75, 95% CI 3.75-8.77, p < 0.00001) in patients with coronavirus infection. The overall rate of urgent-start kidney replacement therapy (urgent-start KRT) use was 8.9% (95% CI: 5.0%-13.8%) and those who received urgent-start KRT had a higher risk of mortality (OR = 3.43, 95% CI 2.02-5.85, p < 0.00001). Patients with known chronic kidney disease (CKD) had a higher mortality than those without CKD (OR = 1.97, 95% CI 1.56-2.49, p < 0.00001). The incidence of coronavirus infection was 7.7% (95% CI: 4.9%-11.1%) in prevalent hemodialysis patients with an overall mortality rate of 26.2% (95% CI: 20.6%-32.6%)., Conclusions: Primary kidney involvement is common with coronavirus infection and is associated with significantly increased mortality. The recognition of AKI, CKD, and urgent-start KRT as major risk factors for mortality in coronavirus-infected patients are important steps in reducing future mortality and long-term morbidity in hospitalized patients with coronavirus infection.
- Published
- 2020
- Full Text
- View/download PDF
34. Core Outcome Domains for Trials in Autosomal Dominant Polycystic Kidney Disease: An International Delphi Survey.
- Author
-
Cho Y, Rangan G, Logeman C, Ryu H, Sautenet B, Perrone RD, Nadeau-Fredette AC, Mustafa RA, Htay H, Chonchol M, Harris T, Gutman T, Craig JC, Ong ACM, Chapman A, Ahn C, Coolican H, Kao JT, Gansevoort RT, Torres V, Pei Y, Johnson DW, Viecelli AK, Teixeira-Pinto A, Howell M, Ju A, Manera KE, and Tong A
- Subjects
- Adolescent, Adult, Africa epidemiology, Aged, Asia epidemiology, Caregivers psychology, Child, Consensus, Delphi Technique, Female, Health Personnel psychology, Humans, Intracranial Aneurysm etiology, Kidney Failure, Chronic epidemiology, Kidney Failure, Chronic etiology, Male, Middle Aged, Pain etiology, Patient Reported Outcome Measures, Patients psychology, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant epidemiology, Polycystic Kidney, Autosomal Dominant psychology, Qualitative Research, Quality of Life, Self Concept, Socioeconomic Factors, Stress, Psychological, Young Adult, Polycystic Kidney, Autosomal Dominant therapy
- Abstract
Rationale & Objective: Outcomes reported in trials involving patients with autosomal dominant polycystic kidney disease (ADPKD) are heterogeneous and rarely include patient-reported outcomes. We aimed to identify critically important consensus-based core outcome domains to be reported in trials in ADPKD., Study Design: An international 2-round online Delphi survey was conducted in English, French, and Korean languages., Setting & Participants: Patients/caregivers and health professionals completed a 9-point Likert scale (7-9 indicating critical importance) and a Best-Worst Scale., Analytical Approach: The absolute and relative importance of outcomes were assessed. Comments were analyzed thematically., Results: 1,014 participants (603 [60%] patients/caregivers, 411 [40%] health professionals) from 56 countries completed round 1, and 713 (70%) completed round 2. The prioritized outcomes were kidney function (importance score, 8.6), end-stage kidney disease (8.6), death (7.9), blood pressure (7.9), kidney cyst size/growth (7.8), and cerebral aneurysm (7.7). Kidney cyst-related pain was the highest rated patient-reported outcome by both stakeholder groups. Seven themes explained the prioritization of outcomes: protecting life and health, directly encountering life-threatening and debilitating consequences, specificity to ADPKD, optimizing and extending quality of life, hidden suffering, destroying self-confidence, and lost opportunities., Limitations: Study design precluded involvement from those without access to internet or limited computer literacy., Conclusions: Kidney function, end-stage kidney disease, and death were the most important outcomes to patients, caregivers, and health professionals. Kidney cyst-related pain was the highest rated patient-reported outcome. Consistent reporting of these top prioritized outcomes may strengthen the value of trials in ADPKD for decision making., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
35. The positive effect of selective prostaglandin E2 receptor EP2 and EP4 blockade on cystogenesis in vitro is counteracted by increased kidney inflammation in vivo.
