Abstract
Background:
To study the gestational age-specific risk factors and outcomes of severe acute kidney injury (AKI) in neonates with necrotizing enterocolitis (NEC).
Methods:
Retrospective cohort study comparing Gestational age (GA)-specific clinical data between infants without severe AKI (stage 0 /1 AKI) and those with severe AKI (stages 2 and 3 AKI) stratified by GA ≤27 weeks and >27 weeks
Results:
Infants with GA ≤27 weeks had double the rate of severe AKI (46.3% vs. 20%). In infants with GA> 27 weeks, male sex, out born, and nephrotoxic medication exposure were associated with severe AKI. On multivariable logistic regression, in infants with GA ≤27 weeks, surgical NEC (OR 35.08(CI 5.05, 243.73), p<0.001) and ostomy (OR 6.2(CI 1.29, 29.73), p=0.027) were associated with significantly higher odds of severe AKI.
Surgical NEC infants with GA >27 weeks and severe AKI were significantly more likely to be out born, have later NEC onset, need dopamine, and have longer hospitalization (158 days [110;220] vs.75.5 days [38.8;105]; p=0.007 than those with non-severe AKI.
Conclusion:
In neonates with NEC, surgical intervention was associated with moderate to severe AKI in infants with GA <=27 weeks and with longer hospitalization in infants with GA >27 weeks.
Introduction:
Necrotizing enterocolitis (NEC) is the most common acute gastrointestinal illness, affecting about 5–10% of preterm neonates with a birth weight ≤1500 grams1,2. NEC remains a leading cause of morbidity and mortality among preterm neonates and leads to increased health care burden. NEC-associated severe systemic inflammatory response causing multi-organ dysfunction and prolonged exposure to nephrotoxic medications increase the risk of acute kidney injury (AKI), especially in neonates who have underdeveloped kidneys.
AKI during the neonatal period affects approximately 30% of infants admitted to the neonatal intensive care unit and is associated with poor clinical outcomes3,4. AKI following NEC has been previously reported5–8. However, prior studies examining the associations between AKI and NEC in this population have been limited due to the small sample size and to the lack of urine output (UOP) AKI diagnostic criteria, a limitation which increases the likelihood of misclassification bias9–12. In our recent study, we reported on adjusted model, surgical NEC, out born, exposure to antenatal steroids, and positive blood culture sepsis were associated with increased odds for severe AKI and longer hospitalization13. However, to our knowledge, the extent to which risk factors for and outcomes of NEC-associated AKI differ by gestational age are not fully understood. The gestational age evaluation is important as lower birthweight and gestational age are associated with greater morbidity and mortality.
In this single-center, retrospective cohort study, we sought to determine the gestational age-based demographics, clinical parameters, and interventions that were associated with severe AKI within the 14 days after NEC onset in premature neonates. In this study, we investigated the factors associated with severe AKI status in preterm infants within each gestational age group (GA ≤ 27 weeks and GA > 27 weeks) in both the whole cohort and surgical cohort. We also compared the gestational age-based changes in sodium, urine output and serum creatinine (SCr) following NEC in those with and without severe AKI.
Methods:
Population and Study Design:
The study was conducted at the level 4 Neonatal Intensive Care Unit after IRB approval at the University of Mississippi Medical Center with approximately 1000 admissions annually. All neonates admitted between January 1, 2013 and December 31, 2018, with a diagnosis of NEC (Bell stage II and above) were included in the study14. Neonates with a diagnosis of spontaneous intestinal perforation, cyanotic congenital heart disease, intestinal atresia, or kidney anomalies (hydronephrosis, posterior urethral valves, polycystic and multicystic dysplastic kidneys) were excluded.
Demographic Variables:
We collected demographic data including gestational age (GA), birth weight (BW), sex, small for gestational age status, race, out born status, mode of delivery, and Apgar scores ≤6 at 5 min. We also collected maternal variables including maternal pregnancy-induced hypertension (PIH), chorioamnionitis, and antenatal steroids. We classified our cohort into two groups: infants born less than or equal to 27 weeks’ gestation and those born greater than 27 weeks’ gestation.
NEC Variables:
We recorded information on the age (in days) at the time of NEC diagnosis. The diagnosis of NEC was made based on characteristic radiographic findings including pneumatosis, portal venous gas, and pneumoperitoneum on abdominal X-ray. The frequency of medical and surgical NEC (Bell stage II and III) were also collected14. Neonates who died within 48 hours after NEC onset and massive bowel necrosis was found during laparotomy or autopsy were classified as having fulminant NEC. At our center, preterm infants with pneumoperitoneum who weigh < 1 kg at NEC/SIP diagnosis and are hemodynamically unstable are treated first with a Penrose drain at the bedside but may later receive laparotomy based on clinical deterioration. We also collected the frequency of cholestasis (serum bilirubin >2 mg/dl) up to 12 weeks following the NEC diagnosis. Our unit mainly used intralipids. Omegaven was used in cases with direct bilirubin more than 2.5 mg/dl.
