Risk factors and mortality rate in premature babies with acute kidney injury

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J Clin Lab Anal. 2018;32:e22441. wileyonlinelibrary.com/journal/jcla |_{1 of 10}

https://doi.org/10.1002/jcla.22441

1 | INTRODUCTION

Using advanced technical and pharmacological interventions in re- cent years, effective treatment of many life- threatening issues in neonatal period became possible and survival rate of very low birth weight (VLBW) and extremely low birth weight babies (ELBW) has been increased.^1,2 Nevertheless, morbidities in those babies have not been changed significantly.^2,3

Acute renal damage (AKI) results in decreased renal function, accumulation of nitrogenous waste products, loss of fluid balance and loss of electrolyte, and acid- base homeostasis. The incidence of AKI in neonates who were admitted to the neonatal intensive care units (NICU) ranges from 3.4%- 71%. This wide range is partly due

to the lack of a universally accepted definition of AKI in premature babies.^4-11

Development of kidneys is a dynamic event that lasts up to the 36th week.¹² Because the susceptibility of immature kidney to cer- tain conditions such as hypotension, symptomatic patent ductus arteriosus (PDA), and sepsis as well as to some agents which were used in the treatment such as nonsteroidal anti- inflammatory drugs (NSAIDs) and aminoglycosides, can cause to or increase risk for AKI in premature babies. All these factors, alone or in combination, can lead to AKI and can affect the final number, size, morphology, and maturation of glomerules.^13,14 It is known that being a premature is only an independent risk factor for AKI due to an incomplete nephro- genesis and low number of nephrons.^5-7 It has been also suggested Received: 28 November 2017

|

Accepted: 2 March 2018

DOI: 10.1002/jcla.22441

R E S E A R C H A R T I C L E

Risk factors and mortality rate in premature babies with acute kidney injury

Ahmet Taner Elmas

¹

| Yılmaz Tabel

¹

| Ramazan Özdemir

²

1Department of Pediatric

Nephrology, Faculty of Medicine, University of İnönü, Malatya, Turkey

2Departments of Neonatology, Faculty of Medicine, University of İnönü, Malatya, Turkey

Correspondence

Ahmet Taner Elmas, Turgut Özal Tıp Merkezi, Pediatrik Nefroloji, İnönü Üniversitesi, Malatya, Turkey.

Email: drtelmas@hotmail.com

Background: Acute kidney injury (AKI) is a common morbidity in neonatal intensive care units and associated with poor outcome. This study aimed to determine the prevalence of AKI and provide a demographic data and risk factors associated with the mortality and morbidity.

Methods: This is a retrospective study included 105 premature babies. Diagnosis of AKI was based on neonatal KDIGO classification criteria. The babies were stratified into two groups according to AKI status during the hospitalization. Clinical and laboratory characteristics of the AKI group were compared to non- AKI group.

Results: AKI occurred in 21 (20.0%) of 105 premature babies, and mortality rate in these babies was 61.9%. Lower gestational weeks, lower Apgar scores at 5 minutes, lower systolic blood pressures, and inotropic supports were independent risk factors for the development of AKI in preterm babies (P < .05, for each). Oliguria, preeclamp- sia/eclampsia, resuscitation at birth, lower diastolic blood pressure, patent ductus arteriosus (PDA), inotropic support, and furosemide treatment were associated with the mortality (P < .05, for each).

Conclusions: Prenatal risk factors and medical interventions are associated with AKI, and AKI is associated with increased morbidity and mortality. Therefore, identifica- tion of AKI is very important in this vulnerable population and it should be performed as quickly as possible in all babies who are at high risk for developing of AKI.

K E Y W O R D S

acute kidney injury, neonatal intensive care unit, premature babies

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that preterm babies with reduced nephron numbers are at increased risk for development of chronic kidney disease later in life.^13,15 So, it is obvious that neonatal AKI is common and is associated with poor outcomes.

Although the risk of developing AKI in ELBW babies is higher than the other babies, this situation is not studied well. Therefore, in this study, we aimed to determine the prenatal and postnatal risk factors associated with AKI in ELBW babies. We also aimed to determine the mortality rate and the presence of various risk factors in nonsurvivor group of AKI.

2 | METHODS

For this cohort study, 114 premature babies whose gestational ages between 28 and 34 weeks, who were admitted to the NICU between November 2012 and April 2013, were included. Enrolled premature babies were prospectively followed for AKI development during the first 7 postnatal days by measuring serum creatinine (SCr) at least once every other day. We excluded premature babies in whom SCr levels were not determined, babies with known renal or other congenital anomalies, chromosomal abnormalities or those who died in the first 72 hours after birth, and those with a maternal history of renal failure. The final study group composed of a total of 105 critically ill preterm babies.

Flowchart regarding the selection process was shown on Figure 1.

They were stratified into two groups according to AKI status during the hospitalization. Of the 105 preterm babies, 21 preterm babies fulfilled the criteria for AKI during the first 7 days of life.

Clinical and laboratory characteristics of the AKI group were compared to non- AKI group.

