Enalapril and Acute Kidney Injury in a Hypertensive Premature Newborn – Should It Be Used or Not?

Abstract

Extremely low birth weight infants (birth weight ≤1000 g) have a significantly lower nephron number. The glomerular filtration rate (GFR) is usually sufficient under normal conditions but is unable to meet the needs during stress, which results in acute kidney injury (AKI). We describe the case of an extremely low birth weight infant (970 g) with a gestational age of 27 weeks (immature preterm) who was mechanically ventilated because of hyaline membrane disease. AKI with anuria and a rise in serum creatinine to 3.4 mg/dL developed in the second week. Diuresis was restored after diuretics and dopamine were administered intravenously and kidney function recovered in the next two weeks. However, he slowly became hypertensive, so intravenous enalapril was introduced in the 6^th week. After the third dose, he suffered another AKI. After cessation of enalapril, kidney function recovered over the next few days. Although angiotensin-converting enzyme inhibitors (ACEi) may cause kidney injury, it can be used with great caution in the treatment of hypertension or heart failure in preterm infants. There remains a real dilemma of whether enalapril should be used in extremely low birth weight immature infants.

Introduction

Nephrogenesis begins in the 9^th week of gestation and the kidney is fully mature in the 36^th week of gestation when nephrogenesis is completed, but 60 % of the nephrons mature between 27 and 36 weeks of gestation.¹ Nephrogenesis is completed 40 days after birth, irrespective of gestation.² This is the crucial problem of immature newborns of ≤ 27 weeks' gestation. Prematurity means a more immature kidney with fewer nephrons.^3,4 The glomerular filtration rate (GFR) of very low birth weight newborns is sufficient under normal conditions, but cannot meet the needs under stress, and this can lead to acute kidney injury (AKI).⁵

Case Report

A male infant (birth weight 970 g) was born in the 27^th week of gestation after a non-complicated pregnancy by urgent cesarean section because of placenta previa and hemorrhage. The Apgar scores after 1, 5 and 10 minutes were 7, 8, and 8, respectively.

He was mechanically ventilated with synchronized intermittent mandatory ventilation with a peak inspiratory pressure of 20 to 25 kPa and a positive end-expiratory pressure of 4.5 kPa. Transfusion was required in the first 24 hours. Besides antibiotics (ampicillin and gentamicin), he required analgesics (paracetamol and/or piritramide). His was circulatory stable, well hydrated with good diuresis, and the serum creatinine (sCr) value on day 2 was 1.2 mg/dL. Due to worsening respiratory distress, he was put on high-frequency oscillatory ventilation (HFOV) with a continuous distending pressure of 14.5 cm H₂O and an amplitude of 17 cm H₂O. Dopamine (3 microg/kg/min) and a diuretic (furosemide 0.5 mg/kg once or twice daily) were administered because of positive water balance and edema. Diuresis improved, the edema disappeared and the sCr value on day 8 was normal (0.63 mg/dL). On day 11, diuresis decreased, and sCr rose (1.18 mg/dL), hence gentamicin was discontinued. Diuresis was forced with boluses of 0.9% saline and intravenous diuretics. At the age of 16 days, he became oliguric and three days later, anuric, with an elevated sCr (3.13 mg/dL). Treatment with a continuous infusion of furosemide (1.5 mg/kg/hour) was initially unsuccessful. After an additional furosemide bolus (2.3 mg/kg) and a change in ventilation mode (SIMV), diuresis resumed. SCr rose to 3.4 mg/dL, but over a few days, it returned to the normal value (0.42 mg/dL).

After recovery of his kidney function, he slowly became hypertensive. At the postnatal age of one month, his blood pressure was 15% above the 95^th percentile for gestation. Blood pressure was measured every three hours non-invasively with automatic oscillometric monitors using the standard protocol for newborns<2500 g.⁶ The criteria for normal blood pressure recommended by Dionne et al were used.⁷ Diagnostic evaluation (urine analysis, ultrasound of the kidneys and heart, Doppler of the kidney vessels, thyroid hormones, renin, aldosterone) did not reveal the cause of his hypertension. His blood pressure remained high despite conservative measures and diuretic therapy. Intravenous enalapril was started at a postnatal age of 43 days (33 weeks PMA) at a dose of 0.07 mg/kg once daily, following which his blood pressure fell to the 50^th percentile. After three doses, enalapril was discontinued because of AKI (oliguria, sCr 1.73 mg/dL). Twenty-four hours after the last dose, diuresis normalized, and sCr and electrolytes gradually returned to normal values over the next few days. His blood pressure gradually reached the 95^th P and then remained stable. We resumed conservative measures. The infant was discharged at the age of 3 months (PMA 42 weeks) with blood pressure on the 95^th percentile.

