Syndromes of impaired ion handling in the distal nephron: pseudohypoaldosteronism and familial hyperkalemic hypertension.

The distal nephron, which is the site of the micro-regulation of water absorption and ion handling in the kidneys, is under the control of aldosterone. Impairment of the mineralocorticoid signal transduction pathway results in resistance to the action of aldosterone and of mineralocorticoids in general. Herein, we review two syndromes in which ion handling in the distal nephron is impaired: pseudohypoaldosteronism (PHA) and familial hyperkalemic hypertension (FHH). PHA is a rare inherited syndrome characterized by mineralocorticoid resistance, which leads to salt loss, hypotension, hyperkalemia and metabolic acidosis. There are two types of this syndrome: a renal (autosomal dominant) type due to mutations of the mineralocorticoid receptor (MR), and a systemic (autosomal recessive) type due to mutations of the epithelial sodium channel (ENaC). There is also a transient form of PHA, which may be due to urinary tract infections, obstructive uropathy or several medications. FHH is a rare autosomal dominant syndrome, characterized by salt retention, hypertension, hyperkalemia and metabolic acidosis. In FHH, mutations of WNK (with-no-lysine kinase) 4 and 1 alter the activity of several ion transportation systems in the distal nephron. The study of the pathophysiology of PHA and FHH greatly elucidated our understanding of the renin-angiotensin-aldosterone system function and ion handling in the distal nephron. The physiological role of the distal nephron and the pathophysiology of diseases in which the renal tubule is implicated may hence be better understood and, based on this understanding, new drugs can be developed.