Demographic and perinatal characteristics including gestational age (GA), gender, birth weight (BW), small for gestational age (SGA) status, mode of delivery, intubation at birth, resuscitation at birth, Apgar scores at 1st and 5th minutes, systolic and diastolic blood pressure (mm Hg) were recorded. Additional parameters such as result of blood gases at the admission, use of mechanical ventilation and/or continuous positive airway pressure (CPAP) for respiratory distress, use of postnatal steroids and surfactant, insertion of any central line, and presence of oliguria (urine output <0.5 mL/

kg per hour for more than 8 hours after birth) were also recorded.

Urine output measurement through bag or catheter collection was performed by 8- hour intervals. All babies were also evaluated for the presence of respiratory distress syndrome (RDS), suspected or culture- proven sepsis, severe perinatal asphyxia, pneumothorax, intraventricular hemorrhage (IVH), congenital heart disease (CHD), necrotizing enterocolitis (NEC), meconium aspiration syndrome (MAS), and hyperbilirubinemia. Any treatment including surfactant, NSAIDs (ibuprofen or indomethacin), loop diuretics (furosemide), inotropic support (dopamine and/or dobutamine), use of antibiotics (single or in combination), and/or antifungal was recorded. Results from cranial and renal USG, chest X- ray, and echocardiogram were also recorded.

Maternal characteristics such as age, gravidity, parity, and type of delivery were also collected. All preterm babies were evaluated for possible prenatal risk factors for AKI (fever, preeclampsia/eclampsia, chronic or pregnancy- induced hypertension, maternal diabetes, maternal urinary tract infection, premature rupture of membranes, clinical chorioamnionitis, maternal kidney dysfunction, or any other systemic illness), and prenatal drug exposure (including prenatal steroid, magnesium sulfate, and all antibiotics).

Blood and urine samples of all patients were obtained on the 1st, 3rd, and 7th day of life. Biochemical parameters such as serum glucose, blood urea nitrogen (BUN), SCr, serum uric acid, serum electrolytes including serum sodium, potassium, chloride, and total calcium, and urinary parameters including urine sodium and urine creatinine were evaluated. At least 3 mL of venous whole blood samples taken for biochemical analyzes was placed in BD Vacutainer^® (SST II Advance) with gel plastic tubes with yellow cap (BD- Beliver Industrial Estate; Beliver way, Roborough, Plymouth, PL67BP UK) centrifuged at 70 434 g for 15 minutes, and the ob- tained serum samples were immediately examined. All serum parameters such as serum glucose, BUN, SCr, uric acid, and serum electrolytes levels were measured by the Kinetic Calorimetric Jaffe method (Roche Diagnostics GmbH, Mannheim, Germany) with Cobas 8000 (Roche) auto- analyzer, and levels were expressed as milligrams per deciliter.

2.1 | Definition of variables

Gestational age of the babies was determined by early fetal ultra- sound and new Ballard score after birth. Prematurity was defined as gestational age at birth less than 37 weeks. Premature rupture of membranes was defined as membrane rupture before the onset of labor. Asphyxia was diagnosed when patients met the following criteria: (i) metabolic or severe, combined acidemia (pH less than 7.0) in umbilical artery or first blood gas sample; (ii) Apgar score 3 or less at 5th minute of life; (iii) neonatal neurological manifestations (seizures, coma, or hypotonia); (iv) multisystemic organ dysfunction, that is cardiovascular, gastrointestinal, hematological, pulmonary, or renal systems).¹⁶ Asphyxia was staged according to Sarnat and Sarnat Scoring System.¹⁷ Respiratory distress syndrome was defined on the basis of clinical, laboratory, and radiological findings.

Sepsis was defined as a positive blood culture or urine culture along F I G U R E 1 Selection of study subjects

114 preterm neonates

106 cases 8 cases

(Two or more serum creatinine (No serum creatinine and urine output) and urine output) 105 cases 1 cases (died in the first 72h of life)

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with clinical signs of infection.¹⁸ Metabolic acidosis was diagnosed if blood pH <7.20 and HCO3 ≤ 12 mmol/L or base excess ≥6¹⁹

Diagnosis of AKI was based on serum Cr >1.5 mg/dL on the first 3 days of life (sustained at least 48 hours, while the mother of the neonate has normal renal function) and on the neonatal AKI KDIGO classification criteria.²⁰ Neonatal AKI KDIGO classification criteria were as follows: Stage 0 AKI was defined as a no change in SCr or rise >0.3 mg/dL and urine output ≥0.5 mL/kg/h; Stage I AKI SCr rise

≥0.3 mg/dL within 48 hour or SCr rise ≥1.5- 1.9 X reference SCrâ within 7 d (a: Reference SCr will be defined as the lowest previous SCr value) and urine output <0.5 mL/kg/h for 6- 12 hour; Stage II AKI SCr rise ≥2.0- 2.9 X reference SCrâ and urine output <0.5 mL/kg/h for ≥12 hour; Stage III SCr rise ≥3 reference SCrâ or SCr≥2.5 mg/dL^b or Receipt of dialysis (b: SCr value of 2.5 mg/dL represents, 10 mL/

min/1.73 m²) and urine output <0.3 mL/kg/h for ≥24 hour or anuria for ≥12 hour.²⁰ Estimated GFR (mL/min/1.73 m²) was calculated on the 1st, 3rd^, and7th days of life. Estimated GFR was calculated using Schwartz Formula. Estimated GFR: k × height/Cr, the constant k was used as 0.33 for premature babies who were born before gestational week of 34.²¹