- Author
-
Lannoy M, Valluru MK, Chang L, Abdela-Ali F, Peters DJM, Streets AJ, and Ong ACM
- Subjects
- Animals, Cyclic AMP, Dogs, Humans, Inflammation drug therapy, Kidney, Mice, Dinoprostone, Receptors, Prostaglandin E, EP2 Subtype
- Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a major cause of end-stage kidney disease in man. The central role of cyclic adenosine monophosphate (cAMP) in ADPKD pathogenesis has been confirmed by numerous studies including positive clinical trial data. Here, we investigated the potential role of another major regulator of renal cAMP, prostaglandin E
2 (PGE2 ), in modifying disease progression in ADPKD models using selective receptor modulators to all four PGE2 receptor subtypes (EP1-4). In 3D-culture model systems utilizing dog (MDCK) and patient-derived (UCL93, OX161-C1) kidney cell lines, PGE2 strikingly promoted cystogenesis and inhibited tubulogenesis by stimulating proliferation while reducing apoptosis. The effect of PGE2 on tubulogenesis and cystogenesis in 3D-culture was mimicked or abolished by selective EP2 and EP4 agonists or antagonists but not those specific to EP1 or EP3. In a Pkd1 mouse model (Pkd1nl/nl ), kidney PGE2 and COX-2 expression were increased by two-fold at the peak of disease (week four). However, Pkd1nl/nl mice treated with selective EP2 (PF-04418948) or EP4 (ONO-AE3-208) antagonists from birth for three weeks had more severe cystic disease and fibrosis associated with increased cell proliferation and macrophage infiltration. A similar effect was observed for the EP4 antagonist ONO-AE3-208 in a second Pkd1 model (Pax8rtTA-TetO-Cre-Pkd1f/f ). Thus, despite the positive effects of slowing cyst growth in vitro, the more complex effects of inhibiting EP2 or EP4 in vivo resulted in a worse outcome, possibly related to unexpected pro-inflammatory effects., (Copyright © 2020 International Society of Nephrology. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
36. Global microRNA profiling in human urinary exosomes reveals novel disease biomarkers and cellular pathways for autosomal dominant polycystic kidney disease.
- Author
-
Magayr TA, Song X, Streets AJ, Vergoz L, Chang L, Valluru MK, Yap HL, Lannoy M, Haghighi A, Simms RJ, Tam FWK, Pei Y, and Ong ACM
- Subjects
- Animals, Biomarkers, Gene Expression Profiling, Humans, Kidney, Mice, Exosomes genetics, MicroRNAs genetics, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
MicroRNAs (miRNAs) play an important role in regulating gene expression in health and disease but their role in modifying disease expression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains uncertain. Here, we profiled human urinary exosome miRNA by global small RNA-sequencing in an initial discovery cohort of seven patients with ADPKD with early disease (eGFR over 60ml/min/1.73m
2 ), nine with late disease (eGFR under 60ml/min/1.73m2 ), and compared their differential expression with six age and sex matched healthy controls. Two kidney-enriched candidate miRNA families were identified (miR-192/miR-194-2 and miR-30) and selected for confirmatory testing in a 60 patient validation cohort by quantitative polymerase chain reaction. We confirmed that miR-192-5p, miR-194-5p, miR-30a-5p, miR-30d-5p and miR-30e-5p were significantly downregulated in patient urine exosomes, in murine Pkd1 cystic kidneys and in human PKD1 cystic kidney tissue. All five miRNAs showed significant correlations with baseline eGFR and ultrasound-determined mean kidney length and improved the diagnostic performance (area under the curve) of mean kidney length for the rate of disease progression. Finally, inverse correlations of these two miRNA families with increased expression in their predicted target genes in patient PKD1 cystic tissue identified dysregulated pathways and transcriptional networks including novel interactions between miR-194-5p and two potentially relevant candidate genes, PIK3R1 and ANO1. Thus, our results identify a subset of urinary exosomal miRNAs that could serve as novel biomarkers of disease progression and suggest new therapeutic targets in ADPKD., (Copyright © 2020 International Society of Nephrology. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
37. Cellular signaling in PKD: foreword.
- Author
-
Torres VE and Ong ACM
- Subjects
- History, 20th Century, History, 21st Century, Humans, Cells metabolism, Polycystic Kidney Diseases metabolism, Polycystic Kidney Diseases pathology, Signal Transduction
- Abstract
This monograph is dedicated to the memory of Dr. Jared James Grantham (1936-2016), a wonderful man, a compassionate physician, a passionate researcher, and an exceptional scientist. Without his vision, achievements and impact on countless collaborators and disciples, the field of Polycystic Kidney Disease would not be where it is today. His intellect, tenacity, modesty and kindness continue to be an inspiration to all., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
38. Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease.
