Incidence, Risk Factors, and Outcome of Acute Kidney Injury in Critically Ill Neonates

doi:10.21203/rs.3.rs-3303385/v1

Background. Acute kidney injury is a common problem in critically ill neonates in Neonatal Intensive Care Unit (NICU). Critically ill neonates commonly have various risk factors for renal injury, including prematurity, asphyxia, sepsis, nephrotoxic drug exposure, dehydration and bleeding episode. We intended to analyze the incidence, risk factors, and outcome of acute kidney injury in neonates.

Method. This prospective cohort study was conducted at NICU of Prof. Dr. R.D. Kandou General Hospital, Manado, in August 2019 to January 2020. Subjects were neonates who had received parental consent to participate and was willing to fill out a research form. The data obtained were analyzed using the chi-square test to compare groups of categorical variables and logistic regression test to determine the potential for predictive covariates in acute renal injury. This study was conducted under the approval of the Health Ethics Committee of Prof. Dr. Dr. R.D. Kandou, Manado.

Result. This study found significant and strong association between sepsis and nephrotoxic drug exposure with acute kidney injury. Asphyxia with kidney disorders had strong relationship with renal injury. There was weak, significant association between respiratory distress and kidney injury. Meanwhile, bleeding and dehydration status were not significantly associated with kidney injury. Prematurity and acute kidney injury had significant negative relationship. From all the variables, sepsis, nephrotoxic drug exposure and prematurity were significantly associated with renal injury. This study also found weak association between acute kidney injury and mortality in critically ill neonates.

Pediatrics

Acute kidney injury

renal injury

neonates

critically ill

Acute kidney injury (AKI) is still a common clinical problem found in patients treated in hospitals as well as in the Neonatal Intensive Care Unit (NICU). The incidence of AKI in neonates in hospital is estimated to be between 6% -24%.¹ The incidence of AKI correlates with increased mortality in neonates. Infants with AKI have a risk of chronic kidney disease and hypertension later-on. Compared to older infants, neonates have certain physiological characteristics that increase the risk of AKI, including higher susceptibility to hypoperfusion, higher vascular resistance, increased plasma renin activity, and decreased sodium reabsorption in proximal tubules. In addition, premature infants often show conditions that are known to be associated with an increased risk of AKI, including hypoxemia, sepsis, necrotizing enterocolitis (NEC), and patent ductus arteriosus (PDA).¹

The consumption of non-steroidal anti-inflammatory drugs during pregnancy and the treatment of ibuprofen in neonates is reported as an additional risk factor for AKI. Diagnostic criteria and stage systems for AKI are based on acute quantitative changes in serum creatinine (SCr) and/or urine output (UOP) levels. The Kidney Disease Improving Global Outcomes (KDIGO) organization also issues a set of clinical practice guidelines for AKI in adults and children, including the AKI stages system based on SCr and UOP. However, it must be realized that creatinine is not a sensitive and specific examination to diagnose AKI because serum creatinine only assesses loss of kidney function and not damage to kidney tissue.²

Shalaby MA, et al in their study found that AKI was diagnosed in more than half (56%) of all critically ill neonates in NICU with various risk factors including prematurity, asphyxia, sepsis, nephrotoxic drug exposure. AKI events are associated with increased mortality and length of stay.²

Serum creatinine is said to increase if 25–50% of kidney function is disrupted. Increased serum creatinine occurs later than loss of renal function, and changes in serum creatinine after severe AKI are highly dependent on initial renal function.^3,4

In addition, serum creatinine levels are strongly affected by race, muscle mass, age, sex, hydration status and protein intake. Therefore, clearer knowledge is needed about the predictive factors for developing AKI in neonates. This study aims to determine the incidence, risk factors, outcome of acute renal injury in neonates.