2.2 | Management

The babies who have developed AKI were treated according to the standard protocol: insuring adequate hydration [insensible loss (mL)+urine output (mL)], maintaining optimal fluid- electrolyte balance (serial measurement of electrolytes), normalizing arterial blood pressure, and minimizing nephrotoxic exposure. As the levels of nephrotoxic agents were not routinely monitored, doses and interval of these agents were calculated based on the glomerular filtration rate to minimize the exposure of nephrotoxicity or the agent was discontinued as quickly as possible. We checked fluid and electrolyte requirement every 8 hours. The diagnosis of RDS was made according to clinical and radiological criteria. The PDA was defined as ductus arteriosus not closing after the first 72 hours of life according to echocardiography findings performed by pediatric cardi- ologist, and ibuprofen therapy was given to the symptomatic PDA patients prophylactically via oral route. In the treatment of symptomatic PDA, ibuprofen was administered at an initial dose of 10 mg/

kg/d followed by 5 mg/kg/d for 24 hours at 2 doses. Dopamine treatment (5 μg/kg/min initial dose) was started to raise BP in hemodynamically impaired hypotonic babies and up to a maximum of 15- 20 μg/kg/min if needed according to hemodynamic parameters. Dobutamine therapy (5- 20 μg/kg/min) was added to the hy- potensive babies without response to dopamine treatment. These treatments continued until hemodynamic stabilization, or hypotension was corrected.

Peritoneal dialysis was performed for those who not responded to conventional treatment and developed severe oliguria, severe metabolic acidosis, persistent hyperkalemia, and fluid overload with evidence of hypertension and/or pulmonary edema, those who have neurologic symptoms and calcium/phosphate imbalance with hypo- calcemic tetany.

The procedures were in accordance with the ethical standard for human experimentations established by the Declaration of Helsinki in 1975, which was revised in 1983. The study was approved by the Ethic Committee of Inonu University, and informed consent forms were signed by the parents of all patients, before participating to the study.

2.3 | Statistical analysis

Statistical data were analyzed using the Statistical Package for Social Sciences program (SPSS) for Windows version 16.0 (SPSS Inc., Chicago, IL, USA). As a first step, normal distribution of the sample was analyzed by Shapiro- Wilk test. Normal distribution was repre- sented by mean and standard deviation (SD), whereas skewed distribution was expressed by median and interquartile range. Unpaired t test or Mann- Whitney U test was used for comparison of two groups. Categorical variables in proportions or percentages were analyzed by chi- squared test or Fisher’s exact test. Univariate binary logistic regression analysis was used to determine whether all variables were a predictor of AKI at the time of diagnosis. Significant variables were entered into a stepwise multivariate logistic regres- sion analysis, independent of potential confounders. A P value less than .05 was considered statistically significant.

3 | RESULTS

The study group consisted of 105 preterm babies, 48 boys (45.7%), 57 girls (54.3%). Of the 105 preterm babies, 21 preterm babies fulfilled the criteria for AKI during the first 7 days of life (20%).

According to neonatal AKI KDIGO classification criteria; 9 patients (42.8%) were stage 1; 7 patients (33.3%) were stage 2; and 5 patients (23.8%) were stage 3 (6 patients had oliguria). There were 8 boy (38%) and 13 girl (62%) preterm babies with AKI and 40 boys (47.6%) and 44 girls (52.4%) in the preterm babies without AKI. No significant difference was detected in number of the babies and gender between groups (P > .05, for each). Gestational age and birth weight of babies with AKI and their controls were 29 (28.5- 32.5) vs 31 (30- 34) weeks, (P = .036) and 1338.5 ± 376.9 g vs 1609.7 ± 460.3 g, (P = .014), respectively. There was a significant difference in 1st and 5th minute Apgar scores between babies with and without AKI (3 (3- 3) vs 5 (3- 5) for 1st minute Apgar scores (P = .0001) and 5 (3- 5) vs 7 (5- 7) for 5th minute Apgar scores (P = .0001). In addition, there was a significant difference in systolic and diastolic blood pressure (mmHg), oliguria, ampicillin and netilmicin treatment, inotropic support (dopamine and/or dobutamine treatment), and furosemide treatment between babies with and without AKI (P = .0001, for each). Other parameters such as umbilical catheter, central venous catheter, CHD, PDA treated with ibuprofen, perinatal asphyxia, IVH, suspected or culture- proven sepsis, and NEC in AKI group were also significantly higher than control group (P = .0002, P = .001, P = .002, P = .012, P = .001, P = .001, P = .003, P = .028, respectively). In ad- dition, premature babies who required intubation (P = .001) and

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resuscitation (P = .007) at birth and placed on mechanical ventilation (P = .004) thereafter were prone to AKI development significantly higher than the others. There was a significant difference in cefotaxime, metronidazole, meropenem and teicoplanin, and vancomycin treatment between babies with and without AKI (P = .001, P = .001, P = .008, and P = .006, respectively). The overall mortality rates in babies with AKI were significantly higher than the control group dur- ing their hospitalization (61.9 vs 3.6%) (P = .0001). Risk factors in AKI and non- AKI babies were summarized in Table 1.

