Abstract

Introduction

Acute kidney injury (AKI), is an acute and reversible increment in serum creatinine (SCr) levels with a reduction in urine output (UO) oliguria, or anuria [1], AKI imposes a high risk of morbidity and mortality in critically ill neonates [2], with a major economic effect on the health-care expenditure of countries, particularly in low-income and middle-income countries (LMIC) [3, 4].

Perico and Remuzzi [3] Globally, the incidence of AKI among neonates has fluctuated from 8.4% to 63.3% [5], similarly a multi-national multicenter (24 centers) study showed that 30% of neonates have developed AKI in Neonatal Intensive Care Unit (NICU).

The fact that AKI survivors have an increased risk of developing chronic kidney disease(CKD)or end-stage renal disease (ESRD), the poor prognosis of many patients after an episode of AKI, the public health ramifications of progression to late-stage chronic kidney disease (CKD), and the need to identify clinical risk factors for progression in patients with and without pre-existing chronic kidney disease (CKD) who have survived an episode of AKI are urgently needed [6].

As different studies indicate, the magnitude of AKI among neonates remains high, presenting a significant public health problem, For instance, studies in Sudan 54.1% [7], in Kenya 36.1% [8], in Tanzania 31.5% [9] in Egypt 10.8% [10] in Saudi Arabia 56% [11] in Taiwan 56% [12] Serbia 44% [13], in turkey 20% [14] of neonates developed AKI. The magnitude of AKI in Ethiopia is 18.27%, and it is a major public health concern [15].

These studies documented that different factors contribute to the development of AKI in neonates, such as perinatal asphyxia, respiratory distress syndrome (RDS), prematurity, sepsis, umbilical catheterization, early drug administration, especially aminoglycosides, necrotizing enterocolitis (NEC), hypovolemia, placental insufficiency, intrauterine growth restriction (IUGR), maternal medication, hemodynamically significant patent ductus arteriosus, and urogenital abnormalities [11, 16, 17]. However the sodium and potassium derangement also another factor of acute kidney injury.

To alleviate these problems different strategies and interventions were designed and implemented like the Kidney Disease Improving Global Outcome (KDIGO) guideline, and the Ethiopia Federal Ministry of Health has given due attention to the expansion of high-impact quality neonatal care to reduce neonatal morbidity like AKI [18].

Implementation of this program in low- and middle-income countries faces serious obstacles due to lack of resources, lack of information on the epidemiology, cause-and-effect relationships, and determinants of AKI in our countries, especially in neonatal intensive care unit guidelines, lack of resources for diagnosis and treatment of AKI, and lack of knowledge on the impact of AKI and treatment outcomes. a result, the increase in regular health care costs for newborns in the first month of life remains a major community health problem in a low-income country such as Ethiopia. These high medical costs can burden parents, their families, and the community at large [19, 20]. Esethere is limited evidence regarding AKI and its associated factors. Therefore, this study aims to assess the incidence and predictors of acute kidney injury among newborns admitted to Northwest Ethiopia comprehensive specialized hospitals, 2023.

Methods

Study variables

Result

A total of 634 neonates who were admitted from January 2020 to December 2022 in selected Amhara comprehensive specialized hospitals were included.

Socio-demographic characteristics of mothers and neonates

In the neonatal socio-demographics, the majority of patients at admission 575 (90.69%) were between the ages of the first seven days. Out of 634 neonates, 392 (61.83%) were male neonates. The majority of the neonates, 567 (89.43%), were born in health institutions with skilled health professionals. The mean maternal age of the neonates was 29.15+6.457 SD years, with 425 (67.03) being between the ages of 20 and 34. More than half of the mothers were urban residents (53%) (Table 1).

