Pseudohypoaldosteronism

Updated: Mar 15, 2017
  • Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Robert P Hoffman, MD  more...
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Overview

Background

Pseudohypoaldosteronism (PHA) comprises a heterogeneous group of disorders of electrolyte metabolism characterized by an apparent state of renal tubular unresponsiveness or resistance to the action of aldosterone. It is manifested by hyperkalemia, metabolic acidosis, and a normal glomerular filtration rate (GFR). Volume depletion or hypervolemia; renal salt wasting or retention; hypotension or hypertension; and elevated, normal, or low levels of renin and aldosterone may be observed in the various conditions that result in this syndrome.

Since primary PHA was first described, it has been further subclassified into PHA type I (PHA-I), which is the classic form, and PHA type II (PHA-II), which is also referred to as Gordon syndrome or chloride shunt syndrome. PHA-I itself has been recognized as a heterogeneous syndrome that includes at least 2 clinically distinguishable entities with either renal or multiple target organ defects (MTOD). Early childhood hyperkalemia, or renal tubular acidosis (RTA) type IV subtype 5, is a variant of the renal form of PHA-I.

PHA-II is a rare familial renal tubular defect characterized by hypertension and hyperkalemic metabolic acidosis in the presence of low renin and aldosterone levels. Paver and Pauline first reported PHA-II in 1964, [1] though it was Gordon who first described it as a new clinical entity in 1970. [2] In addition to Gordon syndrome, PHA-II includes what is known as adolescent hyperkalemic syndrome.

The molecular basis for most individuals who have PHA-II was linked to loss-of-function mutations in WNK1 or WNK4. [3, 4, 5, 6, 7] WNKs are a family of serine-threonine protein kinases that have an unusual placement of the catalytic lysine as compared with all other protein kinases. WNK1 or WNK4 regulate chloride cotransporters of the distal nephron and other epithelia.

Characteristics of PHA-I and PHA-II are summarized in the Table below. In addition to the 2 types of primary PHA, an acquired or secondary form of PHA has been described.

Table. Characteristics of Primary Pseudohypoaldosteronism (Types I and II) (Open Table in a new window)

Details PHA Type I PHA Type II
Renal PHA-I MTOD PHA-I Early Childhood Hyperkalemia PHA-II
Synonyms Classic PHA of infancy, Cheek and Perry syndrome, autosomal dominant PHA-I, subtype 4 RTA IV Autosomal recessive PHA-I Subtype 5 RTA IV Adolescent hyperkalemic syndrome, Spitzer-Weinstein syndrome, subtype 3 RTA IV Gordon syndrome, mineralocorticoid-resistant hyperkalemia, chloride shunt syndrome
Age Newborn period, infancy Newborn period, infancy Infancy, childhood Childhood Adulthood
Organs Kidney Kidney, sweat glands, salivary glands, colon Kidney Kidney Kidney
Genetics Autosomal dominant, sporadic Autosomal recessive, sporadic Unknown Unknown Autosomal dominant, sporadic
Mechanism Heterozygous MLR mutations (possible) Defective Na transport in organs that contain ENaC Maturation disorder in the number or function of aldosterone receptors Chloride shunt Chloride shunt
Serum potassium High High High High High
Acidosis Present Present Present Present Present
Serum sodium Normal or low Normal or low Normal Normal Normal
PRA* High High Normal or high Normal or low Low
Aldosterone High High Normal or high Normal or low Low
Blood volume Normovolemia, hypovolemia Normovolemia, hypovolemia Normovolemia Hypervolemia Hypervolemia
Blood pressure Normal or low Normal or low Normal or low Normal or low Normal or low
GFR Normal Normal Normal Normal Normal
Salt wasting Renal Renal, sweat or salivary glands, colon Absent Absent Absent
Hypercalciuria Present or absent Absent Absent Present Present
Therapy Na supplementation, K-binding resins High-Na, low-K diet, K-binding resins, hydrochlorothiazide Na bicarbonate, K-binding resins Dietary Na restriction, hydrochlorothiazide Dietary Na restriction, hydrochlorothiazide
Prognosis Outgrow by age 2 y Lifelong therapy Outgrow by age 5 y Lifelong therapy Lifelong therapy
*Plasma renin activity.



ENaC = epithelial sodium channel; GFR = glomerular filtration rate; MLR = mineralocorticoid receptor gene; PHA = pseudohypoaldosteronism; RTA = renal tubular acidosis.



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Pathophysiology

Renal PHA-I (including the early childhood hyperkalemia variant) is probably due to a maturation disorder in the number or function of aldosterone receptors. This autosomal dominant disorder has been associated with mutations in the human mineralocorticoid receptor gene (MLR) in numerous kindreds and also in sporadic cases.