Hemodynamic Variables:
Additional clinical information included mechanical ventilation exposure, presence of patent ductus arteriosus (PDA) and indomethacin/ibuprofen therapy for PDA treatment (before NEC), inotrope (dopamine) use 24 hours after NEC onset, and daily serum sodium following NEC onset for 1 week.
Sepsis Variables:
Sepsis-related variables included blood culture-proven sepsis at the time of NEC onset and type of antimicrobials (vancomycin, gentamicin, piperacillin/tazobactam, metronidazole, amikacin, and fluconazole) used for 2 weeks following NEC diagnosis. We did not collect any antibiotic use data before and 14 days after the NEC onset. In our unit we used vancomycin and amikacin as the first line treatment for infants with NEC and late onset sepsis. Gentamicin was mainly used in cases who were referred to our hospital from other hospitals. The antibiotics peak and trough levels of nephrotoxic medications were monitored, and the doses were adjusted if not in the recommended therapeutic window.
Kidney Function Data:
We collected all SCr measurements, daily UOP, and daily serum sodium levels. We collected patient weights starting the day before NEC diagnosis, at NEC onset, and at 24, 48, 72, 96 hours after NEC diagnosis. We also recorded all these variables at 7 and 14 days after NEC diagnosis. We defined AKI as occurring within the 14 days after NEC onset using the modified neonatal AKI staging criteria as previously described in the kidney disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline15,16. Baseline SCr was defined as the lowest SCr documented in the patient’s clinical record before NEC onset. Stage 1 AKI was defined as a rise in SCr by ≥0.3 mg/dl or a rise by ≥1.5–1.9 times above baseline, and/or UOP <1 ml/kg/hour over the last 24 hours. Stage 2 AKI was defined as an increase in SCr ≥2–2.9 times above baseline and/or UOP <0.5 ml/kg/hour. Stage 3 AKI was defined as an increase in SCr ≥ 3 times above baseline or SCr >2.5 mg/dl and/or UOP <0.3 ml/kg/hour. The maximum AKI stage was defined as the highest SCr or lowest UOP reached within 14 days after NEC onset. We did not record any data about any episode of AKI before NEC onset or 14 days after the NEC onset. The UMMC hospital laboratories measure SCr using the isotope dilution mass spectrometry method. The UOP is estimated using weighed diapers recorded clinically by bedside nurses in the electronic health record. We classified neonates as no or mild AKI (no AKI or stage 1 AKI) or moderate-to-severe AKI (stage 2 and 3 AKI)3,17.
Outcome Data:
The primary outcome was the development of severe AKI (stage 2 and 3 AKI) by gestational age group. In addition, we analyzed gestational age-specific clinical risk factors for severe AKI. Finally, we examined the association between severe AKI and outcomes including mortality and hospital length of stay by gestational age group. The length of stay was defined as the total duration of hospitalization from the day of admission until discharge or death due to any cause before hospital discharge.
Statistical Methods:
We analyzed all the continuous variables using the Mann-Whitney U-test and summarized with median and inter-quartile range (Quartile 1; Quartile 3). Similarly, all the categorical variables were tested using Chi-squared test or Fisher’s exact test. We divided the gestational age variable into two groups such as =< 27 weeks and >27 weeks. Then we assessed patients’ demographic, sepsis, kidney function, NEC, hemodynamic data across the two groups of gestational age in both the combined cohort and surgical cohort separately. We followed a simple framework for variable selection where we only selected the significant variables from the bivariate analyses in the multiple logistic regression. Adjusted odds ratios were reported as effect size along with 95% confidence interval and P value. P values less than 0.05 were considered as significant in all the analyses. Statistical analyses were performed in R Statistical Software (version 4.2.1; The R Foundation for Statistical Computing).
Results:
Whole Cohort (Medical and surgical NEC infants combined):
Two hundred and two infants with medical and surgical NEC were included in the analysis. 97/202 (48%) of infants had gestational age less than or equal to 27 weeks and 105/202 (52%) of infants had GA greater than 27 weeks. The patient inclusion diagram is shown in Figure 1. The data is summarized in Table 1 and 2.
Figure 1:
Flow diagram showing the patient enrollment in preterm infants with medical and surgical NEC
Table 1.
