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Phthalates cause a low-renin phenotype commonly found in premature infants with idiopathic neonatal hypertension

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Abstract

Since the 1970s, when the initial reports of neonatal hypertension related to renal artery thromboembolism were published, other secondary causes of neonatal hypertension have been reported. Those infants with no identifiable cause of hypertension were labeled with a variety of terms. Herein, we describe such infants as having idiopathic neonatal hypertension (INH). Most, but not all, of these hypertensive infants were noted to have bronchopulmonary dysplasia (BPD). More recently, reports described common clinical characteristics seen in INH patients, whether or not they had BPD. This phenotype includes low plasma renin activity, presentation near 40 weeks postmenstrual age, and a favorable response to treatment with spironolactone. A small prospective study in INH patents showed evidence of mineralocorticoid receptor activation due to inhibition of 11β-HSD2, the enzyme that converts cortisol to the less potent mineralocorticoid—cortisone. Meanwhile, phthalate metabolites have been shown to inhibit 11β-HSD2 in human microsomes. Premature infants can come in contact with exceptionally large phthalate exposures, especially those infants with BPD. This work describes a common low-renin phenotype, commonly seen in patients categorized as having INH. Further, we review the evidence that hypertension in INH patients with the low-renin phenotype may be mediated by phthalate-associated inhibition of 11β-HSD2. Lastly, we review the implications of these findings regarding identification, treatment, and prevention of the low-renin hypertension phenotype seen in premature infants categorized as having INH.

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Abbreviations

BPD:

Bronchopulmonary dysplasia

PRA:

Plasma renin activity

HTN:

Hypertension

INH:

Idiopathic neonatal hypertension

DEHP:

Di-2-ethylhexyl phthalate

11β-HSD2:

11β-Hydroxysteroid dehydrogenase type 2

MR:

Mineralocorticoid receptor

ENaC:

Epithelial sodium channel

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Acknowledgements

We thank A. Stout and M. Jenkins for the editing support and D. Rozansky for the scientific content and graphic support.

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  1. Oregon Health & Science University, 707 SW Gaines Rd., Mail Code CDRC-P, Portland, OR, 97239, USA

    Randall D. Jenkins

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Jenkins, R.D. Phthalates cause a low-renin phenotype commonly found in premature infants with idiopathic neonatal hypertension. Pediatr Nephrol 38, 1717–1724 (2023). https://doi.org/10.1007/s00467-022-05773-1

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