Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury

Abstract

Background: The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown.

Study design: Cross-sectional analysis from multicenter prospective cohort.

Settings & participants: Hospitalized deceased kidney donors on whom kidney biopsies were performed at the time of organ procurement for histologic evaluation.

Predictors: (1) AKI diagnosed by change in Scr concentration during donor hospitalization and (2) concentrations of urinary biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], liver-type fatty acid-binding protein [L-FABP], interleukin 18 [IL-18], and kidney injury molecule 1 [KIM-1]) measured at organ procurement.

Outcome: Histologic acute tubular injury.

Results: Of 581 donors, 98 (17%) had mild acute tubular injury and 57 (10%) had severe acute tubular injury. Overall, Scr-based AKI had poor diagnostic performance for identifying histologic acute tubular injury and 49% of donors with severe acute tubular injury did not have AKI. The area under the receiver operating characteristic curve (AUROC) of change in Scr concentration for diagnosing severe acute tubular injury was 0.58 (95% CI, 0.49-0.67) and for any acute tubular injury was 0.52 (95% CI, 0.45-0.58). Compared with Scr concentration, NGAL concentration demonstrated higher AUROC for diagnosing both severe acute tubular injury (0.67; 95% CI, 0.60-0.74; P=0.03) and any acute tubular injury (0.60; 95% CI, 0.55-0.66; P=0.005). In donors who did not have Scr-based AKI, NGAL concentrations were higher with increasing severities of acute tubular injury (subclinical AKI). However, compared with Scr concentration, AUROCs for acute tubular injury diagnosis were not significantly higher for urinary L-FABP, IL-18, or KIM-1.

Limitations: The spectrum of AKI cause in deceased donors may be different from that of a general hospitalized population.

Conclusions: Concentrations of Scr and kidney injury biomarkers (L-FABP, IL-18, and KIM-1) lack accuracy for diagnosing acute tubular injury in hospitalized deceased donors. Although urinary NGAL concentration had slightly higher discrimination for acute tubular injury than did Scr concentration, its overall AUROC was still modest.

Keywords: Acute kidney injury (AKI); IL-18; KIM-1; L-FABP; NGAL; acute tubular injury (ATI); diagnostic performance; kidney biopsy; kidney histology; kidney injury biomarker; serum creatinine (Scr); subclinical AKI.

Figure 1. Performance of delta serum creatinine for histological ATI

Stage I AKI defined by a SCr rise of ≥0.3 mg/dl or ≥ 50% from baseline; Stage II AKI defined as ≥100% rise in SCr. SCr: serum creatinine, ATI: acute tubular injury, AKI: acute kidney injury. Any ATI includes mild, moderate and severe ATI. Severe ATI includes moderate and severe ATI.

Figure 2. Association of donor characteristics with 6-month recipient eGFR

Multivariable regression of donor SCr-based AKI, histological ATI and biomarker-based AKI on 6-month recipient eGFR controlling for KDRI score components (excluding serum creatinine) and SCr-based AKI. For ATI, (+) and (−) indicate presence and absence of ATI, respectively. For SCr, (+) and (−) indicate presence and absence of AKI. Biomarker cut-offs obtained from Coca et. al. JASN 2014 ATI, acute tubular injury; AKI, acute kidney injury; KDRI, kidney disease risk index; eGFR, estimated glomerular filtration rate. Severe ATI includes moderate and severe ATI