Article of the Month - Apr 2022

ASSOCIATION BETWEEN ELEVATED URINE NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN AND POSTOPERATIVE ACUTE KIDNEY INJURY IN NEONATES

J Pediatr. 2021 Nov;238:193-201.e2. doi: 10.1016/j.jpeds.2021.07.041. PMID: 34371091

Slagle CL, et al.

Reviewed by: Jacob Little, MD; Seattle Children's Hospital

Background:

Previous research in neonates with congenital heart disease undergoing cardiac surgery showed that elevation in postoperative urine neutrophil gelatinase-associated lipocalin (uNGAL) and uNGAL kinetics predict severity of postoperative AKI. In that study, following cardiopulmonary bypass uNGAL concentrations of >150 ng/mL were associated with higher postoperative dialysis rate, longer ICU stay, and increased mortality. Research related to the association between noncardiac surgeries and neonatal AKI is lacking. A recent single center retrospective study suggested an association between AKI and abdominal surgeries in neonates but did not evaluate urine biomarkers.

What was the purpose of the studies?

The purpose of the study was to evaluate the relationship between postoperative uNGAL levels and AKI development in neonates undergoing general abdominal and thoracic surgery. The authors hypothesized that elevated uNGAL concentrations postoperatively would be associated with postoperative AKI and that individual percent change of uNGAL concentrations from pre to postoperative would predict development of AKI. The primary outcome was postoperative AKI. Secondary outcomes were severe postoperative AKI (stage 2 or 3), length of hospital stay, and death prior to hospital discharge.

What were study design and methods?

This was a single center prospective cohort of 141 term and preterm neonates admitted to the NICU at a large tertiary care pediatric hospital. Median gestational age of enrolled subjects was 35 weeks (IQR 30, 37). Inclusion criteria were infants undergoing a general abdominal or thoracic surgical procedure and who were less than 6 months corrected gestational age. AKI and associated stage were defined by the nKDIGO AKI serum creatinine and urine output definitions. Post-baseline serum creatinine was required to be above 0.5 mg/dL to be defined as AKI. Postoperative AKI was defined as a continuation or worsening stage of preoperative AKI or occurrence of AKI following the procedure to postoperative day 5. Urine samples were collected preoperatively and at 12, 24, 36, 48, 72, and 96 hours postoperatively. Urine output was recorded every 2 to 4 hours. Serum creatinine values were collected at the discretion of the clinical team. Performance of uNGAL and uNGAL/urine creatinine ratios at specific time points to predict postoperative AKI was assessed using sensitivities, specificities, and area under the receiver operator characteristic (AUC-ROC) curves. uNGAL was also log transformed and the longitudinal trajectory of uNGAL between AKI and no AKI groups assessed using generalized additive mixed models.

What were the results of the study?

AKI incidence following procedures was 19% (36/192 procedures) which occurred in 33 subjects. 3 subjects had a second occurrence of postoperative AKI following a subsequent procedure.

Risk factors for post-op AKI were previous AKI history, preoperative nephrotoxic medication exposure, younger corrected gestational age at time of procedure, and need for emergent procedure.

uNGAL concentration at 24 hours had the best performance to predict AKI (when procedures with preoperative AKI were included AUC-ROC 0.81, cut-off 144 ng/mL, specificity 74%, sensitivity 81%; when procedures with preoperative AKI were excluded AUC-ROC 0.79, cut-off 81 ng/mL, specificity 63%, sensitivity 91%).

The percent change in uNGAL concentrations from preoperatively to 24 hours postoperatively was greater in subjects with post-AKI (190.2% vs 0.7%, p = 0.037). When subjects with preoperative AKI were excluded, the difference increased (529.8% vs 1.2%, p = 0.017).

The temporal relationship between uNGAL increase and AKI diagnosis was assessed. Subjects with preoperative AKI or without a UNGAL obtained prior to meeting AKI criteria were excluded (n = 22). 12 of 14 remaining (86%) had elevated uNGAL (>81 ng/mL) prior to meeting AKI criteria.

What was the conclusion?

The major finding was that at 24 hours postoperatively uNGAL had a strong prediction performance for AKI, with a sensitivity of 91% using a cut-off of 81 ng/mL when preoperative AKI subjects were excluded. In this study, uNGAL was elevated at 24 hours following 19% (37/192) without any evidence of functional loss. This finding suggests a need for analysis of uNGAL against other outcomes such as mortality, LOS, and chronic kidney disease.

8 occurrences of AKI were defined by serum creatinine alone. 5 of these 8 occurrences were in subjects with no preoperative AKI, which the authors note had the potential to be missed if not for postoperative serum creatinine screening. Postoperative AKI occurred after 12% of nonemergent surgeries which suggests that infants should be assessed for AKI development after routine surgeries. However, serum creatinine screening continues to be a challenge in the NICU due to challenges with anemia, pain, and difficult access.

Why is this important?

This is a large prospective cohort study of neonates undergoing noncardiac surgical intervention which is an understudied population. Importantly, this study assessed preoperative uNGAL and a large portion of the cohort had indwelling urinary catheters in the postoperative period which improved diagnosis of AKI by urine output criteria. This study demonstrated that elevated uNGAL at 24 hours post general thoracic or abdominal procedure was associated with AKI in neonates. Additionally, this study showed that change of uNGAL from preoperative baseline is a useful tool in diagnosing postoperative AKI in neonates. Preoperative uNGAL was not associated with AKI in neonates who had thoracic or abdominal procedures.