|Year : 2018 | Volume
| Issue : 3 | Page : 185-189
Transient hyperaldosteronism and neonatal hypertension: Case series and literature review
Essa Hamdan Al Awad1, Kamran Yusuf1, Amuchou Singh Soraisham2, Halah Obaid1, Arun Sundaram1, Veronica Samedi1, Albert Akierman1
1 Peter Lougheed Centre, University of Calgary, Calgary, Canada
2 Foothills Medical Centre, University of Calgary and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Canada
|Date of Web Publication||2-Aug-2018|
Dr. Essa Hamdan Al Awad
Section of Neonatology, University of Calgary, Peter Lougheed Centre, 3500, 26th Ave., NE, Calgary, AB T1Y6J4
Source of Support: None, Conflict of Interest: None
Neonatal hypertension is an uncommon but important problem in Neonatal Intensive Care Unit. The most common cause of neonatal hypertension is renovascular disease. In premature neonates, hypertension has been associated with the use of postnatal steroids, maternal history of hypertension, umbilical artery catheterization, acute kidney injury, and bronchopulmonary dysplasia (BPD). The exact mechanism of hypertension in BPD infants is unknown. We present a case series of premature infants with BPD and hypertension associated with transient hyperaldosteronism in the absence of any other cause for the elevated blood pressure. All infants responded to aldosterone antagonists. Transient hyperaldosteronism may have a role in the pathogenesis of hypertension associated with BPD.
Keywords: Aldactazide, bronchopulmonary dysplasia, hyperaldosteronism, hypertension, neonate
|How to cite this article:|
Al Awad EH, Yusuf K, Soraisham AS, Obaid H, Sundaram A, Samedi V, Akierman A. Transient hyperaldosteronism and neonatal hypertension: Case series and literature review. J Clin Neonatol 2018;7:185-9
|How to cite this URL:|
Al Awad EH, Yusuf K, Soraisham AS, Obaid H, Sundaram A, Samedi V, Akierman A. Transient hyperaldosteronism and neonatal hypertension: Case series and literature review. J Clin Neonatol [serial online] 2018 [cited 2019 Dec 15];7:185-9. Available from: http://www.jcnonweb.com/text.asp?2018/7/3/185/238406
Neonatal hypertension is an uncommon but important clinical problem in Neonatal Intensive Care Unit (NICU). The reported incidence is between 0.2% and 3%.,, The two most common causes of neonatal hypertension are renovascular and renal parenchymal disease. In premature neonates, hypertension has been associated with the use of antenatal steroids, maternal history of hypertension, umbilical arterial lines, and acute kidney injury.,,, The most important nonrenal association with neonatal hypertension is bronchopulmonary dysplasia (BPD); however, the exact mechanism of hypertension in BPD infants is not known. Several proposed mechanisms include chronic hypoxemia and lung disease, hypercapnia, pulmonary hypertension, steroid use, or changes in the neurohormonal regulation of catecholamines, angiotensin, or antidiuretic hormone.,,,
Up to 60% of adults with resistant hypertension, defined as failure to achieve target blood pressure on the triple-drug regime of angiotensin-converting enzyme inhibitor, calcium channel blocker, and thiazide diuretic, achieved their targeted blood pressure when spironolactone was added to their treatment regime. Spironolactone is an aldosterone antagonist used for the management of hypertension due to hyperaldosteronism. It may also block the effects of aldosterone on arteriolar smooth muscle.
Aldosterone is a hormone secreted by the zona glomerulosa of adrenal cortex and is an integral part of the renin—angiotensin—aldosterone system (RAAS). This system has an important role in the maintenance of blood pressure and homeostasis of serum sodium and potassium. RAAS is known to be active from at least 16 weeks of fetal life.
The purpose of this case series is to describe our experience with the use of spironolactone, an aldosterone antagonist, in neonates with hypertension and BPD. Our hypothesis is that secondary hyperaldosteronism is one of the mechanisms for hypertension in preterm infants, and the treatment should be with medications that specifically target hyperaldosteronism.
