Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner

Disclosures

Nat Clin Pract Nephrol. 2006;2(11):624-630. 

In This Article

Activating Mineralocorticoid Receptor Mutation

Approximately 6% of pregnancies are associated with hypertension, and it is well established that hypertension in pregnancy increases the risk of morbidity and mortality to the mother and fetus. Whereas the pathophysiologic cause for pregnancy-related hypertension is largely unknown, Lifton et al.[14] described a single gene mutation that caused early-onset hypertension in a family. All family members with this missense mutation had severe hypertension with low renin and aldosterone levels, and presented prior to the age of 21 years. Members of the family without this mutation were normotensive. The mutation—a leucine for serine substitution at codon 810—occurs in the hormone-binding domain of the MCR. The mutation causes the receptor to be constitutively active and alters its specificity such that the steroid hormones, which lack a 21-hydroxyl group and are normally antagonistic (including progesterone and cortisone), act as agonists (Figure 3A).

Figure 3.

Single gene disorders that affect the distal nephron and cause hypertension. (A) Mutation that changes specificity of the MCR and leads to hypertension exacerbated by pregnancy (progesterone). (B) Deficiency of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2)—either inherited (AME) or acquired (licorice)—leads to elevated levels of cortisol, stimulation of MCR and hypertension. (C) Liddle syndrome. Mutations in the β- or γ-subunit of the ENaC prevent binding to Nedd4, a repressor factor, leading to constitutive expression of sodium channels, volume expansion and hypertension. (D) Gordon's syndrome. Mutations in WNK cause: (Da) increased NCCT activity in DCT, sodium and chloride reabsorption with volume expansion and hypertension; and (Db) inhibition of ROMK activity in CCT and hyperkalemia. Abbreviations: AME, apparent mineralocorticoid excess; CCT, cortical collecting tubule; DCT, distal convoluted tubule; ENaC, amiloride-sensitive sodium channel; MCR, mineralocorticoid receptor; NCCT, Na-Cl co-transporter; PT, proximal tubule; ROMK, renal outer medullary potassium channel; WNK, serine-threonine kinase.

Hypertension in females harboring this mutation was markedly exacerbated during pregnancy. The 100-fold increase in progesterone during pregnancy is thought to underlie this marked exacerbation, causing avid retention of sodium and blood volume expansion.[14] These occurrences create a virtual state of hyperaldosteronism in which both plasma renin activity and serum aldosterone levels are suppressed. The exact mechanism by which the missense mutation becomes activated is unknown. Recent data have shown that cortisone, the main metabolite of cortisol in the kidney, can activate the mutation, conferring a potential permanent increase in renal sodium reabsorption—a possible explanation for the severe hypertension evident in young males and in non-pregnant females.[15]

Treatment of this condition differs from those described above. With its low levels of aldosterone, this condition is refractory to standard medical management aimed at reducing aldosterone levels. In fact, spironolactone actually worsens hypertension in affected individuals. The cases reported to date have not been associated with proteinuria, edema or neurological changes, which distinguish them from cases of pre-eclampsia. Nonetheless, the treatment for both of these conditions is the same—delivery of the fetus, which markedly reduces progesterone levels and, subsequently, blood pressure. While delivery improves the hypertension in pregnancy, no definitive therapeutic algorithm has been described for males or non-pregnant females.

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