Kidney Biomarkers of Injury and Repair as Predictors of Contrast-Associated AKI: A Substudy of the PRESERVE Trial

Chirag Parikh, Caroline Liu, Maria K. Mor, Paul M. Palevsky, James S. Kaufman, Heather Thiessen Philbrook, Steven D. Weisbord

Research output: Contribution to journalArticle

Abstract

Rationale & Objective: The PRESERVE trial used a 2 × 2 factorial design to compare intravenous saline solution with intravenous sodium bicarbonate solution and oral N-acetylcysteine with placebo for the prevention of 90-day major adverse kidney events and death (MAKE-D) and contrast-associated acute kidney injury (CA-AKI) among patients with chronic kidney disease undergoing angiography. In this ancillary study, we evaluated the predictive capacities of preangiography injury and repair proteins in urine and plasma for MAKE-D, CA-AKI, and their impact on trial design. Study Design: Longitudinal analysis. Setting & Participants: A subset of participants from the PRESERVE trial. Exposures: Injury (KIM-1, NGAL, and IL-18) and repair (MCP-1, UMOD, and YKL-40) proteins in urine and plasma 1 to 2 hours preangiography. Outcomes: MAKE-D and CA-AKI. Analytical Approach: We analyzed the associations of preangiography biomarkers with MAKE-D and with CA-AKI. We evaluated whether the biomarker levels could enrich the MAKE-D event rate and improve future clinical trial efficiency through an online biomarker prognostic enrichment tool available at prognosticenrichment.com. Results: We measured plasma biomarkers in 916 participants and urine biomarkers in 797 participants. After adjusting for urinary albumin-creatinine ratio and baseline estimated glomerular filtration rate, preangiography levels of 4 plasma (KIM-1, NGAL, UMOD, and YKL-40) and 3 urine (NGAL, IL-18, and YKL-40) biomarkers were associated with MAKE-D. Only plasma KIM-1 level was significantly associated with CA-AKI after adjustment. Biomarker levels provided modest discriminatory capacity for MAKE-D. Screening patients using the 50th percentile of preangiography plasma KIM-1 or YKL-40 levels would have reduced the required sample size by 30% (∼2,000 participants). Limitations: Evaluation of prognostic enrichment does not account for changing trial costs, time needed to screen patients, or loss to follow-up. Most participants were male, limiting the generalizability of our findings. Conclusions: Preangiography levels of injury and repair biomarkers modestly predict the development of MAKE-D and can be used to improve the efficiency of future CA-AKI trials.

Original languageEnglish (US)
JournalAmerican Journal of Kidney Diseases
DOIs
StateAccepted/In press - Jan 1 2019

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Biomarkers
Acute Kidney Injury
Kidney
Wounds and Injuries
Urine
Interleukin-18
Sodium Bicarbonate
Acetylcysteine
Glomerular Filtration Rate
Chronic Renal Insufficiency
Sodium Chloride
Sample Size
Longitudinal Studies
Albumins
Creatinine
Angiography
Proteins
Placebos
Clinical Trials
Costs and Cost Analysis

Keywords

  • Acute kidney injury (AKI)
  • angiography
  • clinical trial design
  • contrast media
  • contrast-associated acute kidney injury (CA-AKI)
  • contrast-induced acute kidney injury (CI-AKI)
  • enrollment criteria
  • event rate
  • MAKE-D
  • plasma biomarkers
  • prognostic biomarker
  • tubular injury
  • urinary biomarkers

ASJC Scopus subject areas

  • Nephrology

Cite this

Kidney Biomarkers of Injury and Repair as Predictors of Contrast-Associated AKI : A Substudy of the PRESERVE Trial. / Parikh, Chirag; Liu, Caroline; Mor, Maria K.; Palevsky, Paul M.; Kaufman, James S.; Thiessen Philbrook, Heather; Weisbord, Steven D.

