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St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev 2024; 10:CD010294. [PMID: 39356039 PMCID: PMC11445802 DOI: 10.1002/14651858.cd010294.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/03/2024]
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is the leading inherited cause of kidney disease. Clinical management has historically focused on symptom control and reducing associated complications. Improved understanding of the molecular and cellular mechanisms involved in kidney cyst growth and disease progression has resulted in new pharmaceutical agents targeting disease pathogenesis and preventing disease progression. However, the role of disease-modifying agents for all people with ADPKD is unclear. This is an update of a review first published in 2015. OBJECTIVES We aimed to evaluate the benefits and harms of interventions to prevent the progression of ADPKD and the safety based on patient-important endpoints, defined by the Standardised Outcomes in NephroloGy-Polycystic Kidney Disease (SONG-PKD) core outcome set, and general and specific adverse effects. SEARCH METHODS We searched the Cochrane Kidney and Transplants Register of Studies up to 13 August 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing any interventions for preventing the progression of ADPKD with other interventions, placebo, or standard care were considered for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently assessed study risks of bias and extracted data. Summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS We included 57 studies (8016 participants) that investigated 18 pharmacological interventions (vasopressin 2 receptor (V2R) antagonists, antihypertensive therapy, mammalian target of rapamycin (mTOR) inhibitors, somatostatin analogues, antiplatelet agents, eicosapentaenoic acids, statins, kinase inhibitors, diuretics, anti-diabetic agents, water intake, dietary intervention, and supplements) in this review. Compared to placebo, the V2R antagonist tolvaptan probably preserves eGFR (3 studies, 2758 participants: MD 1.26 mL/min/1.73 m2, 95% CI 0.73 to 1.78; I2 = 0%) and probably slows total kidney volume (TKV) growth in adults (1 study, 1307 participants: MD -2.70 mL/cm, 95% CI -3.24 to -2.16) (moderate certainty evidence). However, there was insufficient evidence to determine tolvaptan's impact on kidney failure and death. There may be no difference in serious adverse events; however, treatment probably increases nocturia, fatigue and liver enzymes, may increase dry mouth and thirst, and may decrease hypertension and urinary and upper respiratory tract infections. Data on the impact of other therapeutic interventions were largely inconclusive. Compared to placebo, somatostatin analogues probably decrease TKV (6 studies, 500 participants: SMD -0.33, 95% CI -0.51 to -0.16; I2 = 11%), probably have little or no effect on eGFR (4 studies, 180 participants: MD 4.11 mL/min/1.73 m3, 95% CI -3.19 to 11.41; I2 = 0%) (moderate certainty evidence), and may have little or no effect on kidney failure (2 studies, 405 participants: RR 0.64, 95% CI 0.16 to 2.49; I2 = 39%; low certainty evidence). Serious adverse events may increase (2 studies, 405 participants: RR 1.81, 95% CI 1.01 to 3.25; low certainty evidence). Somatostatin analogues probably increase alopecia, diarrhoea or abnormal faeces, dizziness and fatigue but may have little or no effect on anaemia or infection. The effect on death is unclear. Targeted low blood pressure probably results in a smaller per cent annual increase in TKV (1 study, 558 participants: MD -1.00, 95% CI -1.67 to -0.33; moderate certainty evidence) compared to standard blood pressure targets, had uncertain effects on death, but probably do not impact other outcomes such as change in eGFR or adverse events. Kidney failure was not reported. Data comparing antihypertensive agents, mTOR inhibitors, eicosapentaenoic acids, statins, vitamin D compounds, metformin, trichlormethiazide, spironolactone, bosutinib, curcumin, niacinamide, prescribed water intake and antiplatelet agents were sparse and inconclusive. An additional 23 ongoing studies were also identified, including larger phase III RCTs, which will be assessed in a future update of this review. AUTHORS' CONCLUSIONS Although many interventions have been investigated in patients with ADPKD, at present, there is little evidence that they improve patient outcomes. Tolvaptan is the only therapeutic intervention that has demonstrated the ability to slow disease progression, as assessed by eGFR and TKV change. However, it has not demonstrated benefits for death or kidney failure. In order to confirm the role of other therapeutic interventions in ADPKD management, large RCTs focused on patient-centred outcomes are needed. The search identified 23 ongoing studies, which may provide more insight into the role of specific interventions.
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Affiliation(s)
- Kitty St Pierre
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Pharmacy Department, Gold Coast University Hospital, Gold Coast, Australia
| | - Brydee A Cashmore
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Davide Bolignano
- Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Carmine Zoccali
- Institute of Clinical Physiology, CNR - Italian National Council of Research, Reggio Calabria, Italy
| | - Marinella Ruospo
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Bari, Italy
| | - Jonathan C Craig
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Giovanni Fm Strippoli
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Bari, Italy
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | - Andrew J Mallett
- Department of Renal Medicine, Townsville Hospital and Health Service, Townsville, Australia
- Australasian Kidney Trials Network, The University of Queensland, Herston, Australia
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- College of Medicine and Dentistry, James Cook University, Townsville, Australia
| | - Suetonia C Green
- Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand
| | - David J Tunnicliffe
- Sydney School of Public Health, The University of Sydney, Sydney, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
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Nowak KL, Moretti F, Bussola N, Steele CN, Gregory AV, Kline TL, Ramanathan S, Trapletti G, Furlanello C, McCormick L, Chonchol M. Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial. Am J Kidney Dis 2024; 84:275-285.e1. [PMID: 38608748 PMCID: PMC11344693 DOI: 10.1053/j.ajkd.2024.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 02/08/2024] [Accepted: 02/15/2024] [Indexed: 04/14/2024]
Abstract
RATIONALE & OBJECTIVE Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. STUDY DESIGN A retrospective cohort study. SETTING & PARTICIPANTS 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. PREDICTOR Estimates of visceral adiposity extracted from coronal plane magnetic resonance imaging (MRI) scans using deep learning. OUTCOME Annual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. ANALYTICAL APPROACH Multinomial logistic regression and linear mixed models. RESULTS In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of≥7% versus<5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P<0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment ∗ time ∗ visceral adiposity, P=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]). LIMITATIONS Retrospective; rapid progressors; computational demand of deep learning. CONCLUSIONS Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity. PLAIN-LANGUAGE SUMMARY We analyzed images from a previous study with the drug tolvaptan conducted in patients with autosomal dominant polycystic kidney disease (ADPKD) to measure the amount of fat tissue surrounding the kidneys (visceral fat). We had previously shown body mass index can predict kidney growth in this population; now we determined whether visceral fat was an important factor associated with kidney growth. Using a machine learning tool to automate measurement of fat in images, we observed that visceral fat was independently associated with kidney growth, that it was a better predictor of faster kidney growth in lean patients than body mass index, and that having more visceral fat made treatment of ADPKD with tolvaptan less effective.
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Affiliation(s)
- Kristen L Nowak
- Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
| | | | | | - Cortney N Steele
- Anschutz Medical Campus, University of Colorado, Aurora, Colorado
| | - Adriana V Gregory
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Timothy L Kline
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Sumana Ramanathan
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | | | | | - Linda McCormick
- Otsuka Pharmaceutical Development and Commercialization, Princeton, New Jersey
| | - Michel Chonchol
- Anschutz Medical Campus, University of Colorado, Aurora, Colorado
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Mochizuki T, Matsukawa M, Tanaka T, Jiang H. Initial eGFR Changes Predict Response to Tolvaptan in ADPKD. KIDNEY360 2024; 5:522-528. [PMID: 38414126 PMCID: PMC11093546 DOI: 10.34067/kid.0000000000000404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 02/16/2024] [Indexed: 02/29/2024]
Abstract
Key Points This post hoc analysis of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 study investigated the long-term predictive potential of initial changes in eGFR. Initial eGFR change from baseline to week 3 proved to be a significant and independent indicator of the long-term effects of tolvaptan. No correlation was found between the initial change in eGFR and the annual rate of percent growth in total kidney volume. Background Tolvaptan, the only pharmaceutical treatment available for autosomal dominant polycystic kidney disease (ADPKD), reduced the rates of total kidney volume (TKV) increase and kidney function decline in patients with ADPKD in the global phase 3 Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 study. Since tolvaptan initiation is associated with an initial decline in the eGFR, this post hoc analysis of the TEMPO 3:4 study investigated whether initial changes in eGFR from baseline to week 3 after tolvaptan administration can predict its longer-term effects on eGFR and TKV in patients with ADPKD. Methods eGFR was estimated using the CKD Epidemiology Collaboration equation at baseline and up to month 36. TKV was estimated using standardized kidney magnetic resonance imaging at baseline and after 12, 24, and 36 months of tolvaptan treatment. The effect of tolvaptan on kidney function and kidney volume was evaluated by measuring changes in eGFR from week 3 and TKV from baseline up to 36 months. All 961 patients randomized to receive tolvaptan in TEMPO 3:4 were included in this analysis. Results Initial change in eGFR from baseline to week 3 was a significant and independent predictor of the mean rate of change in eGFR per year. By contrast, there was no association between initial change in eGFR and the rate of percent growth in TKV per year. Conclusions Changes in eGFR after 3 weeks of treatment are likely due to the pharmacologic effect of tolvaptan, and these initial changes are predictive of the long-term effects of tolvaptan treatment.
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Affiliation(s)
| | | | - Toshiki Tanaka
- Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Huan Jiang
- Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey
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Mano H, Tanaka Y, Orihara S, Moriya J. Application of sample size re-estimation in clinical trials: A systematic review. Contemp Clin Trials Commun 2023; 36:101210. [PMID: 37842317 PMCID: PMC10568275 DOI: 10.1016/j.conctc.2023.101210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 08/03/2023] [Accepted: 09/15/2023] [Indexed: 10/17/2023] Open
Abstract
Background Sample size re-estimation (SSR) is a method used to recalculate sample size during clinical trial conduct to address a lack of adequate information and can have a significant impact on study size, duration, resources, and cost. Few studies to date have summarized the conditions and circumstances under which SSR is applied. We therefore performed a systematic review of the literature related to SSR to better understand its application in clinical trial settings. Methods PubMed was used as the primary search source, supplemented with information from ClinicalTrials.gov where necessary details were lacking from PubMed. A systematic review was performed according to a pre-specified search strategy to identify clinical trials using SSR. Features of SSR, such as study phase and study start year, were summarized. Results In total, 253 publications met the pre-specified search criteria and 27 clinical trials were subsequently determined as relevant in SSR usage. Among trials where the study phase was provided, 2 (7.4%) trials were Phase I, 5 (18.5%) trials were Phase II, 11 (40.7%) trials were Phase III, and 2 (7.4%) trials were Phase IV. Conclusion Our results showed that SSR is also used in Phase I and II, which involve earlier decision making. We expect that SSR will continue to be used in early-phase trials where sufficient prior information may not be available. Furthermore, no major trends were observed in relation to therapy area or type of SSR, meaning that SSR may become a feasible and widely applied method in the future.
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Affiliation(s)
- Hirotaka Mano
- Biostatistics Group, Biometrics Department, Development Unit, R&D Division, Kyowa Kirin Co., Ltd., Otemachi Financial City Grand Cube, 1-9-2 Otemachi, Chiyoda-ku, Tokyo, Japan
| | - Yuji Tanaka
- Biostatistics Group, Biometrics Department, Development Unit, R&D Division, Kyowa Kirin Co., Ltd., Otemachi Financial City Grand Cube, 1-9-2 Otemachi, Chiyoda-ku, Tokyo, Japan
| | - Shunichiro Orihara
- Biostatistics Group, Biometrics Department, Development Unit, R&D Division, Kyowa Kirin Co., Ltd., Otemachi Financial City Grand Cube, 1-9-2 Otemachi, Chiyoda-ku, Tokyo, Japan
| | - Junji Moriya
- Biostatistics Group, Biometrics Department, Development Unit, R&D Division, Kyowa Kirin Co., Ltd., Otemachi Financial City Grand Cube, 1-9-2 Otemachi, Chiyoda-ku, Tokyo, Japan
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Nakai M, Morikawa K, Sasaki T, Kohya R, Yoshida S, Hosoda S, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Ohara M, Sho T, Suda G, Ogawa K, Sakamoto N. Neutrophil gelatinase-associated lipocalin predicts the efficacy of tolvaptan for ascites in patients with liver cirrhosis. J Gastroenterol 2023; 58:656-667. [PMID: 37103575 DOI: 10.1007/s00535-023-01993-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/08/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND Acute kidney injury (AKI) is associated with liver cirrhosis (LC), water retention, diuretics to treat water retention, and a poor prognosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) reportedly predicts a poor prognosis in decompensated LC. This study investigated the usefulness of uNGAL in predicting the short- and long-term effects of tolvaptan (TVP) and the incidence of AKI post-TVP administration. METHODS Of the LC cases with water retention, 86 with available pre-treatment uNGAL were analyzed. A short-term response was defined as weight loss of ≥ 1.5 kg within the first week; a long-term response was defined as a short-term response without early recurrence. The uNGAL usefulness in predicting the short- and long-term effects of TVP and AKI incidence post-TVP administration was investigated. RESULTS Short-term effects of TVP were observed in 52 patients. Of these, 15 patients had an early recurrence. In multivariate analysis, significant short-term predictive factors were C-reactive protein (CRP) < 1.4 mg/dl, uNa/K ratio ≥ 3.51, and uNGAL < 50.2 ng/ml. Patients were classified according to these three cut-off values, with short-term response rates of 92.9%, 68.8%, 26.7%, and 0% for 0, 1, 2, and 3 points, respectively. CRP < 0.94 mg/dl and uNGAL < 50.2 ng/ml were significant factors for predicting the long-term response of TVP. The AKI incidence post-TVP was 8.1% (n = 7) and was significantly higher among those with uNGAL ≥ 38.1 ng/mL. CONCLUSION uNGAL is a useful predictor of the short- and long-term efficacy of TVP and can be useful in predicting AKI incidence post-TVP administration.