Table 1

Socio-demographic characteristics of mothers and neonates at NICU in Amhara region, Ethiopia, 2023(n=634)

Variables	Frequency(n)	Percentage (%)
Age_ group of the mother
<20	65	10.25
20–34	425	67.03
≥35	144	22.72
Residency
Urban	336	53
Rural	298	47
Age at the admission of the newborn
0<7	575	90.69
8–15	34	5.36
15–28	25	3.94
Sex of the newborn
Male	392	61.83
Female	242	38.17
Place of delivery
Health institution	567	89.43
Home delivery	67	10.57

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Obstetrical history of mother’s, and Obstetric complications of the mother

A total of 599 mothers (94.48%) received antenatal care (ANC) follow-up. Of these, 414 (65.30%) had four more ANC visits, while the remaining mothers had fewer than the minimum required four visits. The majority of mothers in the sample were multipara totaling 450 (70.95%). Among the 634 mothers, 530 (92.01%) were singletons, which accounted for more than half of the 422 mothers (66.56%) mothers who gave birth spontaneously vaginally. In terms of maternal complications, more than one-third of mothers experienced obstetric complications during the index pregnancy. The maternal obstetric complications in the current pregnancy include premature rupture of membranes (PROM) at 223 cases (35.17%), eclampsia at 28 cases (4.42%), placental hemorrhage at 49 cases (7.73%), gestational diabetes at 117 cases (18.45%), and polyhydramnios at 80 cases (12.62%) (Table 2).

Table 2

Obstetric history and obstetric complication of mothers whose neonates were admitted to NICU in Amhara region, Ethiopia, 2023 (n=634)

Variables	Frequency(n)	Percentage (%)
ANC visit
Yes	599	94.48
No	35	5.52
Number of ANC visit (n=506)
1–3	185	29.18
≥4	414	65.30
Parity
Primi para	184	29.02
Multi-para	450	70.98
Mode of delivery
SVD	422	66.56
C/S	86	13.56
ISD	126	19.87
Current pregnancy
Multiple	46	7.99
Single	530	92.01
PIH
Yes	121	19.09
No	513	80.91
Pre-eclampsia
Yes	91	14.35
No	543	85.65
Eclampsia
Yes	28	4.42
No	606	95.58
GDM
Yes	117	18.45
No	517	81.55
APH
Yes	49	7.73
NO	585	92.27
Polyhydramnios
Yes	80	12.62
NO	554	87.38
Oligohydramnios
Yes	87	13.72
NO	447	86.28
PROM
Yes	223	35.17
NO	411	64.83
Prenatal steroid
Yes	85	13.41
NO	549	86.59
Prenatal antibiotics
Yes	121	19.09
NO	513	80.91

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^aPIH pregnancy induced hypertension APH ante partum hemorrhage PROM prolonged rupture of membrane ANC=Antenatal Care SVD=spontaneous Vaginal Delivery

Neonatal-related factors and neonatal clinical comorbidities

More than half of the 634 neonatal records reviewed showed that the 373 neonates (58.83%) had birth weights greater than 2500 g. The mean birth weight was 2813 g (SD±720) grams. In terms of gestational age, more half of the babies (324, 51.10%) were born after 37 completed weeks of gestation, and over three-fourths of the neonates (502, 79.18%) had an appropriate weight for gestational age. Regarding co-morbidities, more than three-fourths of the neonates admitted to the NICU had neonatal sepsis (259, 40.85%), while 170 (26.81%) had meningitis, and another 170 (26.81%) had perinatal asphyxia, according to a review of 634 charts (Table 3).

Table 3

Characteristics of neonates and clinical co-morbidities who were admitted at NICU in Northwest Amhara, Ethiopia, 2023 (n=634)

Variable	Frequency	Percentage
Birth weight
Low birth weight	235	37.07
Normal birth weight	373	58.83
Macrosomic	26	4.10
Gestational age
Preterm	275	43.38
Term	324	51.10
Post term	35	5.52
Weight for gestation
AGA	502	79.18
SGA	90	14.20
LGA	42	6.62
APGAR score first minute
Low	109	17.19
Mild	72	11.36
Normal	453	71.45
APGAR score five minute
Sever	92	14.51
Mild	89	14.04
Normal	453	71.45
Sepsis
Yes	259	40.85
No	375	59.15
NEC
Yes	120	18.93
No	514	81.07
Shock
Yes	99	15.62
No	535	84.38
Chromosomal abnormality
Yes	49	7.73
No	585	92.27
Pneumonia
Yes	44	6.94
No	590	93.06
Surgical disorder
Yes	39	6.15
No	595	93.85
MAS
Yes	145	22.87
No	489	77.13
CHD
Yes	44	6.94
No	590	93.06
RDS
Yes	148	23.34
No	486	76.66
IVH
Yes	40	6.31
No	594	93.69
PNA
Yes	189	29.81
No	445	70.19
HIE
Stage1	8	1.26
Stage 2	66	10.41
Stage 3	74	11.67
Meningitis
Yes	170	26.81
No	464	73.19
Sodium
Hyponatremia	180	28.39
Normal sodium level	331	52.21
Hypernatremia	123	19.40
Potassium
Hypokalemia	71	11.20
Normo- potassium level	374	58.99
Hyperkalemia	189	29.81
Gentamicin
Yes	206	32.49
No	428	67.51
Gentamicin
Yes	206	32.49
No	428	67.51