In: American Journal of Kidney Diseases, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Rationale & Objective: The PRESERVE trial used a 2 × 2 factorial design to compare intravenous saline solution with intravenous sodium bicarbonate solution and oral N-acetylcysteine with placebo for the prevention of 90-day major adverse kidney events and death (MAKE-D) and contrast-associated acute kidney injury (CA-AKI) among patients with chronic kidney disease undergoing angiography. In this ancillary study, we evaluated the predictive capacities of preangiography injury and repair proteins in urine and plasma for MAKE-D, CA-AKI, and their impact on trial design. Study Design: Longitudinal analysis. Setting & Participants: A subset of participants from the PRESERVE trial. Exposures: Injury (KIM-1, NGAL, and IL-18) and repair (MCP-1, UMOD, and YKL-40) proteins in urine and plasma 1 to 2 hours preangiography. Outcomes: MAKE-D and CA-AKI. Analytical Approach: We analyzed the associations of preangiography biomarkers with MAKE-D and with CA-AKI. We evaluated whether the biomarker levels could enrich the MAKE-D event rate and improve future clinical trial efficiency through an online biomarker prognostic enrichment tool available at prognosticenrichment.com. Results: We measured plasma biomarkers in 916 participants and urine biomarkers in 797 participants. After adjusting for urinary albumin-creatinine ratio and baseline estimated glomerular filtration rate, preangiography levels of 4 plasma (KIM-1, NGAL, UMOD, and YKL-40) and 3 urine (NGAL, IL-18, and YKL-40) biomarkers were associated with MAKE-D. Only plasma KIM-1 level was significantly associated with CA-AKI after adjustment. Biomarker levels provided modest discriminatory capacity for MAKE-D. Screening patients using the 50th percentile of preangiography plasma KIM-1 or YKL-40 levels would have reduced the required sample size by 30{\%} (∼2,000 participants). Limitations: Evaluation of prognostic enrichment does not account for changing trial costs, time needed to screen patients, or loss to follow-up. Most participants were male, limiting the generalizability of our findings. Conclusions: Preangiography levels of injury and repair biomarkers modestly predict the development of MAKE-D and can be used to improve the efficiency of future CA-AKI trials.",
keywords = "Acute kidney injury (AKI), angiography, clinical trial design, contrast media, contrast-associated acute kidney injury (CA-AKI), contrast-induced acute kidney injury (CI-AKI), enrollment criteria, event rate, MAKE-D, plasma biomarkers, prognostic biomarker, tubular injury, urinary biomarkers",
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AU - Liu, Caroline

AU - Mor, Maria K.

AU - Palevsky, Paul M.

AU - Kaufman, James S.

AU - Thiessen Philbrook, Heather

AU - Weisbord, Steven D.

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N2 - Rationale & Objective: The PRESERVE trial used a 2 × 2 factorial design to compare intravenous saline solution with intravenous sodium bicarbonate solution and oral N-acetylcysteine with placebo for the prevention of 90-day major adverse kidney events and death (MAKE-D) and contrast-associated acute kidney injury (CA-AKI) among patients with chronic kidney disease undergoing angiography. In this ancillary study, we evaluated the predictive capacities of preangiography injury and repair proteins in urine and plasma for MAKE-D, CA-AKI, and their impact on trial design. Study Design: Longitudinal analysis. Setting & Participants: A subset of participants from the PRESERVE trial. Exposures: Injury (KIM-1, NGAL, and IL-18) and repair (MCP-1, UMOD, and YKL-40) proteins in urine and plasma 1 to 2 hours preangiography. Outcomes: MAKE-D and CA-AKI. Analytical Approach: We analyzed the associations of preangiography biomarkers with MAKE-D and with CA-AKI. We evaluated whether the biomarker levels could enrich the MAKE-D event rate and improve future clinical trial efficiency through an online biomarker prognostic enrichment tool available at prognosticenrichment.com. Results: We measured plasma biomarkers in 916 participants and urine biomarkers in 797 participants. After adjusting for urinary albumin-creatinine ratio and baseline estimated glomerular filtration rate, preangiography levels of 4 plasma (KIM-1, NGAL, UMOD, and YKL-40) and 3 urine (NGAL, IL-18, and YKL-40) biomarkers were associated with MAKE-D. Only plasma KIM-1 level was significantly associated with CA-AKI after adjustment. Biomarker levels provided modest discriminatory capacity for MAKE-D. Screening patients using the 50th percentile of preangiography plasma KIM-1 or YKL-40 levels would have reduced the required sample size by 30% (∼2,000 participants). Limitations: Evaluation of prognostic enrichment does not account for changing trial costs, time needed to screen patients, or loss to follow-up. Most participants were male, limiting the generalizability of our findings. Conclusions: Preangiography levels of injury and repair biomarkers modestly predict the development of MAKE-D and can be used to improve the efficiency of future CA-AKI trials.

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KW - Acute kidney injury (AKI)

KW - angiography

KW - clinical trial design

KW - contrast media

KW - contrast-associated acute kidney injury (CA-AKI)

KW - contrast-induced acute kidney injury (CI-AKI)

KW - enrollment criteria

KW - event rate

KW - MAKE-D

KW - plasma biomarkers

KW - prognostic biomarker

KW - tubular injury

KW - urinary biomarkers

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