Mineralocorticoid Resistance

David S. Geller

Disclosures

Clin Endocrinol. 2005;62(5):513-520. 

In This Article

Autosomal Recessive PHA1

Patients with autosomal recessive PHA1 (arPHA1) suffer from life-threatening salt wasting and hyperkalaemia, and they require massive doses of sodium coupled with the chronic use of potassium binding resins to maintain electrolyte homeostasis and stay alive. This form of the disorder has sometimes been called generalized PHA1, as there is evidence of salt wasting not only from the kidney but also from the colon, sweat glands and salivary glands. Although Armanini's initial studies had hinted that MR mutations might underlie arPHA1, no mutations in MR could be identified in affected kindreds. Progress eventually came with the realization that mutations anywhere in the aldosterone effector pathway could cause clinical mineralocorticoid resistance. As ENaC was known to be the primary mediator of aldosterone-dependent sodium transport in the distal nephron, the subunits of ENaC became logical candidate genes, and it was soon demonstrated that homozygous mutations in either the alpha, beta or gamma subunit of ENaC cause arPHA1.[18,19] A variety of mutations, including missense, nonsense, frameshift and splice-site mutations, have been identified in these genes (Fig. 1). Included in this list are a number of N-terminal stop codons and frameshift mutations, suggesting that these mutations bring about a complete loss of function. The mutations identified are located primarily in exonic regions of the genes, but this is likely to reflect an observational bias, and indeed, a large homozygous deletion in the promoter region of β-ENAC has also been demonstrated to cause arPHA1.[20] To date, there are no reports of patients with recessive PHA1 with mutations in any other gene, and so this phenotype is believed to be restricted to mutations in the ENaC subunits. While homozygous loss-of-function mutations in the MR lead to a PHA1 phenotype in mice,[21] this mutation has never been identified in humans.

arPHA1 is caused by mutations in subunits of ENaC. The identity and location of all published mutations in the α, β and γ subunits of the epithelial sodium channel causing arPHA1 are depicted. For each gene, mutations are dispersed throughout the gene. fr, frameshift; spl, splice-site mutation; X, stop codon.

Clinical phenotypes in arPHA1 are not limited to the kidney; patients have evidence of salt-wasting from the sweat and salivary glands and colon as well.[17] Young arPHA1 patients suffer from a novel pulmonary syndrome characterized by recurrent episodes of chest congestion, coughing and wheezing in the absence of airway infection with Staphylococcus aureus or Pseudomonas aeruginosa , which stems from a decreased ability to absorb liquid from airway surfaces and consequent increased lung water.[22] Consistent with this, mice lacking α - or β-ENaC die at birth from respiratory failure due to an inability to resorb lung water,[23,24] and γ -ENaC-deficient mice have a mild respiratory phenotype reminiscent of what is observed in human arPHA1 patients.[25]

Two clinical disorders feature similar phenotypes to arPHA1 and must be distinguished. The first is autosomal dominant PHA1 (adPHA1, described below), which, like arPHA1, features renal salt wasting, hyperkalaemia and increased aldosterone levels. However, arPHA1 has a much more severe course.[17] Patients with arPHA1 typically present in the first 2 weeks of life with weakness, failure to thrive, and the electrolyte disturbances described above, while adPHA1 patients may present much later or not at all. A history of parental consanguinity argues strongly for recessive disease, as do elevated sweat and salivary sodium levels.[17] Finally, while parents of a child with arPHA1 generally have normal serum aldosterone levels, a parent of a child with adPHA1 may have markedly elevated aldosterone levels in the absence of hypertension, indicating that he or she is an asymptomatic carrier of the disease gene.

Autosomal recessive PHA1 must also be distinguished from Bartter's syndrome type 2, caused by homozygous loss-of-function mutations in the ROMK2 potassium channel.[26] Unlike patients with other forms of Bartter's syndrome, who present with hypokalaemia and metabolic alkalosis, patients with this form of Bartter's syndrome often present with a clinical picture similar to PHA1, with the neonatal onset of salt wasting, hyperkalaemia and acidosis. However, the hyperkalaemia and acidosis present at birth in patients with Bartter's syndrome type 2 disappears with sodium resuscitation, and the more characteristic clinical picture of Bartter's syndrome, including hypokalaemia and metabolic alkalosis, becomes apparent.[27] The transient hyperkalaemia these patients experience at birth suggests the crucial role of ROMK in aldosterone-dependent potassium secretion at birth and suggests that other distal nephron aldosterone-dependent potassium secretory channels develop postnatally.