In MTOD PHA-I, other organs are involved, including the sweat glands, salivary glands, and colon. The fundamental abnormality is a loss-of-function mutation in the alpha or beta subunits of the epithelial sodium channel (ENaC), resulting in defective sodium transport in many organs containing this channel (eg, kidneys, lungs, colon, and sweat and salivary glands). [8]

This amiloride-sensitive member of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels comprises 3 homologous units (alpha, beta, gamma) and is expressed in the apical membrane of epithelial cells lining the airway, colon, and distal nephron. ENaC plays an essential role in transepithelial sodium and fluid balance.

The state of hyperreninism and hyperaldosteronism in these children is the result of sustained extracellular fluid (ECF) volume depletion and is not due to peripheral resistance to mineralocorticoids.

The primary abnormality in type II PHA is thought to be a specific defect of the renal secretory mechanism for potassium, which limits the kaliuretic response to, but not the sodium and chloride reabsorptive effect of, mineralocorticoids. In PHA-IIB and IIC, the defect involves absent WNK1 or WNK4 kinase function in the distal nephron. [3, 5, 6, 7] WNK4 is exclusively expressed in the distal nephron, whereas WNK1 functions in most polarized epithelia (cells that line the lumen of hepatic biliary ducts, gallbladder, pancreatic ducts, epididymis, sweat ducts, and colonic crypts).

These kinases regulate the thiazide-sensitive Na-Cl cotransporter (NCCT) in the distal nephron. Specifically, loss-of-function mutations in WNK1 or WNK4 abolish WNK regulation of NCCT, resulting in the uninhibited NCCT activity that causes PHA-II.

Earlier studies had implicated both proximal and tubular defects. Enhanced chloride absorption in the distal nephron had been suggested as the primary abnormality; thus, the name chloride shunt syndrome was proposed. This increased reabsorptive avidity of the distal nephron for chloride, in turn, limits the sodium-dependent and mineralocorticoid-dependent voltage that is the driving force for potassium and hydrogen ion secretion, resulting in hyperkalemia and acidosis.

The increased reabsorption of sodium chloride results in hyperchloremia with ensuing volume expansion and hypertension. [9] Volume expansion results in secondary hypoaldosteronism and, consequently, in hyporeninemia. Evidence suggests that enhanced sodium chloride reabsorption takes place in several nephron segments proximal to the potassium-secreting sites (ie, proximal to the proximal tubule and the thick ascending limb of the loop of Henle).

An alternative mechanism for explaining the renal tubular defect in this syndrome is abnormally low levels of urinary prostaglandin metabolites, a product of renal prostaglandin synthesis. Mutations in the thiazide-sensitive NCCT gene have been excluded as a cause.

Other authors continue to speculate that Gordon syndrome could result from a generalized increase in the activity of the bumetanide-sensitive Na-K-Cl cotransporter; however, this possibility has not been evaluated. On the basis of a lack of response to the infusion of atrial natriuretic peptide (ANP), an increased proximal tubular reabsorption caused by inherited insensitivity to the action of the natriuretic factor has been proposed; however, other authors have not confirmed this process.

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Etiology

Renal PHA-I appears to be inherited in an autosomal dominant pattern with variable expression. Many children have been found to have a loss-of-function mutation in the human mineralocorticoid receptor gene (NR3C2; band 4q31.1). Autosomal dominant PHA-I is caused by heterozygous mutation in the mineralocorticoid receptor gene (NR3C2, OMIM#600983). The renal PHA phenotype is due to either haploinsufficiency (loss of 1 of the 2 functional alleles) of the MR or a negative dominant effect of the mutated MR on the activity of the wild-type MR. [10] Even though many cases appear to be sporadic, elevated plasma aldosterone levels were found in some of the apparently asymptomatic parents.

MTOD PHA-I is most likely inherited as an autosomal recessive disorder. There is a high incidence of consanguinity among parents, and the degree of penetrance varies. Most studied kindreds have had a loss-of-function mutation in any gene of the 3 subunits of the epithelial sodium channel (ENaC), the alpha (α), beta (β), or gamma (γ). Autosomal recessive PHA-I can be caused by homozygous or compound heterozygous mutation in any 1 of 3 genes encoding subunits of the ENaC: the α subunit (SCNN1A, OMIM# 600228), the β subunit (SCNN1B, OMIM# 600760), or the γ subunit (SCNN1G, OMIM# 600761).

Patients with this form of PHA have either a homozygous or compound heterozygous mutation of the ENaC, with both alleles expressing an abnormal protein. Sporadic cases have also been suggested, and these have been postulated to arise from polymorphisms that alone do not result in negative salt balance but together may interact negatively.