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Affiliation(s)
- Masato Nakai
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Takashi Sasaki
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Risako Kohya
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Sonoe Yoshida
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Shunichi Hosoda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita-15 Nishi-7, Kita-Ku, Sapporo-shi, Hokkaido, 060-8638, Japan.
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Márquez-Nogueras KM, Vuchkovska V, Kuo IY. Calcium signaling in polycystic kidney disease- cell death and survival. Cell Calcium 2023; 112:102733. [PMID: 37023534 PMCID: PMC10348384 DOI: 10.1016/j.ceca.2023.102733] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/20/2023] [Accepted: 03/30/2023] [Indexed: 04/03/2023]
Abstract
Polycystic kidney disease is typified by cysts in the kidney and extra-renal manifestations including hypertension and heart failure. The main genetic underpinning this disease are loss-of function mutations to the two polycystin proteins, polycystin 1 and polycystin 2. Molecularly, the disease is characterized by changes in multiple signaling pathways including down regulation of calcium signaling, which, in part, is contributed by the calcium permeant properties of polycystin 2. These signaling pathways enable the cystic cells to survive and avoid cell death. This review focuses on the studies that have emerged in the past 5 years describing how the structural insights gained from PC-1 and PC-2 inform the calcium dependent molecular pathways of autophagy and the unfolded protein response that are regulated by the polycystin proteins and how it leads to cell survival and/or cell death.
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Affiliation(s)
- Karla M Márquez-Nogueras
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Ave, Maywood, IL, USA
| | - Virdjinija Vuchkovska
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Ave, Maywood, IL, USA; Graduate School, Loyola University Chicago, 2160 S. First Ave, Maywood, IL, USA
| | - Ivana Y Kuo
- Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Ave, Maywood, IL, USA.
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Márquez-Nogueras KM, Knutila RM, Vuchkosvka V, Kuo IY. TRiPPing the sensors: The osmosensing pathway of Polycystin 2. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.09.540007. [PMID: 37214815 PMCID: PMC10197615 DOI: 10.1101/2023.05.09.540007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Mutations to polycystin-2 (PC2), a non-selective cation permeant transient receptor potential channel, results in polycystic kidney disease (PKD). Despite the disease relevance of PC2, the physiological agonist that activates PC2 has remained elusive. As one of the earliest symptoms in PKD is a urine concentrating deficiency, we hypothesized that shifts in osmolarity experienced by the collecting duct cells would activate PC2 and loss of PC2 would prevent osmosensing. We found that mice with inducible PC2 knocked out (KO) in renal tubules had dilute urine. Hyperosmotic stimuli induced a rise in endoplasmic reticulum (ER)-mediated cytosolic calcium which was absent in PC2 KO mice and PC2 KO cells. A pathologic point mutation that prevents ion flux through PC2 inhibited the calcium rise, pointing to the centrality of PC2 in the osmotic response. To understand how an extracellular stimulus activated ER-localized PC2, we examined microtubule-ER dynamics, and found that the osmotically induced calcium increase was preceded by microtubule destabilization. This was due to a novel interaction between PC2 and the microtubule binding protein MAP4 that tethers the microtubules to the ER. Finally, disruption of the MAP4-PC2 interaction prevented incorporation of the water channel aquaporin 2 following a hyperosmotic challenge, in part explaining the dilute urine. Our results demonstrate that MAP4-dependent microtubule stabilization of ER-resident PC2 is required for PC2 to participate in the osmosensing pathway. Moreover, osmolarity represents a bona fide physiological stimulus for ER-localized PC2 and loss of PC2 in renal epithelial cells impairs osmosensing ability and urine concentrating capacity.
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Woznicki P, Siedek F, van Gastel MD, dos Santos DP, Arjune S, Karner LA, Meyer F, Caldeira LL, Persigehl T, Gansevoort RT, Grundmann F, Baessler B, Müller RU. Automated Kidney and Liver Segmentation in MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease: A Multicenter Study. KIDNEY360 2022; 3:2048-2058. [PMID: 36591351 PMCID: PMC9802567 DOI: 10.34067/kid.0003192022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 09/19/2022] [Indexed: 12/31/2022]
Abstract
Background Imaging-based total kidney volume (TKV) and total liver volume (TLV) are major prognostic factors in autosomal dominant polycystic kidney disease (ADPKD) and end points for clinical trials. However, volumetry is time consuming and reader dependent in clinical practice. Our aim was to develop a fully automated method for joint kidney and liver segmentation in magnetic resonance imaging (MRI) and to evaluate its performance in a multisequence, multicenter setting. Methods The convolutional neural network was trained on a large multicenter dataset consisting of 992 MRI scans of 327 patients. Manual segmentation delivered ground-truth labels. The model's performance was evaluated in a separate test dataset of 93 patients (350 MRI scans) as well as a heterogeneous external dataset of 831 MRI scans from 323 patients. Results The segmentation model yielded excellent performance, achieving a median per study Dice coefficient of 0.92-0.97 for the kidneys and 0.96 for the liver. Automatically computed TKV correlated highly with manual measurements (intraclass correlation coefficient [ICC]: 0.996-0.999) with low bias and high precision (-0.2%±4% for axial images and 0.5%±4% for coronal images). TLV estimation showed an ICC of 0.999 and bias/precision of -0.5%±3%. For the external dataset, the automated TKV demonstrated bias and precision of -1%±7%. Conclusions Our deep learning model enabled accurate segmentation of kidneys and liver and objective assessment of TKV and TLV. Importantly, this approach was validated with axial and coronal MRI scans from 40 different scanners, making implementation in clinical routine care feasible.Clinical Trial registry name and registration number: The German ADPKD Tolvaptan Treatment Registry (AD[H]PKD), NCT02497521.
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Affiliation(s)
- Piotr Woznicki
- Institute of Diagnostic and Interventional Radiology, University of Cologne, University Hospital Cologne, Cologne, Germany,Department of Diagnostic and Interventional Radiology, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Florian Siedek
- Institute of Diagnostic and Interventional Radiology, University of Cologne, University Hospital Cologne, Cologne, Germany
| | - Maatje D.A. van Gastel
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Daniel Pinto dos Santos
- Institute of Diagnostic and Interventional Radiology, University of Cologne, University Hospital Cologne, Cologne, Germany,Institute of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Frankfurt, Germany
| | - Sita Arjune
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Larina A. Karner
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Franziska Meyer
- Institute of Diagnostic and Interventional Radiology, University of Cologne, University Hospital Cologne, Cologne, Germany
| | - Liliana Lourenco Caldeira
- Institute of Diagnostic and Interventional Radiology, University of Cologne, University Hospital Cologne, Cologne, Germany
| | - Thorsten Persigehl
- Institute of Diagnostic and Interventional Radiology, University of Cologne, University Hospital Cologne, Cologne, Germany
| | - Ron T. Gansevoort
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Franziska Grundmann
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Bettina Baessler
- Institute of Diagnostic and Interventional Radiology, University of Cologne, University Hospital Cologne, Cologne, Germany,Department of Diagnostic and Interventional Radiology, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Roman-Ulrich Müller
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
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9
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Park H, Paek JH, Kim Y, Park WY, Han S, Jin K. Clinical characteristics and risk factors for kidney failure in patients with autosomal dominant polycystic kidney disease: A retrospective study. Medicine (Baltimore) 2022; 101:e31838. [PMID: 36451428 PMCID: PMC9704897 DOI: 10.1097/md.0000000000031838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary and progressive renal disease. By the age of 65 years, 45% to 70% of patients with ADPKD reach end-stage renal disease (ESRD). Although there are various treatments for this condition, no standard therapy exists to delay the progression of ADPKD. Hence, understanding the factors that affect disease progression may be helpful for the treatment of ADPKD. The medical records of 288 patients with ADPKD at Keimyung University Dongsan Medical Center between January 1989 and August 2018 were analyzed retrospectively. Furthermore, we inspected the risk factors involved in the progression of ADPKD and the kidney survival rates of patients using the Cox proportional hazards model and Kaplan-Meier survival analysis. The mean age at the time of diagnosis was 43.1 ± 14.1 years, and there were 146 males (50.7%). In total, 197 patients (68.4%) had hypertension and 11 patients (3.8%) had cerebral aneurysm. Stroke occurred in 35 patients (12.1%), including 11 cases of cerebral hemorrhage and 24 cases of cerebral infarction. Twenty-eight patients (9.7%) died during the follow-up period (117.1 ± 102.1 months). Infection (42.9%) was the most common cause of mortality, followed by sudden cardiac death (25.0%). Overall, 132 patients (45.8%) progressed to ESRD and 104 patients (36.1%) required renal replacement therapy (RRT). The mean duration from diagnosis to RRT was 110.8 ± 93.9 months. Age at diagnosis after 30 years (odd's ratio [OR], 2.737; 95% confidence interval [CI], 1.320-5.675; P = .007), baseline serum creatinine levels (OR, 1.326; 95% CI, 1.259-1.396; P < .001), and cyst infection (OR, 2.065; 95% CI, 1.242-3.433; P = .005) were the independent risk factors for kidney failure in multivariable analysis. To delay the advance of ADPKD to ESRD, early diagnosis and close observation for the onset of cyst infection are crucial.
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Affiliation(s)
- Hanil Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Keimyung University Kidney Institute, Daegu, Korea
| | - Jin Hyuk Paek
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Keimyung University Kidney Institute, Daegu, Korea
| | - Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Keimyung University Kidney Institute, Daegu, Korea
| | - Woo Yeong Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Keimyung University Kidney Institute, Daegu, Korea
| | - Seungyeup Han
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Keimyung University Kidney Institute, Daegu, Korea
| | - Kyubok Jin
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
- Keimyung University Kidney Institute, Daegu, Korea
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10
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Bais T, Gansevoort RT, Meijer E. Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease. Drugs 2022; 82:1095-1115. [PMID: 35852784 PMCID: PMC9329410 DOI: 10.1007/s40265-022-01745-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2022] [Indexed: 12/16/2022]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation that ultimately leads to kidney failure in most patients. Approximately 10% of patients who receive kidney replacement therapy suffer from ADPKD. To date, a vasopressin V2 receptor antagonist (V2RA) is the only drug that has been proven to attenuate disease progression. However, aquaresis-related adverse events limit its widespread use. Data on the renoprotective effects of somatostatin analogues differ largely between studies and medications. This review discusses new drugs that are investigated in clinical trials to treat ADPKD, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and micro RNA inhibitors, and drugs already marketed for other indications that are being investigated for off-label use in ADPKD, such as metformin. In addition, potential methods to improve the tolerability of V2RAs are discussed, as well as methods to select patients with (likely) rapid disease progression and issues regarding the translation of preclinical data into clinical practice. Since ADPKD is a complex disease with a high degree of interindividual heterogeneity, and the mechanisms involved in cyst growth also have important functions in various physiological processes, it may prove difficult to develop drugs that target cyst growth without causing major adverse events. This is especially important since long-standing treatment is necessary in this chronic disease. This review therefore also discusses approaches to targeted therapy to minimize systemic side effects. Hopefully, these developments will advance the treatment of ADPKD.
