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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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          Most cited references 16

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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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            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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              Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease.

              Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                September 2020
                12 August 2020
                : 51
                : 9
                : 745-751
                aNephrology Center, Toranomon Hospital, Tokyo, Japan
                bOkinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
                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
                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.

                Page count
                Figures: 2, Tables: 2, Pages: 7
                Patient-Oriented, Translational Research: Research Article


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