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Multicenter Study
. 2023 Jul 1;34(7):1253-1263.
doi: 10.1681/ASN.0000000000000125. Epub 2023 Mar 28.

Detecting Neonatal AKI by Serum Cystatin C

Xin Xu  1 , Sheng Nie  1 , Hong Xu  2 , Bicheng Liu  3 , Jianping Weng  4 , Chunbo Chen  5 , Huafeng Liu  6 , Qiongqiong Yang  7 , Hua Li  8 , Yaozhong Kong  9 , Guisen Li  10 , Qijun Wan  11 , Yan Zha  12 , Ying Hu  13 , Gang Xu  14 , Yongjun Shi  15 , Yilun Zhou  16 , Guobin Su  17 , Ying Tang  18 , Yanqin Li  1 , Licong Su  1 , Ruixuan Chen  1 , Yue Cao  1 , Peiyan Gao  1 , Shiyu Zhou  1 , Xiaodong Zhang  1 , Fan Luo  1 , Ruqi Xu  1 , Qi Gao  1 , Fan Fan Hou  1
Affiliations
Multicenter Study

Detecting Neonatal AKI by Serum Cystatin C

Xin Xu et al. J Am Soc Nephrol. .

Abstract

Significance statement: Serum creatinine is not a sensitive biomarker for neonatal AKI because it is confounded by maternal creatinine level, gestational age, and neonatal muscle mass. In this multicenter cohort study of 52,333 hospitalized Chinese neonates, the authors proposed serum cystatin C-related criteria (CyNA) for neonatal AKI. They found that cystatin C (Cys-C) is a robust and sensitive biomarker for identifying AKI in neonates who are at an elevated risk of in-hospital mortality and that CyNA detects 6.5 times as many cases as the modified Kidney Disease Improving Global Outcomes creatinine criteria. They also show that AKI can be detected using a single test of Cys-C. These findings suggest that CyNA shows promise as a powerful and easily applicable tool for detecting AKI in neonates.

Background: Serum creatinine is not a sensitive biomarker for AKI in neonates. A better biomarker-based criterion for neonatal AKI is needed.

Methods: In this large multicenter cohort study, we estimated the upper normal limit (UNL) and reference change value (RCV) of serum cystatin C (Cys-C) in neonates and proposed cystatin C-based criteria (CyNA) for detecting neonatal AKI using these values as the cutoffs. We assessed the association of CyNA-detected AKI with the risk of in-hospital death and compared CyNA performance versus performance of modified Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria.

Results: In this study of 52,333 hospitalized neonates in China, Cys-C level did not vary with gestational age and birth weight and remained relatively stable during the neonatal period. CyNA criteria define AKI by a serum Cys-C of ≥2.2 mg/L (UNL) or an increase in Cys-C of ≥25% (RCV) during the neonatal period. Among 45,839 neonates with measurements of both Cys-C and creatinine, 4513 (9.8%) had AKI detected by CyNA only, 373 (0.8%) by KDIGO only, and 381 (0.8%) by both criteria. Compared with neonates without AKI by both criteria, neonates with AKI detected by CyNA alone had an increased risk of in-hospital mortality (hazard ratio [HR], 2.86; 95% confidence interval [95% CI], 2.02 to 4.04). Neonates with AKI detected by both criteria had an even higher risk of in-hospital mortality (HR, 4.86; 95% CI, 2.84 to 8.29).

Conclusions: Serum Cys-C is a robust and sensitive biomarker for detecting neonatal AKI. Compared with modified KDIGO creatinine criteria, CyNA is 6.5 times more sensitive in identifying neonates at elevated risk of in-hospital mortality.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Distribution of serum Cystatin C (Cys-C) and creatinine stratified by day after birth in the neonates. Figure 1 can be viewed in color online at www.jasn.org.
Figure 2
Figure 2
RCVs of Cys-C in neonates were similar across a wide spectrum of Cys-C levels. The shaded area denotes the 95% intervals of the estimated RCVs. The dotted black horizontal line indicates the overall RCV of Cys-C ratio, which was 1.25. Figure 2 can be viewed in color online at www.jasn.org.
Figure 3
Figure 3
Higher Cys-C level and Cys-C ratio were associated with an increased risk of in-hospital death. (A) The effect of Cys-C and the Cys-C ratio on the risk of in-hospital mortality estimated using a Cox regression model with adjustment for admission to ICU and comorbidities. Cys-C ratio and admission to ICU were coded as time-varying variables. A restricted cubic spline was used to allow for nonlinear effect. The gray areas cover the 95% CIs of the estimated effects. The dotted vertical lines indicate the UNL (left) and the RCV (right) of Cys-C. (B) Kaplan-Meier curves of in-hospital death stratified by initial level of Cys-C and increase in Cys-C. Left: The neonates with initial Cys-C value above UNL had a significantly higher cumulative incidence of in-hospital death. Right: The K-M curve was estimated in neonates with multiple Cys-C measurement and whose initial Cys-C value was below UNL. The neonates with Cys-C ratio above RCV had a significantly higher cumulative incidence of in-hospital death. The shaded areas cover the 95% confidence intervals (CIs) of the estimates. Figure 3 can be viewed in color online at www.jasn.org.
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