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11
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Pagliarini R, Podrini C. Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD. Front Med (Lausanne) 2021; 8:740087. [PMID: 34901057 PMCID: PMC8652061 DOI: 10.3389/fmed.2021.740087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/25/2021] [Indexed: 12/17/2022] Open
Abstract
Metabolic reprogramming is a key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD) characterized by changes in cellular pathways occurring in response to the pathological cell conditions. In ADPKD, a broad range of dysregulated pathways have been found. The studies supporting alterations in cell metabolism have shown that the metabolic preference for abnormal cystic growth is to utilize aerobic glycolysis, increasing glutamine uptake and reducing oxidative phosphorylation, consequently resulting in ADPKD cells shifting their energy to alternative energetic pathways. The mechanism behind the role of the polycystin proteins and how it leads to disease remains unclear, despite the identification of numerous signaling pathways. The integration of computational data analysis that accompanies experimental findings was pivotal in the identification of metabolic reprogramming in ADPKD. Here, we summarize the important results and argue that their exploitation may give further insights into the regulative mechanisms driving metabolic reprogramming in ADPKD. The aim of this review is to provide a comprehensive overview on metabolic focused studies and potential targets for treatment, and to propose that computational approaches could be instrumental in advancing this field of research.
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Affiliation(s)
- Roberto Pagliarini
- Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
| | - Christine Podrini
- Molecular Basis of Cystic Kidney Disorders Unit, Division of Genetics and Cell Biology, IRCCS-San Raffaele Scientific Institute, Milan, Italy
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12
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Vasileva VY, Sultanova RF, Sudarikova AV, Ilatovskaya DV. Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases. Front Physiol 2021; 12:693130. [PMID: 34566674 PMCID: PMC8456103 DOI: 10.3389/fphys.2021.693130] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/10/2021] [Indexed: 12/18/2022] Open
Abstract
Autosomal dominant (AD) and autosomal recessive (AR) polycystic kidney diseases (PKD) are severe multisystem genetic disorders characterized with formation and uncontrolled growth of fluid-filled cysts in the kidney, the spread of which eventually leads to the loss of renal function. Currently, there are no treatments for ARPKD, and tolvaptan is the only FDA-approved drug that alleviates the symptoms of ADPKD. However, tolvaptan has only a modest effect on disease progression, and its long-term use is associated with many side effects. Therefore, there is still a pressing need to better understand the fundamental mechanisms behind PKD development. This review highlights current knowledge about the fundamental aspects of PKD development (with a focus on ADPKD) including the PC1/PC2 pathways and cilia-associated mechanisms, major molecular cascades related to metabolism, mitochondrial bioenergetics, and systemic responses (hormonal status, levels of growth factors, immune system, and microbiome) that affect its progression. In addition, we discuss new information regarding non-pharmacological therapies, such as dietary restrictions, which can potentially alleviate PKD.
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Affiliation(s)
| | - Regina F Sultanova
- Saint-Petersburg State Chemical Pharmaceutical University, St. Petersburg, Russia.,Department of Physiology, Augusta University, Augusta, GA, United States
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13
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Urinary Aquaporin 2 as a Potential Indicator Predicting Tolvaptan Response in Patients With ADPKD. Kidney Int Rep 2021; 6:2436-2444. [PMID: 34514204 PMCID: PMC8418978 DOI: 10.1016/j.ekir.2021.06.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 06/29/2021] [Accepted: 06/29/2021] [Indexed: 11/26/2022] Open
Abstract
Introduction Tolvaptan is used to treat autosomal dominant polycystic kidney disease (ADPKD) because it inhibits binding of the antidiuretic hormone vasopressin to the vasopressin V2 receptor (V2R), which suppresses the insertion of preformed water channel aquaporin 2 (AQP2) molecules in the luminal membrane of the collecting duct cells. Methods This single-center, prospective observational cohort study investigated whether decreased AQP2 elimination in urine affects the renal prognosis of patients who received tolvaptan. We selected 92 patients with ADPKD who were administered tolvaptan in our hospital. We evaluated correlations between changes in urinary AQP2 (U-AQP2) and clinical parameters and the annual change in total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) as renal prognostic factors using univariable and multivariable multiple regression analyses. Results The observation period was 2.4 ± 1.5 years. U-AQP2 per milligram of urinary creatinine (U-AQP2/Cr) decreased from 67.8 ± 50.6 to 20.7 ± 15.1 fmol/mg urinary creatinine after 1 month of tolvaptan treatment. This initial change in U-AQP2/Cr was correlated with high baseline U-AQP2/Cr, low baseline eGFR, and a large initial change in eGFR (baseline to 1 month). The initial change in U-AQP2/Cr (baseline to 1 month) was strongly correlated with the annual change in TKV and eGFR in multivariable analysis. Conclusion Initial decrease in U-AQP2/Cr in the first month of treatment reflects the pharmacologic effect of tolvaptan and could be an indicator of renal prognosis during tolvaptan treatment.
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14
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The effect of trichlormethiazide in autosomal dominant polycystic kidney disease patients receiving tolvaptan: a randomized crossover controlled trial. Sci Rep 2021; 11:17666. [PMID: 34480075 PMCID: PMC8417075 DOI: 10.1038/s41598-021-97113-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 08/17/2021] [Indexed: 12/11/2022] Open
Abstract
The vasopressin V2 receptor antagonist tolvaptan delays the progression of autosomal dominant polycystic kidney disease (ADPKD). However, some patients discontinue tolvaptan because of severe adverse aquaretic events. This open-label, randomized, controlled, counterbalanced, crossover trial investigated the effects of trichlormethiazide, a thiazide diuretic, in patients with ADPKD receiving tolvaptan (n = 10) who randomly received antihypertensive therapy with or without trichlormethiazide for 12 weeks. The primary and secondary outcomes included amount and osmolarity of 24-h urine and health-related quality-of-life (HRQOL) parameters assessed by the Kidney Disease Quality of Life-Short Form questionnaire, renal function slope, and plasma/urinary biomarkers associated with disease progression. There was a significant reduction in urine volume (3348 ± 584 vs. 4255 ± 739 mL; P < 0.001) and a significant increase in urinary osmolarity (182.5 ± 38.1 vs. 141.5 ± 38.1 mOsm; P = 0.001) in patients treated with trichlormethiazide. Moreover, trichlormethiazide improved the following HRQOL subscales: effects of kidney disease, sleep, emotional role functioning, social functioning, and role/social component summary. No significant differences were noted in renal function slope or plasma/urinary biomarkers between patients treated with and without trichlormethiazide. In patients with ADPKD treated with tolvaptan, trichlormethiazide may improve tolvaptan tolerability and HRQOL parameters.
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15
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Heida JE, Gansevoort RT, Torres VE, Devuyst O, Perrone RD, Lee J, Li H, Ouyang J, Chapman AB. The Effect of Tolvaptan on BP in Polycystic Kidney Disease: A Post Hoc Analysis of the TEMPO 3:4 Trial. J Am Soc Nephrol 2021; 32:1801-1812. [PMID: 33888577 PMCID: PMC8425647 DOI: 10.1681/asn.2020101512] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/01/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The V2 receptor antagonist tolvaptan is prescribed to patients with autosomal dominant polycystic kidney disease to slow disease progression. Tolvaptan may alter BP via various acute and chronic effects. METHODS To investigate the magnitude and time course of the effect of tolvaptan use on BP, we conducted a post hoc study of the TEMPO 3:4 trial, which included 1445 patients with autosomal dominant polycystic kidney disease randomized 2:1 to tolvaptan or placebo for 3 years. We evaluated systolic and diastolic BP, mean arterial pressure, hypertension status, and use and dosing of antihypertensive drugs over the course of the trial. RESULTS At baseline, BP did not differ between study arms. After 3 weeks of tolvaptan use, mean body weight had decreased from 79.7 to 78.8 kg, and mean plasma sodium increased from 140.4 to 142.6 mmol/L (both P<0.001), suggesting a decrease in circulating volume. We observed none of these changes in the placebo arm. Nonetheless, BP remained similar in the study arms. After 3 years of treatment, however, mean systolic BP was significantly lower in participants receiving tolvaptan versus placebo (126 versus 129 mm Hg, respectively; P=0.002), as was mean diastolic BP (81.2 versus 82.6 mm Hg, respectively; P=0.01). These differences leveled off at follow-up 3 weeks after discontinuation of the study medication. Use of antihypertensive drugs remained similar in both study arms during the entire study. CONCLUSIONS Long-term treatment with tolvaptan gradually lowered BP compared with placebo, which may be attributed to a beneficial effect on disease progression, a continued natriuretic effect, or both. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER TEMPO 3:4, NCT00428948.
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Affiliation(s)
- Judith E. Heida
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Ron T. Gansevoort
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Vicente E. Torres
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland,Division of Nephrology, Université Catholique de Louvain, Brussels, Belgium
| | - Ronald D. Perrone
- Division of Nephrology, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts
| | - Jennifer Lee
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
| | - Hui Li
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
| | - John Ouyang
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
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16
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Nowak KL, Steele C, Gitomer B, Wang W, Ouyang J, Chonchol MB. Overweight and Obesity and Progression of ADPKD. Clin J Am Soc Nephrol 2021; 16:908-915. [PMID: 34117082 PMCID: PMC8216617 DOI: 10.2215/cjn.16871020] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/11/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVES On the basis of earlier observations, we evaluated the association between overweight and obesity and rapid progression of autosomal dominant polycystic kidney disease in participants in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial. More importantly, we also determined whether efficacy of tolvaptan was attenuated in individuals with baseline overweight or obesity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 1312 study participants with relatively early-stage autosomal dominant polycystic kidney disease (mean eGFR 78±22 ml/min per 1.73 m2) who were at high risk of rapid progression were categorized by body mass index (BMI; calculated using nonkidney weight) as normal weight (18.5-24.9 kg/m2; n=670), overweight (25.0-29.9 kg/m2; n=429), or obese (≥30 kg/m2; n=213). Linear and multinomial logistic regression models were used to determine the association of baseline overweight and obesity with change in total kidney volume (TKV) over the 3-year study period. RESULTS In fully adjusted models, higher BMI was associated with greater annual percent change in TKV (difference of 1.20 [95% confidence interval (95% CI), 0.85 to 1.55] per five-unit higher BMI). Overweight and obesity were associated with higher odds of annual percent change in TKV of ≥7% versus <5% (overweight: odds ratio, 2.04 [95% CI, 1.45 to 2.87]; obese: odds ratio, 4.31 [95% CI, 2.83 to 6.57] versus normal weight). eGFR decline did not differ according to BMI (fully adjusted difference in decline of -0.95 [95% CI, -2.32 to 0.40] ml/min per 1.73 m2 per year per five-unit higher BMI). The three-way interaction (treatment×time×BMI group) was not statistically significant in linear mixed models with an outcome of TKV (log-transformed estimated coefficient comparing the treatment effect for overweight versus normal weight: 0.56% [95% CI, -0.70% to 1.84%] per year; P=0.38; obese versus normal weight: 0.07% [95% CI, -1.47% to 1.63%] per year; P=0.93) or eGFR (estimated coefficient comparing overweight versus normal weight: -0.07 [95% CI, -0.95 to 0.82] ml/min per 1.73 m2 per year; P=0.88; obese versus normal weight: 0.22 [95% CI, -0.93 to 1.36] ml/min per 1.73 m2 per year; P=0.71). CONCLUSIONS Overweight and particularly obesity are strongly and independently associated with kidney growth, but not eGFR slope, in the TEMPO 3:4 trial, and tolvaptan efficacy is irrespective of BMI categorization. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4, NCT00428948.
