Determinants of progression in early autosomal dominant polycystic kidney disease: Is it blood pressure or renin-angiotensin-aldosterone-system blockade?

• Type of Material: Article
• Authors: Godela M. Brosnahan, University of Colorado; Kaleab Z. Abebe, University of Pittsburgh; Charity G. Moore, University of Pittsburgh; Kyongtae T. Bae, University of Pittsburgh; William E. Braun, Cleveland Clinic; Arlene B Chapman, Emory University; Michael F. Flessner, National Institutes of Health; Peter C. Harris, Mayo Clinic; Marie C. Hogan, Mayo Clinic; Ronald D. Perrone, Tufts Medical Center; Frederic Rahbari Oskoui, Emory University; Theodore I. Steinman, Beth Israel Deaconess Medical Center; Vicente E. Torres, Mayo Clinic
• Language: English
• Date: 2018-01-01
• Publisher: Bentham Science Publishers
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Bentham Science Publishers.
• Final Published Version (URL): http://dx.doi.org/10.2174/1573402114666180322110209
• Title of Journal or Parent Work: Current Hypertension Reviews
• ISSN: 1573-4021
• Volume: 14
• Issue: 1
• Start Page: 39
• End Page: 47
• Grant/Funding Information: Mutation analysis was supported by DK62410-S1 to Dr. Harris and the Mayo Translational PKD Center (DK090728).; Supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK62402 to Dr. Schrier, DK62411 to Dr. Perrone, DK62410 to Dr. Torres, DK082230 to Dr. Moore Patterson, DK62408 to Dr. Chapman, and DK62401 to Washington University in St. Louis) and the National Center for Research Resources General Clinical Research Centers (RR000039 to Emory University, RR000585 to the Mayo Clinic, RR000054 to Tufts Medical Center, RR000051 to the University of Colorado, RR023940 to the University of Kansas Medical Center, and RR001032 to Beth Israel Deaconess Medical Center), National Center for Advancing Translational Sciences Clinical and Translational Science Awards (RR025008 and TR000454 to Emory University, RR024150 and TR00135 to the Mayo Clinic, RR025752 and TR001064 to Tufts University, RR025780 and TR001082 to the University of Colorado, RR025758 and TR001102 to Beth Israel Deaconess Medical Center, RR033179 and TR000001 to the University of Kansas Medical Center, and RR024989 and TR000439 to Cleveland Clinic), by funding from the Zell Family Foundation (to the University of Colorado), and by a grant from the PKD Foundation.; Dr. Perrone has received consulting fees from Sanofi–Genzyme and Vertex Pharmaceuticals and consulting fees and grant support through his institution from Otsuka Pharmaceuticals and Kadmon; Drs. Torres and Harris, grant support from Otsuka Pharmaceuticals; Dr. Steinman, grant support from Kadmon, Fibrogen and AMAG Pharmaceuticals and a consulting fee from Sanofi-Genzyme; Dr. Rahbari-Oskoui, fees for serving on advisory boards from Otsuka, Kadmon, and Astute Medical, and also research support from Otsuka; Dr. Bae, consulting fees from Kadmon; Dr. Chapman, consulting fees from Kadmon, Otsuka and Pfizer, and also grant support from Otsuka; and Dr. Hogan receives research funds from Novartis USA and is a co-Investigator on multiple Otsuka-sponsored tolvaptan studies in ADPKD (at Mayo Clinic site). No other potential conflict of interest relevant to this article was reported.
• Keywords: estimated glomerular filtration rate; total kidney volume.; HALT PKD trials; angiotensin receptor blockers; autosomal dominant polycystic kidneydisease; Angiotensin-converting enzyme inhibitors
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: The HALT PKD trial in early autosomal dominant polycystic kidney disease (ADPKD) showed that intensive control of systolic blood pressure to 95-110 mmHg was associated with a 14% slower rate of kidney volume growth compared to standard control. It is unclear whether this result was due to greater blockade of the renin-angiotensin-aldosterone system (RAAS) by allowing the use of higher drug doses in the low blood pressure arm, or due to the lower blood pressure per se. Methods: In this secondary analysis of HALT PKD Study A, we categorized participants into high and low dose groups based on the median daily equivalent dose of RAAS blocking drugs used after the initial dose titration period. Using linear mixed models, we compared the percent change in total kidney volume and the slope of estimated glomerular filtration rate (eGFR) between the 2 groups. We also assessed the effects of time-varying dose and time-varying blood pressure parameters on these outcomes. Results: Subjects in the high dose group (n=252) did not experience a slower increase in total kidney volume than those in the low-dose (n=225) group, after adjustment for age, sex, genotype, and BP arm. The chronic slope of eGFR decline was similar in the 2 groups. Higher time-varying systolic blood pressure was associated with a steeper decline in eGFR. Conclusion: ADPKD progression (as detected by eGFR decline and TKV increase) was ameliorated by intense blood pressure control as opposed to pharmacologic intensity of RAAS blockade.