Mineralocorticoid resistance

Abstract

Pseudohypoaldosteronism was first described in 1958 by Cheek and Perry, who reported an infant with severe salt wasting in the absence of any renal or adrenal defect. Since then several reports have described patients affected by symptoms consistent with resistance to mineralocorticoid action. The clinical picture is characterized by salt wasting and failure to thrive and is resistant to the administration of exogenous mineralocorticoids. Biological features are invariably high plasma and urinary aldosterone levels and elevated plasma renin activity associated with hyponatremia, hyperkalemia, and metabolic acidosis. The discovery of abnormal binding of aldosterone to the mineralocorticoid receptor (MR) in lymphocytes from affected patients, by analogy to findings in other syndromes of steroid hormone resistance, led to the hypothesis that the disease reflected a molecular defect in MR, which has prompted a series of molecular studies to characterize the defect. In this paper we review mechanisms of mineralocorticoid action, discuss the clinical features of mineralocorticoid resistance, overview the molecular characterization of the MR, and close with some pathophysiological hypotheses and questions.

Increased Na reabsorption via the Na–Cl cotransporter in autosomal recessive pseudohypoaldosteronism

“…The clinical courses of the two genetically different forms also vary considerably. While AD-PHA1 shows a gradual clinical improvement with advancing age, usually allowing the cessation of salt supplementation during infancy, AR-PHA1 persists into adulthood, and no improvement is typically seen with time [1,2]. Here, we report a patient with AR-PHA1 who demonstrated an improvement of clinical severity, leading to the cessation of salt supplementation.…”

“…Pseudohypoaldosteronism type 1 (PHA1) is a heritable disorder characterized by urinary sodium loss due to aldosterone resistance at the distal segment of the nephron [1,2]. The autosomal recessive form of PHA1 (AR-PHA1) [OMIM#264350] is derived from loss-offunction mutations in the amiloride-sensitive epithelial sodium channel (ENaC) subunit genes and manifests as a life-threatening salt-wasting condition displaying multiorgan aldosterone unresponsiveness and involving the salivary glands, distal colon, and sweat glands.…”

Transient type 1 pseudo-hypoaldosteronism: report on an eight-patient series and literature review

“…An autosomal dominant or sporadic form (also called renal form) is associated with a mutation in the mineralocorticoid receptor (MR) gene, which prevents normal receptor function and, hence, causes renal salt wasting [4]. The autosomal recessive PHA1 (the so-called multiple organ form) is associated with mutations in the alpha, beta or gamma subunits of the epithelial sodium channel (ENaC) gene, causing salt wasting not only from the kidney, but also from the colon, sweat glands and salivary glands [1,2].…”

“…Type 1 pseudo-hypoaldosteronism (PHA1) is a rare condition characterized by renal resistance to the action of aldosterone; patients exhibit salt wasting, hyperkalemia and metabolic acidosis associated with high levels of plasma renin and aldosterone [1][2][3]. This rare syndrome starts during the neonatal or early infant period and has a wide spectrum: (a) two genetic forms and (b) a secondary form.…”

Syndromes of glucocorticoid and mineralocorticoid resistance

“…While the clinical presentation is heterogeneous, including severely affected as well as asymptomatic patients, biological abnormalities include invariably high urinary sodium despite hyponatremia, hyperkalemia and metabolic acidosis, high plasma and urinary aldosterone levels, and high plasma renin activity (94). Diagnosis requires proof of renal unresponsiveness to exogenous mineralocorticoid therapy.…”