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Affiliation(s)
- Kristen L. Nowak
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Cortney Steele
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Berenice Gitomer
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Wenchyi Wang
- Otsuka Pharmaceutical Development and Commercialization, Princeton, New Jersey
| | - John Ouyang
- Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland
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17
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Natale P, Hannan E, Sautenet B, Ju A, Perrone RD, Burnette E, Casteleijn N, Chapman A, Eastty S, Gansevoort R, Hogan M, Horie S, Knebelmann B, Lee R, Mustafa RA, Sandford R, Baumgart A, Tong A, Strippoli GFM, Craig JC, Rangan GK, Cho Y. Patient-reported outcome measures for pain in autosomal dominant polycystic kidney disease: A systematic review. PLoS One 2021; 16:e0252479. [PMID: 34043715 PMCID: PMC8158964 DOI: 10.1371/journal.pone.0252479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 05/16/2021] [Indexed: 12/15/2022] Open
Abstract
Pain is a common symptom in people with autosomal dominant polycystic kidney disease (ADPKD), but it is assessed and reported inconsistently in research, and the validity of the measures remain uncertain. The aim of this study was to identify the characteristics, content, and psychometric properties of measures for pain used in ADPKD. We conducted a systematic review including all trials and observational studies that reported pain in people with ADPKD. Items from all measures were categorized into content and measurement dimensions of pain. We assessed the general characteristics and psychometric properties of all measures. 118 studies, we identified 26 measures: 12 (46%) measures were developed for a non-ADPKD population, 1 (4%) for chronic kidney disease, 2 (8%) for polycystic liver disease and 11 (42%) specifically for ADPKD. Ten anatomical sites were included, with the lower back the most common (10 measures [39%]), four measurement dimensions (intensity (23 [88%]), frequency (3 [12%]), temporality (2 [8%]), and sensory (21 [81%]), two pain types, nociceptive including visceral (15 [58%]) and somatic (5 [20%]), and neuropathic (2 [8%]), and twelve impact dimensions, where the most frequent was work (5 [31%]). The validation data for the measures were variable and only the ADPKD Impact Scale reported all psychometric domains. The measures for pain in ADPKD varied in terms of content and length, and most had not been validated in ADPKD. A standardized psychometrically robust measure that captures patient-important dimensions of pain is needed to evaluate and manage this debilitating complication of ADPKD.
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Affiliation(s)
- Patrizia Natale
- Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
- * E-mail:
| | - Elyssa Hannan
- Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
| | - Bénédicte Sautenet
- Service de Néphrologie-Hypertension, Dialyses, Transplantation Rénale, Hôpital de Tours, Tours, France
- Université de Tours, Université de Nantes, INSERM, SPHERE U1246, Tours, France
| | - Angela Ju
- Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
| | - Ronald D. Perrone
- Medicine, Nephrology, Clinical and Translational Research Center, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | | | - Niek Casteleijn
- Department of Urology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Arlene Chapman
- Department of Nephrology, The University of Chicago, Chicago, Illinois, United States of America
| | | | - Ron Gansevoort
- Department of Urology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Marie Hogan
- Division of Nephrology & Hypertension, Department of Internal Medicine Mayo Clinic, Rochester, Minnesota, United States of America
| | - Shigeo Horie
- Department of Urology, Juntendo University, Tokyo, Japan
| | - Bertrand Knebelmann
- Université de Paris APHP, Hôpital Necker, Service de Néphrologie, Paris, France
| | | | - Reem A. Mustafa
- Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Centre, Lawrence, Kansas, United States of America
| | - Richard Sandford
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Amanda Baumgart
- Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
| | - Allison Tong
- Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, NSW, Australia
| | - Giovanni F. M. Strippoli
- Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
- Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Jonathan C. Craig
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Gopala K. Rangan
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
- Department of Medicine, Westmead Hospital, Western Sydney Local Health District, Sydney, NSW, Australia
| | - Yeoungjee Cho
- Australasian Kidney Trials Network, University of Queensland, Brisbane, QLD, Australia
- Translational Research Institute, Brisbane, QLD, Australia
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, QLD, Australia
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18
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Xie X, Cai Q, Guo XY, Bai DH, Sheng HZ, Wang BK, Yan K, Lu AM, Wang XR. Effectiveness of Tolvaptan in the Treatment for Patients with Autosomal Dominant Polycystic Kidney Disease: A Meta-analysis. Comb Chem High Throughput Screen 2021; 23:6-16. [PMID: 31793415 DOI: 10.2174/1386207322666191203092715] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/06/2019] [Accepted: 11/05/2019] [Indexed: 11/22/2022]
Abstract
AIMS AND OBJECTIVE Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common chronic kidney disease that leads to End-Stage Renal Disease (ESRD). The key target of this therapy is to prevent the progression of kidney failure. Tolvaptan could slow kidney cyst growth and are proven highly effective. The aims of this analysis are to perform a systematic review, estimate and evaluate the efficacy and safety of tolvaptan in ADPKD patients. MATERIALS AND METHODS Randomized controlled trials of tolvaptan in ADPKD were identified in PubMed, Ovid, Web of Science and the Cochrane Library electronic database. The changes observed in kidney function, treatment efficiency and the incidence of adverse events between the tolvaptan and placebo groups were compared. Data were analyzed by the RevMan software. RESULTS Eight trials, including 7 double-blinded randomised controlled trials and 1 quasi RCT involving 1,536 patients were extracted. Significant differences in the annual rate of change in the total kidney volume TKV at any stages of CKD (MD = -3.32, 95%CI =-4.57,-2.07, I2 =70%) and the glomerular filtration rate (MD = 1.4, 95%CI = 0.83,1.97, I2 =0%) were observed between the tolvaptan group and the placebo group. Subgroup analysis of patients in different CKD stages also showed the same conclusion. There was an increase in the urine osmolality, and 24-hour urine volume in patients receiving tolvaptan. Tolvaptan reduced the rate of serious hypertension and kidney pain events in ADPKD patients. At higher doses, it increased the rate of adverse events (liver injuries, thirst, pollakiuria, and nocturia). There was no significant risk of bias in the included studies. CONCLUSION Tolvaptan has a beneficial effect on ADPKD, but is associated with an increase in adverse events at high doses when compared with the placebo. Further RCTs on tolvaptan may be required to support this conclusion.
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Affiliation(s)
- Xuan Xie
- Department of Nephropathy, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Qian Cai
- Department of Nephropathy, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xiao-Yuan Guo
- Department of Nephropathy, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Dong-Hai Bai
- Department of Nephropathy, Beijing Fangshan District City Hospital of Traditional Chinese Medicine, Beijing, China
| | - Hai-Zhong Sheng
- Department of Nephropathy, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Bao-Kui Wang
- Department of Nephropathy, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Kai Yan
- Department of Traditional Chinese Medicine, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - An-Ming Lu
- Department of Internal Medicine, First People's Hospital of Dongcheng District, Beijing, China
| | - Xin-Ran Wang
- Department of Acupuncture and Moxibustion, Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
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19
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Duong Phu M, Bross S, Burkhalter MD, Philipp M. Limitations and opportunities in the pharmacotherapy of ciliopathies. Pharmacol Ther 2021; 225:107841. [PMID: 33771583 DOI: 10.1016/j.pharmthera.2021.107841] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/11/2021] [Indexed: 01/10/2023]
Abstract
Ciliopathies are a family of rather diverse conditions, which have been grouped based on the finding of altered or dysfunctional cilia, potentially motile, small cellular antennae extending from the surface of postmitotic cells. Cilia-related disorders include embryonically arising conditions such as Joubert, Usher or Kartagener syndrome, but also afflictions with a postnatal or even adult onset phenotype, i.e. autosomal dominant polycystic kidney disease. The majority of ciliopathies are syndromic rather than affecting only a single organ due to cilia being found on almost any cell in the human body. Overall ciliopathies are considered rare diseases. Despite that, pharmacological research and the strive to help these patients has led to enormous therapeutic advances in the last decade. In this review we discuss new treatment options for certain ciliopathies, give an outlook on promising future therapeutic strategies, but also highlight the limitations in the development of therapeutic approaches of ciliopathies.
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Affiliation(s)
- Max Duong Phu
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University of Tübingen, 72074 Tübingen, Germany
| | - Stefan Bross
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University of Tübingen, 72074 Tübingen, Germany
| | - Martin D Burkhalter
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University of Tübingen, 72074 Tübingen, Germany
| | - Melanie Philipp
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, Section of Pharmacogenomics, Eberhard-Karls-University of Tübingen, 72074 Tübingen, Germany.
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20
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Raina R, Chakraborty R, DeCoy ME, Kline T. Autosomal-dominant polycystic kidney disease: tolvaptan use in adolescents and young adults with rapid progression. Pediatr Res 2021; 89:894-899. [PMID: 32392574 DOI: 10.1038/s41390-020-0942-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND The phase 3 Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) clinical trial demonstrated the beneficial effect of tolvaptan on kidney growth and function in subjects aged 18-50 years over a 3-year period. However, it did not specifically assess the use of tolvaptan in adolescents and young adults (AYAs) with ADPKD. METHODS A post hoc analysis of the TEMPO 3:4 trials was performed for patients aged 18-24 years. The primary outcome was the annual rate of change in total kidney volume (TKV). The secondary outcome was to evaluate long-term safety of tolvaptan using Hy's law of hepatotoxicity. RESULTS A total of 51 patients in the 18-24 age group were analyzed (tolvaptan: 29, placebo: 22). The tolvaptan group had a lower mean percentage of TKV growth per year compared to the placebo group (3.9% vs. 6.5%, P = 0.0491). For secondary outcomes, 63 patients in the AYA subgroup were evaluated. In both the AYA and adult groups, none of the patients met the criteria for Hy's law of hepatotoxicity. CONCLUSIONS This post hoc analysis suggests that tolvaptan, with appropriate patient selection and management, can provide effective and acceptably safe treatment in AYAs with ADPKD. IMPACT Tolvaptan slows the increase in total kidney volume in patients aged 18-24 years with ADPKD. Tolvaptan posed no risk of potential liver injury measured via Hy's law of hepatotoxicity in the AYA stratum. This study suggests that tolvaptan has beneficial outcomes in AYAs. This post hoc analysis suggests the need for additional studies with a larger pediatric patient population. The impact is significant as tolvaptan had not been specifically examined in the AYA patient population previously.
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Affiliation(s)
- Rupesh Raina
- Department of Nephrology, Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH, USA.
| | | | - Meredith E DeCoy
- Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
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21
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Horie S, Muto S, Kawano H, Okada T, Shibasaki Y, Nakajima K, Ibuki T. Preservation of kidney function irrelevant of total kidney volume growth rate with tolvaptan treatment in patients with autosomal dominant polycystic kidney disease. Clin Exp Nephrol 2021; 25:467-478. [PMID: 33471240 PMCID: PMC8038960 DOI: 10.1007/s10157-020-02009-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 12/02/2020] [Indexed: 11/29/2022]
Abstract
Background Tolvaptan slowed the rates of total kidney volume (TKV) growth and renal function decline over a 3-year period in patients with autosomal dominant polycystic kidney disease (ADPKD) enrolled in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial (NCT00428948). In this post hoc analysis of Japanese patients from TEMPO 3:4, we evaluated whether the effects of tolvaptan on TKV and on renal function are interrelated. Methods One hundred and forty-seven Japanese patients from TEMPO 3:4 were included in this analysis (placebo, n = 55; tolvaptan, n = 92). Tolvaptan-treated patients were stratified into the responder group (n = 37), defined as tolvaptan-treated patients with a net decrease in TKV from baseline to year 3, and the non-responder group (n = 55), defined as tolvaptan-treated patients with a net increase in TKV. Results Mean changes during follow-up in the placebo, responder, and non-responder groups were 16.99%, − 8.33%, and 13.95%, respectively, for TKV and − 12.61, − 8.47, and − 8.58 mL/min/1.73 m2, respectively, for estimated glomerular filtration rate (eGFR). Compared with the placebo group, eGFR decline was significantly slowed in both the responder and non-responder groups (P < 0.05). Conclusion Tolvaptan was effective in slowing eGFR decline, regardless of TKV response, over 3 years in patients with ADPKD in Japan. Treatment with tolvaptan may have beneficial effects on slowing of renal function decline even in patients who have not experienced a reduction in the rate of TKV growth by treatment with tolvaptan. Supplementary Information The online version contains supplementary material available at 10.1007/s10157-020-02009-0.
