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Soluble Urokinase Receptor and Acute Kidney Injury.

Publication ,  Journal Article
Hayek, SS; Leaf, DE; Samman Tahhan, A; Raad, M; Sharma, S; Waikar, SS; Sever, S; Camacho, A; Wang, X; Dande, RR; Ibrahim, NE; Baron, RM ...
Published in: N Engl J Med
January 30, 2020

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.).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

January 30, 2020

Volume

382

Issue

5

Start / End Page

416 / 426

Location

United States

Related Subject Headings

  • Urokinase-Type Plasminogen Activator
  • Risk Assessment
  • Receptors, Urokinase Plasminogen Activator
  • Postoperative Complications
  • Podocytes
  • Odds Ratio
  • Middle Aged
  • Mice, Transgenic
  • Mice
  • Male
 

Citation

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Hayek, S. S., Leaf, D. E., Samman Tahhan, A., Raad, M., Sharma, S., Waikar, S. S., … Reiser, J. (2020). Soluble Urokinase Receptor and Acute Kidney Injury. N Engl J Med, 382(5), 416–426. https://doi.org/10.1056/NEJMoa1911481
Hayek, Salim S., David E. Leaf, Ayman Samman Tahhan, Mohamad Raad, Shreyak Sharma, Sushrut S. Waikar, Sanja Sever, et al. “Soluble Urokinase Receptor and Acute Kidney Injury.N Engl J Med 382, no. 5 (January 30, 2020): 416–26. https://doi.org/10.1056/NEJMoa1911481.
Hayek SS, Leaf DE, Samman Tahhan A, Raad M, Sharma S, Waikar SS, et al. Soluble Urokinase Receptor and Acute Kidney Injury. N Engl J Med. 2020 Jan 30;382(5):416–26.
Hayek, Salim S., et al. “Soluble Urokinase Receptor and Acute Kidney Injury.N Engl J Med, vol. 382, no. 5, Jan. 2020, pp. 416–26. Pubmed, doi:10.1056/NEJMoa1911481.
Hayek SS, Leaf DE, Samman Tahhan A, Raad M, Sharma S, Waikar SS, Sever S, Camacho A, Wang X, Dande RR, Ibrahim NE, Baron RM, Altintas MM, Wei C, Sheikh-Hamad D, Pan JS-C, Holliday MW, Januzzi JL, Weisbord SD, Quyyumi AA, Reiser J. Soluble Urokinase Receptor and Acute Kidney Injury. N Engl J Med. 2020 Jan 30;382(5):416–426.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

January 30, 2020

Volume

382

Issue

5

Start / End Page

416 / 426

Location

United States

Related Subject Headings

  • Urokinase-Type Plasminogen Activator
  • Risk Assessment
  • Receptors, Urokinase Plasminogen Activator
  • Postoperative Complications
  • Podocytes
  • Odds Ratio
  • Middle Aged
  • Mice, Transgenic
  • Mice
  • Male