Although the mean age of the mothers in AKI group was lower in control group (28.3 ± 5.4 vs 30.1 ± 5.1 years), there was no sig- nificant difference between groups (P < .05). In addition, other ma- ternal parameters including gravidity, fever, history of any infection, antenatal steroid use, history of preeclampsia/eclampsia, maternal urinary tract infection (UTI), diabetes, early rupture of membrane (PROM), its duration (hour), placenta previa, abruption placenta, clinical chorioamnionitis, and antenatal drugs use were not sta- tistically significant between AKI and control groups (P > .05, for each). Maternal risk factors in AKI and non- AKI babies were given in Table 2.

All factors associated with the preterm babies with AKI and without AKI were assessed by univariate logistic regression analysis (Table 3). Significant variables were identified by univariate analysis (Table 3) and entered into a stepwise multivariate logistic regression analysis, independent of potential confounders. The stepwise multivariate logistic regression analysis identified that lower gestational weeks, lower Apgar scores at 5 minutes, lower systolic blood TA B L E 1 Risk factors in AKI and non- AKI preterm babies

Parameters

AKI (n = 21)

Non- AKI

(n = 84) P^a,b Gestational age

(wk)

29 (28.5- 32.5) 31 (30- 34) .036

Birth weight (g) 1338.5 ± 376.9 1609.7 ± 460.3 .014 Sex (M/F) (n, %) 8/13 (38/62) 40/44

(47.6/52.4)

.473

SGA (n, %) 9 (42.9) 20 (23.8) .103

pH upon admission 7.23 ± 0.12 7.31 ± 0.09 .001 Vaginal delivery (n,

%)

0 (0) 5 (6) .580

Apgar at 1 min 3 (3- 3) 5 (3- 5) .0001

Apgar at 5 min 5 (3- 5) 7 (5- 7) .0001

Systolic blood

pressure (mm Hg) 60 (50- 60) 70 (60- 70) .0001 Diastolic blood

pressure (mm Hg) 30 (20- 30) 30 (30- 40) .0001

Oliguria (n, %) 6 (28.6) 0 (0) .0001

Intubation at birth (n, %)

13 (61.9) 19 (22.6) .001

Resuscitation at birth (n, %)

12 (57.1) 20 (23.8) .007

Mechanical ventilation (n, %)

13 (61.9) 22 (26.2) .004

CPAP (n, %) 7 (33.3) 34 (40.5) .623

Umbilical catheter (n, %)

15 (71.4) 27 (32.1) .002

Central venous

catheter (n, %) 4 (19) 0 (0) .001

RDS (n, %) 8 (38.1) 20 (23.8) .269

CHD except for

PDA (n, %) 8 (38.1) 7 (8.4) .002

PDA treated with ibuprofen (n, %)

9 (42.9) 12 (14.3) .012

Perinatal asphyxia (n, %)

4 (19) 0 (0) .001

İVH (n, %) 4 (19) 0 (0) .001

Hyperbilirubinemia (n, %)

19 (90.5) 68 (81) .517

MAS (n, %) 1 (4.8) 0 (0) .200

Sepsis (n, %) 5 (23.8) 2 (2.4) .003

Necrotising enterocolitis (n, %)

4 (19) 3 (3.6) .028

Pneumothorax (n,

%)

1 (4.8) 1 (1.2) .362

Ampicillin and

netilmicin (n, %) 17 (81) 25 (29.8) .0001

Cefotaxime (n, %) 8 (38.1) 6 (7.1) .001

Metronidazole (n,

%)

7 (33.3) 4 (4.8) .001

(Continues)

Parameters AKI

(n = 21) Non- AKI

(n = 84) P^a,b Meropenem and

teicoplanin (n, %) 5 (23.8) 3 (3.6) .008

Vancomycin (n, %) 4 (19) 1 (1.2) .006

Fluconazole (n, %) 1 (4.8) 0 (0) .202

Amphotericin B (n,

%) 1 (4.8) 0 (0) .202

Surfactant treatment for RDS (n, %)

8 (38.1) 20 (23.8) .269

Dopamine and/or dobutamine (n, %)

13 (61.9) 9 (10.7) .0001

Furosemide (n, %) 9 (42.9) 0 (0) .0001

Exitus (n, %) 13 (61.9) 3 (3.6) .0001

AKI, acute kidney injury; M, male; F, female; SGA, small for gestational age; RDS, respiratory distress syndrome; CHD, congenital heart disease;

PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage; MAS, meconium aspiration syndrome; CPAP, continuous positive airway pressure.

Data were presented as mean ± SD or median with interquartile range or proportion and percentage. P value is for comparison between control and patients.

Bold indicates statistically significant value (P < .05).

aUnpaired t test or Mann- Whitney U test.

bchi- squared test or Fisher’s exact test, P < .05 is significant.

TA B L E 1 (Continued)

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pressures, and inotropic supports were independent risk factors for the development of AKI in preterm babies (Table 4).

