Soluble Urokinase Receptor and Acute Kidney Injury

N Engl J Med. 2020 Jan 30;382(5):416-426. doi: 10.1056/NEJMoa1911481.

Abstract

Background: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target.

Methods: We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.

Results: The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells.

Conclusions: High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury / blood*
  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / prevention & control
  • Aged
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Biomarkers / blood
  • Cardiac Surgical Procedures / adverse effects*
  • Coronary Angiography / adverse effects*
  • Critical Illness
  • Disease Models, Animal
  • Female
  • Humans
  • Intensive Care Units
  • Kidney Tubules / cytology
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Odds Ratio
  • Podocytes / drug effects
  • Podocytes / metabolism
  • Postoperative Complications / blood
  • Postoperative Complications / etiology
  • Receptors, Urokinase Plasminogen Activator / blood*
  • Risk Assessment / methods
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
  • Urokinase-Type Plasminogen Activator / pharmacology

Substances

  • Antibodies, Monoclonal
  • Biomarkers
  • PLAUR protein, human
  • Receptors, Urokinase Plasminogen Activator
  • Urokinase-Type Plasminogen Activator

Grant support