Demographics, NEC, and clinical features of infants with medical and surgical NEC hospitalized with and without severe AKI
| Gestational age less than or equal to 27 weeks | Gestational age more than 27 weeks | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | Combined cohort (N=97) | No/mild AKI (stage 0–1) (N=52) | Moderate to Severe AKI (stage 2–3) (N=45) | P value | N | Combined cohort (N=105) | No/mild AKI (stage 0–1) (N=84) | Severe AKI (stage 2–3) (N=21) | P value | |
| Demographic variables | ||||||||||
| Sex, n (%) | 97 | 1.000 | 105 | 0.024 | ||||||
| Female | 42 (43.3) | 23 (44.2) | 19 (42.2) | 40 (38.1) | 37 (44.0) | 3 (14.3) | ||||
| Male | 55 (56.7) | 29 (55.8) | 26 (57.8) | 65 (61.9) | 47 (56.0) | 18 (85.7) | ||||
| AGA, n (%) | 92 | 0.608 | 103 | 0.064 | ||||||
| Yes | 30 (32.6) | 14 (29.2) | 16 (36.4) | 34 (33.0) | 23 (28.0) | 11 (52.4) | ||||
| Race, n (%) | 96 | 0.155 | 101 | 0.750 | ||||||
| African American | 69 (71.9) | 33 (64.7) | 36 (80.0) | 74 (73.3) | 57 (70.4) | 17 (85.0) | ||||
| Caucasian | 22 (22.9) | 15 (29.4) | 7 (15.6) | 23 (22.8) | 20 (24.7) | 3 (15.0) | ||||
| Hispanic | 2 (2.08) | 2 (3.92) | 0 (0.00) | 2 (1.98) | 2 (2.47) | 0 (0.00) | ||||
| Other | 3 (3.12) | 1 (1.96) | 2 (4.44) | 2 (1.98) | 2 (2.47) | 0 (0.00) | ||||
| Outborn, n (%) | 92 | 53 (57.6) | 24 (48.0) | 29 (69.0) | 0.068 | 104 | 62 (59.6) | 45 (54.2) | 17 (81.0) | 0.048 |
| Gestational Age (weeks, median and IQR) | 97 | 24.6 [23.6;26.0] | 24.6 [23.5;26.2] | 24.5 [23.6;25.4] | 0.974 | 105 | 31.1 [28.5;33.4] | 30.6 [28.9;33.4] | 31.4 [28.0;33.0] | 0.597 |
| Birth weight (g, median and IQR) | 97 | 690 [590;830] | 710 [598;862] | 670 [565;780] | 0.288 | 105 | 1405 [1020;2003] | 1422 [1038;1978] | 1354 [684;2003] | 0.394 |
| Length of stay (days, median and IQR) | 95 | 114 [68.5;173] | 102 [63.5;150] | 122 [76.0;174] | 0.236 | 104 | 80.5 [38.0;134] | 67.5 [35.2;109] | 157 [109;216] | 0.001 |
| NEC Variables | ||||||||||
| Age at NEC onset (days, median and IQR) | 97 | 15.0 [8.00;31.0] | 15.5 [7.75;38.0] | 15.0 [8.00;25.0] | 0.458 | 105 | 15.0 [7.00;28.0] | 15.5 [7.00;28.2] | 15.0 [8.00;23.0] | 0.767 |
| Pneumatosis, n (%) | 95 | 31 (32.6) | 16 (30.8) | 15 (34.9) | 0.837 | 105 | 57 (54.3) | 43 (51.2) | 14 (66.7) | 0.304 |
| Portal venous gas, n (%) | 95 | 2 (2.11) | 1 (1.92) | 1 (2.33) | 1.000 | 103 | 7 (6.80) | 4 (4.88) | 3 (14.3) | 0.148 |
| Pneumoperitoneum, n (%) | 95 | 36 (37.9) | 16 (30.8) | 20 (46.5) | 0.173 | 103 | 20 (19.4) | 13 (15.9) | 7 (33.3) | 0.118 |
| Surgical NEC (Bell stage III), n (%) | 97 | 63 (64.9) | 21 (40.4) | 42 (93.3) | <0.001 | 105 | 41 (39.0) | 22 (26.2) | 19 (90.5) | <0.001 |
| Fulminant NEC, n (%) | 96 | 11 (11.5) | 5 (9.80) | 6 (13.3) | 0.825 | 105 | 15 (14.3) | 8 (9.52) | 7 (33.3) | 0.011 |
| Jejunostomy, n (%) | 62 | 15 (24.2) | 3 (13.0) | 12 (30.8) | 0.205 | 59 | 11 (18.6) | 4 (10.0) | 7 (36.8) | 0.028 |
| Ileostomy, n (%) | 66 | 23 (34.8) | 5 (20.0) | 18 (43.9) | 0.087 | 61 | 17 (27.9) | 9 (21.4) | 8 (42.1) | 0.174 |
| Colostomy, n (%) | 63 | 8 (12.7) | 1 (4.35) | 7 (17.5) | 0.239 | 60 | 4 (6.67) | 2 (4.88) | 2 (10.5) | 0.585 |