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^aAGA appropriate for gestational age, SGA Small for gestational age, LGA large for gestational age, APGAR activity pulse grimace appearance and respiration, HIE hypoxic ischemic encephalopathy, PNA perinatal asphyxia, IVH intraventricular hemorrhage, RDS Respiratory distress syndrome, MAS Meconium Aspiration syndrome, CHD congenital Heart disease, NEC necrotizing enterocolites

Overall neonatal out-com

From the total follow-up outcome, 6.78% were lost to follow-up or left the hospitals without health professionals' permission or against medical advice (Fig. 1).

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Fig. 1

Overall neonatal out-com among neonates admitted in Amhara region comprehensive and specialized hospitals 202 (n=634)

Proportional hazard assumption

Based on the proportional hazard assumption test using Schoenfeld residual, all of the covariates fulfilled the assumption and the overall global model satisfies the proportional hazard assumption (0.6638) Fig. 2.

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Fig. 2

The Cox proportional hazard model, non-parametric Cox- Regression models using Snell residual graph, 2023. Semi-parametric Cox-proportional hazard (AIC=1135.787) models

Overall proportion and incidence rate of AKI in neonates

The overall proportion of neonates that develop the event of interest (AKI) among admitted 634 was found to be neonates, 128 (20.19%) (95% CI: 17.23–23.50). The overall incidence rate of AKI was found to be neonate-days observation for the entire follow-up time was 8573 person-days when 634 from the three hospitals with minimum and maximum follow-up times were 1 and 28 days respectively. The median follow-up survival time was 21 days (95% CI: 22–27). The overall incidence of AKI was 14.9 per 1000 neonate-day observations (95%CI: 12.5–17.7) during the entire follow-up time.

Overall failure Function (survivorship function)

The overall Kaplan–Meier failure function showed that the probability of acute kidney injury among neonates was increased during the follow-up period. During the 5–10 days of admission, a 7% probability of AKI was observed (Fig. 3).

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Fig. 3

Kaplan Meier failure function of AKI among neonates from 2020 to 2022, Amhara régions Ethiopia, 2023 (N=634)

Predictors of AKI among neonates

The test of equality for survival distribution for different categories of variables was performed with Kaplan–Meier and the log-rank test. In general, the pattern that one group's survivorship function lying above another group showed that the upper curve had a better probability of survival compared to the lower curve. On the other hand, the probability of AKI was high among the lower groups described by the Kaplan–Meier survival curve. Furthermore, the log-rank test confirmed whether the observed difference was seen on the KM graph statistical difference or not.

In the current study, newborns born with preterm have lower survival times compared with normal-term and, post-term neonates. Moreover, neonates without sepsis and perinatal asphyxia (PNA) have a more favorable survival probability than those neonates with sepsis and PNA respectively. This study also revealed that mothers who did not take prenatal steroids during antenatal care (ANC) follow-up periods had a better probability of survival compared with those mothers who took prenatal steroids. Furthermore, neonates born from mothers who had taken antenatal corticosteroids had a better probability of survival compared with newborns born from mothers who did not take antenatal corticosteroids during pregnancy while neonates born single had a better survival probability than those born multiple. These differences were statistically significant with a p-value<0.001 in a log-rank test (Fig. 4).

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Fig. 4

Kaplan- Meir survival function among sepsis, PNA, potassium level and gentamicin among neonates from 2020 to 2023, Amhara region Ethiopia, 2023, (634)

Discussion

In a follow-up of 634 newborns among neonates, 128 (20.19%) (95% CI: 17.23–23.50) of them experienced the event of interest (AKI). Throughout the full follow-up period, the overall incidence of AKI was 14.9 per 1000 neonate-day observations (95%CI: 12.5–17.7).