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Affiliation(s)
- Shigeo Horie
- Department of Urology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. .,Department of Advanced Informatics for Genetic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan.
| | - Satoru Muto
- Department of Urology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Advanced Informatics for Genetic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Haruna Kawano
- Department of Urology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.,Department of Advanced Informatics for Genetic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tadashi Okada
- Department of Clinical Development, Otsuka Pharmaceutical Co., Ltd, Osaka, Japan
| | | | - Koji Nakajima
- Medical Affairs, Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan
| | - Tatsuki Ibuki
- Medical Affairs, Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan
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22
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Higashihara E, Fukuhara H, Ouyang J, Lee J, Nutahara K, Tanbo M, Yamaguchi T, Taguchi S, Muto S, Kaname S, Miyazaki I, Horie S. Estimation of Changes in Kidney Volume Growth Rate in ADPKD. Kidney Int Rep 2020; 5:1459-1471. [PMID: 32954070 PMCID: PMC7486344 DOI: 10.1016/j.ekir.2020.06.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/24/2020] [Accepted: 06/10/2020] [Indexed: 10/30/2022] Open
Abstract
Introduction In the Mayo Imaging Classification (MIC) for autosomal dominant polycystic kidney disease (ADPKD), the height-adjusted total kidney volume (HtTKV) growth rate is estimated for classification. Estimated HtTKV slope, termed as eHTKV-α, is calculated by the equation [HtTKV at age t] = K(1+α/100)(t-A), where K = 150 and A = 0 are used in MIC. If eHTKV-α is nearly stable during a standard-of-care period, the change in eHTKV-α from baseline can be used for estimation of the treatment effect on the HtTKV slope. Methods The constancy of eHTKV-α (A = 0 and K = 150) was evaluated using 453 placebo-assigned subjects in the Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 trial. A and K were sought out respectively by a converged pattern of regression lines of log10(HtTKV) plotted against age for subgroups divided according to MIC, and by change in eHTKV-α from baseline. A total of 239 standard-of-care patients from the Kyorin University Cohort (KUC) served as validation. Changes in eHTKV-α from baseline were evaluated in 809 tolvaptan-treated subjects in TEMPO 3:4. Results In placebo-assigned subjects, eHTKV-α (A = 0 and K = 150) changed significantly from baseline at the third year. As regression lines of placebo-assigned subgroups converged around age 0, A was set as 0, which was confirmed by KUC. K = 130 was selected because of minimal change in eHTKV-α from baseline. The KUC validated the constancy of eHTKV-α (A = 0 and K = 130) but not that of eHTKV-α (A=0 and K=150). In tolvaptan-treated subjects, eHTKV-α remained significantly lower than baseline for 3 years. Conclusions eHTKV-α (A = 0 and K = 130) was nearly stable from baseline through follow-up in standard-of-care adults. Treatment effects on the HtTKV slope can be estimated by changes in eHTKV-α from baseline.
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Affiliation(s)
- Eiji Higashihara
- Department of Hereditary Kidney Disease Research, Kyorin University School of Medicine, Tokyo, Japan
| | - Hiroshi Fukuhara
- Department of Urology, Kyorin University School of Medicine, Tokyo, Japan
| | - John Ouyang
- Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland, USA
| | - Jennifer Lee
- Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland, USA
| | - Kikuo Nutahara
- Department of Urology, Kyorin University School of Medicine, Tokyo, Japan
| | - Mistuhiro Tanbo
- Department of Urology, Kyorin University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Yamaguchi
- Department of Urology, Kyorin University School of Medicine, Tokyo, Japan
| | - Satoru Taguchi
- Department of Urology, Kyorin University School of Medicine, Tokyo, Japan
| | - Satoru Muto
- Department of Urology, Juntendo University School of Medicine, Tokyo, Japan
| | - Shinya Kaname
- Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Isao Miyazaki
- Department of Radiology, Kyorin University School of Medicine, Tokyo, Japan
| | - Shigeo Horie
- Department of Urology, Juntendo University School of Medicine, Tokyo, Japan
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23
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Case report: tolvaptan-associated creatine kinase elevation in two patients with autosomal dominant polycystic kidney disease (ADPKD). Eur J Clin Pharmacol 2020; 76:1473-1475. [PMID: 32514744 PMCID: PMC7481148 DOI: 10.1007/s00228-020-02906-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 05/20/2020] [Indexed: 12/14/2022]
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24
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Janssens P, Jouret F, Bammens B, Liebau MC, Schaefer F, Dandurand A, Perrone RD, Müller RU, Pao CS, Mekahli D. Implications of early diagnosis of autosomal dominant polycystic kidney disease: A post hoc analysis of the TEMPO 3:4 trial. Sci Rep 2020; 10:4294. [PMID: 32152377 PMCID: PMC7062834 DOI: 10.1038/s41598-020-61303-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 02/21/2020] [Indexed: 11/18/2022] Open
Abstract
It is unknown whether early diagnosis of autosomal dominant polycystic kidney disease (ADPKD) can enable earlier management and improve outcomes. We conducted a post hoc analysis of data from the TEMPO 3:4 trial. Subjects were stratified by ADPKD diagnosis at age ≤18 (childhood diagnosis [CD]) or>18 (adulthood diagnosis [AD]). Groups were compared for baseline characteristics and total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline over 3 years. 294 CD and 1148 AD subjects were analyzed. At inclusion, CD subjects were younger (mean age 34.2 versus 39.8 years; p < 0.0001) and had better eGFR (mean ± SD 87.4 ± 23.9 versus 80.1 ± 20.7 mL/min/1.73 m2; p < 0.0001), while CD had more severe Mayo risk classification (p < 0.0001) and more PKD1 mutations (p = 0.003). No statistical differences were found in TKV or eGFR change. At study end, placebo-treated CD subjects had better eGFR than projected by a prediction equation (mean difference ±SD for observed versus predicted eGFR: 2.18 ± 10.7 mL/min/1.73 m2; p = 0.0475). However, these results are not confirmed when excluding stage 1 CKD. Whether CD subjects, despite their risk profile, have a slower disease course than predicted remains inconclusive. Future studies are needed to confirm that early diagnosis and management can alter the disease course of ADPKD.
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Affiliation(s)
- Peter Janssens
- PKD Research Group, Laboratory of Pediatrics, University Hospitals Leuven, Leuven, Belgium.,Department of Nephrology, University Hospitals Brussels, Brussels, Belgium
| | - François Jouret
- Division of Nephrology, University of Liège Hospital (ULiège CHU), Liège, Belgium.,Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA), Cardiovascular Sciences, ULiège, Liège, Belgium
| | - Bert Bammens
- Department of Microbiology & Immunology, KU Leuven, Leuven, Belgium.,Department of Nephrology, Dialysis and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Max C Liebau
- Department of Pediatrics and Center for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.,Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany
| | - Franz Schaefer
- Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany
| | - Ann Dandurand
- Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, USA
| | - Ronald D Perrone
- Division of Nephrology, Tufts Medical Center and Tufts University School of Medicine, Boston, USA
| | - Roman-Ulrich Müller
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.,Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany
| | - Christina S Pao
- Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, USA
| | - Djalila Mekahli
- PKD Research Group, Laboratory of Pediatrics, University Hospitals Leuven, Leuven, Belgium. .,Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium.
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25
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Nobakht N, Hanna RM, Al-Baghdadi M, Ameen KM, Arman F, Nobahkt E, Kamgar M, Rastogi A. Advances in Autosomal Dominant Polycystic Kidney Disease: A Clinical Review. Kidney Med 2020; 2:196-208. [PMID: 32734239 PMCID: PMC7380379 DOI: 10.1016/j.xkme.2019.11.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Polycystic kidney disease (PKD) is a multiorgan disorder resulting in fluid-filled cyst formation in the kidneys and other systems. The replacement of kidney parenchyma with an ever-increasing volume of cysts eventually leads to kidney failure. Recently, increased understanding of the pathophysiology of PKD and genetic advances have led to new approaches of treatment targeting physiologic pathways, which has been proven to slow the progression of certain types of the disease. We review the pathophysiologic patterns and recent advances in the clinical pharmacotherapy of autosomal dominant PKD. A multipronged approach with pharmacologic and nonpharmacologic treatments can be successfully used to slow down the rate of progression of autosomal dominant PKD to kidney failure.
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Affiliation(s)
- Niloofar Nobakht
- Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Ramy M. Hanna
- Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Division of Nephrology, Department of Medicine, University of California Irvine, Orange, CA
| | - Maha Al-Baghdadi
- Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Department of Medicine, University of Alabama Birmingham Huntsville Regional Campus, Huntsville, AL
| | - Khalid Mohammed Ameen
- Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Farid Arman
- Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, PA
| | - Ehsan Nobahkt
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University, Washington, DC
| | - Mohammad Kamgar
- Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Anjay Rastogi
- Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
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Cornec-Le Gall E, Blais JD, Irazabal MV, Devuyst O, Gansevoort RT, Perrone RD, Chapman AB, Czerwiec FS, Ouyang J, Heyer CM, Senum SR, Le Meur Y, Torres VE, Harris PC. Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial. Nephrol Dial Transplant 2019; 33:645-652. [PMID: 28992127 PMCID: PMC5888998 DOI: 10.1093/ndt/gfx188] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 04/13/2017] [Indexed: 01/22/2023] Open
Abstract
Background The PROPKD score has been proposed to stratify the risk of progression to end-stage renal disease in autosomal dominant polycystic kidney disease (ADPKD) subjects. We aimed to assess its prognostic value in a genotyped subgroup of subjects from the Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (TEMPO3/4) trial. Methods In the post hoc analysis, PKD1 and PKD2 were screened in 770 subjects and the PROPKD score was calculated in mutation-positive subjects (male: 1 point; hypertension <35 years: 2 points; first urologic event <35 years: 2 points; nontruncating PKD1 mutation: 2 points; truncating PKD1 mutation: 4 points). Subjects were classified into low-risk (LR; 0-3 points), intermediate-risk (IR; 4-6 points) and high-risk (HR; 7-9 points) groups. Results The PROPKD score was calculated in 749 subjects (LR = 132, IR = 344 and HR = 273); age was inversely related to risk (LR = 43.6 years, IR = 39.5 years, HR = 36.2 years; P < 0.001). Subjects from the HR group had significantly higher height-adjusted total kidney volume (TKV) and rates of TKV growth. While baseline renal function was similar across all risk groups, the rate of estimated glomerular filtration rate (eGFR) decline significantly increased from LR to HR in the placebo group. Tolvaptan treatment effectiveness to reduce TKV growth was similar in all three risk categories. While tolvaptan significantly slowed eGFR decline in the IR (tolvaptan = -2.34 versus placebo = -3.33 mL/min/1.73 m2/year; P = 0.008) and HR groups (tolvaptan = -2.74 versus placebo = -3.94 mL/min/1.73 m2/year; P = 0.002), there was no difference in the LR group (tolvaptan = -2.35 versus placebo = -2.50 mL/min/1.73 m2/year; P = 0.72). Excluding the LR subjects from the analysis improved the apparent treatment effect of tolvaptan on eGFR decline. Conclusion This study confirms the prognostic value of the PROPKD score and suggests that it could reduce costs and enhance endpoint sensitivity by enriching future study populations for rapidly progressing ADPKD subjects.
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Affiliation(s)
- Emilie Cornec-Le Gall
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA.,European University of Western Brittany, CHU Brest, Brest, France
| | | | - Maria V Irazabal
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA
| | - Olivier Devuyst
- Institute of Nephrology, University of Zurich, Zurich, Switzerland
| | - Ron T Gansevoort
- Department of Nephrology, University Medical Center of Groningen, Groningen, The Netherlands
| | | | | | | | | | - Christina M Heyer
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA
| | - Sarah R Senum
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA
| | - Yannick Le Meur
- European University of Western Brittany, CHU Brest, Brest, France
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA
| | - Peter C Harris
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA
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27
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Rastogi A, Ameen KM, Al-Baghdadi M, Shaffer K, Nobakht N, Kamgar M, Lerma EV. Autosomal dominant polycystic kidney disease: updated perspectives. Ther Clin Risk Manag 2019; 15:1041-1052. [PMID: 31692482 PMCID: PMC6716585 DOI: 10.2147/tcrm.s196244] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 08/01/2019] [Indexed: 12/17/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited multisystem disorder, characterized by renal and extra-renal fluid-filled cyst formation and increased kidney volume that eventually leads to end-stage renal disease. ADPKD is considered the fourth leading cause of end-stage renal disease in the United States and globally. Care of patients with ADPKD was, for a long time, limited to supportive lifestyle measures, due to the lack of therapeutic strategies targeting the main pathways involved in the pathophysiology of ADPKD. As the first FDA approved treatment of ADPKD, Vasopressin (V2) receptor blocking agent, tolvaptan, is an urgently awaited advance for ADPKD patients. In our review, we also shed some lights on what is beyond Tolvaptan as there are other medications in the pipeline and many medications have been or are currently being studied in clinical trials such as Tesevatinib, Metformin and Pravastatin, with the goal of slowing the rate of progression of ADPKD by reducing the increase in total kidney volume or maintaining eGFR. Here, we review updates in the perspectives and management of ADPKD.
