Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure

SPRINT Research Group

Research output: Contribution to journalArticlepeer-review

Abstract

RATIONALE & OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD.

STUDY DESIGN: Neuroimaging substudy of a randomized trial.

SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR).

INTERVENTION: Participants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering.

OUTCOMES: The magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV).

RESULTS: A total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m 2 (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm 3 (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm 3, respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm 3 (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm 3, respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction).

LIMITATIONS: Measurement variability due to multisite design.

CONCLUSIONS: Among adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease.

FUNDING: SPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases.

TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with study number NCT01206062.

Original languageEnglish (US)
Pages (from-to)677-687.e1
JournalAmerican Journal of Kidney Diseases
Volume79
Issue number5
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
SPRINT was funded by the National Institutes of Health (NIH; including the National Heart, Lung, and Blood Institute [NHLBI], the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke) under contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C and interagency agreement A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. Azilsartan and chlorthalidone (combined with azilsartan) were provided by Takeda Pharmaceuticals International. Computing resources were supported through 1S10OD023495-01, and additional support was provided through the following National Center for Advancing Translational Sciences clinical and translational science awards: UL1TR000439 (awarded to Case Western Reserve University); UL1RR025755 (Ohio State University); UL1RR024134 and UL1TR000003 (University of Pennsylvania); UL1RR025771 (Boston University); UL1TR000093 (Stanford University); UL1RR025752, UL1TR000073, and UL1TR001064 (Tufts University); UL1TR000050 (University of Illinois); UL1TR000005 (University of Pittsburgh); 9U54TR000017-06 (University of Texas Southwestern Medical Center); UL1TR000105-05 (University of Utah); UL1 TR000445 (Vanderbilt University); UL1TR000075 (George Washington University); UL1 TR000002 (University of California, Davis); UL1 TR000064 (University of Florida); and UL1TR000433 (University of Michigan); and by National Institute of General Medical Sciences, Centers of Biomedical Research Excellence award NIGMS P30GM103337 (awarded to Tulane University). The work presented here was also supported by R01DK092241, R01AG055606, and funding from the Alzheimer’s Association. The NIH and the US Department of Veterans Affairs had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; but not in the decision to submit the manuscript for publication. Takeda Pharmaceuticals did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Funding Information:
A list of the members of the SPRINT Study Research Group is available at https://www.sprinttrial.org/public/SPRINT_Publications_Acknowledgement_Long_List.pdf. Manjula Kurella Tamura, MD, MPH, Sarah Gaussoin, MS, Nicholas M. Pajewski, PhD, Greg Zaharchuk, MD, PhD, Barry I. Freedman, MD, Stephen R. Rapp, PhD, Alexander P. Auchus, MD, William E. Haley, MD, Suzanne Oparil, MD, Jessica Kendrick, MD, MPH, Christianne L. Roumie, MD, MPH, Srinivasan Beddhu, MD, Alfred K. Cheung, MD, Jeff D. Williamson, MD, MHS, John A. Detre, MD, Sudipto Dolui, PhD, R. Nick Bryan, MD, PhD, and Ilya M. Nasrallah, MD, PhD. Research idea and study design: MKT, NMP, GZ, RNB, JDW; data acquisition: MKT, GZ, SO, SB, AKC, JDW, JAD, SD, RNB, IMN; data analysis/interpretation: MKT, SG, NMP, GZ, BIF, SRR, APA, WEH, SO, JK, CLR, SB, AKC, JDW, JAD, SD, RNB, IMN; statistical analysis: SG, NMP. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. SPRINT was funded by the National Institutes of Health (NIH; including the National Heart, Lung, and Blood Institute [NHLBI], the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke) under contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C and interagency agreement A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. Azilsartan and chlorthalidone (combined with azilsartan) were provided by Takeda Pharmaceuticals International. Computing resources were supported through 1S10OD023495-01, and additional support was provided through the following National Center for Advancing Translational Sciences clinical and translational science awards: UL1TR000439 (awarded to Case Western Reserve University); UL1RR025755 (Ohio State University); UL1RR024134 and UL1TR000003 (University of Pennsylvania); UL1RR025771 (Boston University); UL1TR000093 (Stanford University); UL1RR025752, UL1TR000073, and UL1TR001064 (Tufts University); UL1TR000050 (University of Illinois); UL1TR000005 (University of Pittsburgh); 9U54TR000017-06 (University of Texas Southwestern Medical Center); UL1TR000105-05 (University of Utah); UL1 TR000445 (Vanderbilt University); UL1TR000075 (George Washington University); UL1 TR000002 (University of California, Davis); UL1 TR000064 (University of Florida); and UL1TR000433 (University of Michigan); and by National Institute of General Medical Sciences, Centers of Biomedical Research Excellence award NIGMS P30GM103337 (awarded to Tulane University). The work presented here was also supported by R01DK092241, R01AG055606, and funding from the Alzheimer's Association. The NIH and the US Department of Veterans Affairs had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; but not in the decision to submit the manuscript for publication. Takeda Pharmaceuticals did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Dr Kurella Tamura has received an honorarium from the American Federation for Aging Research outside the submitted work. Dr Oparil reports grants and support from NIH/NHLBI during the conduct of the study and outside the submitted work, has received personal fees from Preventric Diagnostics and CinCor, and currently serves as Editor-in-Chief for Current Hypertension Reports. Dr Auchus reports grants from the University of Mississippi Medical Center during the conduct of the study. Dr Roumie reports grants from the NIH during the conduct of the study. Dr Beddhu reports grants from NHLBI and NIDDK during the conduct of the study and support from Bayer, Boehringer Ingelheim, Novo Nortis, and UpToDate outside the submitted work. Dr Zaharchuk reports grants from the NIH during the conduct of the study. Dr Freedman reports grants from the NIH during the conduct of the study. Dr Williamson reports grants from the NIH, Biogen, and Alzheimer's Association outside the submitted work. Dr Nasrallah reports grants from NIH during the conduct of the study and fees from Biogen outside the submitted work. The remaining authors declare that they have no relevant financial interests. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of Veterans Affairs, or the US Government. Deidentified participant data will be available in the BioLinCC repository ( https://biolincc.nhlbi.nih.gov/studies/sprint). Received March 2, 2021. Evaluated by 4 external peer reviewers, with direct editorial input from a Statistics/Methods Editor and an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form July 28, 2021. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.