This study is a prospective cohort with a cross-sectional approach from neonates treated at NICU, Prof. RSUP Dr. R.D. Kandou in August 2019 to January 2020. Sampling was carried out by consecutive sampling method. Subjects were included in the study after obtaining parental consent to participate and were willing to fill out the research form. Subjects were excluded from the study if renal agenesis, cloacal exstrophy and prune belly syndrome were found. Criteria for dropping out when the patient is forced to go home, parents change the information concern and incomplete supporting laboratory examinations.

Samples that met the exclusion criteria were taken at least 2 ml of blood. Subjects who experience acute kidney disorders will be observed regarding mortality and length of stay. The data obtained were analyzed using the chi-square test to compare groups of categorical variables and logistic regression tests to determine the potential for predictive covariates in acute renal injury. This study was carried out under the approval of the Health Ethic Committee of Prof. Dr. R.D. Kandou Hospital, Manado.

A total of 183 infants were treated at the NICU during the study period. As many as 31 samples dropped out because there were missing data in the results of the examination. A total of 152 samples met the study inclusion criteria. Subjects characteristics were shown in (Table 1).

From the overall subjects, 84 (55.3%) were male and 68 (44.7%) were female neonates. The mean birth weight was 2,358.16 grams (500 – 4,130 grams). The mean of birth body length was 46.14 cm (31 – 53 cm). The lowest age at entry into the NICU is 0 days and the highest age is 27 days, with a mean value (SD) was 2.15 (4.8) days. The serum creatinine levels were as low as 0.2 mg/dL and the highest was 3.2 mg/dL with a mean value (SD) was 0.87 (0.53) mg/dl. The lowest glomerular filtration rate was 3.48 ml/min/1.72 m² and the highest was 192.2 ml/min/1.72 m² with the mean value (SD) of 28.55 (24.26) ml/min/1.72 m².

In general, neonates born spontaneously with vertex presentation are 80 infants (52.6%) and cesarean section is 27 infants (42.7%). Based on gestational age, 5.3% was extremely preterm, 14.5% was very preterm, 11.8% was moderately preterm, 11.2% was late preterm, 11.2% was early preterm, 42.8% was full term, and 3.3% was late term. Oxygen need with FiO₂ 21% nasal cannula was 24 infants, CPAP FiO₂21-50% was 82 neonates, ventilator with FiO₂>50% was 46 neonates. There were 33 neonates with asphyxia neonatorum. The use of antibiotics was ampicillin and gentamicin in 57.6%, ceftazidime and amikacin in 25.2%, and meropenem in 17.2%. Neonates diagnosed with neonatal sepsis was 50.7%, bleeding was 13.8%, and dehydration was 1.3%. Neonates who experienced mild respiratory distress was 15.8%, moderate respiratory distress was 53.9%, and severe respiratory distress was 30.3%.

Analysis of the relationship between risk factors and incidence of AKI was showed in (Table 2). From the data analysis, there was a significant relationship (X2 = 63,620, p <0.001) between the incidence of sepsis and kidney disorders in neonatal infants, with r_g = 0.933. P <0.001 (very strong). Neonates with asphyxia were also associated with renal injury and the correlation was quite strong (r_g= 0.551, p <0.001). Infants exposed to nephrotoxic drugs were closely related to kidney injury (r_g = 0.933, p <0.001). Bleeding and dehydration did not have a significant relationship with kidney injury (p = 0.461 and p = 0.150, respectively). Neonates with respiratory distress had weak but significant relationship with renal injury (r_g = 0.273). There was a significantly negative relationship between prematurity and kidney injury in neonates.

The relationship between all risk factors (sepsis, asphyxia, prematurity, nephrotoxic exposure, dehydration, bleeding and respiratory distress) with kidney injury was analyzed by multiple logistic regression analysis. These results indicate that of the seven tested variables, there were three factors significantly associated with kidney injury, which were sepsis (p <0.001), nephrotoxic drug exposure (p = 0.001), and prematurity (p <0.001) (Table 3).