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Affiliation(s)
- Anjay Rastogi
- Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Khalid Mohammed Ameen
- Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Maha Al-Baghdadi
- Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Kelly Shaffer
- Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Niloofar Nobakht
- Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Mohammad Kamgar
- Department of Medicine, Division of Nephrology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Edgar V Lerma
- Department of Medicine, Divison of Nephrology, University of Illinois at Chicago/Advocate Christ Medical Center, Section of Nephrology, Oak Lawn, IL, USA
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Hayek SS, Landsittel DP, Wei C, Zeier M, Yu ASL, Torres VE, Roth S, Pao CS, Reiser J. Soluble Urokinase Plasminogen Activator Receptor and Decline in Kidney Function in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol 2019; 30:1305-1313. [PMID: 31171572 DOI: 10.1681/asn.2018121227] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 04/09/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Levels of soluble urokinase plasminogen activator receptor (suPAR), an inflammation marker, are strongly predictive of incident kidney disease. Patients with autosomal dominant polycystic kidney disease (ADPKD) experience progressive decline in renal function, but rates of decline and outcomes vary greatly. Whether suPAR levels are predictive of declining kidney function in patients with ADPKD is unknown. METHODS We assessed suPAR levels in 649 patients with ADPKD who underwent scheduled follow-up for at least 3 years, with repeated measurements of height-adjusted total kidney volume and creatinine-derived eGFR. We used linear mixed models for repeated measures and Cox proportional hazards to characterize associations between baseline suPAR levels and follow-up eGFR or incident ESRD. RESULTS The median suPAR level was 2.47 ng/ml and median height-adjusted total kidney volume was 778, whereas mean eGFR was 84 ml/min per 1.73 m2. suPAR levels were associated with height-adjusted total kidney volume (β=0.02; 95% confidence interval, 0.01 to 0.03), independent of age, sex, race, hypertension, and eGFR. Patients in the lowest suPAR tertile (<2.18 ng/ml) had a 6.8% decline in eGFR at 3 years and 22% developed CKD stage 3, whereas those in the highest tertile (suPAR>2.83 ng/ml) had a 19.4% decline in eGFR at 3 years and 68% developed CKD stage 3. suPAR levels >2.82 ng/ml had a 3.38-fold increase in the risk of incident ESRD. CONCLUSIONS suPAR levels were associated with progressive decline in renal function and incident ESRD in patients with ADPKD, and may aid early identification of patients at high risk of disease progression.
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Affiliation(s)
- Salim S Hayek
- Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor Michigan;
| | | | - Changli Wei
- Department of Medicine, Rush University Medical Center, Chicago, Illinois
| | - Martin Zeier
- Division of Nephrology, University of Heidelberg, Heidelberg, Germany
| | - Alan S L Yu
- Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas
| | | | - Sharin Roth
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
| | - Christina S Pao
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
| | - Jochen Reiser
- Department of Medicine, Rush University Medical Center, Chicago, Illinois;
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29
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Gansevoort RT, van Gastel MDA, Chapman AB, Blais JD, Czerwiec FS, Higashihara E, Lee J, Ouyang J, Perrone RD, Stade K, Torres VE, Devuyst O. Plasma copeptin levels predict disease progression and tolvaptan efficacy in autosomal dominant polycystic kidney disease. Kidney Int 2019; 96:159-169. [PMID: 30898339 DOI: 10.1016/j.kint.2018.11.044] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 11/19/2018] [Accepted: 11/29/2018] [Indexed: 02/08/2023]
Abstract
In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance ≥60 ml/min and total kidney volume ≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay. In placebo-treated subjects, baseline copeptin predicted kidney growth and eGFR decline over 3 years. These associations were independent of sex, age, and baseline eGFR, but were no longer statistically significant after additional adjustment for baseline total kidney volume. In tolvaptan-treated subjects, copeptin increased from baseline to week 3 (6.3 pmol/L versus 21.9 pmol/L, respectively). In tolvaptan-treated subjects with higher baseline copeptin levels, a larger treatment effect was noted with respect to kidney growth rate and eGFR decline. Tolvaptan-treated subjects with a larger percentage increase in copeptin from baseline to week 3 had a better disease outcome, with less kidney growth and eGFR decline after three years. Copeptin holds promise as a biomarker to predict outcome and tolvaptan treatment efficacy in ADPKD.
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Affiliation(s)
- Ron T Gansevoort
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
| | - Maatje D A van Gastel
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Arlene B Chapman
- Section of Nephrology, University of Chicago, Chicago, Illinois, USA
| | - Jaime D Blais
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland, USA
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland, USA
| | - Eiji Higashihara
- Department of ADPKD Research, Kyorin University School of Medicine, Tokyo, Japan
| | - Jennifer Lee
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland, USA
| | - John Ouyang
- Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland, USA
| | - Ronald D Perrone
- Department of Medicine, Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
| | | | - Vicente E Torres
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland; and Division of Nephrology, Université Catholique de Louvain, Brussels, Belgium
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30
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Edwards ME, Blais JD, Czerwiec FS, Erickson BJ, Torres VE, Kline TL. Standardizing total kidney volume measurements for clinical trials of autosomal dominant polycystic kidney disease. Clin Kidney J 2018; 12:71-77. [PMID: 30746130 PMCID: PMC6366146 DOI: 10.1093/ckj/sfy078] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 07/21/2018] [Indexed: 12/27/2022] Open
Abstract
Background The ability of unstandardized methods to track kidney growth in clinical trials for autosomal dominant polycystic kidney disease (ADPKD) has not been critically evaluated. Methods The Tolvaptan Efficacy and Safety Management of ADPKD and its Outcomes (TEMPO) 3:4 study involved baseline and annual magnetic resonance follow-up imaging yearly for 3 years. Total kidney volume (TKV) measurements were performed on these four time points in addition to the baseline imaging in TEMPO 4:4, initially by Perceptive Informatics (Waltham, MA, USA) using planimetry (original dataset) and for this study by the Mayo Translational PKD Center using semiautomated and complementary automated methods (sequential dataset). In the original dataset, the same reader was assigned to all scans of individual patients in TEMPO 3:4, but readers were reassigned in TEMPO 4:4. Two placebo-treated cohorts were included. In the first (n = 158), intervals between the end of TEMPO 3:4 and the start of TEMPO 4:4 scan visits ranged from 12 to 403 days; in the second (n = 95), the same scan (measured twice) visit was used for both. Results Growth rates in TEMPO 3:4 were similar in the original and sequential datasets (5.5 and 5.9%/year). Growth rates during the TEMPO 3:4 to TEMPO 4:4 interval were higher in the original (13.7%/year) but were not different in the sequential dataset (4.0%/year). Comparing volumes from the same images, TKVs showed a bias of 2.2% [95% confidence interval (CI) −5.2–9.7] in the original and −0.16% (95% CI −1.91–1.58) in the sequential dataset. Conclusions Despite using the same software, TKV and growth rate changes were present, likely due to reader differences in the transition from TEMPO 3:4 to TEMPO 4:4 in the original but not in the sequential dataset. Robust, standardized methods are essential in ADPKD trials to minimize errors in serial TKV measurements.
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31
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Turco D, Valinoti M, Martin EM, Tagliaferri C, Scolari F, Corsi C. Fully Automated Segmentation of Polycystic Kidneys From Noncontrast Computed Tomography: A Feasibility Study and Preliminary Results. Acad Radiol 2018; 25:850-855. [PMID: 29331360 DOI: 10.1016/j.acra.2017.11.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/16/2017] [Accepted: 11/21/2017] [Indexed: 10/18/2022]
Abstract
RATIONALE AND OBJECTIVES Total kidney volume is an important biomarker for the evaluation of autosomal dominant polycystic kidney disease progression. In this study, we present a novel approach for automated segmentation of polycystic kidneys from non-contrast-enhanced computed tomography (CT) images. MATERIALS AND METHODS Non-contrast-enhanced CT images were acquired from 21 patients with a diagnosis of autosomal dominant polycystic kidney disease. Kidney volumes obtained from the fully automated method were compared to volumes obtained by manual segmentation and evaluated using linear regression and Bland-Altman analyses. Dice coefficient was used for performance evaluation. RESULTS Kidney volumes from the automated method well correlated with the ones obtained by manual segmentation. Bland-Altman analysis showed a low percentage bias (-0.3%) and narrow limits of agreements (11.0%). The overlap between the three-dimensional kidney surfaces obtained with our approach and by manual tracing, expressed in terms of Dice coefficient, showed good agreement (0.91 ± 0.02). CONCLUSIONS This preliminary study showed the proposed fully automated method for renal volume assessment is feasible, exhibiting how a correct use of biomedical image processing may allow polycystic kidney segmentation also in non-contrast-enhanced CT. Further investigation on a larger dataset is needed to confirm the robustness of the presented approach.
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Kline TL, Korfiatis P, Edwards ME, Blais JD, Czerwiec FS, Harris PC, King BF, Torres VE, Erickson BJ. Performance of an Artificial Multi-observer Deep Neural Network for Fully Automated Segmentation of Polycystic Kidneys. J Digit Imaging 2018; 30:442-448. [PMID: 28550374 PMCID: PMC5537093 DOI: 10.1007/s10278-017-9978-1] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Deep learning techniques are being rapidly applied to medical imaging tasks—from organ and lesion segmentation to tissue and tumor classification. These techniques are becoming the leading algorithmic approaches to solve inherently difficult image processing tasks. Currently, the most critical requirement for successful implementation lies in the need for relatively large datasets that can be used for training the deep learning networks. Based on our initial studies of MR imaging examinations of the kidneys of patients affected by polycystic kidney disease (PKD), we have generated a unique database of imaging data and corresponding reference standard segmentations of polycystic kidneys. In the study of PKD, segmentation of the kidneys is needed in order to measure total kidney volume (TKV). Automated methods to segment the kidneys and measure TKV are needed to increase measurement throughput and alleviate the inherent variability of human-derived measurements. We hypothesize that deep learning techniques can be leveraged to perform fast, accurate, reproducible, and fully automated segmentation of polycystic kidneys. Here, we describe a fully automated approach for segmenting PKD kidneys within MR images that simulates a multi-observer approach in order to create an accurate and robust method for the task of segmentation and computation of TKV for PKD patients. A total of 2000 cases were used for training and validation, and 400 cases were used for testing. The multi-observer ensemble method had mean ± SD percent volume difference of 0.68 ± 2.2% compared with the reference standard segmentations. The complete framework performs fully automated segmentation at a level comparable with interobserver variability and could be considered as a replacement for the task of segmentation of PKD kidneys by a human.
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Affiliation(s)
- Timothy L Kline
- Department of Radiology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN, 55905, USA.
| | - Panagiotis Korfiatis
- Department of Radiology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN, 55905, USA
| | - Marie E Edwards
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Jaime D Blais
- Otsuka Pharmaceutical Development & Commercialization Inc., Rockville, MD, USA
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development & Commercialization Inc., Rockville, MD, USA
| | - Peter C Harris
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Bernard F King
- Department of Radiology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN, 55905, USA
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Bradley J Erickson
- Department of Radiology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN, 55905, USA
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McEwan P, Bennett Wilton H, Ong ACM, Ørskov B, Sandford R, Scolari F, Cabrera MCV, Walz G, O'Reilly K, Robinson P. A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model. BMC Nephrol 2018; 19:37. [PMID: 29439650 PMCID: PMC5810027 DOI: 10.1186/s12882-017-0804-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 12/18/2017] [Indexed: 01/05/2023] Open
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. Electronic supplementary material The online version of this article (10.1186/s12882-017-0804-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Phil McEwan
- Swansea Centre for Health Economics, Swansea University, Swansea, UK.,Health Economics and Outcomes Research Ltd, Cardiff, UK
| | | | - Albert C M Ong
- Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, UK.,Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Bjarne Ørskov
- Department of Internal Medicine, Section of Nephrology, Zealand University Hospital, Roskilde, Denmark
| | - Richard Sandford
- Academic Laboratory of Medical Genetics, Addenbrooke's Treatment Centre, Cambridge, UK
| | | | | | - Gerd Walz
- Department of Nephrology, University Medical Centre Freiburg, Freiburg, Germany
| | - Karl O'Reilly
- Otsuka Pharmaceutical Europe Ltd, Gallions Wexham Springs, Framewood Road, Wexham, SL3 6PJ, UK. KO'
| | - Paul Robinson
- Otsuka Pharmaceutical Europe Ltd, Gallions Wexham Springs, Framewood Road, Wexham, SL3 6PJ, UK
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Devuyst O, Chapman AB, Shoaf SE, Czerwiec FS, Blais JD. Tolerability of Aquaretic-Related Symptoms Following Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Results From TEMPO 3:4. Kidney Int Rep 2017; 2:1132-1140. [PMID: 29270521 PMCID: PMC5733681 DOI: 10.1016/j.ekir.2017.07.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 07/07/2017] [Accepted: 07/17/2017] [Indexed: 11/06/2022] Open
Abstract
Introduction In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. Methods A post hoc analysis of tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. Results In total, 750 of 961 tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. Discussion In this study, AAEs were common but well tolerated in ADPKD patients on tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding tolvaptan dosing and titration decisions in the future.
