Soluble Urokinase Receptor and Acute Kidney Injury.
Acute Kidney Injury
/ blood
Aged
Animals
Antibodies, Monoclonal
/ pharmacology
Biomarkers
/ blood
Cardiac Surgical Procedures
/ adverse effects
Coronary Angiography
/ adverse effects
Critical Illness
Disease Models, Animal
Female
Humans
Intensive Care Units
Kidney Tubules
/ cytology
Male
Mice
Mice, Transgenic
Middle Aged
Odds Ratio
Podocytes
/ drug effects
Postoperative Complications
/ blood
Receptors, Urokinase Plasminogen Activator
/ blood
Risk Assessment
/ methods
Urokinase-Type Plasminogen Activator
/ antagonists & inhibitors
Journal
The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562
Informations de publication
Date de publication:
30 01 2020
30 01 2020
Historique:
entrez:
30
1
2020
pubmed:
30
1
2020
medline:
6
2
2020
Statut:
ppublish
Résumé
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. 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. 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. High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).
Sections du résumé
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.).
Identifiants
pubmed: 31995687
doi: 10.1056/NEJMoa1911481
pmc: PMC7065830
mid: NIHMS1565140
doi:
Substances chimiques
Antibodies, Monoclonal
0
Biomarkers
0
PLAUR protein, human
0
Receptors, Urokinase Plasminogen Activator
0
Urokinase-Type Plasminogen Activator
EC 3.4.21.73
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
416-426Subventions
Organisme : NIH Clinical Center
ID : 2P01HL086773
Pays : International
Organisme : NINDS NIH HHS
ID : R01 NS064162
Pays : United States
Organisme : NIH Clinical Center
ID : 1R56HL126558-01
Pays : International
Organisme : NHLBI NIH HHS
ID : R01 HL142093
Pays : United States
Organisme : NHLBI NIH HHS
ID : R21 HL145246
Pays : United States
Organisme : NIH Clinical Center
ID : HL89650-01
Pays : International
Organisme : NHLBI NIH HHS
ID : R01 HL141205
Pays : United States
Organisme : BLRD VA
ID : I01 BX002006
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL086773
Pays : United States
Organisme : NIH Clinical Center
ID : DK101350
Pays : International
Organisme : NIH Clinical Center
ID : 1RF1AG051633-01
Pays : International
Organisme : NIH Clinical Center
ID : 5P01HL101398-02
Pays : International
Organisme : NIH Clinical Center
ID : 1DP3DK094346-01
Pays : International
Organisme : NIH Clinical Center
ID : HL089650-01
Pays : International
Organisme : NIDDK NIH HHS
ID : DP3 DK094346
Pays : United States
Organisme : NIH Clinical Center
ID : HL095479-01
Pays : International
Organisme : NIH Clinical Center
ID : 1U10HL110302-01
Pays : International
Organisme : NIH Clinical Center
ID : 1P20HL113451-01
Pays : International
Organisme : NIDDK NIH HHS
ID : R01 DK106051
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL089650
Pays : United States
Organisme : BLRD VA
ID : IK2 BX002912
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK111024
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101350
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG042127
Pays : United States
Organisme : NIA NIH HHS
ID : U54 AG062334
Pays : United States
Organisme : NIDDK NIH HHS
ID : K23 DK106448
Pays : United States
Organisme : NIH Clinical Center
ID : NS064162-01
Pays : International
Organisme : NHLBI NIH HHS
ID : R01 HL095479
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG051633
Pays : United States
Organisme : NHLBI NIH HHS
ID : P20 HL113451
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL101398
Pays : United States
Organisme : American Heart Association
ID : 0000031288
Pays : International
Organisme : NIH Clinical Center
ID : K23DK106448
Pays : International
Organisme : NHLBI NIH HHS
ID : R61 HL138657
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK109720
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2020 Massachusetts Medical Society.
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