The relationship of kidney injury with mortality was tested by X₂ test and Gamma correlation analysis (Table 4). X₂ test showed X₂ = 1.643 (p = 0.100) and Gamma correlation was r_g = -0.250 (p = 0.211). The results of this test showed weak, insignificant negative relationship between kidney injury and mortality in neonates.

The relationship of kidney injury with length of stay was tested by Pearson correlation analysis. The results of this test showed r = 0.593 (p <0.001), (Figure 1). The results of showed fairly strong and significant positive relationship between kidney injury and length of stay in neonates.

This study aims to determine the incidence, risk factors, outcome of acute renal injury in critically ill neonates. In this study, the incidence of acute renal injury in neonates was 40.1%. This study is in line with research by Shalaby MA et al² in 2018 that found the incidence of acute renal injury in neonates was 56%.

Statistical test results showed significant relationship between sepsis, nephrotoxic drug exposure, and prematurity with acute renal injury. The results of this study are in line with research by Mwamanenge NA et al⁵ which found that sepsis was the main cause of acute renal injury.

The response of the innate immune system to infection triggers an adaptive mechanism that can affect renal tubules, vascular function and glomerulus. Decreased glomerular filtration rate (GFR) is an important thing that occurs in acute kidney injury due to sepsis. Low GFR is considered a protective mechanism against further damage. A reduction in GFR means reduced damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) filtration which then limits the exposure of toxins and stress to tubular cells. Reducing GFR also means a decrease in energy consumption due to decrease of sodium that needs to be filtered and reabsorbed.⁶

Statistical test showed significant and very strong relationship between nephrotoxic drug exposure and renal injury in neonates. This finding is in line with a research conducted by Pambudi B et al⁷, in which stated that average increase in urine kidney injury molecule-1 (KIM-1) level before getting gentamicin was 2.89 ng/ml to 3.04 ng/ml after gentamicin administration. Serum creatinine level was reduced from 0.73 mg/dl before receiving gentamicin to 0.43 mg/dl after administration of gentamicin.

The results of this study state that there is a significant and negative relationship between prematurity and kidney disorders in neonatal infants. This study is in line with research by Chien-chung et al⁸ in its publication found that kidney failure occurred in preterm infants around 56% out of 276 neonates. Specifically, AKI in risk stage was 30%, in injury stage 17%, and in failure stage 9%. Infants with gestational age < 37 weeks with acute renal injury have a greater mortality rate with a hazard ratio (HR) of 5.34. In infants with failure stage AKI, higher mortality with HR 10.60 was reported.

This study showed significant and strong relationship between asphyxia and kidney injury in neonates. Similar finding was also noted by a research by Ali MA et al⁹, in which acute renal injury in neonates is significantly related to asphyxia and sepsis. Hypoxemia, which causes hypoxia and ischemia in infants, causes organ damage, mostly in kidneys (50%), central nervous system (28%), cardiovascular system (25%) and lungs (23%).³ Kidney is the most sensitive organ to low oxygen content. Renal insufficiency can occur 24 hours after hypoxia and ischemia. If hypoxia is not treated, it will cause irreversible renal cortex necrosis.¹⁰

This study found significant weak relationship between respiratory distress and kidney injury in neonates. Pradhan, et al found 6% incidence of acute renal injury in critically ill neonates.¹¹ Low APGAR score in preterm neonates with respiratory distress is one of the most significant risk factor for acute renal injury.¹² Bansal, et al found significant association between low APGAR scores in the first to five minutes with acute renal injury. This low score on APGAR is related to the incidence of respiratory distress.¹³ This is also supported by the research of Malek, et al that proposed the relationship between acute kidney injury through increased circulation of cytokines, chemokines, innate immune cells that attack the lungs and lead to acute pulmonary injury to respiratory distress. Researchers claim that the cause of respiratory distress in neonates is most often due to acute renal injury in the neonatal period.¹⁴

