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Clinical Research
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Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury

Sherry G. Mansour, Pavan K. Bhatraju, Steven G. Coca, Wassim Obeid, Francis P. Wilson, Ian B. Stanaway, Yaqi Jia, Heather Thiessen-Philbrook, Alan S. Go, T. Alp Ikizler, Edward D. Siew, Vernon M. Chinchilli, Chi-yuan Hsu, Amit X. Garg, W. Brian Reeves, Kathleen D. Liu, Paul L. Kimmel, James S. Kaufman, Mark M. Wurfel, Jonathan Himmelfarb, Samir M. Parikh, Chirag R. Parikh and for the ASSESS-AKI Consortium*
JASN March 2022, 33 (3) 613-627; DOI: https://doi.org/10.1681/ASN.2021060757
Sherry G. Mansour
1Clinical Translational Research Accelerator, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
2Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
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Pavan K. Bhatraju
3Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington
4Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
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Steven G. Coca
5Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Wassim Obeid
6Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
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Francis P. Wilson
1Clinical Translational Research Accelerator, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
2Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut
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Ian B. Stanaway
4Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
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Yaqi Jia
6Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
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Heather Thiessen-Philbrook
6Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
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Alan S. Go
7Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, California
8Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
9Division of Nephrology, Department of Medicine, Stanford University, Palo Alto, California
10Department of Health Research and Policy, Stanford University, Palo Alto, California
11Division of Research, Kaiser Permanente Northern California, Oakland, California
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T. Alp Ikizler
12Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Edward D. Siew
13Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Nashville, Tennessee
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Vernon M. Chinchilli
14Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania
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Chi-yuan Hsu
7Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, California
11Division of Research, Kaiser Permanente Northern California, Oakland, California
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Amit X. Garg
15Division of Nephrology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
16Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
17ICES, Ontario, Canada
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W. Brian Reeves
18Division of Nephrology, Department of Medicine, University of Texas Joe and Teresa Long School of Medicine, San Antonio, Texas
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Kathleen D. Liu
7Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, California
19Department of Anesthesia, Division of Critical Care Medicine, University of California, San Francisco, San Francisco, California
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Paul L. Kimmel
20Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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James S. Kaufman
21Division of Nephrology, Veterans Affairs New York Harbor Healthcare System and New York University School of Medicine, New York, New York
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Mark M. Wurfel
3Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington
4Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
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Jonathan Himmelfarb
4Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington
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Samir M. Parikh
22Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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Chirag R. Parikh
6Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
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This article has a correction. Please see:

  • Correction: Beneficial Effects of Myo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI - March 01, 2022

Visual Abstract

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Significance Statement

Mechanisms underlying long-term effects after AKI remain unclear. Because vessel instability is an early response to endothelial injury, the authors studied markers of blood vessel homeostasis (the plasma angiopoietins angiopoietin-1 and angiopoietin-2) in a multicenter prospective cohort that included 1503 adults, half of whom had AKI. Three months after hospitalization, the highest quartile of plasma angiopoietin-1:angiopoietin-2 ratio compared with the lowest quartile associated with 72% less risk of CKD progression, 94% less risk of heart failure, and 82% less risk of death among those with AKI; those without AKI exhibited similar but less pronounced reductions in risk of heart failure and mortality. Angiopoietins may serve as a common pathway to explain the progression of kidney and heart disease after AKI and may point to potential future interventions.

Abstract

Background The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure.

Methods To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later.

Results Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression.

Conclusions A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.

  • angiopoietin-1
  • angiopoietin-2
  • acute kidney injury
  • chronic kidney disease
  • heart failure
  • mortality
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (3)
Journal of the American Society of Nephrology
Vol. 33, Issue 3
March 2022
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Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury
Sherry G. Mansour, Pavan K. Bhatraju, Steven G. Coca, Wassim Obeid, Francis P. Wilson, Ian B. Stanaway, Yaqi Jia, Heather Thiessen-Philbrook, Alan S. Go, T. Alp Ikizler, Edward D. Siew, Vernon M. Chinchilli, Chi-yuan Hsu, Amit X. Garg, W. Brian Reeves, Kathleen D. Liu, Paul L. Kimmel, James S. Kaufman, Mark M. Wurfel, Jonathan Himmelfarb, Samir M. Parikh, Chirag R. Parikh, for the ASSESS-AKI Consortium*
JASN Mar 2022, 33 (3) 613-627; DOI: 10.1681/ASN.2021060757

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Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury
Sherry G. Mansour, Pavan K. Bhatraju, Steven G. Coca, Wassim Obeid, Francis P. Wilson, Ian B. Stanaway, Yaqi Jia, Heather Thiessen-Philbrook, Alan S. Go, T. Alp Ikizler, Edward D. Siew, Vernon M. Chinchilli, Chi-yuan Hsu, Amit X. Garg, W. Brian Reeves, Kathleen D. Liu, Paul L. Kimmel, James S. Kaufman, Mark M. Wurfel, Jonathan Himmelfarb, Samir M. Parikh, Chirag R. Parikh, for the ASSESS-AKI Consortium*
JASN Mar 2022, 33 (3) 613-627; DOI: 10.1681/ASN.2021060757
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Keywords

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  • angiopoietin-2
  • acute kidney injury
  • chronic kidney disease
  • heart failure
  • mortality

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