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Affiliation(s)
- Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland.,Division of Nephrology, Université catholique de Louvain Medical School, Brussels, Belgium
| | - Arlene B Chapman
- Division of Nephrology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Susan E Shoaf
- Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland, USA
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland, USA
| | - Jaime D Blais
- Otsuka Pharmaceutical Development & Commercialization, Rockville, Maryland, USA
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Devuyst O, Chapman AB, Gansevoort RT, Higashihara E, Perrone RD, Torres VE, Blais JD, Zhou W, Ouyang J, Czerwiec FS. Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial. J Am Soc Nephrol 2017; 28:1592-1602. [PMID: 27920153 PMCID: PMC5407721 DOI: 10.1681/asn.2016040448] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 10/26/2016] [Indexed: 12/17/2022] Open
Abstract
The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to tolvaptan, and whether change in Uosm associated with key trial end points. At baseline, lower Uosm independently associated with female sex, presence of hypertension, lower eGFR, higher total kidney volume (TKV), and higher age. Tolvaptan consistently reduced Uosm by 200-300 mOsm/kg over 36 months. The Uosm response to tolvaptan depended on baseline eGFR and Uosm. Subjects with greater change in Uosm experienced a significant reduction in clinical progression events. Among subjects receiving tolvaptan, those with a greater suppression of Uosm had slower renal function decline. Assessment at follow-up, off medication, revealed a significant decrease in Uosm in both placebo and treated groups. Tolvaptan significantly increased plasma osmolality, which returned to baseline at follow-up. In conclusion, baseline Uosm in ADPKD reflects age, renal function, and TKV, and baseline Uosm, eGFR, and TKV influence the effect of tolvaptan on Uosm. The greatest renal benefit occurred in subjects achieving greater suppression of Uosm, that is, those with better eGFR at baseline. These results support the link between vasopressin V2 receptor signaling and ADPKD progression.
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Affiliation(s)
- Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland;
| | - Arlene B Chapman
- Division of Nephrology, University of Chicago, Chicago, Illinois
| | - Ron T Gansevoort
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Eiji Higashihara
- Department of Urology, Kyorin University School of Medicine, Mitaka, Japan
| | - Ronald D Perrone
- Department of Medicine, Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; and
| | - Jaime D Blais
- Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland
| | - Wen Zhou
- Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland
| | - John Ouyang
- Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development and Commercialization, Rockville, Maryland
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Al Therwani S, Rosenbæk JB, Mose FH, Bech JN, Pedersen EB. Effect of tolvaptan on renal water and sodium excretion and blood pressure during nitric oxide inhibition: a dose-response study in healthy subjects. BMC Nephrol 2017; 18:86. [PMID: 28288570 PMCID: PMC5347830 DOI: 10.1186/s12882-017-0501-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 03/07/2017] [Indexed: 01/17/2023] Open
Abstract
Background Tolvaptan is a selective vasopressin receptor antagonist. Nitric Oxide (NO) promotes renal water and sodium excretion, but the effect is unknown in the nephron’s principal cells. In a dose-response study, we measured the effect of tolvaptan on renal handling of water and sodium and systemic hemodynamics, during baseline and NO-inhibition with L-NMMA (L-NG-monomethyl-arginine). Methods In a randomized, placebo-controlled, double blind, cross over study, 15 healthy subjects received tolvaptan 15, 30 and 45 mg or placebo. L-NMMA was given as a bolus followed by continuous infusion during 60 min. We measured urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP) and central blood pressure (cBP). Results During baseline, FENa was unchanged. Tolvaptan decreased u-ENaCγ dose-dependently and increased p-AVP threefold, whereas u-AQP2 was unchanged. During tolvaptan with NO-inhibition, UO and CH2O decreased dose-dependently. FENa decreased dose-independently and u-ENaCγ remained unchanged. Central BP increased equally after all treatments. Conclusions During baseline, fractional excretion of sodium was unchanged. During tolvaptan with NO-inhibition, renal water excretion was reduced dose dependently, and renal sodium excretion was reduced unrelated to the dose, partly via an AVP dependent mechanism. Thus, tolvaptan antagonized the reduction in renal water and sodium excretion during NO-inhibition. Most likely, the lack of decrease in AQP2 excretion by tolvaptan could be attributed to a counteracting effect of the high level of p-AVP. Trial registration Clinical Trial no: NCT02078973. Registered 1 March 2014. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0501-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Safa Al Therwani
- University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark.
| | - Jeppe Bakkestrøm Rosenbæk
- University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark
| | - Frank Holden Mose
- University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark
| | - Jesper Nørgaard Bech
- University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark
| | - Erling Bjerregaard Pedersen
- University Clinic in Nephrology and Hypertension, Department of Medical Research, Holstebro Hospital, Aarhus University, Hospital Unit Jutland West, Laegaardvej 12, 7500, Holstebro, Denmark
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37
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Shoaf SE, Chapman AB, Torres VE, Ouyang J, Czerwiec FS. Pharmacokinetics and Pharmacodynamics of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Phase 2 Trials for Dose Selection in the Pivotal Phase 3 Trial. J Clin Pharmacol 2017; 57:906-917. [PMID: 28218410 PMCID: PMC5480307 DOI: 10.1002/jcph.880] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 01/16/2017] [Indexed: 12/17/2022]
Abstract
In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2‐receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient‐reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split‐dose regimen: a single ascending‐dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split‐dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8‐week open‐label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to <300 mOsm/kg for 24 hours. The 45/15‐mg regimen was well tolerated and effective in suppressing Uosm in >50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30‐mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate.
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Affiliation(s)
- Susan E Shoaf
- Otsuka Pharmaceutical Development & Commercialization, Rockville, MD, USA
| | - Arlene B Chapman
- Division of Nephrology, Emory University School of Medicine, Atlanta, GA, USA
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - John Ouyang
- Otsuka Pharmaceutical Development & Commercialization, Rockville, MD, USA
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development & Commercialization, Rockville, MD, USA
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Torres VE, Devuyst O, Chapman AB, Gansevoort RT, Perrone RD, Ouyang J, Blais JD, Czerwiec FS, Sergeyeva O. Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease. Am J Nephrol 2017; 45:257-266. [PMID: 28166521 DOI: 10.1159/000456087] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 01/09/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND In TEMPO 3:4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function. METHODS Prospective, phase 3b, multi-center, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD). The primary endpoint was estimated glomerular filtration rate (eGFR) change from pre-treatment baseline to post-treatment follow-up. Secondary endpoints included annualized eGFR slope, incidence of ADPKD complications, and overall and hepatic safety profiles. Participants were 18-55 year-old ADPKD patients with baseline eGFR ≥25 and ≤65 mL/min/1.73 m2 or 56-65 year-old with eGFR ≥25 and ≤44 mL/min/1.73 m2 and evidence of eGFR decline >2.0 mL/min/1.73 m2 per year. Daily split doses of tolvaptan were titrated to tolerance (30/15, 45/15, 60/30, or 90/30 mg) and maintained for 12 months, after an 8-week pre-randomization period to screen out subjects unable to tolerate at least 60/30 mg for 3 weeks. RESULTS Of 1,495 subjects who entered the tolvaptan titration period, 125 (8.4%) discontinued the study before randomization. One thousand three hundred seventy subjects (684 tolvaptan, 686 placebo) from 213 centers across 21 countries were randomized. Baseline demographics were well balanced across treatment arms. Information collected during the study included eGFR, survey scores (PKD history and outcome), adverse events, vital signs, hematology, urinalysis, and serum chemistry tests. CONCLUSION Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) determines whether tolvaptan administered over 1 year exhibits disease-modifying properties in ADPKD patients with late stage 2 to early stage 4 CKD, which provides an important therapeutic advancement for this difficult-to-treat disease.
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Affiliation(s)
- Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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Cadnapaphornchai MA. Clinical Trials in Pediatric Autosomal Dominant Polycystic Kidney Disease. Front Pediatr 2017; 5:53. [PMID: 28386535 PMCID: PMC5362630 DOI: 10.3389/fped.2017.00053] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 02/28/2017] [Indexed: 12/14/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is associated with concerning long-term implications for kidney function and cardiovascular health. Early intervention is needed in order to mitigate these long-term complications. Herein, we review important findings from recent clinical trials in ADPKD and their relevance to affected children and young adults and consider future directions for intervention. Recent clinical trials support aggressive control of blood pressure with blockade of the renin-angiotensin-aldosterone system as well as potential benefit of pravastatin therapy in children and young adults with ADPKD. There are several other candidate therapies, some of which have shown benefit in adult ADPKD, which require further investigation in affected children.
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Abstract
Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined. Autosomal Dominant Polycystic Kidney Disease is the most common renal cystic disease, caused by disruption of polycystin-1 and polycystin-2 transmembrane proteins, which evidence suggests must localize to primary cilia for proper function. To understand how the absence of these proteins in primary cilia may be remediated, we review intracellular trafficking of polycystins to the primary cilium. We also examine the controversial mechanisms by which primary cilia transduce flow-mediated mechanical stress into intracellular calcium. Further, to better understand ciliary function in the kidney, we highlight the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease.
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Casteleijn NF, Blais JD, Chapman AB, Czerwiec FS, Devuyst O, Higashihara E, Leliveld AM, Ouyang J, Perrone RD, Torres VE, Gansevoort RT. Tolvaptan and Kidney Pain in Patients With Autosomal Dominant Polycystic Kidney Disease: Secondary Analysis From a Randomized Controlled Trial. Am J Kidney Dis 2016; 69:210-219. [PMID: 27856088 PMCID: PMC5497700 DOI: 10.1053/j.ajkd.2016.08.028] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 08/08/2016] [Indexed: 11/20/2022]
Abstract
Background Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3:4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is difficult to measure, the incidence of kidney pain leading to objective medical interventions was used in the present study to assess pain. Study Design Secondary analysis from a randomized controlled trial. Setting & Participants Patients with ADPKD with preserved kidney function. Intervention Tolvaptan or placebo. Outcomes Kidney pain events defined by objective medical interventions. Measurements Kidney pain events were recorded and independently adjudicated. Incidence of a first kidney pain event was assessed overall and categorized into 5 subgroups according to severity. Results Of 1,445 participating patients (48.4% women; mean age, 39 ± 7 [SD] years; mean estimated glomerular filtration rate, 81 ± 22 mL/min/1.73 m2; median total kidney volume, 1,692 [IQR, 750–7,555] mL), 50.9% reported a history of kidney pain at baseline. History of urinary tract infections, kidney stones, or hematuria (all P < 0.001) and female sex (P < 0.001) were significantly associated with history of kidney pain. Tolvaptan use resulted in a significantly lower incidence of kidney pain events when compared to placebo: 10.1% versus 16.8% (P < 0.001), with a risk reduction of 36% (HR, 0.64; 95% CI, 0.48–0.86). The reduction in pain event incidence by tolvaptan was found in all groups irrespective of pain severity and was independent of predisposing factors (P for interaction > 0.05). The effect of tolvaptan was explained at least in part by a decrease in incidence of urinary tract infections, kidney stones, and hematuria when compared to placebo. Limitations Trial has specific inclusion criteria for total kidney volume and kidney function. Conclusions Tolvaptan decreased the incidence of kidney pain events independent of patient characteristics predisposing for kidney pain and possibly in part due to reductions in ADPKD-related complications.
