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

SPRINT Research Group

Research output: Contribution to journalArticle

Abstract

Background: Random assignment to the intensive systolic blood pressure (SBP) arm (<120 mm Hg) 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 < 140 mm Hg). 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 < 60 mL/min/1.73 m2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline. Outcomes & Measurements: Urine biomarkers of tubule function (β2-microglobulin [B2M], α1-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 ± 9.4 mL/min/1.73 m2 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 3.3 mL/min/1.73 m2 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 1 2019

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Kidney Tubules
Chronic Renal Insufficiency
Blood Pressure
Wounds and Injuries
Glomerular Filtration Rate
Biomarkers
Creatinine
Urine
Hemodynamics
Uromodulin
Kidney
Cystatin C
Interleukin-18

Keywords

  • blood pressure (BP)
  • Chronic kidney disease (CKD)
  • CKD progression
  • eGFR decline
  • estimated glomerular filtration rate (eGFR)
  • hemodynamics
  • hypertension
  • intensive BP control
  • kidney tubule cell
  • renal perfusion
  • tubular injury
  • urinary biomarkers
  • urine

ASJC Scopus subject areas

  • Nephrology

Cite this

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

In: American Journal of Kidney Diseases, Vol. 73, No. 1, 01.01.2019, p. 21-30.

Research output: Contribution to journalArticle

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abstract = "Background: Random assignment to the intensive systolic blood pressure (SBP) arm (<120 mm Hg) 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 < 140 mm Hg). 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 < 60 mL/min/1.73 m2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline. Outcomes & Measurements: Urine biomarkers of tubule function (β2-microglobulin [B2M], α1-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 ± 9.4 mL/min/1.73 m2 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 3.3 mL/min/1.73 m2 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.",
keywords = "blood pressure (BP), Chronic kidney disease (CKD), CKD progression, eGFR decline, estimated glomerular filtration rate (eGFR), hemodynamics, hypertension, intensive BP control, kidney tubule cell, renal perfusion, tubular injury, urinary biomarkers, urine",
author = "{SPRINT Research Group} and Rakesh Malhotra and Timothy Craven and Ambrosius, {Walter T.} and Killeen, {Anthony A.} and Haley, {William E.} and Cheung, {Alfred K.} and Michel Chonchol and Mark Sarnak and Chirag Parikh and Shlipak, {Michael G.} and Ix, {Joachim H.}",
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T1 - Effects of Intensive Blood Pressure Lowering on Kidney Tubule Injury in CKD

T2 - A Longitudinal Subgroup Analysis in SPRINT

AU - SPRINT Research Group

AU - Malhotra, Rakesh

AU - Craven, Timothy

AU - Ambrosius, Walter T.

AU - Killeen, Anthony A.

AU - Haley, William E.

AU - Cheung, Alfred K.

AU - Chonchol, Michel

AU - Sarnak, Mark

AU - Parikh, Chirag

AU - Shlipak, Michael G.

AU - Ix, Joachim H.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Random assignment to the intensive systolic blood pressure (SBP) arm (<120 mm Hg) 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 < 140 mm Hg). 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 < 60 mL/min/1.73 m2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline. Outcomes & Measurements: Urine biomarkers of tubule function (β2-microglobulin [B2M], α1-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 ± 9.4 mL/min/1.73 m2 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 3.3 mL/min/1.73 m2 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.

AB - Background: Random assignment to the intensive systolic blood pressure (SBP) arm (<120 mm Hg) 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 < 140 mm Hg). 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 < 60 mL/min/1.73 m2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline. Outcomes & Measurements: Urine biomarkers of tubule function (β2-microglobulin [B2M], α1-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 ± 9.4 mL/min/1.73 m2 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 3.3 mL/min/1.73 m2 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.

KW - blood pressure (BP)

KW - Chronic kidney disease (CKD)

KW - CKD progression

KW - eGFR decline

KW - estimated glomerular filtration rate (eGFR)

KW - hemodynamics

KW - hypertension

KW - intensive BP control

KW - kidney tubule cell

KW - renal perfusion

KW - tubular injury

KW - urinary biomarkers

KW - urine

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U2 - 10.1053/j.ajkd.2018.07.015

DO - 10.1053/j.ajkd.2018.07.015

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JO - American Journal of Kidney Diseases

JF - American Journal of Kidney Diseases

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