This is a retrospective case series conducted at Peter Lougheed Hospital, a Level II NICU in Calgary, Alberta, Canada, from 2013 to 2018. Preterm infants with BPD who had neonatal hypertension as defined by blood pressure >95th centile of the normative data and who had plasma renin activity (PRA) and aldosterone levels done as part of their investigations for hypertension were included. BPD was defined, and severity was graded according to the National Institute of Child Health and Human Development (NICHD) consensus definition. Medical records for eligible infants were reviewed for data collection. Data collection included maternal characteristics such as age, smoking and drug use, history of pregnancy-induced hypertension, preeclampsia, gestational diabetes, antenatal steroids, and mode of delivery. Neonatal characteristics included gestational age, birth weight, sex, intrauterine growth restriction, Apgar scores, insertion of umbilical arterial catheterization, and the presence of BPD, patent ductus arteriosus (PDA), and intraventricular hemorrhage. In our units, as part of hypertension workup, all infants had serum creatinine, electrolytes, urinalysis, plasma renin, plasma aldosterone, renal ultrasound, and cardiac echocardiography. Data collected also included age at diagnosis of hypertension, age at the initiation of treatment, medications used, response to treatment, and follow-up.
During the study period, 12 cases of neonatal hypertension were identified. The maternal and neonatal characteristics are presented in [Table 1]. The mean gestational age was 26 ± 1.5 weeks (range: 24—29 weeks), and the mean birth weight was 844 ± 217 g (range 440—1235 g). Ten infants had umbilical artery catheterization during hospital stay. Three infants were delivered to mothers with severe preeclampsia; six were delivered by cesarean section. All infants had BPD as per the NICHD definition, and there is no relationship between hypertension with the severity of BPD. None of our infants received postnatal steroid as a treatment for BPD.
Investigations for hypertension are illustrated in [Table 2]. All infants had a normal renal function, normal renal Doppler, and normal urine output and urinalysis. Serum aldosterone was elevated in four cases; however, PRA was markedly reduced in 11 of 12 infants. Aldosterone-to-renin ratio (ARR) was significantly elevated (>35) in 10 infants. Only two infants had left ventricular hypertrophy, and five infants had nephrocalcinosis (mild).
Hypertension was diagnosed at the mean postmenstrual age of 37.5 ± 1.4 weeks (range: 36—40 weeks). However, medications were started when there was persistent hypertension >99th centile [Table 3]. Three infants were initially started on amlodipine and furosemide with no response and were later changed to aldactazide. Two infants received only furosemide initially with no response. Seven of the remaining infants were started on aldactazide as a first-line treatment to treat as hyperaldosteronism. All infants responded within 48 h of treatment with aldactazide. Eight infants developed mild hyponatremia which required sodium chloride supplementation until aldactazide was discontinued. A majority (10/12) infants were treated with antihypertensive medication for <1 year.
The RAAS is an important regulator of blood pressure and fluid balance through both systemic and intrarenal actions of angiotensin. The constituents of the RAAS are highly expressed in the developing kidney and play an important role in mediating nephrogenesis. Newborn infants have higher renin levels due to increased secretory rate and decreased excretion rate. Martinerie et al. in a prospective study involving 48 healthy newborns and their mothers showed that renin and aldosterone levels were significantly higher in newborn infants compared with their mothers. High positive correlation between neonatal plasma renin and aldosterone demonstrates that the RAAS is strongly stimulated at birth. The study also demonstrates that the healthy newborn infants exhibit partial aldosterone resistance with high-plasma levels of aldosterone and renin, contrasting with biologic signs of functional hypoaldosteronism including hyponatremia, hyperkalemia, and urinary sodium loss. High renin and aldosterone levels gradually reach normal adult levels by 12 months of age, suggesting progressive normalization of mineralocorticoid tubular responsiveness with age. Sulyok et al. in a study, involving seven healthy preterm infants with mean gestational age of 31 weeks, measured PRA, plasma aldosterone, and urinary aldosterone excretion weekly for 6 weeks and found that all were significantly elevated at 7 days of age, and they reach maximum values between 3rd and 4th week of life followed by a gradual decrease by the 6th week of life demonstrating that RAAS in premature infants is active. Bourchier measured plasma aldosterone levels in a study of 50 infants <30 weeks' gestation and demonstrated that plasma aldosterone levels were significantly higher in preterm infants than term infants, and it was regulated mainly by the illness severity and the serum sodium concentrations. All these studies suggest that both renin and aldosterone levels are elevated in preterm neonates and both return to normal adult levels by 1 year of age.