| Any Ostomy, n (%) | 66 | 44 (66.7) | 9 (36.0) | 35 (85.4) | <0.001 | 62 | 30 (48.4) | 14 (32.6) | 16 (84.2) | 0.001 |
| Cholestasis, n (%) | 62 | 41 (66.1) | 11 (47.8) | 30 (76.9) | 0.039 | 57 | 25 (43.9) | 13 (33.3) | 12 (66.7) | 0.038 |
| Hemodynamic variables | ||||||||||
| Assisted ventilation, n (%) | 95 | 0.029 | 101 | 0.017 | ||||||
| Intubation | 83 (87.4) | 40 (78.4) | 43 (97.7) | 61 (60.4) | 42 (52.5) | 19 (90.5) | ||||
| CPAP | 3 (3.16) | 3 (5.88) | 0 (0.00) | 8 (7.92) | 8 (10.0) | 0 (0.00) | ||||
| High flow | 7 (7.37) | 6 (11.8) | 1 (2.27) | 20 (19.8) | 19 (23.8) | 1 (4.76) | ||||
| Room air | 2 (2.11) | 2 (3.92) | 0 (0.00) | 12 (11.9) | 11 (13.8) | 1 (4.76) | ||||
| Patent ductus arteriosus, n (%) | 97 | 53 (54.6) | 30 (57.7) | 23 (51.1) | 0.656 | 103 | 45 (43.7) | 35 (41.7) | 10 (52.6) | 0.539 |
| PDA surgical ligation, n (%) | 97 | 5 (5.15) | 1 (1.92) | 4 (8.89) | 0.180 | 104 | 2 (1.92) | 2 (2.38) | 0 (0.00) | 1.000 |
| Dopamine use 24 h after NEC, n (%) | 96 | 67 (69.8) | 32 (62.7) | 35 (77.8) | 0.168 | 101 | 46 (45.5) | 30 (37.0) | 16 (80.0) | 0.001 |
| Indomethacin/Ibuprofen, n (%) | 79 | 17 (21.5) | 9 (20.0) | 8 (23.5) | 0.919 | 96 | 6 (6.25) | 5 (6.17) | 1 (6.67) | 1.000 |
| Apgar score <6 at 5 min, n (%) | 95 | 26 (27.4) | 14 (28.0) | 12 (26.7) | 1.000 | 104 | 26 (25.0) | 19 (22.6) | 7 (35.0) | 0.389 |
| Sepsis variables | ||||||||||
| Blood culture-positive sepsis, n (%) | 97 | 34 (35.1) | 11 (21.2) | 23 (51.1) | 0.004 | 104 | 25 (24.0) | 20 (24.1) | 5 (23.8) | 1.000 |
| Antibiotics duration (days, median and IQR) | 64 | 7.00 [5.75;10.0] | 7.00 [7.00;11.5] | 7.00 [5.00;10.0] | 0.731 | 48 | 7.00 [4.75;10.0] | 7.00 [4.25;7.00] | 10.0 [7.00;13.5] | 0.025 |
| Vancomycin, n (%) | 97 | 83 (85.6) | 46 (88.5) | 37 (82.2) | 0.560 | 104 | 90 (86.5) | 73 (88.0) | 17 (81.0) | 0.474 |
| Gentamicin, n (%) | 97 | 30 (30.9) | 19 (36.5) | 11 (24.4) | 0.287 | 104 | 52 (50.0) | 47 (56.6) | 5 (23.8) | 0.015 |
| Piperacillin/Tazobactam, n (%) | 96 | 5 (5.21) | 4 (7.69) | 1 (2.27) | 0.371 | 103 | 3 (2.91) | 2 (2.44) | 1 (4.76) | 0.499 |
| Metronidazole, n (%) | 96 | 42 (43.8) | 18 (34.6) | 24 (54.5) | 0.079 | 103 | 33 (32.0) | 24 (29.3) | 9 (42.9) | 0.353 |
| Amikacin, n (%) | 96 | 73 (76.0) | 42 (80.8) | 31 (70.5) | 0.347 | 103 | 83 (80.6) | 67 (81.7) | 16 (76.2) | 0.549 |
| Fluconazole, n (%) | 96 | 9 (9.38) | 5 (9.62) | 4 (9.09) | 1.000 | 102 | 7 (6.86) | 5 (6.17) | 2 (9.52) | 0.631 |
| Outcomes | ||||||||||
| Length of stay (days, median and IQR) | 95 | 114 [68.5;173] | 102 [63.5;150] | 122 [76.0;174] | 0.236 | 104 | 80.5 [38.0;134] | 67.5 [35.2;109] | 157 [109;216] | 0.001 |
| Death | 97 | 0.658 | 105 | 0.776 | ||||||
| Discharged, n (%) | 70 (72.2) | 39 (75.0) | 31 (68.9) | 81 (77.1) | 64 (76.2) | 17 (81.0) | ||||
| Death, n (%) | 27 (27.8) | 13 (25.0) | 14 (31.1) | 24 (22.9) | 20 (23.8) | 4 (19.0) | ||||
Table 2:
AKI by gestational age in preterm infants with surgical and medical NEC
| AKI by KDIGO classification in preterm infants greater than 27 weeks | |||||
|---|---|---|---|---|---|
| AKI by urine output | |||||