- Author
-
Hopp K, Cornec-Le Gall E, Senum SR, Te Paske IBAW, Raj S, Lavu S, Baheti S, Edwards ME, Madsen CD, Heyer CM, Ong ACM, Bae KT, Fatica R, Steinman TI, Chapman AB, Gitomer B, Perrone RD, Rahbari-Oskoui FF, Torres VE, and Harris PC
- Subjects
- Female, High-Throughput Nucleotide Sequencing, Humans, Mosaicism, Mutation, TRPP Cation Channels genetics, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
39. Renal monocyte chemoattractant protein-1: an emerging universal biomarker and therapeutic target for kidney diseases?
- Author
-
Tam FWK and Ong ACM
- Subjects
- Biomarkers, Chemokine CCL2, Humans, Kidney, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Kidney Diseases
- Published
- 2020
- Full Text
- View/download PDF
40. A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2 -/- phenotype.
- Author
-
Metzner A, Griffiths JD, Streets AJ, Markham E, Philippou T, Van Eeden FJM, and Ong ACM
- Subjects
- Animals, Animals, Genetically Modified metabolism, Apoptosis drug effects, Dogs, Embryo, Nonmammalian drug effects, Embryo, Nonmammalian metabolism, High-Throughput Screening Assays, Humans, Madin Darby Canine Kidney Cells, Phenotype, Polycystic Kidney, Autosomal Dominant metabolism, Polycystic Kidney, Autosomal Dominant pathology, Receptor, Transforming Growth Factor-beta Type I metabolism, Receptors, Androgen metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries metabolism, TRPP Cation Channels deficiency, TRPP Cation Channels metabolism, Zebrafish, Zebrafish Proteins deficiency, Zebrafish Proteins metabolism, Receptor, Transforming Growth Factor-beta Type I antagonists & inhibitors, Signal Transduction drug effects, Small Molecule Libraries pharmacology, TRPP Cation Channels genetics, Zebrafish Proteins genetics
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α-androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.
- Published
- 2020
- Full Text
- View/download PDF
41. Tuberous Sclerosis Complex (TSC): Expert Recommendations for Provision of Coordinated Care.
- Author
-
Annear NMP, Appleton RE, Bassi Z, Bhatt R, Bolton PF, Crawford P, Crowe A, Tossi M, Elmslie F, Finlay E, Gale DP, Henderson A, Jones EA, Johnson SR, Joss S, Kerecuk L, Lipkin G, Morrison PJ, O'Callaghan FJ, Cadwgan J, Ong ACM, Sampson JR, Shepherd C, and Kingswood JC
- Published
- 2019
- Full Text
- View/download PDF
42. A rapid high-performance semi-automated tool to measure total kidney volume from MRI in autosomal dominant polycystic kidney disease.