Relatively, the proportion of acute kidney injury is comparable to or in line with studies conducted in the United States (21%) and Turkey (21%). However, it is lower than in multinational studies;30% [25] in Cairo, in Egypt 41% [26] in 56% in Saudi Arabia [11] This marked difference might be attributed to some factors,. The study was conducted in Saudi Arabia as a single-center, prospective design, utilizing urine output and creatinine measurements. Being single-center, it may reflect specific institutional protocols, expertise, and regional treatment variations. Prospective studies can be observational, monitoring participants without intervention, or interventional, involving specific treatments. In contrast, retrospective studies collect data from existing records or databases prior to the study's initiation. In addition the study in Egypt was conducted with a small sample size; this random variation can have a greater impact on the results which could be due to a difference. Multinational studies often involve participants from different countries or regions with diverse cultural, social, and genetic backgrounds, and heterogeneity can introduce variations in the study population, including differences in disease prevalence, lifestyle factors, healthcare systems, or genetic predispositions.

On the contrary, the proportion in this study was higher than the prospective study was Egypt 10.8% [27] in Turkey 8.4 [28] in India 12% [29] in Iran 1.54% [30] in USA 9% [31]. This variation might be due to differences in the source population, study design, and small sample size as well as study population as the study conducted in India followed preterm neonates, while this study population was all neonates. When compared to term infants, preterm neonates' kidneys are not fully mature and functional.

In this study, the hazards of developing acute kidney injury increased more than threefold in neonates admitted with sepsis compared with their control group; This finding was supported by a study conducted in Kenya and South Africa [8, 32] South Africa [33] Sri Lnka [34] Egypt [27]. The potential rationale Neonatal sepsis systemic inflammation can lead to impaired renal blood flow and oxygen delivery to the kidneys, causing renal ischemia and injury [29]. Neonatal sepsis can cause hypotension and hemodynamic instability, leading to reduced blood flow to the kidneys. Inadequate perfusion and oxygenation of the renal tissue can result in ischemic injury and contribute to the development of AKI [35, 36]. The gene expression profile of septic AKI showed increased upregulation of several genes related to inflammation, metabolism, and apoptosis [37]. therefore prevention of neonatal sepsis and/or early diagnosis and treatment of neonates suspected of sepsis can minimize the occurrence of acute kidney injury.

The risk of AKI was 2.70 higher in neonates born with perinatal asphyxia than in neonates born without perinatal asphyxia. This finding is supported by the study conducted in Congo [38] India [39] Kenyan [40] Sudan [41]. It might be due to Perinatal asphyxia leads to inadequate oxygenation, and perfusion can result in hypoxic-ischemic injury to the renal tissue, leading to AKI. There is a redistribution of blood flow to vital organs, such as the kidneys. This altered blood flow can cause renal hypo perfusion and ischemia, contributing to the development of AKI.

Jha and Tamrakar [42] in addition, reperfusion injury leads to the buildup of reactive oxygen species and the release of inflammatory mediators, both of which can cause further damage to the renal tissue and exacerbate AKI. The inflammatory response can lead to the release of inflammatory cytokines and mediators that can directly injure the kidneys and contribute to the development of AKI [43–45]. eventually, severe asphyxia in neonates results in widespread tubular injury and deformity due to sodium depletion or continued water reabsorption, leading to decreased glomerular filtration rate, high renin activity, and high renal vascular resistance in neonates with acute tubular necrosis after asphyxia, after developing tubular necrosis or cortical necrosis the neonates decrease glomerular filtration as well as develop acute kidney injury [26, 46, 47]. Asphyxiated neonates need strict follow-up to prevent secondary complications.

The neonates treated with gentamicin had 1.74 times the risk of developing compared with neonates not taking gentamicin medication. This study is supported by studies in the USA [9], Alabama [48] other study in, the USA [49, 50]. The possible reasons might be age-related immaturity, pharmacogenomics, severity of illness, the dosage of a drug, duration, and concomitant medication, all of which may be nephrotoxic, as well as the epidemiology impact of AKI. Whenever patients with AKI had an increased length of stay in the hospital, it was noted that the majority of nephrotoxic medications to which patients were exposed were antimicrobial agents [49, 50]. It is valuable if the neonates are provided with the gentamycin antibiotic under all important precautions, if needed.