Finding in this study indicated weak and insignificant relationship between bleeding episodes and kidney injury in neonates. In certain circumstances, bleeding can cause tissue hypoperfusion. Hypoperfusion is by far the leading cause of acute renal injury in neonates secondary to hypovolemia (e.g., placental abruption, inadequate fluid resuscitation).^15,16 The effect of GFR due to disruption of blood volume regulation and electrolyte hemostasis will further worsen kidney function, resulting in further development of kidney injury.¹⁷

This study showed no significant relationship between dehydration and kidney injury in neonates. In some studies, dehydration can cause pre-renal injury which can subsequently develop into intrinsic kidney failure.^18,19 Research by Mahesh, et al correlating the incidence of dehydration severity with acute renal injury showed that neonates with mild hypernatremic dehydration did not have acute renal injury.¹⁸

In the initial phase of dehydration, kidney function is affected by pre-renal function, which is a low intravascular volume, but when the severity of dehydration increases, acute kidney injury occurs and thus causes kidney function to become increasingly damaged and even to the occurrence of acute kidney failure.²⁰ It can be seen, that the relationship between dehydration and acute kidney function disorders arises when there is a worse dehydration progression, maybe in this study the situation has not been able to reach the stage of damage to the kidneys, so the correlation has not been significant.

This study showed weak and insignificant negative relationship between renal injury and mortality, and there was fairly strong and significant positive relationship between renal injury and length of stay in neonatal infants. This result contrasts with the study by Shalaby MA et al² obtained from 214 neonates that found that gestational age (RR, 4.8; 95% CI, 3–9) and perinatal depression (RR 10; 95% CI, 2–46) are significantly associated with an increased risk of acute kidney injury. Acute renal injury was significantly associated with death but not with length of hospital stay (LOS). Our finding is in line with research by Jetton JG, et al in a multicenter study, observational cohort obtained from 2,162 critically ill neonates that found that 30% of them had acute renal injury. Neonates with acute renal injury had higher mortality compared to neonates without acute renal injury (OR 7 − 5, 95% CI 4.5–12.7; p < 0.0001). Based on the length of stay, there was an average of 23 days of treatment for acute renal injury and 19 days for non-acute renal injury (estimated parameter 14.9 days, 95% CI 11.6–18.1; p < 0.0001).²¹

This study is the first study in Manado to look at the incidence, risk factors and outcomes of acute renal injury in neonates. The results of this study can provide understanding for scientists and practitioners in the field of health, particularly in the field of pediatric health sciences and also input and additional knowledge about our understanding of risk factors that cause acute kidney disorders in neonates and outcomes.

This study has limitations, namely the measurement of serum creatinine levels is only done once, namely at the age of the fifth day. Periodic monitoring is needed in patients with acute kidney problems who are recovering.

Incidence of acute kidney injury in critically ill neonates in our study was 40%. Sepsis, nephrotoxic drug exposure, and prematurity were significant risk factors for acute kidney injury. Acute kidney injury associated with length of stay, but not with mortality.

CONFLICT OF INTEREST

M. R. Bahar., A. Umboh., S. Gunawan., R. Wilar., J. Rompis, stated that there is no conflict of interest from all of us authors.

FUNDING

Source of funding for this article is acquired through personal funding of the author.

ACKNOWLEDGEMENT

We would thank Natharina Yolanda, MD for her contribution in data collecting and manuscript editing.

