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      Genetics May Predict Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease


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          Background: Tolvaptan is the only therapeutic drug for autosomal dominant polycystic kidney disease (ADPKD). The influence of mutations in polycystic kidney disease 1 and 2 genes ( PKD1 and PKD2) on the treatment effects of tolvaptan is not well documented in the literature. Methods: We retrospectively evaluated the relationship between genotype and the efficacy of tolvaptan in 18 patients with ADPKD who had been treated at Toranomon Hospital and undergone genetic testing between April 2016 and February 2020. Results: The annual change in estimated glomerular filtration rate (ΔeGFR/y) from before to after tolvaptan was from a median of −5.5 to −2.5 mL/min/1.73 m<sup>2</sup> in the PKD1 truncating group, −3.3 to −2.4 mL/min/1.73 m<sup>2</sup> in the PKD1 non-truncating group, −3.1 to −1.6 mL/min/1.73 m<sup>2</sup> in the PKD2 group, and −1.9 to −2.6 mL/min/1.73 m<sup>2</sup> in the group with no PKD1/2 mutation. The median degrees of improvement of ΔeGFR/y were 2.5 (45%), 0.4 (10%), 0.6 (28%), and −0.7 (−37%) mL/min/1.73 m<sup>2</sup>, respectively. Compared with the group of patients with any PKD1/ 2 mutation, the group with no PKD1/ 2 mutation showed significantly less improvement in ΔeGFR/y with tolvaptan (0.6 vs. −0.7 mL/min/1.73 m<sup>2</sup>, respectively; p = 0.01) and significantly less improvement in the annual rate of increase in total kidney volume (TKV) with tolvaptan (−6.7 vs. −1.1%, respectively; p = 0.02). Conclusion: Patients with ADPKD and no PKD1/ 2 mutation showed less improvement in ΔeGFR/y and the annual rate of increase in TKV with tolvaptan. Detecting PKD1/ 2 mutations may be useful for predicting the effectiveness of tolvaptan.

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          Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

          In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown.
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            Type of PKD1 mutation influences renal outcome in ADPKD.

            Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.
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              Autosomal dominant polycystic kidney disease

              Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and one of the most common causes of end-stage kidney disease. Multiple clinical manifestations, such as enlarged kidneys filled with growing cysts, hypertension, and multiple extrarenal complications, including liver cysts, intracranial aneurysms, and cardiac valvular disease, show that ADPKD is a systemic disorder. New information derived from clinical research using molecular genetics and advanced imaging techniques has provided enhanced tools for assessing the diagnosis and prognosis for individual patients and their families. Phase 3 randomised, placebo-controlled clinical trials have clarified aspects of disease management and a disease-modifying therapeutic drug is now available for patients with high risk of rapid disease progression. These developments provide a strong basis on which to make clear recommendations about the management of affected patients and families. Implementation of these advances has the potential to delay kidney failure, reduce the symptom burden, lessen the risk of cardiovascular complications, and prolong life.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                September 2020
                12 August 2020
                : 51
                : 9
                : 745-751
                [_a] aNephrology Center, Toranomon Hospital, Tokyo, Japan
                [_b] bOkinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
                [_c] cDepartment of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
                Author notes
                *Junichi Hoshino, Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon Minato-ku, Tokyo 105-8470 (Japan), hoshino@toranomon.gr.jp
                Author information
                509817 Am J Nephrol 2020;51:745–751
                © 2020 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 12 May 2020
                : 25 June 2020
                Page count
                Figures: 2, Tables: 2, Pages: 7
                Patient-Oriented, Translational Research: Research Article

                Cardiovascular Medicine,Nephrology
                Polycystic kidney disease 1,Tolvaptan,Polycystic kidney disease 2,Genotype,Autosomal dominant polycystic kidney disease


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