Use of Biomarkers to Identify Acute Kidney Injury to Help Detect Sepsis in Patients With Infection

Crit Care Med. 2021 Apr 1;49(4):e360-e368. doi: 10.1097/CCM.0000000000004845.


Objectives: Although early recognition of sepsis is vital to improving outcomes, the diagnosis may be missed or delayed in many patients. Acute kidney injury is one of the most common organ failures in patients with sepsis but may not be apparent on presentation. Novel biomarkers for acute kidney injury might improve organ failure recognition and facilitate earlier sepsis care.

Design: Retrospective, international, Sapphire study.

Setting: Academic Medical Center.

Patients: Adults admitted to the ICU without evidence of acute kidney injury at time of enrollment.

Interventions: None.

Measurements and main results: We stratified patients enrolled in the Sapphire study into three groups-those with a clinical diagnosis of sepsis (n = 216), those with infection without sepsis (n = 120), and those without infection (n = 387) at enrollment. We then examined 30-day mortality stratified by acute kidney injury within each group. Finally, we determined the operating characteristics for kidney stress markers (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) for prediction of acute kidney injury as a sepsis-defining organ failure in patients with infection without a clinical diagnosis of sepsis at enrollment. Combining all groups, 30-day mortality was 23% for patients who developed stage 2-3 acute kidney injury within the first 3 days compared with 14% without stage 2-3 acute kidney injury. However, this difference was greatest in the infection without sepsis group (34% vs 11%; odds ratio, 4.09; 95% CI, 1.53-11.12; p = 0.005). Using a (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) cutoff of 2.0 units, 14 patients (11.7%), in the infection/no sepsis group, tested positive of which 10 (71.4%) developed stage 2-3 acute kidney injury. The positive test result occurred a median of 19 hours (interquartile range, 0.8-34.0 hr) before acute kidney injury manifested by serum creatinine or urine output. Similar results were obtained using a cutoff of 1.0 for any stage of acute kidney injury.

Conclusions: Use of the urinary (tissue inhibitor of metalloproteinases-2) × (insulin-like growth factor binding protein 7) test could identify acute kidney injury in patients with infection, possibly helping to detect sepsis, nearly a day before acute kidney injury is apparent by clinical criteria.

Trial registration: NCT01209169.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / blood*
  • Acute Kidney Injury / diagnosis*
  • Aged
  • Biomarkers / blood
  • Creatinine / blood
  • Critical Illness
  • Female
  • Humans
  • Infections / complications
  • Infections / diagnosis*
  • Male
  • Middle Aged
  • Retrospective Studies
  • Sepsis / complications
  • Sepsis / diagnosis*
  • Severity of Illness Index*
  • Tissue Inhibitor of Metalloproteinase-2 / blood


  • Biomarkers
  • Tissue Inhibitor of Metalloproteinase-2
  • Creatinine

Associated data