- Author
-
Simms RJ, Doshi T, Metherall P, Ryan D, Wright P, Gruel N, van Gastel MDA, Gansevoort RT, Tindale W, and Ong ACM
- Subjects
- Adult, Aged, Cross-Sectional Studies, Disease Progression, Female, Glomerular Filtration Rate physiology, Humans, Magnetic Resonance Imaging methods, Male, Middle Aged, Organ Size physiology, Polycystic Kidney, Autosomal Dominant physiopathology, Prognosis, Retrospective Studies, Young Adult, Kidney pathology, Polycystic Kidney, Autosomal Dominant pathology
- Abstract
Objectives: To develop a high-performance, rapid semi-automated method (Sheffield TKV Tool) for measuring total kidney volume (TKV) from magnetic resonance images (MRI) in patients with autosomal dominant polycystic kidney disease (ADPKD)., Methods: TKV was initially measured in 61 patients with ADPKD using the Sheffield TKV Tool and its performance compared to manual segmentation and other published methods (ellipsoidal, mid-slice, MIROS). It was then validated using an external dataset of MRI scans from 65 patients with ADPKD., Results: Sixty-one patients (mean age 45 ± 14 years, baseline eGFR 76 ± 32 ml/min/1.73 m
2 ) with ADPKD had a wide range of TKV (258-3680 ml) measured manually. The Sheffield TKV Tool was highly accurate (mean volume error 0.5 ± 5.3% for right kidney, - 0.7 ± 5.5% for left kidney), reproducible (intra-operator variability - 0.2 ± 1.3%; inter-operator variability 1.1 ± 2.9%) and outperformed published methods. It took less than 6 min to execute and performed consistently with high accuracy in an external MRI dataset of T2-weighted sequences with TKV acquired using three different scanners and measured using a different segmentation methodology (mean volume error was 3.45 ± 3.96%, n = 65)., Conclusions: The Sheffield TKV Tool is operator friendly, requiring minimal user interaction to rapidly, accurately and reproducibly measure TKV in this, the largest reported unselected European patient cohort with ADPKD. It is more accurate than estimating equations and its accuracy is maintained at larger kidney volumes than previously reported with other semi-automated methods. It is free to use, can run as an independent executable and will accelerate the application of TKV as a prognostic biomarker for ADPKD into clinical practice., Key Points: • This new semi-automated method (Sheffield TKV Tool) to measure total kidney volume (TKV) will facilitate the routine clinical assessment of patients with ADPKD. • Measuring TKV manually is time consuming and laborious. • TKV is a prognostic indicator in ADPKD and the only imaging biomarker approved by the FDA and EMA.- Published
- 2019
- Full Text
- View/download PDF
43. Small-molecule allosteric activators of PDE4 long form cyclic AMP phosphodiesterases.
- Author
-
Omar F, Findlay JE, Carfray G, Allcock RW, Jiang Z, Moore C, Muir AL, Lannoy M, Fertig BA, Mai D, Day JP, Bolger G, Baillie GS, Schwiebert E, Klussmann E, Pyne NJ, Ong ACM, Bowers K, Adam JM, Adams DR, Houslay MD, and Henderson DJP
- Subjects
- Animals, Cell Line, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Cyclic Nucleotide Phosphodiesterases, Type 4 drug effects, Dogs, Enzyme Activation drug effects, Humans, Madin Darby Canine Kidney Cells, Phosphorylation, Polycystic Kidney Diseases metabolism, Protein Isoforms, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism
- Abstract
Cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) enzymes degrade cAMP and underpin the compartmentalization of cAMP signaling through their targeting to particular protein complexes and intracellular locales. We describe the discovery and characterization of a small-molecule compound that allosterically activates PDE4 long isoforms. This PDE4-specific activator displays reversible, noncompetitive kinetics of activation (increased V
max with unchanged Km ), phenocopies the ability of protein kinase A (PKA) to activate PDE4 long isoforms endogenously, and requires a dimeric enzyme assembly, as adopted by long, but not by short (monomeric), PDE4 isoforms. Abnormally elevated levels of cAMP provide a critical driver of the underpinning molecular pathology of autosomal dominant polycystic kidney disease (ADPKD) by promoting cyst formation that, ultimately, culminates in renal failure. Using both animal and human cell models of ADPKD, including ADPKD patient-derived primary cell cultures, we demonstrate that treatment with the prototypical PDE4 activator compound lowers intracellular cAMP levels, restrains cAMP-mediated signaling events, and profoundly inhibits cyst formation. PDE4 activator compounds thus have potential as therapeutics for treating disease driven by elevated cAMP signaling as well as providing a tool for evaluating the action of long PDE4 isoforms in regulating cAMP-mediated cellular processes., Competing Interests: Conflict of interest statement: D.J.P.H., F.O., J.E.F., R.W.A., Z.J., G.C., C.M., A.L.M., K.B., J.M.A., D.R.A., and M.D.H. are employees of Mironid, Limited. N.J.P., E.K., and A.C.M.O. act as consultants to Mironid, Limited., (Copyright © 2019 the Author(s). Published by PNAS.)- Published