Mean BUN, SCr, serum uric acid, and eGFR values in AKI group were significantly higher than control group both on the 3rd and 7th postnatal days of life (P = .0001, for each). No significant difference was detected in serum glucose and serum electrolyte levels between groups in the preterm babies with and without AKI on the 1st, 3rd, and 7th postnatal days of life (P > .05, for each). Only serum calcium levels in preterm babies with AKI on the postnatal day 3 were signifi- cantly lower than preterm babies without AKI (P = .003). Laboratory parameters of the preterm babies with and without AKI on postnatal days were given in Table 5.

Thirteen of 21 infants (61.9%) with AKI died in the first 7 days of life; 7 patients (38.1%) survived. The causes of death in AKI patients were multifactorial. While 4 patients died due to major CHD;

3 patients died because of only symptomatic large PDA. The re- maining 6 patients died due to various combined causes such as severe RDS, sepsis, perinatal asphyxia, or intracranial hemorrhage etc. 2 patients underwent peritoneal dialysis treatment. There was

a significant relationship between KDIGO staging and mortality rate in AKI patients (P = .005). In addition, there was a significant associ- ation between mortality rate in preterm babies with AKI and oliguria, resuscitation at birth, diastolic hypotension, PDA treated with ibuprofen, inotropic support (dopamine and/or dobutamine), and furo- semide treatment (P = .046, P = .048, P = .032, P = .005, P = .001 and P = .005, respectively). However, the distribution of preeclampsia/

eclampsia was significantly higher in survivor group when compared with nonsurvivors, and there was inverse association between mortality rate in preterm babies with AKI and preeclampsia/eclampsia (P = .012). Although the proportion of babies with low birth weight (LBW), VLBW, and ELBW were higher in nonsurvivors than in sur- vivors, these findings were not statistically significant (P > .05, for each). Other parameters were not statistically significant between AKI group and control group (P > .05, for each). Risk factors for mor- tality of patients with AKI were given in Table 6.

4 | DISCUSSION

Acute kidney injury is frequent in very preterm babies and is associated with increased risk of morbidity and mortality, after adjust- ment for confounders, although outcomes in very preterm babies have improved over the past few decades.^7-11,22-43 To adjust for likely mixers, we developed a binary logistic regression model to study potential risk factors associated with AKI in premature babies. The results of our study revealed that AKI was common in LBW babies and that lower gestational ages, lower Apgar scores at 5 minutes, lower systolic blood pressures upon admission NICU, and inotropic supports (dopamine and/or dobutamine treatment due to hemodynamic instability or hypotension) were independent risk factors of AKI in LBW babies. We have also shown that LBW babies with AKI have a high mortality (61.9%) and oliguria, preeclampsia/eclampsia, lower diastolic blood pressures, PDA, inotropic supports, and furosemide treatment were associated with the mortality of these babies (P < .05, for each).

Many possible risk factors such as low GA, low BW, low Apgar scores at 1 and 5 minutes, male gender, SGA, low cord pH, intubation at birth, mechanical ventilation, umbilical artery/venous catheters, lower mean arterial pressures, congenital heart disease, perinatal depression, assisted ventilation, oliguria/anuria, exposure to various medications such as blood pressure medications (pressor/inotropic support), antenatal corticosteroids, ampicillin, ceftazidime, cefotaxime, gentamicin, vancomycin, ibuprofen treatment, and multiorgan failure including disseminated intravascular coagulation (DIC) and shock for the development of AKI in neonates have been clari- fied.^4-11,22-43 When compared to term babies, premature babies are at more risk of developing AKI because they are exposed to various risk factors including prenatal fetal distress and postnatal other multiple risk factors such as perinatal asphyxia, IVH, sepsis, PDA, RDS, bronchopulmonary dysplasia (BPD), NEC, intrauterine growth retar- dation, placental insufficiency, pneumothorax, and various medications. Furthermore, postnatal progression of preterm babies is usually TA B L E 2 Maternal risk factors in AKI and non- AKI preterm

babies

Parameters AKI

(n = 21) Non- AKI

(n = 84) P^a,b Maternal age (y) 28.3 ± 5.4 30.1 ± 5.1 .157

Pregnancy number 1.7 ± 1.0 2.3 ± 1.6 .069

Multiple pregnancies (n, %)

10 (47.6) 22 (26.2) .067

Prenatal steroids (n, %) 5 (23.8) 13 (15.5) .350

Preeclampsia (n, %) 4 (19) 21 (25.0) .776

Fever (n, %) 0 (0) 5 (6.0) .580

Infectious disease (n,

%)

0 (0) 2 (2.4) 1.000

Diabetes mellitus Type 2 (n, %)

1 (4.8) 6 (7.1) 1.000

Gestational diabetes (n, %)

0 (0) 2 (2.4) 1.000

PRM (n, %) 3 (14.3) 13 (15.5) 1.000

PRM duration (h) 6.8 ± 17.2 6.2 ± 15.8 .885

Maternal UTI (n, %) 0 (0) 1 (1.2) 1.000

Placenta previa (n, %) 0 (0) 3 (3.6) 1.000

Abruption placenta (n,

%)

2 (9.5) 0 (0) .380

Clinical chorioamnionitis (n, %)

1 (4.8) 2 (2.4) .492

Drugs (n, %) 0 (0) 3 (3.6) 1.000

AKI, acute kidney injury; PMR, premature rupture of membrane; UTI, urinary tract infection.

