Effects of Intensive Blood Pressure Lowering on Kidney Tubule Injury in CKD: A Longitudinal Subgroup Analysis in SPRINT

SPRINT Research Group

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Abstract

BACKGROUND: Random assignment to the intensive systolic blood pressure (SBP) arm (<120mmHg) in the Systolic Blood Pressure Intervention Trial (SPRINT) resulted in more rapid declines in estimated glomerular filtration rates (eGFRs) than in the standard arm (SBP<140mmHg). Whether this change reflects hemodynamic effects or accelerated intrinsic kidney damage is unknown.

STUDY DESIGN: Longitudinal subgroup analysis of clinical trial participants.

SETTINGS & PARTICIPANTS: Random sample of SPRINT participants with prevalent chronic kidney disease (CKD) defined as eGFR<60mL/min/1.73m 2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline.

OUTCOMES & MEASUREMENTS: Urine biomarkers of tubule function (β 2-microglobulin [B2M], α 1-microglobulin [A1M]), and uromodulin), injury (interleukin 18, kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin), inflammation (monocyte chemoattractant protein 1), and repair (human cartilage glycoprotein 40) at baseline, year 1, and year 4. Biomarkers were indexed to urine creatinine concentration and changes between arms were evaluated using mixed-effects linear models and an intention-to-treat approach.

RESULTS: 978 SPRINT participants (519 in the intensive and 459 in the standard arm) with prevalent CKD were included. Mean age was 72±9 years and eGFR was 46.1±9.4mL/min/1.73m 2 at baseline. Clinical characteristics, eGFR, urinary albumin-creatinine ratio, and all 8 biomarker values were similar across arms at baseline. Compared to the standard arm, eGFR was lower by 2.9 and 3.3mL/min/1.73m 2 in the intensive arm at year 1 and year 4. None of the 8 tubule marker levels was higher in the intensive arm compared to the standard arm at year 1 or year 4. Two tubule function markers (B2M and A1M) were 29% (95% CI, 10%-43%) and 24% (95% CI, 10%-36%) lower at year 1 in the intensive versus standard arm, respectively.

LIMITATIONS: Exclusion of persons with diabetes, and few participants had advanced CKD.

CONCLUSIONS: Among participants with CKD in SPRINT, random assignment to the intensive SBP arm did not increase any levels of 8 urine biomarkers of tubule cell damage despite loss of eGFR. These findings support the hypothesis that eGFR declines in the intensive arm of SPRINT predominantly reflect hemodynamic changes rather than intrinsic damage to kidney tubule cells.

Original languageEnglish (US)
Pages (from-to)21-30
Number of pages10
JournalAmerican Journal of Kidney Diseases
Volume73
Issue number1
DOIs
StatePublished - Jan 2019

Bibliographical note

Funding Information:
Support: This work was supported by the National Institutes of Health (NIH) and the National Research Service Award through National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK098234 and K24DK110427 (to Dr Ix), and the American Heart Association (grant 14EIA18560026 to Dr Ix). SPRINT is funded with federal funds from the NIH, including the National Heart, Lung, and Blood Institute, the NIDDK, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under contract numbers HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Inter-Agency Agreement Number A-HL-13-002-001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals Int, Inc. All components of the SPRINT protocol were designed and implemented by the investigators, and the investigative team collected, analyzed, and interpreted the data. We also acknowledge support from the following Clinical and Translational Science Awards funded by National Center for Advancing Translational Sciences of the NIH (Case Western Reserve University: UL1TR000439; Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston University: UL1RR025771; Stanford University: UL1TR000093; Tufts University: UL1RR025752, UL1TR000073 and UL1TR001064; University of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; University of Texas Southwestern: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1TR000445; George Washington University: UL1TR000075; University of California, Davis: UL1TR000002; University of Florida: UL1TR000064; University of Michigan: UL1TR000433; and Tulane University: P30GM103337 COBRE Award NIGMS. The funders did not have a role in study design; collection, analysis, and interpretation of the data; and writing of the manuscript.

Publisher Copyright:
© 2018

Keywords

  • CKD progression
  • Chronic kidney disease (CKD)
  • blood pressure (BP)
  • eGFR decline
  • estimated glomerular filtration rate (eGFR)
  • hemodynamics
  • hypertension
  • intensive BP control
  • kidney tubule cell
  • renal perfusion
  • tubular injury
  • urinary biomarkers
  • urine
  • Glomerular Filtration Rate
  • Humans
  • Middle Aged
  • Hypertension/complications
  • Male
  • Renal Insufficiency, Chronic/complications
  • Biomarkers/urine
  • Aged, 80 and over
  • Female
  • Aged
  • Kidney Tubules/physiopathology

PubMed: MeSH publication types

  • Randomized Controlled Trial
  • Journal Article

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