Cystatin C in acute kidney injury diagnosis: early biomarker or alternative to serum creatinine?

Abstract

Background: Early acute kidney injury (AKI) diagnosis is needed to pursue treatment trials. We evaluated cystatin C (CysC) as an early biomarker of serum creatinine (SCr)-AKI and an alternative to define AKI.

Methods: We studied 160 non-cardiac children in the intensive care unit (ICU). We measured daily CysC and SCr. AKI was staged by KDIGO (Kidney Disease: Improving Global Outcomes) guidelines using SCr and CysC (CysC-AKI). We calculated area under the curve (AUC) for (1) neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1) and urine CysC to diagnose SCr- and CysC-AKI; and (2) for CysC to diagnose SCr-AKI. We evaluated AKI associations with length of stay and ventilation duration.

Results: We found that 44 % of patients developed SCr-AKI; 32 % developed CysC-AKI. Early ICU NGAL was most diagnostic of CysC-AKI (AUC 0.69, 95% CI 0.54-0.84); IL-18 was most diagnostic for SCr-AKI (AUC 0.69 95% CI 0.55-0.82). Combining SCr and CysC-AKI definition led to higher biomarker diagnostic AUC's. CysC-AKI was not more strongly associated with clinical outcomes. Early ICU CysC predicted SCr-AKI development (AUC 0.70, 95 % CI 0.53-0.89).

Conclusions: Our findings do not support replacing SCr by CysC to define AKI. Early ICU CysC predicts SCr-AKI development and combined SCr-CysC-AKI definition leads to stronger AKI biomarker associations.

Figure 1. Study flow chart

Displays the flow, beginning with the total number recruited, exclusions to final analysis populations. PICU: pediatric intensive care unit; CysC: Cystatin C; SCr: serum creatinine; AKI: acute kidney injury; SCr-AKI: AKI defined by SCr rise criteria; CysC-AKI: AKI defined by CysC rise criteria.

Figure 2. Peak pediatric intensive care unit biomarker concentrations by acute kidney injury severity stratum, using SCr-AKI and CysC-AKI definitions

A) Demonstrates box plots (middle line is the median; upper and lower box bordes are the 75^th and 25^th percentile values, respectively) of biomarker concentrations for urine neutrophil gelatinase-associated lipocalin, interleukin-18, kidney injury molecule-1 and urine cystatin C across AKI severity strata (no AKI, Stage 1 AKI and Stages 2 or 3 AKI). P-values are from performance of a non-parametric test for trend across groups. B) Represents identical analyses but with AKI defined by rise in CysC from baseline (CysC-AKI). SCr: serum creatinine; SCR-AKI: acute kidney injury defined by rise in serum creatinine from baseline; NGAL: neutrophil gelatinase-associated lipocalin; AKI: acute kidney injury; IL-18: interleukin-18; KIM-1: kidney injury molecule-1; CysC: Cystatin C; CysC-AKI: acute kidney injury defined by rise in serum cystatin C from baseline.

Figure 3. Comparison of peak biomarker concentrations across 4 AKI categories: No AKI, SCr-AKI only, CysC-AKI only, both SCr + CysC AKI

For all 4 studied biomarkers, biomarker concentrations are compared between 4 groups: patients with no AKI by SCr or CysC rise; patients who only have acute kidney injury by SCr rise; patients who only have acute kidney injury by CysC rise; patients who have acute kidney injury using both methods. The p-values within the graphs are from performance of a non-parametric test for trend across groups. NGAL: neutrophil gelatinase-associated lipocalin; AKI: acute kidney injury; SCR-AKI: acute kidney injury defined by rise in serum creatinine from baseline; CysC-AKI: acute kidney injury defined by rise in serum cystatin C from baseline; SCr+CysC-AKI: acute kidney injury defined by rise in serum creatinine and Cystatin C from baseline; IL-18: interleukin-18; KIM-1: kidney injury molecule-1; CysC: cystatin C.

Figure 4. Prediction of SCr-AKI using CysC from 2 to 0 days before SCr-AKI (a to c) and from early PICU admission (d and e)

The figures represent receiver operating characteristic curves for CysC concentrations to diagnose SCr-AKI. Figure A) represents the receiver operating characteristic curve for CysC obtained 2 days before AKI diagnosis; B) for CysC from 1 day before diagnosis; C) for CysC from the day of AKI diagnosis; D) for CysC obtained in early PICU admission to predict SCr-AKI development within 48 hours; E) for CysC obtained in early PICU admission to predict SCr-AKI stage 2 development within 48 hours. Within each graph, the area under the curve (with associated 95% confidence intervals) is shown. To the right of each curve, the sensitivity, specificity and likelihood ratio for selected CysC concentrations cutoffs are shown in association with each graph. SCR-AKI: acute kidney injury defined by rise in serum creatinine from baseline; AUC: area under the curve; CI: confidence interval; CysC: Cystatin C; AKI: acute kidney injury; Sens: sensitivity; Spec: specificity; LR+: positive likelihood ratio; SCr-AKI 2: acute kidney injury stage 2.