Data were presented as mean ± SD or median with interquartile range or proportion and percentage. P value is for comparison between control and patients.

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problematic owing to the call for cardiovascular support, hypotension, and hypoxia.^7-11,22-43 Moreover, to be only prematurity is an independent risk factor for AKI because of an insufficient nephro- genesis and low nephron count.^6,7 Much of the studies performed on risk factors that cause AKI is followed by univariate analysis. There are few studies that have performed multivariate analysis to determine the risk factors for AKI, independent of potential confounders, and these studies revealed that lower BW, lower GA, lower Apgar scores at 1 and 5 minutes, and inotropic supports were independent risk factors for AKI in premature babies, similar to our results.^8,23,28,37 TA B L E 3 Predictive factors in preterm babies with acute kidney

injury according to univariate binary logistic regression analysis

Parameters Odds ratio (OR)

95%

Confidence Interval (95%CI) P Gestational age

(wk)

0.781 0.615- 0.990 .041

Birth weight (g) 0.998 0.997- 1.000 .017

Male gender 0.677 0.252- 1.802 .435

SGA 0.417 0.153- 1.132 .086

pH upon admission 0.000 0.000- 0.047 .002

C/S delivery 0.000 0.000 .999

Apgar at 1 min 0.183 0.085- 0.396 .0001

Apgar at 5 min 0.303 0.178- 0.513 .0001

Systolic blood pressure (mm Hg)

0.825 0.751- 0.906 .0001

Diastolic blood pressure (mm Hg)

0.804 0.706- 0.916 .001

Oliguria 0.000 0.000 .999

Intubation at birth 0.180 0.065- 0.498 .001 Resuscitation at

birth

0.234 0.086- 0.687 .004

Mechanical ventilation

0.218 0.080- 0.597 .003

CPAP 1.360 0.497- 3.721 .549

Umbilical catheter 0.189 0.066- 0.542 .002

Central venous catheter

0.000 0.000 .999

RDS 0.508 0.184- 1.400 .190

CHD except for PDA

0.148 0.046- 0.477 .001

PDA treated with

ibuprofen 0.222 0.077- 0.640 .005

Perinatal asphyxia 0.000 0.000 .999

İVH 0.000 0.000 .999

Hyperbilirubinemia 0.447 0.094- 2.119 .311

MAS 0.000 0.000 1.000

Sepsis 0.078 0.014- 0.438 .004

Necrotising

enterocolitis 0.157 0.032- 0.769 .022

Pneumothorax 0.241 0.014- 4.020 .322

Ampicillin and

netilmicin 0.100 0.030- 0.326 .0001

Cefotaxime 0.125 0.037- 0.419 .001

Metronidazole 0.100 0.026- 0.387 .001

Meropenem and

teicoplanin 0.119 0.026- 0.547 .006

Vancomycin 0.051 0.005- 0.487 .010

Fluconazole 0.000 0.000 1.000

Amphotericin B 0.000 0.000 1.000

(Continues)

Parameters

Odds ratio (OR)

95%

Confidence Interval (95%CI) P Surfactant

treatment for RDS

0.508 0.184- 1.400 .190

Inotropic support 0.074 0.024- 0.226 .0001

Furosemide 0.000 0.000 .999

AKI, acute kidney injury; M, male; F, female; SGA, small for gestational age;

RDS, respiratory distress syndrome; CHD, congenital heart disease; PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage; MAS, meconium aspiration syndrome; CPAP, continuous positive airway pressure.

TA B L E 3 (Continued)

TA B L E 4 Predictive factors in preterm babies with acute kidney injury according to multivariate binary logistic regression analysis

Predictive

factors Odds ratio (OR) 95% Confidence Interval (95%CI) P Gestational age

(wk)

3.207 1.106- 9.301 .032

Apgar at 1 min 0.004 0.000- 1.041 .052

Apgar at 5 min 0.137 0.024- 0.785 .026

Systolic blood pressure (mm Hg)

0.729 0.537- 0.790 .043

Diastolic blood pressure (mm Hg)

0.636 0.316- 1.281 .205

Intubation at birth

16.475 0.188- 1.447 .095

Umbilical catheter

0.000 0.000- 1.473 .056

Patent ductus arteriosus

95.966 0.213- 43.325 .143

Sepsis 0.000 0.000- 3.064 .086

Necrotising enterocolitis

0.000 0.000- 1.207 .054

Cefotaxime 10.593 0.360- 3.119 .072

Meropenem and

teicoplanin 7.079 0.287- 17.451 .100

Inotropic support

0.000 0.000- 1.023 .050

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It has been noted that the incidence of AKI varies between 3.4%

and 71% in critical neonates admitted to the NICU.^4-11,22-43 In our study, the incidence of AKI in premature babies was 20%, which was consistent with the previous studies.

Although oliguria is another clinical finding associated with AKI, preterm babies with AKI are often nonoliguric. Nonoliguric patients have a better prognosis than oliguric patients because of less renal damage and better fluid and electrolyte homeostasis.³⁴ In our study, 28.6%

of our patients had AKI associated with oliguria, and a big proportion had a nonoliguric AKI (71.4%), which was consistent with the literature.

