Mineralocorticoid Resistance

David S. Geller

Disclosures

Clin Endocrinol. 2005;62(5):513-520. 

In This Article

Summary and Introduction

The mineralocorticoid aldosterone plays a crucial role in regulation of volume and electrolyte homeostasis. In recent years there has been considerable progress in deciphering the role of aldosterone in human physiology by the study of monogenic disorders exhibiting mineralocorticoid resistance. Although these disorders are rare, the elucidation of their molecular basis has yielded many insights into aldosterone biology that are proving relevant to the care of patients with a wide variety of cardiovascular diseases. Recent advances in understanding the molecular basis of syndromes of mineralocorticoid resistance are reviewed with a view towards an improved understanding of the role of aldosterone in renal sodium transport and its relationship to cardiovascular disease.

Since its original isolation by Simpson and Tait,[1] aldosterone has occupied a prominent place in our understanding of physiological mechanisms by which the kidney regulates salt and electrolyte balance. As the final effector molecule in the renin—angiotensin—aldosterone pathway, aldosterone plays a crucial role in the regulation of blood pressure and potassium homeostasis. Secreted in response to hypotension or hyperkalaemia, aldosterone binds to the mineralocorticoid receptor (MR ) in the distal nephron, triggering increased sodium reabsorption via the epithelial sodium channel (ENaC) to restore intravascular volume. The electrical gradient created by sodium reabsorption provides a driving force for potassium and proton secretion, giving aldosterone a prominent role in electrolyte homeostasis as well. Although the importance of aldosterone to human physiology has never been questioned, aldosterone has been largely overlooked in clinical practice for some time, noted only in those rare patients exhibiting hypertension and hypokalaemia. Recent years, however, have witnessed an upsurge in interest in aldosterone biology, driven primarily by clinical findings implicating aldosterone as an important culprit in cardiovascular disease. Studies have shown important benefits of aldosterone antagonism in a variety of important clinical conditions, including heart failure[2,3] and renal disease.[4—6] Similarly, the realization that excess aldosterone effect may cause hypertension in the absence of hypokalaemia has led to the suggestion that aldosteronism may underlie a significant proportion of what has previously been considered to be essential hypertension;[7] specific measures to decrease aldosterone effect in these patients may be highly effective in reducing blood pressure. These findings have triggered a marked upsurge in the use of antimineralocorticoid agents.[8]

Although the benefits of mineralocorticoid antagonism in these and other clinical conditions are clear, the mechanism by which antimineralocorticoid agents exert their beneficial effects remains in question. It has been proposed that mineralocorticoid antagonism exerts beneficial effects via blockade of MR specific effects in the heart and vascular tissue itself,[9—11] but others argue that the principal benefit of mineralocorticoid blockade is alteration of renal sodium reabsorption. Clarifying this issue is of great importance, as it will suggest mechanisms by which outcomes may be further improved in these patients. In all likelihood, further insights will require improved understanding of aldosterone biology and physiology.

One avenue for clarification of aldosterone biology in humans has involved the study of patients resistant to the effects of aldosterone. Mineralocorticoid resistance occurs in a variety of clinical conditions, both genetic and acquired, and recent years have witnessed significant advances in our understanding of mechanisms by which aldosterone resistance occurs. Here, we review a variety of clinical conditions featuring mineralocorticoid resistance and use insights gained from these states in an attempt to clarify underlying mechanisms of aldosterone biology.

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