Detecting Neonatal Acute Kidney Injury by Serum Cystatin C

JASN Published Ahead of Print. doi: 10.1681/ASN.0000000000000125

Xin Xu,  Sheng Nie, Hong Xu, Bicheng Liu , Jianping Weng, Chunbo Chen, Huafeng Liu, Qiongqiong Yang, Hua Li, Yaozhong Kong, Guisen Li, Qijun Wan, Yan Zha, Ying Hu, Gang Xu, Yongjun Shi, Yilun Zhou, Guobin Su, Ying Tang, Yanqin Li, Licong Su, Ruixuan Chen, Yue Cao, Peiyan Gao, Shiyu Zhou, Xiaodong Zhang, Fan Luo, Ruqi Xu, Qi Gao, and Fan Fan Hou

Reviewed by: Erin Rademacher

Background:

Creatinine based definitions of acute kidney injury (AKI) have limitations when applied to neonates due to the unique neonatal kidney physiology. Neonatal creatinine reflects maternal creatinine with a small contribution of creatinine generation by the neonate itself. Neonatal creatinine values will usually decline over time but the rate of decline varies with gestational age and in the youngest gestational age group, creatinine may actually rise and plateau before falling. In contrast, cystatin C (CysC) does not cross the placenta and therefore reflects only the neonate's kidney function. Large studies establishing normal values for CysC in neonates are lacking and no study has reported the reference change value (RCV) for CysC in neonates. RCV can be described as the minimum difference between sequential test values in a patient to consider the change in values significant.

Objective:

1.) To establish the upper normal limit and RCV for serum CysC in neonates 2.) To propose CysC criteria for neonatal AKI 3.) Compare the proposed CysC AKI definition to the established KDIGO definition

Study Design:

Cohort study using data from the China Renal Data System in which neonates without ICD10 codes for congenital renal failure, congenital malformation of the urinary system, or congenital renal artery stenosis or malformation; had at least one CysC measured in first 28 days, survived to 28 days, and did not require dialysis.

Results:

52,333 neonates met entry criteria (5964 had ≥ 1 CysC measured). The majority (65%) were born at gestational age ≥ 37 weeks. 26% had birthweight < 2.5 kg. 69% were in ICU. Median length of stay in the neonates with only 1 measurement of CysC was 8 days while those with multiple measurements had a longer median LOS (19 days).

CysC was normally distributed on day of birth and did not vary with GA or birthweight. CysC median for first two days of life was 1.73 mg/L then median fell to 1.55 mg/L and remained at this level through end of the 4th week. The upper limit of normal for CysC using the 95th percentile of the entire population was 2.2 mg/L (2.17 for GA ≥ 37; 2.29 for GA 28-36, 2.30 for GA < 28). RCV for the population was 1.25.

Using this data, they proposed a definition of AKI as CysC ≥ 2.2 or an increase in CysC of ≥ 25%. Neonates who met this definition of AKI had a 1.9 fold increase in the risk of in-hospital mortality (HR 2.91, CI 2.24-3.78). 45,839 neonates had both creatinine and CysC available. 4513 (9.8%) had AKI by the proposed CysC definition only, 373 (0.8%) by KDIGO only, and 381 (0.8%) by both definitions. When compared to the reference group on neonates without AKI by either definition, the adjusted HR for in-hospital mortality was 2.15 for the KDIGO definition group, 2.86 for the CysC definition group, and 4.86 for the group that met both definitions.

Conclusions:

Given the lack of variability of CysC over the first month of life, it may have advantages in detecting neonatal AKI over creatinine based definitions.  AKI detected by CysC was associated with increased in-hospital mortality.

Limitations:

Normative values were derived solely from a Chinese database of hospitalized neonates. The ULN and RCV might be different in different ethnic groups.

Significance:

Since the neonatal KDIGO definition relies on detecting a rise in creatinine, it misses neonates who have a slower than normal decline in creatinine or with an initially high creatinine. Use of the proposed CysC definition using the ULN or RCV criteria allows identification of these patients.