Funding Information:
Dr Kurella Tamura has received an honorarium from the American Federation for Aging Research outside the submitted work. Dr Oparil reports grants and support from NIH/NHLBI during the conduct of the study and outside the submitted work, has received personal fees from Preventric Diagnostics and CinCor, and currently serves as Editor-in-Chief for Current Hypertension Reports. Dr Auchus reports grants from the University of Mississippi Medical Center during the conduct of the study. Dr Roumie reports grants from the NIH during the conduct of the study. Dr Beddhu reports grants from NHLBI and NIDDK during the conduct of the study and support from Bayer, Boehringer Ingelheim, Novo Nortis, and UpToDate outside the submitted work. Dr Zaharchuk reports grants from the NIH during the conduct of the study. Dr Freedman reports grants from the NIH during the conduct of the study. Dr Williamson reports grants from the NIH, Biogen, and Alzheimer’s Association outside the submitted work. Dr Nasrallah reports grants from NIH during the conduct of the study and fees from Biogen outside the submitted work. The remaining authors declare that they have no relevant financial interests.

Publisher Copyright:
© 2021

Keywords

  • Hypertension
  • albuminuria
  • blood pressure (BP)
  • cerebral perfusion
  • chronic kidney disease (CKD)
  • intensive BP control
  • magnetic resonance imaging (MRI)
  • neuroimaging
  • white matter injury
  • white matter lesions
  • Blood Pressure/physiology
  • Renal Insufficiency, Chronic
  • Glomerular Filtration Rate
  • Humans
  • Male
  • Cerebrovascular Circulation
  • Perfusion
  • Antihypertensive Agents/pharmacology
  • Female
  • Aged

PubMed: MeSH publication types

  • Randomized Controlled Trial
  • Journal Article

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