Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure

SPRINT Research Group

doi:10.1053/j.ajkd.2021.07.024

Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure

SPRINT Research Group

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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 language	English (US)
Pages (from-to)	677-687.e1
Journal	American Journal of Kidney Diseases
Volume	79
Issue number	5
DOIs	https://doi.org/10.1053/j.ajkd.2021.07.024
State	Published - 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.

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
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1053/j.ajkd.2021.07.024

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Cite this

@article{e0602d99f30443dfb9bcefca793135d3,

title = "Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure",

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.",

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",

author = "{SPRINT Research Group} and {Kurella Tamura}, Manjula and Sarah Gaussoin and Pajewski, {Nicholas M.} and Greg Zaharchuk and Freedman, {Barry I.} and Rapp, {Stephen R.} and Auchus, {Alexander P.} and Haley, {William E.} and Suzanne Oparil and Jessica Kendrick and Roumie, {Christianne L.} and Srinivasan Beddhu and Cheung, {Alfred K.} and Williamson, {Jeff D.} and Detre, {John A.} and Sudipto Dolui and Bryan, {R. Nick} and Nasrallah, {Ilya M.} and Paul Whelton and Johnson, {Karen C.} and Joni Snyder and Diane Bild and Denise Bonds and Nakela Cook and Jeffrey Cutler and Lawrence Fine and Peter Kaufmann and Paul Kimmel and Lenore Launer and Claudia Moy and William Riley and Laurie Ryan and Eser Tolunay and Song Yang and David Reboussin and Jeff Williamson and Ambrosius, {Walter T.} and William Applegate and Greg Evans and Capri Foy and Dalane Kitzman and Mary Lyles and Nick Pajewski and Steve Rapp and Scott Rushing and Killeen, {Anthony A.} and Paul Drawz and Lama Ghazi and Areef Ishani and Yelena Slinin",

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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2021",

year = "2022",

month = may,

doi = "10.1053/j.ajkd.2021.07.024",

language = "English (US)",

volume = "79",

pages = "677--687.e1",

journal = "American Journal of Kidney Diseases",

issn = "0272-6386",

publisher = "W.B. Saunders Ltd",

number = "5",

}

TY - JOUR

T1 - Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure

AU - SPRINT Research Group

AU - Kurella Tamura, Manjula

AU - Gaussoin, Sarah

AU - Pajewski, Nicholas M.

AU - Zaharchuk, Greg

AU - Freedman, Barry I.

AU - Rapp, Stephen R.

AU - Auchus, Alexander P.

AU - Haley, William E.

AU - Oparil, Suzanne

AU - Kendrick, Jessica

AU - Roumie, Christianne L.

AU - Beddhu, Srinivasan

AU - Cheung, Alfred K.

AU - Williamson, Jeff D.

AU - Detre, John A.

AU - Dolui, Sudipto

AU - Bryan, R. Nick

AU - Nasrallah, Ilya M.

AU - Whelton, Paul

AU - Johnson, Karen C.

AU - Snyder, Joni

AU - Bild, Diane

AU - Bonds, Denise

AU - Cook, Nakela

AU - Cutler, Jeffrey

AU - Fine, Lawrence

AU - Kaufmann, Peter

AU - Kimmel, Paul

AU - Launer, Lenore

AU - Moy, Claudia

AU - Riley, William

AU - Ryan, Laurie

AU - Tolunay, Eser

AU - Yang, Song

AU - Reboussin, David

AU - Williamson, Jeff

AU - Ambrosius, Walter T.

AU - Applegate, William

AU - Evans, Greg

AU - Foy, Capri

AU - Kitzman, Dalane

AU - Lyles, Mary

AU - Pajewski, Nick

AU - Rapp, Steve

AU - Rushing, Scott

AU - Killeen, Anthony A.

AU - Drawz, Paul

AU - Ghazi, Lama

AU - Ishani, Areef

AU - Slinin, Yelena

N1 - 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. Publisher Copyright: © 2021

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

KW - Hypertension

KW - albuminuria

KW - blood pressure (BP)

KW - cerebral perfusion

KW - chronic kidney disease (CKD)

KW - intensive BP control

KW - magnetic resonance imaging (MRI)

KW - neuroimaging

KW - white matter injury

KW - white matter lesions

KW - Blood Pressure/physiology

KW - Renal Insufficiency, Chronic

KW - Glomerular Filtration Rate

KW - Humans

KW - Male

KW - Cerebrovascular Circulation

KW - Perfusion

KW - Antihypertensive Agents/pharmacology

KW - Female

KW - Aged

UR - http://www.scopus.com/inward/record.url?scp=85121243697&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85121243697&partnerID=8YFLogxK

U2 - 10.1053/j.ajkd.2021.07.024

DO - 10.1053/j.ajkd.2021.07.024

M3 - Article

C2 - 34543687

AN - SCOPUS:85121243697

SN - 0272-6386

VL - 79

SP - 677-687.e1

JO - American Journal of Kidney Diseases

JF - American Journal of Kidney Diseases

IS - 5

ER -

Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure

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