| Stage 0 | Stage 1 | Stage 2 | Stage 3 | Total | |
| AKI by creatinine | |||||
| Stage 0 | 75 (71.4%) | 2 (1.9%) | 5 (4.8%) | 2 (1.9%) | 84 (80.0%) |
| Stage 1 | 7 (6.7%) | 0 (0.00%) | 2 (1.9%) | 1 (0.9%) | 10 (9.5%) |
| Stage 2 | 1 (1.0%) | 0 (0.00%) | 1 (0.9%) | 2 (1.9%) | 4 (3.8%) |
| Stage 3 | 4 (3.8%) | 1 (0.9%) | 1 (0.9%) | 1 (0.9%) | 7 (6.7%) |
| Total | 87 (82.9%) | 3 (2.9%) | 9 (8.6%) | 6 (5.7%) | 105 (100%) |
| AKI by KDIGO classification in preterm infants less than 27 weeks | |||||
| AKI by urine output | |||||
| AKI by creatinine | Stage 0 | Stage 1 | Stage 2 | Stage 3 | Total |
| Stage 0 | 33 (34.0%) | 1 (1.0%) | 11 (11.3%) | 2 (2.1%) | 47 (48.5%) |
| Stage 1 | 18 (18.6%) | 0 (0.00%) | 6 (6.2%) | 0 (0.00%) | 24 (24.7%) |
| Stage 2 | 7 (7.2%) | 0 (0.00%) | 3 (3.1%) | 4 (4.1%) | 14 (14.4%) |
| Stage 3 | 7 (7.2%) | 0 (0.00%) | 2 (2.1%) | 3 (3.1%) | 12 (12.4%) |
| Total | 65 (67.0%) | 1 (1.0%) | 22 (22.7%) | 9 (9.3%) | 97 (100%) |
Data presented as N (%)
Among infants born less than or equal to 27 weeks, 24/97 (24.7%) had stage 1 AKI, 14/97 (14.4%) had stage 2 AKI, and 12/97 (12.4%) had stage 3 AKI by serum creatinine. In addition, 1/97(1%) infants had stage 1 AKI by UOP criteria, 22/97(22.7%) had stage 2, and 9/97 (9.3%) had stage 3 AKI. 45/97(46.3%) preterm infants had AKI stage 2–3 by both serum creatinine and urine output criteria. 52/105 (53.6%) infants had AKI stage 0–1 by both serum creatinine and urine output criteria.
Among infants with GA more than 27 weeks, 10/105 (9.5%) had stage 1 AKI, 4/105 (3.8%) had stage 2, and 7(6.7%) had stage 3 AKI by serum creatinine and 3/105(2.9%) had stage 1, 9/105(8.6%) had stage 2, 6/105 (5.7%) had stage 3 AKI by urine output criteria. 21/105 (20%) preterm infants had AKI stage 2–3 by both serum creatinine and urine output criteria. 84/105 infants had AKI stage 0–1 by both serum creatinine and urine output criteria.
Gestational age group less than or equal to 27 weeks:
Risk Factors Assessment:
In the group with GA less than or equal to 27 weeks, surgical NEC [42 (93.3%) vs. 21 (40.4%), p<0.001], ostomy placement [35 (85.4%) vs. 9 (36%), p<0.001], cholestasis [30 (76.9%) vs. 11 (47.8%), p=0.04], intubation with mechanical ventilation [43 (97.7%) vs. 40 (78.4%), p=0.029] and positive blood cultures obtained at NEC onset [23(51.1%) vs. 11(21.2%),p=0.004] were more common in infants with moderate to severe AKI compared to infants with no to mild AKI.
Gestational age group more than 27 weeks:
Risk Factors Assessment:
In the group with GA more than 27 weeks, the infants with severe AKI were more likely to be male, out born (17 (81.0%) vs. 45 (54.2%), p=0.048), had surgical NEC [19 (90.5%) vs. 22 (26.2%), p<0.001], had more fulminant NEC (7 (33.3%) vs. 8 (9.52%), p=0.011), had more Jejunostomy [7 (36.8%) vs. 4 (10.0%), p=0.028], frequently had cholestasis (12 (66.7%) vs. 13 (33.3%), p=0.038), were intubated more (19 (90.5%) vs. 42 (52.5%)) and received antibiotics for longer duration (days) (10.0 [7.00; 13.5] vs. 7.00 [4.25; 7.00], p=0.025) compared to infants with non-severe AKI (Table 1).