- 2019
- Full Text
- View/download PDF
44. Imaging of Kidney Cysts and Cystic Kidney Diseases in Children: An International Working Group Consensus Statement.
- Author
-
Gimpel C, Avni EF, Breysem L, Burgmaier K, Caroli A, Cetiner M, Haffner D, Hartung EA, Franke D, König J, Liebau MC, Mekahli D, Ong ACM, Pape L, Titieni A, Torra R, Winyard PJD, and Schaefer F
- Subjects
- Child, Consensus, Europe, Humans, Diagnostic Imaging standards, Kidney Diseases, Cystic diagnostic imaging
- Abstract
Kidney cysts can manifest as focal disease (simple and complex kidney cysts), affect a whole kidney (eg, multicystic dysplastic kidney or cystic dysplasia), or manifest as bilateral cystic disease (eg, autosomal recessive polycystic kidney disease [ARPKD] or autosomal dominant polycystic kidney disease [ADPKD]). In children, as opposed to adults, a larger proportion of kidney cysts are due to genetic diseases (eg, HNF1B nephropathy, various ciliopathies, and tuberous sclerosis complex), and fewer patients have simple cysts or acquired cystic kidney disease. The purpose of this consensus statement is to provide clinical guidance on standardization of imaging tests to evaluate kidney cysts in children. A committee of international experts in pediatric nephrology, pediatric radiology, pediatric US, and adult nephrology prepared systematic literature reviews and formulated recommendations at a consensus meeting. The final statement was endorsed by the European Society of Pediatric Radiology, the European Federation of Societies for Ultrasound in Medicine and Biology, the European Society of Pediatric Nephrology, and reviewed by the European Reference Network for Rare Kidney Diseases. Main recommendations are as follows: US is the method of choice when assessing pediatric kidney cysts, with selected indications for MRI and contrast-enhanced US. CT should be avoided whenever possible because of ionizing radiation. Renal US yields essential diagnostic information in many cases. In patients with ARPKD or other ciliopathies, abdominal US is needed for diagnosis and screening of portal hypertension. US is usually sufficient for follow-up kidney imaging, but MRI can be valuable for clinical trials in patients with ADPKD or in older children with tuberous sclerosis complex to evaluate both kidney cysts and angiomyolipomas., (© RSNA, 2018 Online supplemental material is available for this article.)
- Published
- 2019
- Full Text
- View/download PDF
45. Magnetic resonance imaging biomarkers for chronic kidney disease: a position paper from the European Cooperation in Science and Technology Action PARENCHIMA.
- Author
-
Selby NM, Blankestijn PJ, Boor P, Combe C, Eckardt KU, Eikefjord E, Garcia-Fernandez N, Golay X, Gordon I, Grenier N, Hockings PD, Jensen JD, Joles JA, Kalra PA, Krämer BK, Mark PB, Mendichovszky IA, Nikolic O, Odudu A, Ong ACM, Ortiz A, Pruijm M, Remuzzi G, Rørvik J, de Seigneux S, Simms RJ, Slatinska J, Summers P, Taal MW, Thoeny HC, Vallée JP, Wolf M, Caroli A, and Sourbron S
- Subjects
- Disease Progression, Humans, Renal Insufficiency, Chronic therapy, Biomarkers analysis, Magnetic Resonance Imaging methods, Renal Insufficiency, Chronic classification, Renal Insufficiency, Chronic pathology
- Abstract
Functional renal magnetic resonance imaging (MRI) has seen a number of recent advances, and techniques are now available that can generate quantitative imaging biomarkers with the potential to improve the management of kidney disease. Such biomarkers are sensitive to changes in renal blood flow, tissue perfusion, oxygenation and microstructure (including inflammation and fibrosis), processes that are important in a range of renal diseases including chronic kidney disease. However, several challenges remain to move these techniques towards clinical adoption, from technical validation through biological and clinical validation, to demonstration of cost-effectiveness and regulatory qualification. To address these challenges, the European Cooperation in Science and Technology Action PARENCHIMA was initiated in early 2017. PARENCHIMA is a multidisciplinary pan-European network with an overarching aim of eliminating the main barriers to the broader evaluation, commercial exploitation and clinical use of renal MRI biomarkers. This position paper lays out PARENCHIMA's vision on key clinical questions that MRI must address to become more widely used in patients with kidney disease, first within research settings and ultimately in clinical practice. We then present a series of practical recommendations to accelerate the study and translation of these techniques.