The mortality of nonoliguric AKI patients ranges from 4.5%- 40%, compared to 25%- 78% for patients with oligo- anuric AKI.^4,35,36 In our study, the mortality rate in the group of preterm babies with oliguric AKI was high (46.2%) (Table 5) ^4,35,36 and we detected that AKI was associated with increased risk of mortality similar to other studies.^7-11,22-43

Patent ductus arteriosus is prevalent in preterm babies, and a clinically apparent PDA is associated with increased risk of morbidity and mortality. Large, right to left shunt and aortic flow associated with the PDA may cause undesirable cardiac output volume and may lead to inadequate renal perfusion.^6,39 It has also been shown in the association between nephrotoxic drug use such as NSAIDs, especially ibuprofen, and development of AKI in postnatal period in premature babies.^6,40 In our study, the univariate analysis found that CHD except for PDA or only symptomatic PDA treated with ibuprofen was associated with the babies with AKI, which is consistent with the previous report, but multivariate analysis did not support this finding. However, we found that PDA treated with ibuprofen is a risk factor for mortality in preterm babies with AKI. This may be thought to be associated with nephrotoxicity of ibuprofen and a lethal con- sequence of severe AKI, or it may depend on the large PDA itself.

Parameters PND

AKI (n = 21)

Non- AKI

(n = 84) P^a

Glucose (mg/dL) 1 76 (39.5- 94.5) 60.5 (35.5- 85) .189

3 80 (54.5- 94) 75.5 (57.5- 85.2) .200

7 72 (53.5- 94.5) 71 (61.7- 85.2) .335

BUN (mg/dL) 1 11.5 ± 5.6 11.7 ± 5.0 .902

3 19.5 ± 14.4 11.1 ± 7.4 .0001

7 12.0 85.0- 38.0) 5.5 (4.0- 8.2) .012

Serum creatinine (mg/

dL)

1 0.63 ± 0.13 0.66 ± 0.14 .472

3 0.90 ± 0.36 0.61 ± 0.10 .0001

7 0.96 ± 0.41 0.56 ± 0.11 .0001

Serum uric acid (mg/dL) 1 6.3 ± 2.1 5.8 ± 2.0 .352

3 6.8 ± 5.5 3.3 ± 1.5 .0001

7 5.9 ± 3.7 2.5 ± 0.8 .0001

eGFR (mL/min/1.73 m²) 1 21.1 (16.6- 23.4) 20.8 (17.5- 24.0) .591 3 15.7 (10.5- 22.6) 21.2 (18.6- 24.6) .0001 7 13.4 (10.2- 19.9) 23.0 (20.1- 27.2) .0001

Serum sodium (mg/dL) 1 134.4 ± 3.6 133.8 ± 14.1 .873

3 137.7 ± 8.9 138.7 ± 3.9 .454

7 138.1 ± 7.6 137.4 ± 4.2 .626

Serum potassium (mg/

dL) 1 5.5 ± 1.0 5.3 ± 0.8 .391

3 5.5 ± 1.4 4.9 ± 0.9 .048

7 4.7 ± 1.8 4.8 ± 0.8 .804

Serum chloride (mg/dL) 1 108.2 ± 4.9 104.8 ± 15.9 .354

3 107.2 ± 3.9 108.1 ± 4.1 .374

7 104.7 ± 5.2 106.8 ± 4.4 .112

Serum calcium (mg/dL) 1 7.8 ± 0.8 7.9 ± 1.0 .598

3 7.4 ± 1.1 8.3 ± 1.1 .003

7 7.9 (6.9- 9.5) 9.3 (9.0- 9.9) .051

PND, postnatal days, AKI, acute kidney injury, BUN, blood urea nitrogen, Estimated GFR—Schwartz’s estimated creatinine clearance.

Data were presented as mean ± SD or median with interquartile range. P value is for comparison between control and patients.

aUnpaired t test or Mann- Whitney U test, P < .05 is significant.

TA B L E 5 Comparison of laboratory parameters of the preterm babies with and without acute kidney injury on postnatal day 1, 3, and 7

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Some studies have shown that in babies born from preeclamptic mothers has a significantly lower frequency of AKI than in babies born to mothers without preeclampsia.^8,23 However, in a previous study, we found that preeclamptic mothers and/or pregnancy- induced hypertension were associated with AKI in preterm babies.³⁷ In our study, we found that preeclampsia and/or pregnancy- induced hypertension were not associated with AKI in preterm babies, consistent with the previous studies,^8,23 but there was an inverse

relationship between AKI and preeclampsia/eclampsia and mortality rate in preterm babies.