There is limited information of on normal range for plasma aldosterone and renin activity based on gestational age and day of life. The normal range of PRA in the premature infant is 11—167 ng/ml/h, while the range in infants is 1.4—7.8 ng/ml/h. The normal range of plasma aldosterone in infants is 2—70 ng/dL. The ARR — that is, the ratio of plasma aldosterone (expressed in ng/dL) to PRA, (expressed in ng/mL/h) — is the most sensitive means of differentiating primary from secondary causes of hyperaldosteronism. It can be obtained under random conditions of sodium intake. The ARR of at least 35 has 100% sensitivity and 92.3% specificity in diagnosing primary hyperaldosteronism in adults.
The most important factors that can interfere with the diagnostic reliability of the ARR test are drugs and renal impairment. The factors associated with increased aldosterone level include sodium-restricted diet, hyperkalemia, renal dysfunction, and nonsteroidal anti-inflammatory drugs (NSAIDs). All our cases were on full enteral feeds (140—150 ml/kg/day), and none of them had evidence of significant PDA or fluid overload, or any NSAIDs at the time of diagnosis and evaluation for hypertension.
In this case series, we report elevated plasma aldosterone with low-renin levels along with elevated ARR suggestive of hyperaldosteronism. Aldosterone secretion is controlled primarily not only by the RAAS through blood pressure and plasma volume but also by adrenocorticotropic hormone, serum sodium, and serum potassium levels. Blood pressures in these infants were not responsive to the commonly used antihypertensive such as calcium channel blockers and loop diuretics, but all achieved targeted blood pressure with aldactazide. Aldactazide is a combination drug of a thiazide diuretic and spironolactone, an aldosterone antagonist. The exact relationship between BPD and hyperaldosteronism is unknown. Hypertension resolved in all these infants and the medications were discontinued within 16 months of age as reported in other studies with infants with BPD. The resolution of hypertension within 2 years and the absence of family history of hypertension in all the infants are not suggestive of familial hyperaldosteronism. In patient, one genetic testing for familial hyperaldosteronism was negative and aldosterone levels normalized with age. Transient hyperaldosteronism is the likely cause of hypertension in these neonates and medications such as spironolactone, an aldosterone antagonist, would be the first-line drug to manage neonatal hypertension with elevated ARRs. Elevated renin and aldosterone levels have been demonstrated in preterm neonates in many studies; however, transient secondary hyperaldosteronism with low-renin levels is not a well-described entity in preterm neonates. It is unclear, whether it is related to prematurity or BPD.
We acknowledge our study limitations, most notably, the retrospective nature of the study design and small sample size. The lack of normative data makes it difficult to interpret the plasma renin and aldosterone levels in preterm neonates; however, the elevated ARR, blood pressure response to the aldosterone antagonist, and transient nature of hypertension are highly suggestive of transient secondary hyperaldosteronism.
Our case series demonstrates the preterm infants with BPD and hypertension are associated with elevated aldosterone and low renin without any other apparent cause for hypertension. All infants responded to aldactazide, an aldosterone antagonist containing medication.
In preterm infants with hypertension, investigations for hypertension should also include plasma renin and aldosterone levels. Transient hyperaldosteronism is one of the possible causes for hypertension in preterm infants, and an aldosterone antagonist should be the preferred drug to treat the elevated blood pressure. More studies should be done to evaluate the etiology and incidence of hyperaldosteronism with low-renin levels in preterm infants.
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[Table 1], [Table 2], [Table 3]
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