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Affiliation(s)
- Niek F Casteleijn
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jaime D Blais
- Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD
| | - Arlene B Chapman
- Division of Nephrology, Emory University School of Medicine, Atlanta, GA
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD
| | - Olivier Devuyst
- Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Eiji Higashihara
- Department of Urology, Kyorin University School of Medicine, Mitaka, Japan
| | - Anna M Leliveld
- Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - John Ouyang
- Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, MD
| | - Ronald D Perrone
- Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Ron T Gansevoort
- Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Mallett A, Lee VW, Mai J, Lopez-Vargas P, Rangan GK. KHA-CARI Autosomal Dominant Polycystic Kidney Disease Guideline: Pharmacological Management. Semin Nephrol 2016; 35:582-589.e17. [PMID: 26718162 DOI: 10.1016/j.semnephrol.2015.10.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- Andrew Mallett
- Kidney Health Service and Conjoint Kidney Research Laboratory, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Centre for Kidney Disease Research, Centre for Chronic Disease and CKD, School of Medicine and Centre for Rare Diseases Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
| | - Vincent W Lee
- Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Sydney, Australia; Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Westmead, Sydney, Australia
| | - Jun Mai
- Department of Nephrology, Liverpool and Bankstown Hospital, South Western Sydney Local Health District, Sydney, Australia
| | - Pamela Lopez-Vargas
- KHA-CARI Guidelines, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Sydney, Australia; Sydney School of Public Health, The University of Sydney, Sydney, Australia
| | - Gopala K Rangan
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Westmead, Sydney, Australia; Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Sydney, Australia
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Rysz J, Gluba-Brzózka A, Franczyk B, Banach M, Bartnicki P. Combination drug versus monotherapy for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Pharmacother 2016; 17:2049-56. [DOI: 10.1080/14656566.2016.1232394] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Irazabal MV, Blais JD, Perrone RD, Gansevoort RT, Chapman AB, Devuyst O, Higashihara E, Harris PC, Zhou W, Ouyang J, Czerwiec FS, Torres VE. Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial. Kidney Int Rep 2016; 1:213-220. [PMID: 29142926 PMCID: PMC5678619 DOI: 10.1016/j.ekir.2016.08.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/29/2016] [Accepted: 08/01/2016] [Indexed: 01/26/2023] Open
Abstract
Introduction Patients with slowly progressive autosomal dominant polycystic kidney disease (ADPKD) are unlikely to experience outcomes during randomized controlled trials (RCTs). An image classification of ADPKD into typical (diffuse cyst distribution) class 1A to E (by age- and height-adjusted total kidney volume [TKV]) and atypical (asymmetric cyst distribution) class 2 was proposed for prognostic enrichment design, recommending inclusion of only classes 1C to 1E in RCTs. Methods A post hoc exploratory analysis was conducted of the TEMPO 3:4 Trial, a prospective, randomized, double-blinded, controlled clinical trial in adult subjects with ADPKD, an estimated creatinine clearance >60 ml/min and total kidney volume >750 ml. Results Due to the entry criteria, the study population of TEMPO 3:4 was enriched for classes 1C-E (89.5 % of 1436 patients with baseline magnetic resonance images) compared to unselected populations (e.g., 60.5% of 590 Mayo Clinic patients). The effects of tolvaptan on TKV and eGFR slopes were greater in classes 1C to E than in 1B. In TEMPO 3:4, tolvaptan reduced TKV and eGFR slopes from 5.51% to 2.80% per year and from −3.70 to −2.78 ml/min/1.73 m2 per year, and lowered the risk for a composite endpoint of clinical progression events (hazard ratio = 0.87). Restricting enrollment to classes 1C to E would have reduced TKV and eGFR slopes from 5.78% to 2.91% per year and from −3.93 to −2.82 ml/min/1.73 m2 per year, and the risk of the composite endpoint (hazard ratio = 0.84, P = 0.003), with 10.5% fewer patients. Discussion Prognostic enrichment strategies such as the entry criteria used for TEMPO 3:4 or preferably the proposed image classification should be used in RCTs for ADPKD to increase power and to reduce cost.
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Affiliation(s)
- Maria V Irazabal
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Jaime D Blais
- Otsuka Pharmaceutical Development and Commercialization Inc.; Global Medical Affairs, Princeton, NJ
| | | | | | - Arlene B Chapman
- Division of Nephrology, University of Chicago, Chicago, Illinois, USA
| | - Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Eiji Higashihara
- Department of Urology, Kyorin University School of Medicine, Mitaka, Japan
| | - Peter C Harris
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Wen Zhou
- Otsuka Pharmaceutical Development and Commercialization Inc., Biostatistics, Rockville, Maryland, USA
| | - John Ouyang
- Otsuka Pharmaceutical Development and Commercialization Inc., Biostatistics, Rockville, Maryland, USA
| | - Frank S Czerwiec
- Otsuka Pharmaceutical Development and Commercialization Inc., Global Clinical Development, Rockville, Maryland, USA
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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Abstract
Tolvaptan (Jinarc(®)) is a highly selective vasopressin V2 receptor antagonist indicated for use in patients with autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is the first pharmaceutical agent to be approved in Europe for delaying the progression of ADPKD in adults with stage 1-3 chronic kidney disease at initiation of treatment. In the large phase III TEMPO 3:4 trial in adults with ADPKD, 3 years' treatment with oral tolvaptan significantly reduced growth in total kidney volume and slowed renal function decline relative to placebo. Tolvaptan was also associated with a significantly lower rate of events for the composite secondary endpoint of time to investigator-assessed clinical progression relative to placebo, an effect that was largely attributable to reductions in the risk of worsening renal function and the risk of worsening kidney pain. Many of the most common adverse events in the tolvaptan group were related to its aquaretic mechanism of action (e.g. polyuria, nocturia, polydipsia and thirst). Tolvaptan was also associated with idiosyncratic elevations of liver enzymes which were reversible on discontinuation of the drug. Although the use of tolvaptan requires careful consideration and balancing of benefits and risks, current evidence suggests that tolvaptan is a promising new treatment option for patients with ADPKD.
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Hirai K, Shimomura T, Moriwaki H, Ishii H, Shimoshikiryo T, Tsuji D, Inoue K, Kadoiri T, Itoh K. Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment. Eur J Clin Pharmacol 2016; 72:1177-1183. [PMID: 27395406 DOI: 10.1007/s00228-016-2091-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 07/01/2016] [Indexed: 12/14/2022]
Abstract
PURPOSE The long-term efficacy of tolvaptan, a vasopressin V2 receptor antagonist, has been reported. However, the safety of long-term treatment remains to be fully elucidated. We assessed the safety profile of tolvaptan with respect to hypernatremia. METHODS This retrospective study included 371 patients treated with tolvaptan. Risk factors for hypernatremia (serum sodium concentration ≥147 mEq/L) were determined. RESULTS Hypernatremia occurred in 95 patients (25.6 %), of whom 71 (19.1 %) developed hypernatremia within 7 days of tolvaptan treatment (early onset). Stepwise logistic regression analysis demonstrated that baseline serum sodium ≥140 mEq/L, an initial tolvaptan dosage >7.5 mg, and a BUN/serum creatinine ratio ≥20 were independent risk factors for early onset of hypernatremia. Tolvaptan was prescribed for more than 7 days to 233 patients, of whom 123 were administrated tolvaptan for more than 1 month. Hypernatremia occurred in 24 of these patients (10.3 %) (late onset). Predictive factors for late onset of hypernatremia were an average daily dosage of tolvaptan >7.5 mg and age ≥75 years. CONCLUSIONS A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia.
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Affiliation(s)
- Keita Hirai
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Tatsuki Shimomura
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Hideaki Moriwaki
- Department of Cardiology, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Hidetoshi Ishii
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Department of Pharmacy, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Takayuki Shimoshikiryo
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Daiki Tsuji
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Kazuyuki Inoue
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan.,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Toshihiko Kadoiri
- Department of Pharmacy, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan
| | - Kunihiko Itoh
- Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Japan. .,Laboratory of Clinical Pharmacogenomics, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka, 420-8527, Japan.
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Polyuria due to vasopressin V2 receptor antagonism is not associated with increased ureter diameter in ADPKD patients. Clin Exp Nephrol 2016; 21:375-382. [PMID: 27339446 DOI: 10.1007/s10157-016-1297-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 06/10/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal function loss. Therefore, we aimed to investigate the effect of tolvaptan-induced polyuria on ureter diameter in ADPKD patients. METHODS 70 ADPKD patients were included (51 were randomized to tolvaptan and 19 to placebo). At baseline and after 3 years of treatment renal function was measured (mGFR) and MRI was performed to measure TKV and ureter diameter at the levels of renal pelvis and fifth lumbar vertebral body (L5). RESULTS In these patients [65.7 % male, age 41 ± 9 years, mGFR 74 ± 27 mL/min/1.73 m2 and TKV 1.92 (1.27-2.67) L], no differences were found between tolvaptan and placebo-treated patients in 24-h urine volume at baseline (2.5 vs. 2.5 L, p = 0.8), nor in ureter diameter at renal pelvis and L5 (4.0 vs. 4.2 mm, p = 0.4 and 3.0 vs. 3.1 mm, p = 0.3). After 3 years of treatment 24-h urine volume was higher in tolvaptan-treated patients when compared to placebo (4.7 vs. 2.3 L, p < 0.001), but no differences were found in ureter diameter between both groups (renal pelvis: 4.2 vs. 4.4 mm, p = 0.4 and L5: 3.1 vs. 3.3 mm, p = 0.4). CONCLUSIONS Tolvaptan-induced polyuria did not lead to an increase in ureter diameter, suggesting that tolvaptan is a safe therapy from a urological point of view.
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Torres VE, Higashihara E, Devuyst O, Chapman AB, Gansevoort RT, Grantham JJ, Perrone RD, Ouyang J, Blais JD, Czerwiec FS. Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial. Clin J Am Soc Nephrol 2016; 11:803-811. [PMID: 26912543 PMCID: PMC4858477 DOI: 10.2215/cjn.06300615] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 01/27/2016] [Indexed: 11/23/2022]
Abstract
BACKGROUND and objectives The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 study demonstrated a significant beneficial effect of the vasopressin V2 receptor antagonist tolvaptan on rates of kidney growth and eGFR decline in autosomal dominant polycystic kidney disease (ADPKD). This post hoc analysis was performed to reassess the primary and secondary efficacy endpoints by CKD stage at baseline. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, 1445 patients with ADPKD (age 18-50 years), with total kidney volume (TKV) ≥750 ml and estimated creatinine clearance ≥60 ml/min, were randomly assigned 2:1 to split-dose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo. The primary endpoint was annualized rate of TKV change. Secondary endpoints included a composite endpoint of time to multiple composite ADPKD-related events (worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney function decline. RESULTS Tolvaptan reduced annualized TKV growth by 1.99%, 3.12%, and 2.61% per year (all P<0.001; subgroup-treatment interaction, P=0.17) and eGFR decline by 0.40 in CKD1 (P=0.23), 1.13 in CKD2 (P<0.001) and 1.66 ml/min per 1.73 m(2) per year in CKD3 (P<0.001) with a trend for a positive subgroup-treatment interaction (P=0.07) across CKD1, CKD2 and CKD3. ADPKD-related events were less frequent in tolvaptan recipients than in placebo recipients among those with CKD1 (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.70-0.98; P=0.03) and those with CKD 3 (HR, 0.71; 95% CI, 0.57-0.89; P=0.003), but not among those with CKD2 (HR, 1.02; 95% CI, 0.85-1.21; P=0.86). Aquaresis-related adverse events (more frequent in the tolvaptan group) and ADPKD-related adverse events (more frequent in the placebo group) were not associated with CKD stage. Hypernatremia events in tolvaptan-treated patients with CKD3 and plasma aminotransferase elevations in tolvaptan-treated patients across CKD stages 1-3 occurred more frequently than in placebo recipients. CONCLUSIONS This post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.
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Affiliation(s)
- Vicente E Torres
- Due to the number of contributing authors, the affiliations are provided in the Supplemental Material
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Kim H, Hwang YH. Clinical Trials and a View Toward the Future of ADPKD. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 933:105-121. [PMID: 27730438 DOI: 10.1007/978-981-10-2041-4_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In light of the advances in the understanding of cystogenesis in clinical syndromes, potential therapeutic targets have been proposed. Among ciliopathies, autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary disease, and is characterized by the progressive enlargement of bilateral renal cysts, resulting in end-stage kidney failure. Progress in genetics and molecular pathobiology has enabled the development of therapeutic agents that can modulate aberrant molecular pathways. Recently, clinical trials using somatostatin analogs and vasopressin receptor antagonists were conducted, and resulted in the approval of tolvaptan in managing kidney disease in some countries. We will summarize the developments of therapeutic agents based on pathogenesis, and discuss recent findings in clinical trials. Moreover, issues such as the timing of the intervention and outcome assessment will be discussed.
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Affiliation(s)
- Hyunsuk Kim
- Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
| | - Young-Hwan Hwang
- Department of Internal Medicine, Eulji General Hospital, 14, Hangeulbiseok-gil, Nowon-gu, Seoul, 01830, South Korea
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Validation of Effective Therapeutic Targets for ADPKD Using Animal Models. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 933:71-84. [DOI: 10.1007/978-981-10-2041-4_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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