On multivariable logistic regression
On multivariable logistic regression in preterm infants with GA less than 27 weeks, surgical NEC (aOR 35.08, 95% CI 5.05 – 243.73, p<0.001) and ostomy presence (aOR 6.2 95% CI 1.29 – 29.73, p=0.027) were significantly associated with higher odds of severe AKI. Similar association was estimated from the model for surgical NEC in infants with gestational age less than 27 weeks (Table 3).
Table 3.
Association between the predictors and severe AKI in preterm infants using multiple logistic regression.
| Model 1 (GA ≤ 27 weeks) |
Model 2 (GA > 27 weeks) |
|||||
|---|---|---|---|---|---|---|
| Predictors | aOR | 95% CI | P value | aOR | 95% CI | P value |
| Surgical NEC | ||||||
| No | Ref. | Ref. | ||||
| Yes | 35.08 | (5.05, 243.73) | <0.001 | 81.03 | (4.79, 6420.48) | 0.013 |
| Ostomy | ||||||
| No | Ref. | Ref. | ||||
| Yes | 6.2 | (1.29, 29.73) | 0.027 | 2 | (0.07, 40.96) | 0.642 |
| Cholestasis | ||||||
| No | Ref. | Ref. | ||||
| Yes | 3.25 | (0.66, 16.07) | 0.164 | 0.24 | (0.01, 2.54) | 0.3 |
| Assisted Ventilation | ||||||
| Othera | Ref. | Ref. | ||||
| Invasive | 0.14 | (0.00, 5.96) | 0.366 | 1.37 | (0.04, 52.69) | 0.852 |
| Positive Blood Culture | ||||||
| No | Ref. | |||||
| Yes | 2.36 | (0.49, 11.48) | 0.306 | |||
| Sex | ||||||
| Female | Ref. | |||||
| Male | 1.14 | (0.07, 18.85) | 0.922 | |||
| Pressor Support 24 hours | ||||||
| No | Ref. | |||||
| Yes | 1.36 | (0.08, 21.25) | 0.82 | |||
| Outborn | ||||||
| No | Ref. | |||||
| Yes | 14.57 | (0.94, 625.19) | 0.09 | |||
| Fulminant NEC | ||||||
| No | Ref. | |||||
| Yes | 11.91 | (0.81, 687.73) | 0.122 | |||
Abbreviations: NEC represents Necrotizing Enterocolitis; aOR represents adjusted odds ratio; CI represents confidence interval
Other represents high flow, CPAP, room air
Model 1 includes surgical nec, positive blood culture, ostomy, cholestasis and assisted ventilation in neonates with gestational age less than or equal to 27 weeks.
Model 2 includes all variables from model 1 except positive blood culture and added sex, pressor support 24 hours, outborn and fulminant nec in neonates with gestational age greater than 27 weeks.
Trends of Serum Creatinine and urine output
Trends of SCr, UOP, serum sodium, and anthropometric values for the cohort categorized by AKI status and gestational age are demonstrated in Figure 2, 3 and Supplemental Table 3. Among those with severe AKI in infants with gestational age less than 27 weeks, the median SCr levels remained significantly increased until 24 hours after NEC onset (p=0.008) and then began to approach a nadir between after 48 hours to 2 weeks following NEC onset. In infants with severe AKI and gestational age more than 27 weeks, the median SCr levels remained significantly increased until 96 hours after NEC onset (p=<0.003) and then began to approach a nadir between after 96 hours to 2 weeks following NEC onset. The UOP decreased on the day of NEC onset to a more significant degree in those with severe AKI vs. those without severe AKI [p< 0.001] in both gestational age groups. In those with severe AKI, UOP remained decreased for 24 hours after NEC onset compared to those without severe AKI (p=<0.001). Importantly, as opposed to SCr, which took days to improve, the UOP began to improve 24 hours after NEC onset. The data is summarized in Supplemental Table 3, Figure 2 and Figure 3.
Figure 2:
Trend of Serum creatinine and Urine Output parameters at different time points before and after NEC onset among NEC preterm infants by GA with and without Severe AKI. The astrerix (*) on X-axis represents P <0.05 at that time point after NEC onset. Zero (0) day on X-axis represents the day of NEC onset.
Figure 3:
Trend of serum sodium and weight change parameters at different time points before and after NEC onset among NEC preterm infants by GA with and without Severe AKI. The astrerix (*) on X-axis represents P <0.05 at that time point after NEC onset. Zero (0) day on X-axis represents the day of NEC onset.
Surgical NEC Cohort:
One hundred and four infants with surgical NEC were included in the analysis. 63/104 infants had gestational age less than 27 weeks (Group A) and 41/104 infants (Group B) had GA more than 27 weeks. The data are shown in Supplemental Figure 1 and 2, Supplemental Table 1 and Supplemental Table 2 and Supplemental Table 4.