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Table 1. Subjects characteristics

Characteristics	Neonates
Gender, n (%)
Male	84 (55.3)
Female	68 (44.7)
Delivery method, n (%)
Spontaneous, vertex presentation	80 (52.6)
Sectio Caesarea Vacuum extraction Spontaneous, breech presentation Spontaneous, feet presentation	65 (42.7) 2 (1.3) 3 (1.9) 2 (1.3)
Birth weight, mean (SD), gram	2358.16 (856.2)
Length weight, mean (SD), cm	46.14 (25.7)
Gestational age, n (%) Extremely Preterm Very preterm Moderately preterm Late Preterm Early Preterm Full Term Late Term	8 (5.3) 22 (14.5) 18 (11.8) 17 (11.2) 17 (11.2) 65 (42.8) 5 (3.3)
Neonatorum asphyxia, n (%)
Apgar score on minute 5 < 3 Apgar score on minute 5 > 3	33 (21.7) 119 (78.3)
Antibiotic use, n (%)
Ampicillin + Gentamicin Ceftazidime + Amikacin Meropenem Neonatal sepsis, n (%) Yes No Bleeding, n (%) Yes No Dehydration, n (%) Yes No Respiratory distress, n (%) Mild Moderate Severe Acute kidney injury, n (%) None Risk Injury Failure Loss End-stage	87 (57.6) 38 (25.2) 26 (17.2) 77 (50.7) 75 (49.3) 21 (13.8) 131 (86.2) 2 (1.3) 150 (98.7) 24 (15.8) 82 (53.9) 46 (30.3) 91 (59.9) 31 (20.4) 16 (10.5) 14 (9.2) 0 0

Table 2. Distribution of risk factors of renal injury and test result

Risk Factor		Renal injury		Total	Test
Risk Factor		No, n (%)	Yes, n (%)	Total	Test
Sepsis	No	69 (75.8)	6 (9.8)	75	X² = 63.620 (p < 0,001)
	Yes	22 (24.2)	55 (90.2)	77	r_g = 0.933 (p < 0.001)
Nephrotoxic medication	No	45 (49.5)	2 (3.3)	47	X² = 36.499 (p < 0,001)
	Yes	46 (50.5)	59 (96.7)	105	r_g = 0,933 (p < 0,001)
Bleeding	No	80 (87.9)	51 (83.6)	131	X² = 0.569 (p = 0.225)
	Yes	11 (12.1)	10 (16.4)	21	r_g = 0,176 (p < 0.001)
Dehydration	No	91 (100)	59 (96.7)	150	X² = 3.023 (p = 0.159)
	Yes	0 (0)	2 (3.3)	2
Respiratory distress	Mild	21 (23.1)	3 (4.9)	24	X² = 9.157 (p = 0.005)
	Moderate	44 (48.4)	38 (62.3)	82
	Severe	26 (28.6)	20 (32.8)	46	r_g = 0.273 (p < 0,047)
Gestational age	Extremely preterm	0 (0)	8(13.1)	8	X² = 32.566 (p < 0.001)
	Very preterm	6 (6.6)	16 (26.2)	22
	Moderately preterm Late preterm Early preterm Full term Late term	9 (9.9) 10 (11.0) 12 (13.2) 51 (56.0) 3 (3.3)	9 (13.8) 7 (11.5) 5 (8.2) 14 (23.0) 2 (3.3)	18 17 17 65 5	r_g = -0.568 (p < 0,001)

Table 3. Result of multiple logistic regression analysis

Variables	Coefficient	Significancy (p)
Sepsis	3,358	< 0,001
Nephrotoxic	2,850	0,001
Gestational age	-0,629	0,001
Constant	-2,016	0,057

Table 4. Relationship between acute kidney injury and mortality

Renal disorder	Mortality		Total	Test
Renal disorder	Death, n (%)	Recovered, n (%)	Total	Test
No	16 (50)	75 (62.5)	91	X² = 1.643 (p = 0.100)
Yes	16 (50)	45 (37.5)	61	r_g = -0.250 (p = 0,211)
Total	32	120

Incidence, Risk Factors, and Outcome of Acute Kidney Injury in Critically Ill Neonates

Status:

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Abstract

Figures

1 INTRODUCTION

2 METHOD

3 RESULT

4 DISCUSSION

5 CONCLUSION

Declarations

References

Tables

Status:

Version 1