PHA-II is a genetically heterogenous group of disorders. It is grouped into types PHA-II A thru E that represent various inheritance patterns and differing affected genes. PHA-IIA has been mapped to 1q31-q42, PHA-IIB is caused by mutations in the WNK4 gene on 17q21 (OMIM # 601844), PHA-IIC is caused by mutations in the WNK1 gene on 12p13 (OMIM # 605232), PHA-IID is caused by mutations in the KLHL3 gene (OMIM # 605775) on 5q31, and PHA-IIE is caused by mutations in the CUL3 gene (OMIM# 603136) on 2q36. [11]

Secondary PHA is limited to the kidneys and has been described in infants and children with obstructive uropathy, urinary tract infection, tubulointerstitial nephritis, sickle cell nephropathy, systemic lupus erythematosus, amyloidosis, and neonatal medullary necrosis, as well as in some infants who have had unilateral renal vein thrombosis. Cases have also been reported in patients with multiple myeloma and renal transplantation. Tubular injury is presumed to be responsible for the diminished response to aldosterone in these disorders.

Drugs can impair renin or aldosterone synthesis or cause mineralocorticoid resistance. Drugs that can cause PHA include the following:

  • Cyclooxygenase inhibitors (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]) – These agents can cause hyperkalemia and metabolic acidosis as a result of inhibition of renin release
  • Beta-adrenergic antagonists – These agents alter potassium distribution and interfere with the renin-aldosterone system, resulting in hyperkalemia
  • Heparin – Heparin inhibits aldosterone synthetase and causes hyperkalemia as a result of impaired aldosterone synthesis
  • Angiotensin-converting enzyme (ACE) inhibitors – These agents can result in hypoaldosteronism with hyperkalemic acidosis by inhibiting angiotensin II formation
  • Potassium-sparing diuretics (eg, amiloride, triamterene, and spironolactone) – These agents impair distal potassium secretion; spironolactone antagonizes the effects of aldosterone, and amiloride and triamterene directly close the sodium channel in the luminal membrane of the collecting tubular cell
  • Trimethoprim
  • Cyclosporine A – Cyclosporine inhibits basolateral sodium-activated and potassium-activated adenosine triphosphatase, thereby decreasing intracellular potassium

Because of the risk of hyperkalemia, these drugs should be used with caution in patients with tubulointerstitial nephritis, mild-to-moderate impairment of renal function, and diabetic nephropathy.

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Epidemiology

Since the first description of renal PHA-I in 1958, more than 70 cases of this salt-wasting syndrome have been reported in the literature. [12] This condition, also called Cheek and Perry syndrome or classic PHA of infancy, represents the most common form of PHA-I. The early childhood hyperkalemia variant of renal PHA-I is the most common subtype of RTA type IV in children and is found with equal frequency in males and females. Occasionally, several siblings are affected.

MTOD PHA-I has been reported in several kindreds. PHA-II is rare. Secondary (acquired) PHA is also rare but may occur more frequently in clinical practice.

Renal PHA-I occurs only in newborns and infants and usually improves with age. Early childhood hyperkalemia occurs in infants and young children and is found with equal frequency in males and females. MTOD PHA-I occurs in newborns and infants but persists into adulthood. PHA-II occurs in older children and adults. Although the defect is present at birth, the disease is not usually diagnosed until adolescence. Secondary PHA may occur at any age.

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Prognosis

Individuals with renal PHA-I may present with severe symptoms early after birth and throughout the first 2 weeks of life, or they may be asymptomatic. The disease tends to be transient, and symptoms resolve in patients older than 2 years. A progressive decrease in urinary salt wastage occurs as the renal tubule matures throughout infancy. Older children may be asymptomatic with normal salt intake, but plasma aldosterone remains elevated. Plasma renin activity (PRA) decreases to normal with advancing age.

Adult patients with PHA-I have normal serum electrolytes without salt supplementation but may be more vulnerable to electrolyte disturbances under stress. Plasma aldosterone levels remain elevated throughout life. Whether affected adults have a higher lifetime risk for nephrolithiasis is unclear; thus, annual visits to a nephrologist or informed primary care provider are prudent.

Children with early childhood hyperkalemia usually achieve normal height within 6 months; at about 5 years, therapy is no longer needed.

In MTOD PHA-I, salt wasting is more severe. This form of PHA has a poorer outcome than the renal form. Patients are prone to developing respiratory symptoms; death may ensue during the neonatal period. Improvement with advancing age does not occur, as it does in the isolated renal form of PHA. Therapy must be maintained throughout childhood and probably throughout life.

Most individuals with PHA-II are asymptomatic until adolescence, when hypertension develops. These patients require lifelong therapy.

In patients with secondary PHA, all abnormalities tend to disappear after medical or surgical therapy; however, hyperkalemia may last as long as 3 years. Polyuria and renal sodium loss may transiently become more severe during the early period following relief of obstruction, and some degree of polyuria may persist. Abnormalities improve or disappear after discontinuance of drugs that can impair renin or aldosterone synthesis or cause mineralocorticoid resistance.

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