- Published
- 2018
- Full Text
- View/download PDF
46. Linear and Nonlinear Estimated GFR Slopes in ADPKD Patients Reaching ESRD.
- Author
-
Neagu M, Coca D, and Ong ACM
- Subjects
- Creatinine, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Polycystic Kidney, Autosomal Dominant
- Published
- 2018
- Full Text
- View/download PDF
47. A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model.
- Author
-
McEwan P, Bennett Wilton H, Ong ACM, Ørskov B, Sandford R, Scolari F, Cabrera MV, Walz G, O'Reilly K, and Robinson P
- Subjects
- Adult, Aged, Antidiuretic Hormone Receptor Antagonists therapeutic use, Double-Blind Method, Female, Humans, Male, Middle Aged, Polycystic Kidney, Autosomal Dominant drug therapy, Predictive Value of Tests, Tolvaptan therapeutic use, Treatment Outcome, Disease Progression, Models, Theoretical, Polycystic Kidney, Autosomal Dominant diagnosis, Polycystic Kidney, Autosomal Dominant epidemiology
- Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics., Methods: The ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population., Results: A cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles., Conclusions: The ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice.
- Published
- 2018
- Full Text
- View/download PDF
48. Polycystic kidney disease: Tolvaptan slows disease progression in late-stage ADPKD.
- Author
-
Ong ACM
- Published
- 2018
- Full Text
- View/download PDF
49. Targeting new cellular disease pathways in autosomal dominant polycystic kidney disease.
- Author
-
Chang MY and Ong ACM
- Published
- 2017
- Full Text
- View/download PDF
50. Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD): study protocol for establishing a core outcome set in polycystic kidney disease.
- Author
-
Cho Y, Sautenet B, Rangan G, Craig JC, Ong ACM, Chapman A, Ahn C, Chen D, Coolican H, Kao JT, Gansevoort R, Perrone R, Harris T, Torres V, Pei Y, Kerr PG, Ryan J, Gutman T, Howell M, Ju A, Manera KE, Teixeira-Pinto A, Hamiwka LA, and Tong A
- Subjects
- Consensus, Delphi Technique, Humans, Nephrology methods, Polycystic Kidney, Autosomal Dominant diagnosis, Stakeholder Participation, Systematic Reviews as Topic, Treatment Outcome, Endpoint Determination standards, Nephrology standards, Patient Outcome Assessment, Polycystic Kidney, Autosomal Dominant therapy, Research Design standards
- Abstract
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life threatening inherited kidney disease and is responsible for 5-10% of cases of end-stage kidney disease (ESKD). Cystic kidneys may enlarge up to 20 times the weight of a normal kidney due to the growth of renal cysts, and patients with ADPKD have an increased risk of morbidity, premature mortality, and other life-time complications including renal and hepatic cyst and urinary tract infection, intracranial aneurysm, diverticulosis, and kidney pain which impair quality of life. Despite some therapeutic advances and the growing number of clinical trials in ADPKD, the outcomes that are relevant to patients and clinicians, such as symptoms and quality of life, are infrequently and inconsistently reported. This potentially limits the contribution of trials to inform evidence-based decision-making. The Standardised Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) project aims to establish a consensus-based set of core outcomes for trials in PKD (with an initial focus on ADPKD but inclusive of all stages) that patients and health professionals identify as critically important., Methods: The five phases of SONG-PKD are: a systematic review to identify outcomes that have been reported in existing PKD trials; focus groups with nominal group technique with patients and caregivers to identify, rank, and describe reasons for their choices; qualitative stakeholder interviews with health professionals to elicit individual values and perspectives on outcomes for trials involving patients with PKD; an international three-round Delphi survey with all stakeholder groups (including patients, caregivers, healthcare providers, policy makers, researchers, and industry) to gain consensus on critically important core outcome domains; and a consensus workshop to review and establish a set of core outcome domains and measures for trials in PKD., Discussion: The SONG-PKD core outcome set is aimed at improving the consistency and completeness of outcome reporting across ADPKD trials, leading to improvements in the reliability and relevance of trial-based evidence to inform decisions about treatment and ultimately improve the care and outcomes for people with ADPKD.
- Published
- 2017
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.