In this study, being preterm neonates was an independent predictor of AKI that increased the hazard of AKI two times in neonates compared with term infants, This finding is confirmed by the studies conducted in Italy [51] France [52] University of Alabama [2], and University of Wisconsin-Madison [53]. may be due to the following Preterm infants are at high risk for acute kidney injury (AKI) due to vasomotor nephropathy; their glomerular filtration rate (GFR) is low and unstable; they have a lower adaptability to stressful situations, hemodynamic instability, and nephrotoxic drugs commonly used in neonatal intensive care units (NICU) [52, 54, 55]. Since preterm neonates’ organ function is inadequate because of immaturity, advance care and follow-up are important to decrease kidney injury.

Hyponatremia increases the risk of AKI almost twofold compared with neonates with normal sodium levels. This finding is supported by studies in Sudan [7], and India [56]. A possible reason might be that the capacity of sodium reabsorption is limited, and when the amount of sodium reaching the distal tubules increases significantly, reabsorption does not occur proportionally and the amount of sodium is excreted in the urine. Other Contributing Factors to Hyponatremia may lead to contraction of intravascular volume, further limiting renal function. Asphyxia-induced reduction in the number of functional nephrons leading to ARF elicits compensatory hypertrophy of the remaining nephrons, resulting in improved renal function in the first months of life and decreased creatinine clearance, renal tubular acidosis, or concentration defect. AKI was predicted by abnormal renal electrolyte imbalance and hyponatremia [56–58].

Neonates diagnosed with hyperkalemia had three times the risk of developing AKI compared with neonates with normal potassium levels. This study finding is supported by the studies conducted at Maimonides Medical Center [59], and USA [60]. The possible cause may be because severe hyperkalemia requires the administration of calcium to stabilize the myocardium, followed by drugs that shift extracellular potassium to the intracellular compartment, such as bicarbonate, glucose-insulin drip, and inhaled beta-agonists. Following this hyperkalemia, a neonates is at risk for acute renal injury. which results in decreased glomerular filtration rate, decreased tubular potassium secretion, tissue breakdown with intracellular potassium release, and metabolic acidosis with a transcellular potassium shift per 0.1 unit decrease in arterial PH. Increase serum potassium by 0.3 mEq/L [60]. Electrolyte balance can maintain the kidney function of neonates.

Limitations

Because this was a secondary design and/or retrospective data, the study could not exhaustively examine all predictor variables that might have an impact on AKI. the next researcher will be studying prospective studies including measuring urine or a put maternal paternal, and economic status.

Conclusions

This study found that the incidence of acute kidney injury in neonates was high. Besides, the overall incidence rate of AKI was 14.9 per 1000 neonates. Premature infants and neonates with sepsis who suffered perinatal asphyxia and had taken gentamicin drugs, whose sodium levels decreased and whose potassium levels increased, were at higher risk of developing acute kidney injury. Therefore, premature neonates and neonates with neonatal sepsis should get appropriate follow-up, and neonates diagnosed with asphyxia should not be treated with gentamycin antibiotics. Also, neonates’ electrolytes should be kept at a normal level, especially potassium and sodium, to decrease the incidence of AKI. Moreover, future researchers should conduct an interventional study to address further significant predictors of AKI in neonates.

Supplementary Information

Acknowledgements

Abbreviations

Authors’ contributions

Authors’ contributions GDG: conceptualization, methodology, software, formal analysis, writing original draft. BTL, YSE, HSM, AGA, &ATA validation, data curation, writing reviewing & editing. TMS&GBM: methodology, writing-review & editing. FBG, DTD & MTT: conceptualization, methodology, writing-review & editing. WTW&ATG: methodology, writing-review & editing, data curation. RAS, TGA & ZAG: methodology, writing-review & editing, data curation, validation. Finally, all authors approved the manuscript.

Funding

This study was funded by the University of Gondar. However, the funder had no role in data collection, preparation of the manuscript, and decision to publish.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to confidentiality but are available from the corresponding author on reasonable request.

Declarations

Footnotes

Contributor Information

Gezahagn Demsu Gedefaw, Email: moc.liamg@86usmedngahazeg.

Bruck Tesfaye Legesse, Email: moc.liamg@341eyafsetkcurb.

References