In group with GA < 27 weeks
In group with GA < 27 weeks, The infants with severe AKI were significantly more likely to be African American (78% vs 47.6%; p=0.009), intubated more frequently following NEC onset (42/42 (100%) vs 18 (85.7%); p=0.033) and had positive blood culture sepsis following NEC 22/42 (52.4%) vs. 3/21 (14.3%); p=0.008) and had longer TPN days (115 days[56.3] vs. 84[56.4];p=0.03)and the time to reach full feeds (87 days[53.2] vs.50 days [36.2];p=0.02) compared to infants with non-severe AKI.
In group with GA > 27 weeks
In group with GA > 27 weeks, the infants with severe AKI were significantly out born (16/19 (84.2%) vs. 11/22 (50%); p=0.048), had later age of NEC onset (14.0 [6.50; 23] vs. 5.00 [2.00; 9.75]; p=0.045), needed dopamine support at 24 hours following NEC (15 (78.9%) vs. 10 (45.5%); p=0.033), less exposed to gentamicin (26.3% vs 63.6%,p=0.038) and had longer hospital stay (158 [110; 220] vs. 75.5 [38.8; 105]; p=0.007) compared to infants with non-severe AKI.
Trends of SCr, UOP, serum sodium, and anthropometric values for the surgical cohort categorized by AKI status and gestational age are demonstrated in Supplemental Figure 2, Supplemental Figure 3 and Supplemental Table 4.
Discussion:
NEC is a life-threatening condition and is associated with high morbidities, mortality and poor neurodevelopmental outcomes, and we know from previous analysis that it is associated with AKI in 60% of infants. Building off of our prior work in this cohort, we demonstrated that potential risk factors for severe AKI varied by GA. In this report, we have noticed that AKI rates were almost double (46% vs 20%) in neonates with GA < 27 weeks following NEC receiving laparotomy and blood culture positive sepsis, African American ethnicity and need to mechanical ventilation were most likely risk factors in lower GA group and took longer time to reach full feeds and received parenteral nutrition for more number of days compared to higher GA infants. However, in infants with GA >27 weeks, sex (male), fulminant NEC and the antibiotic duration are the major factors and had longer length of hospital stay. We also noticed that infants with GA <27 weeks had any AKI by SCr in 51% vs. 19% and any AKI by UOP in 33% vs. 17% of infants with GA >27 weeks which is better delineation of extent of AKI in preterm infants compared to our previous report. Among those with severe AKI in infants with GA < 27 weeks, the median SCr levels remained significantly elevated for 24 hours compared to 96 hours in preterm infants with GA>27 weeks following NEC. It is important to know the GA differences because the neonatal outcomes vary by the different GA. Because of the lack of reliable kidney function biomarkers that diagnose AKI early, clinical risk stratification based on GA is an essential part of AKI mitigation strategies.
The double rate of severe AKI in infants GA<27 weeks could be due to this population having more underdeveloped kidneys that are subsequently at greater risk of injury secondary to any surgical intervention for NEC than infants with GA >27 weeks. Although this study did not show a statistically significant difference in the mortality between those with severe AKI vs. non-severe/no AKI, we document significant morbidity in the neonates with severe AKI regardless of gestational age strata. In both cohorts, the clinical factors such as need of surgery, stoma, cholestasis and ventilation were more likely associated with severe AKI. The severe AKI in neonates requiring surgery for NEC points towards more severe multiorgan dysfunction in these patients. However, in addition male sex, out born status and higher exposure to nephrotoxic medications were more likely associated with severe AKI in neonates with GA>27 weeks. The association of severe AKI with higher gestation and out born status could be due to transferability and lower immediate risk of mortality in infants with GA >27 weeks.
Based on our adjusted models, surgical NEC remained significantly associated with severe AKI in both groups, a finding that indicates the need for closer monitoring in this group to allow for early recognition and management of AKI.The higher severity of AKI following surgical NEC is most likely contributed by blood and fluid loss in the intestine or via ostomy leading to hypotension affecting the renal perfusion. In our cohort, the surgical NEC infants are more likely to receive a red blood cell transfusion (76.7% vs. 53.1%, p = 0.001) within 48 h after diagnosis18. Infants with GA > 27 weeks with severe AKI had higher rates of hypotension and inotropic support need following surgical NEC compared to the non-severe AKI group. Moreover, infants with surgical NEC are commonly exposed to a number of sedatives attributing to hypotension and secondarily affecting renal blood flow, which needs further evaluation. In our cohort, infants with severe AKI had an ostomy more often which increases the risk of fluid imbalance and subsequent kidney hypo perfusion (pre-renal)1,19 and significantly increase the risk of AKI due to recurrent episodes of hypo perfusion injury. In our cohort, we noted lower weight gain in severe AKI group. Our study design precluded our ability to infer why we observed this finding. A prospective study with detailed assessments of fluid status and body composition is needed to make meaningful inferences about that finding.