Discussion

We describe the case of an extremely low birth weight infant who developed two episodes of AKI. The second episode developed after three doses of enalapril, which was given for the treatment of hypertension. The kidneys recovered without dialysis. The incidence of AKI in critically ill neonates hospitalized in intensive care units is up to 24%, and preterm infants are particularly affected.¹⁰ Enalapril is known to produce AKI in a preterm infants with hypertension who suffered parenchymal or reno-vascular impairment and kidney malformation.^11–15 Cases of AKI in preterm newborns with cardiac disease have been reported.^16–19 The Table contains case reports and a retrospective cohort study with angiotensin-converting enzyme inhibitors (ACEi) induced nephrotoxicity in preterm infants with hypertension or cardiac disease, are compiled.

Table.

Case Reports and a Retrospective Cohort Study With Acei-Induced Nephrotoxicity In Preterm Infants

Reference (n)	Gestation age, wks (PMA, wks)	Exposure, days	Indication (Etiology)	Medication	Outcome
Hymes11 (n=1)	33 (38)	35	Hypertension (bilateral renovascular involvement)	captopril 0.3 mg/kg twice daily	oliguria, hypotension, elevated creatinine; captopril dose decreased
Tack12 (n=8)	25–32 (34–84)	18–69	Hypertension (8 BPD with cor pulmonale, 3 also had parenchymal or renovascular lesions)	captopril 0.3 mg/kg, subsequently halved, plus diuretics	4 hypotension with oliguria, 4 hypotension, 2 died; 2 captopril discontinued
Wells13 (n=10)	26–36 (29–44)	2–17	Hypertension (6 renal or renovascular lesions, 4 cause not known with certainty)	enalaprilat 7.4-22.9 mcg/kg/day, once daily or divided into two or three doses IV ; 5 also received diuretics	2 oliguria - enalaprilat discontinued, 3 elevated creatinine, 2 hyperkalemia, 2 died
Wood20 (n=1)	33 (at least 37 wks)	unknown	afterload reduction (after repair of coarctation of the aorta)	captopril 1.1 mg/kg/every 6 hour, plus furosemide, digoxin	elevated creatinine, oliguria, hyperkalemia; captopril discontinued
Schilder14 (n=1)	25 (26)	9	Hypertension (increased renin activity)	enalapril 0.1 mg/kg/day orally	anuria, survived; dose decreased
Krishna21 (n=1)	32 (52)	140	congestive heart failure (right-to-left shunt)	captopril 0.17 mg/kg/day divided into three doses orally, plus diuretics, digoxin	anuria; died
Dutta16 (n=1)	37 (37)	6	congestive cardiac failure (left-to-right shunts)	enalapril 0.1 mg/kg/day orally, plus diuretic, digoxin	anuria- dialysis, survived; enalapril discontinued
Lanzarini15 (n=1)	35 (unknown†)	unknown	Hypertension (renal malformation)	amlodipine, enalapril/no data regardings dosage	no adverse effects
Maliheh22 (n=1)	33 (33)	2	congestive heart failure (aortic coarctation, VSD)	captopril 0.5mg/kg plus digoxin, furosemide	anuria, hypotension; captopril discontinued
Lee17 (n=3)	27 – 36 (30–36)	5–21	3 congestive heart failure (2 left-to-right shunts, 1 fetal hydrops due to “twin-twin” transfusion syndrome)	2 captopril 0.1 mg/kg every 8 hours orally. One patient received also enalapril 0.11mg/kg/day plus furosemide	3 oliguria, 3 hypotension, 1 NEC 1 died; captopril and enalapril discontinued
Tan23 (n=1)	34 (36)	21	congestive heart failure (large left-to-right shunt)	captopril 0.1 mg/kg every 8 hours plus furosemide	oliguria, elevated creatinine, hyperkalemia; captopril discontinued
Insignares-Vizcaíno18 (n=1)	29.5 (30)	6	congestive heart failure (large left-to-right shunt)	enalapril 0.08 mg/kg/day plus furosemide	oliguria, hypotension; enalapril discontinued
Ku24 (n=662)	30 (27, 36)‡ 38 (35,40)‡	25 (10,78)‡	hypertension or heart failure, significant structural cardiac disease	enalapril/no data regardings dosage	13% hyperkalemia, 5% elevated serum creatinine, 4% hypotension, 0.5% death

AKI, acute kidney injury; BPD, bronchopulmonary dysplasia; NEC, necrotizing enterocolitis; PMA, postmenstrual age in weeks at first exposure; VSD, ventricular septal defect

* postnatal age at first exposure in days

† postnatal age at first exposure unknown

‡ median,(25th, 75th percentiles)