Approximately half of AKI in premature babies is associated with exposure to various medications after birth.⁴¹ It has been in- dicated that babies with AKI have been exposed to antibiotics, NSAIDs, and diuretics for a long time.⁶ The association between the uses of many drugs, for example, the use of inotropic support (dopamine and/or dobutamine),^23,33 NSAIDs (ibuprofen), and various TA B L E 6 Risk factors for mortality of preterm babies with acute kidney injury

Parameters

Nonsurvivors (n = 13)

Survivor

(n = 8) P^a,b

Gestational age (wk) 29.0 (28.0- 30.5) 31.5 (29.25- 33.75) .640

Birth weight (g) 1290 (915.5- 1598.0) 1425 (1149.2- 1681.5) .645

pH upon admission 7.27 (7.16- 7.30) 7.25 (7.20- 7.32) .916

Apgar at 1 min 3 (3) 3 (3- 4.5) .374

Apgar at 5 min 5 (5) 5 (5- 6.5) .268

Systolic blood pressure (mm Hg) 55 (52.5- 68.75) 60 (50- 60) .145

Diastolic blood pressure (mm Hg) 30 (20- 30) 30 (30) .048

Oliguria (n, %) 6 (46.2) 0 (0) .046

Sex (M/F) (n) 3/5 5/8 1.00

SGA (n, %) 5 (38.5) 4 (50) .673

Prenatal steroids (n, %) 4 (30.8) 1 (12.5) .606

Preeclampsia/eclampsia (n, %) 0 (0) 4 (50) .012

PRM (n, %) 2 (15.4) 1 (12.5) 1.00

Placenta previa (n, %) 0 (0) 0 (0) -

Abruption placenta (n, %) 1 (7.7) 1 (12.5) 1.00

Clinical chorioamnionitis (n, %) 0 (0) 1 (12.5) .381

Intubation at birth (n, %) 10 (76.9) 3 (37.5) .164

Resuscitation at birth (n, %) 10 (76.9) 2 (25) .032

Mechanical ventilation (n, %) 10 (76.9) 3 (37.5) .164

Umbilical lines (n, %) 11 (84.6) 4 (50) .146

Central venous lines (n, %) 4 (30.8) 0 (0) .131

RDS treated with surfactant (n, %) 6 (46.2) 2 (25) .400

Sepsis (n, %) 3 (23.1) 2 (25) 1.00

MAS (n, %) 0 (0) 1 (12.5) .381

Perinatal asphyxia (n, %) 4 (30.8) 0 (0) .131

IVH (n, %) 4 (30.8) 0 (0) .131

CHD except for PDA (n, %) 6 (46.2) 2 (25) .400

PDA treated with ibuprofen (n, %) 9 (69.2) 0 (0) .005

Necrotising enterocolitis (n, %) 3 (23.1) 1 (12.5) 1.00

Pneumothorax (n, %) 1 (7.7) 0 (0) 1.00

Inotropic support (n, %) 12 (92.3) 1 (12.5) .001

Furosemide (n, %) 9 (69.2) 0 (0) .005

AKI, acute kidney injury; M, male; F, female; SGA, small for gestational age; RDS, respiratory distress syndrome; CHD, congenital heart disease; PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage; MAS, meconium aspiration syndrome.

Data were presented as mean ± SD or median with interquartile range or proportion and percentage. P value is for comparison between control and patients.

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antibiotics,6,23,26,32,33,37,42 and the development of AKI has been shown in neonates. In our study, the univariate analysis found that the use of many drugs was associated with the babies with AKI, which is consistent with the previous report,6,23,26,32,33,37,42 but multivariate analysis did not support this finding.

Except in the case of several congenital or primary renal disorders, most AKI in neonates is reversible and transient with the correction of the underlying cause.^4-11,22-43 A high mortality rate has been reported in neonate with AKI (range 25%- 80%), which is consistent with our findings (our mortality rate was 61.9% in patients with AKI).^4-11,22-43

There are some limitations in this work. The first one is a retrospective review that does not contain all the necessary information and is based on a file review. Second, as families cannot be followed for a long time, survivors’ long- term outcomes and late- developed AKI could not be assessed. Third, we measured SCr levels at 48- 72- hour intervals, which may be related to the high prevalence of AKI in neonates. Fourth, single center data reduce generalizability.

5 | CONCLUSION

In our study, we showed that AKI was common in preterm babies and lower GA, lower Apgar scores at 5 minutes, lower systolic blood pressure, and inotropic supports were associated with the development of AKI. In addition, we found that KDIGO staging, lower diastolic blood pressures, oliguria, preeclampsia/eclampsia, large PDA, inotropic support, and furosemide treatment were associated with higher mortality in these babies. Prenatal factors and medical devices were also associated with AKI. It is very important to identify all preterm babies who are at high risk of developing AKI as quickly as possible. Early interventions should be considered in the management of LBW babies at risk for the development of AKI. We should remember that early detection of risk factors can reduce the mortality of AKI patients.

6 | COMPLIANCE WITH ETHICAL STANDARDS

Research ethics approval was obtained from the İnönü University ethic committee and conducted in accordance with the Declaration of Helsinki.

ORCID

Ahmet Taner Elmas http://orcid.org/0000-0002-9749-6115 Yılmaz Tabel http://orcid.org/0000-0001-7359-4944 Ramazan Özdemir http://orcid.org/0000-0003-4722-1188

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How to cite this article: Elmas AT, Tabel Y, Özdemir R. Risk factors and mortality rate in premature babies with acute kidney injury. J Clin Lab Anal. 2018;32:e22441. https://doi.

org/10.1002/jcla.22441