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,
though it was Gordon who first described it as a new clinical entity in 1970.
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.
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. |
|||||