In our patient, there was no apparent reason for the first AKI. There was no evidence of structural nephrourological pathology, kidney artery anomalies, heart failure, or overt infection. He received gentamicin in the first ten days of life. Although gentamicin is known to be nephrotoxic, there was no direct clinical association between the use of gentamicin and the increase in sCr or potassium. However, the infant had additional risk factors for AKI: extremely low birth weight, and a diuretic. He also suffered occasional hypoxia and hemodynamic impairment with low cardiac output due to high intrapleural pressure and decreased venous return in HFOV with high continuous distending pressure.^14,25 In our opinion, the combination of these factors in conjunction with gentamicin could have provoked the first AKI. There was an association between the application of enalapril and the second episode. According to Naranjo adverse drug reaction probability scale, enalapril was assessed as probable inducing AKI.²⁶ Angiotensin-converting enzyme inhibitors (ACEi) (captopril, enalapril) are used in infants for the treatment of hypertension, congestive heart failure, or after heart operations.²⁴

In five retrospective studies and case reports on the treatment of hypertension with ACEi, 21 preterm infants with a gestational age of 25 to 36 weeks are reported.^11–15 Their first exposure to ACEi (captopril, enalaprilat, or enalapril) was between 29 and 84 postmenstrual weeks. Nine had at least one adverse event (hypotension, kidney injury, four died). The indications for ACEi were kidney parenchymal or renovascular diseases (e.g., kidney artery thrombosis), and autosomal recessive polycystic kidney disease.

There are several reviews and case reports on the use of ACEi in heart failure or after cardiac surgery accompanied by AKI in preterm infants.^{16–18, 20–24} In seven reports, nine preterm infants of 27 – 29 weeks' gestation were first exposed to ACEi between 30 and 52 postmenstrual weeks.^{16–18, 20–23} All of them experienced adverse reactions (kidney failure and/or hypotension, two died). Infants with significant structural heart disease (e.g., hypoplastic left heart syndrome, transposition of the great arteries) were included, and one had Down syndrome. Many had drug combinations, and additional risk factors for kidney injury in vulnerable infants.¹⁹ The high incidence of adverse events raises the question of the justifiable use of ACEi in preterm infants.

Ku et al. carried out a large retrospective cohort study of 662 preterm infants with a median gestational age of 30 weeks, of whom 203 had a gestational age ≤27 weeks.²⁴ The indications for enalapril were hypertension or heart failure without any significant structural heart disease. They were first exposed to enalapril at the age of 38 weeks (including 203 immature infants). They found a much lower incidence of adverse effects compared to previous reports (13% hyperkalemia, 5% elevated serum creatinine, 4% hypotension, 0.5% death).^11–15

These differences may be due to different indications for ACEi, diverse populations, different doses of enalapril and potential combinations of nephrotoxic drugs, and varying observation periods. The comparisons must be seen in light of these differences which, in our opinion, could justify the different results.

Kidney injury is the most important side effect of ACEi. Hypotension decreases kidney perfusion and lowers filtration, but a direct nephrotoxic effect might also contribute.¹⁶ The GFR in newborns with low mean blood pressure is dependent on post-glomerular efferent arteriolar vasoconstriction, which is critically dependent on angiotensin II. Inhibiting angiotensin convertase means lowering the perfusion pressure.¹⁷

Low gestational age is a risk factor for kidney impairment, the most problematic newborns being those with a body surface area less than 0.33 m².²⁷ The more premature newborns have fewer glomeruli, while 60% of nephrons are formed in the last 12 weeks of pregnancy and glomerulogenesis arrests 40 days after preterm birth.² In the presence of relative dehydration or diuretic therapy, inhibition of angiotensin convertase might critically lower the GFR, leading to AKI.¹⁹ ACEi also disturbs nephrogenesis. Typical changes are papillary and tubular atrophy and changes in the intrarenal arteriolar wall.²⁸ Incomplete kidney development has long-term consequences, hence avoidance of the use of ACEi in infants until 44 weeks PMA is strongly recommended.⁷

Conclusion

The presented case supports and confirms all the above-mentioned data. Our patient's immature kidneys were injured in the second week of life. After recovery, a low dose of enalapril was introduced and, despite careful blood pressure monitoring, the second episode of AKI occurred. The second AKI was clearly associated with the enalapril. To our knowledge, this is one of the rare case reports of an extremely low birth weight infant who suffered AKI caused by enalapril after recovering from a previous episode of kidney injury. Our case may have some potential clinical implications. Low birth weight infants are extremely vulnerable and are classified as patients at high risk. If hypertension develops in such an infant, ACEi should not be recommended as first-choice treatment for hypertension, especially if there is a history of previous kidney injury of any cause.

ABBREVIATIONS

ACEi

angiotensin-converting enzyme inhibitors

AKI

acute kidney injury

BPD

bronchopulmonary dysplasia

GFR

glomerular filtration rate

NEC

necrotizing enterocolitis

PMA

postmenstrual age in weeks

sCr

serum creatinine

VSD

ventricular septal defect