In this cohort, the infants with severe AKI were exposed to nephrotoxic medications for longer duration in GA>27 weeks. The association between AKI and nephrotoxic antibiotic exposure has been reported in many studies20–22. There is need to develop renal protection bundle and monitor urinary biomarkers23 for infants exposed to longer duration of nephrotoxic medications including regular monitoring of serum creatinine in preterm infants with surgical NEC. A large prospective study is needed to understand if shorter duration of antibiotics is not inferior to the standard duration of antibiotics.
In this cohort, infants with severe AKI had blood culture positive sepsis and cholestasis in preterm infants with GA < 27 weeks as reported in our previous report24. Coggins et al. also reported increased odds of AKI in infants with late-onset sepsis25. The sepsis-associated AKI in neonates most likely due to inflammation, altered hemodynamics, and nephrotoxic drugs20,26. As we have previously shown24, cholestasis was an independent risk factor for sepsis in infants with NEC, which points to sepsis-associated liver injury27. Cholestasis may also be related to lower birth weight and gestation and/or higher need for intravenous nutrition in neonates with surgical NEC.
In surgical sub-cohort of gestational age more than 27 weeks infants with severe AKI had longer hospital stay compared to infants with non-severe AKI. The longer length of stay in GA group >27 weeks may be due to higher rates of Jejunostomy and greater severity of NEC illness in infants with GA > 27 weeks. Bakoum et al. reported length of stay was not significantly longer among neonates with AKI compared to neonates without AKI10. However, many studies have shown that severe AKI is associated with prolonged hospital stay in other critically ill pediatric patients. In our cohort, the mortality was not significant in two groups on the bivariate analysis. It will lead to bias to assess the effect of NEC on mortality independent of AKI, because AKI most likely mediates this relationship.
Strengths of this study include that this report evaluates NEC and neonatal AKI by GA using both UOP and serum creatinine criteria and looked at how UOP and Cr change through the course of NEC. It’s important to pay attention to both biomarkers as is becoming clear in the literature. The inclusion of UOP facilitated greater recognition of AKI. Our data provides useful clinical information to clinicians and is a platform for further GA-specific research regarding neonatal AKI and implementation of renal protection strategies in preterm infants with surgical NEC.
Our study is limited by its single center, retrospective design and three fourth of infants were African American. The relatively small sample size reduces the generalizability of the study and the statistical power to detect associations between clinical factors, NEC, and AKI, especially when stratified by GA. Second, we did not evaluate what interventions may or may not have contributed to AKI or recovery (e.g., fluid balance). Further, multiple comparisons yield a higher probability of type I errors. The UOP assessed via diaper weights also leads to measurement limitations. We used KDIGO criteria which is the most widely accepted AKI criteria in this population, though it does not consider GA. We need large studies to develop GA-specific definitions of AKI that are based on short and long-term outcomes.
In conclusion, our results confirm that AKI is a common comorbid condition in infants with NEC, especially those who underwent surgery, and suggest that risk factors for AKI in infants with NEC may vary by GA at birth. However, future studies are needed to determine whether AKI further increases the risk of morbidity and mortality among infants with NEC, whether and to what extent causal relationships exist among NEC, AKI, and worse clinical outcomes, and to validate the presence of modifiable risk factors for AKI that, if prevented or treated, improve clinical outcomes in this population, including later development of chronic kidney disease. Further investigation is needed to determine whether diagnosing and managing AKI more promptly in infants with NEC improves outcomes, including decreasing the risk of chronic kidney disease. Finally, future investigations should validate and better determine if GA modifies these relationships in a clinically meaningful way.
Supplementary Material
Impact:
In both cohorts need for surgery, stoma, cholestasis, and mechanical ventilation were associated with severe AKI, however, the infants with GA <27 weeks had twice the risk of severe AKI than GA>27 weeks group.
The longer exposure to nephrotoxic medication and referral need were significant risk factors for AKI in GA >27 weeks group.
GA-specific kidney protective and monitoring strategies to prevent AKI and its consequences are needed to improve the clinical outcomes in neonates with NEC. Understanding the risk factors and short- and long-term outcomes unique to different GA groups will help inform those strategies.
Acknowledgment:
The Mississippi Center for Clinical and Translational Research for supporting NEC research.
Funding:
Dr. Parvesh Mohan Garg and Dr. William Hillegass are partially supported by the NIGMS of the NIH under Award Number 5U54GM115428. Dr. Andrew South has funding from the NHBLI K23-HL148394, R01-HL146818, L40-HL148910-2, and R56-HL164434. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Consent: Patient consent is not required as per IRB
Category of study: Clinical science
Conflicts of interest: The authors disclose no conflicts.
Data User Agreement:
All data generated and analyzed during this study are included in this article and its supplementary information files.
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Supplementary Materials
Data Availability Statement
All data generated and analyzed during this study are included in this article and its supplementary information files.