Comparison of serum creatinine and serum cystatin C as biomarkers to detect sepsis-induced acute kidney injury and to predict mortality in CD-1 mice

Am J Physiol Renal Physiol. 2014 Oct 15;307(8):F939-48. doi: 10.1152/ajprenal.00025.2013. Epub 2014 Aug 20.

Abstract

Acute kidney injury (AKI) dramatically increases sepsis mortality, but AKI diagnosis is delayed when based on serum creatinine (SCr) changes, due in part, to decreased creatinine production. During experimental sepsis, we compared serum cystatin C (sCysC), SCr, and blood urea nitrogen (BUN) to inulin glomerular filtration rate (iGFR) before or 3-18 h after cecal ligation and puncture (CLP)-induced sepsis in CD-1 mice. sCysC had a faster increase and reached peak levels more rapidly than SCr in both sepsis and bilateral nephrectomy (BiNx) models. sCysC was a better surrogate of iGFR than SCr during sepsis. Combining sCysC with SCr values into a composite biomarker improved correlation with iGFR better than any biomarker alone or any other combination. We determined the renal contribution to sCysC handling with BiNx. sCysC and SCr were lower post-BiNx/CLP than post-BiNx alone, despite increased inflammatory and nonrenal organ damage biomarkers. Sepsis decreased CysC production in nephrectomized mice without changing body weight or CysC space. Sepsis decreased sCysC production and increased nonrenal clearance, similar to effects of sepsis on SCr. sCysC, SCr, and BUN were measured 6 h postsepsis to link AKI with mortality. Mice with above-median sCysC, BUN, or SCr values 6 h postsepsis died earlier than mice with below-median values, corresponding to a substantial AKI association with sepsis mortality in this model. sCysC performs similarly to SCr in classifying mice at risk for early mortality. We conclude that sCysC detects AKI early and better reflects iGFR in CLP-induced sepsis. This study shows that renal biomarkers need to be evaluated in specific contexts.

Keywords: Kaplan-Meier; bilateral nephrectomy; glomerular filtration rate; receiver-operating characteristic curve; survival.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acute Kidney Injury / blood
  • Acute Kidney Injury / mortality*
  • Acute Kidney Injury / physiopathology
  • Animals
  • Biomarkers / blood*
  • Blood Urea Nitrogen
  • Cecum / injuries
  • Creatinine / blood*
  • Cystatin C / blood*
  • Glomerular Filtration Rate
  • Inulin
  • Ligation
  • Male
  • Mice
  • Nephrectomy
  • Punctures
  • Sepsis / complications
  • Sepsis / mortality*

Substances

  • Biomarkers
  • Cystatin C
  • Inulin
  • Creatinine