In the kidney, ENaC is expressed in the distal nephron, localizing primarily to the cortical collecting tubule's principal cell. Electrogenic sodium reabsorption via ENaC into the principal cell results in a net negative charge in the tubular lumen, creating a powerful charge stimulus for the distal nephron either to resorb a negatively charged chloride ion via paracellular transport pathways or alternatively to secrete a positively charged potassium or hydrogen ion into the tubular lumen. The absence of a functional ENaC in PHA1 patients prevents principal cell sodium reabsorption, resulting in salt wasting and, furthermore, an inability of the distal nephron to appropriately secrete potassium and hydrogen ions. Thus, the characteristic hyperkalaemia, metabolic acidosis, elevated renin and aldosterone levels and salt wasting of PHA1 can all be explained on the basis of the loss of function in the epithelial sodium channel. The remarkable inability of arPHA1 patients to regulate potassium and hydrogen ion balance highlights the crucial role of ENaC-mediated sodium reabsorption for electrolyte homeostasis.

The severe phenotype of patients with arPHA1 comes perhaps as a bit of a surprise, as primers on kidney function have long suggested a relatively minor role of the collecting duct in the reclamation of the filtered sodium load. Traditional estimates have suggested that two-thirds of filtered sodium is reclaimed in the proximal tubule, a further 20—25% is reabsorbed in the loop of Henle, via the Na-K-2Cl cotransporter (NKCC2), 7% is reclaimed in the distal convoluted tubule via the thiazide-sensitive cotransporter (TSC), and only 2% is reabsorbed via ENaC in the collecting duct. It is thus somewhat surprising to note that although patients who lack NKCC2 (Bartter's syndrome)[28] or TSC (Gitelman's syndrome)[29] do indeed have reduced arterial blood pressure, the primary clinical sequelae are more often caused by electrolyte disturbances related to potassium, calcium and magnesium handling; these patients do not die of salt wasting.[30] Similarly, mice deficient in NHE3, believed to be the principal sodium transport pathway in the proximal tubule, have low blood pressure, but again, their principal problems stem from altered electrolyte balance.[31,32] In contrast to humans lacking these more proximal sodium transport systems, humans lacking ENaC function have a catastrophic course, with frequent neonatal death from volume depletion and hyperkalaemia. The severity of disease in these individuals makes it clear that aldosterone-mediated sodium transport through ENaC plays a much more important role in sodium and electrolyte homeostasis than is suggested by reports claiming it is responsible for reabsorbing only 2% of the filtered sodium load.

How is it that humans lacking NCCT or NKCC2, transporters responsible for large amounts of the filtered sodium load, maintain volume homeostasis, while humans lacking ENaC have significant haemodynamic compromise when stressed? Tubuloglomerular feedback, the process by which the kidney regulates glomerular filtration in response to alterations in tubular flow, probably plays a role;[33] in the setting of volume depletion, the kidney reduces filtration at the glomerulus, thereby decreasing the work of tubular sodium reabsorption to a more manageable level. Another mechanism by which Bartter's and Gitelman's syndrome patients maintain volume homeostasis is via the activation of the renin—angiotensin—aldosterone system, which markedly upregulates sodium transport in the distal nephron. Although the collecting duct resorbs only 2% of the filtered sodium load at baseline conditions, recent data suggest that aldosterone induces amiloride-sensitive sodium currents via ENaC in the adjacent connecting tubule. Sodium transport in this region, largely undetectable at baseline, rises to roughly 10% of the filtered sodium load, making the connecting tubule an important and perhaps somewhat overlooked region for maintenance of sodium homeostasis.[34] Supporting the important role of the connecting tubule in renal sodium reabsorption is the finding that whereas mice lacking ENaC have massive life-threatening salt wasting, mice lacking ENaC specifically in the collecting duct are phenotypically normal, suggesting strongly that aldosterone-sensitive ENaC-mediated sodium transport outside the collecting tubule (and presumably also in the connecting tubule) contributes significantly to sodium homeostasis.[35] This activity is absent in arPHA1 patients, rendering them more or less defenceless against volume challenges and forcing them to maintain high sodium intake for survival. Importantly, the potency of this activity suggests that the efficacy of loop and thiazide diuretics for the treatment of hypertension and oedematous states can be markedly enhanced by the concurrent use of agents that inhibit ENaC, such as amiloride or spironolactone.

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