- Author: Alicia Diaz-Thomas, MD, MPH; Chief Editor: Stephen Kemp, MD, PhD more...
Renal pseudohypoaldosteronism type I
The clinical characteristics of pseudohypoaldosteronism (PHA) type I (PHA-I) are those of hypoaldosteronism (ie, hyponatremia, hyperkalemic metabolic acidosis, hyperreninemia, and renal salt wasting) despite normal or elevated aldosterone levels. Overall renal function is normal. The condition does not respond to the administration of exogenous mineralocorticoids.
Although hyponatremia is usually present, it may be masked by hemoconcentration. Hyperkalemia and metabolic acidosis are typically present despite a normal glomerular filtration rate (GFR). The plasma potassium concentration ranges from moderately to greatly increased values. Occasionally, hypercalciuria and nephrocalcinosis have also been described.
The diagnosis is made by demonstrating inappropriately high urinary sodium losses in the presence of hyponatremia, decreased urinary potassium excretion, a normal GFR, normal adrenal function, and increased levels of aldosterone and renin. Plasma aldosterone concentration, urinary aldosterone excretion, and plasma renin activity (PRA) are all usually elevated. Sweat and salivary sodium and chloride determinations are characteristicallynormal.
Plasma deoxycorticosterone and corticosterone concentrations are within the reference range. The ratio of plasma 18-hydroxycorticosterone to aldosterone is within the reference range. The ratio of urinary excretion of tetrahydroaldosterone to 18-hydroxytetrahydro-compound A is within the reference range in contrast to primary hypoaldosteronism.
Children with the early childhood hyperkalemia variant of renal PHA-I (renal tubular acidosis [RTA] type IV subtype 5) have consistently normal or elevated PRA and 24-hour urinary aldosterone excretion. The only biochemical abnormality in these patients is the presence of hyperkalemia and hyperchloremic (non–anion gap) metabolic acidosis. Azotemia and sodium chloride wasting are notably absent.
Functional evaluation reveals a normal ability to acidify urine, low ammonium and potassium excretion, and a mild defect in bicarbonate reabsorption (ie, functional markers of RTA type IV). Renal bicarbonate wasting can be observed with high-dose alkali therapy, but unlike proximal RTA type II, early childhood hyperkalemia is not associated with kaliuria. Unlike RTA type I and II, this subtype is not characterized by hypercalciuria but, rather, by relative hyperreabsorption of calcium and high urinary citrate excretion; thus, nephrocalcinosis is absent.
Multiple target organ defects pseudohypoaldosteronism type I
Like renal PHA-I, multiple target organ defects (MTOD) PHA-I is characterized by urinary salt wastage, which can occur from the salivary glands, sweat glands, respiratory tract, and colon. A variant of MTOD PHA-I has been described in which salt wastage is limited to sweat and salivary glands, without associated renal salt wasting. Urinary sodium is typically elevated, sweat and salivary sodium concentrations are elevated, and active sodium transport in the rectal mucosa is impaired.
Pseudohypoaldosteronism type II
Hyperkalemia, hyperchloremic metabolic acidosis, and a normal GFR are present. Renin and aldosterone levels are low to normal; renin and aldosterone levels increase if volume expansion is corrected by diuretics or salt restriction. Although aldosterone levels may be within the reference range in some cases, they are probably not appropriately elevated for the degree of hyperkalemia.
Sodium wasting is absent, in contrast to renal PHA-I and mineralocorticoid deficient states.
Patients with PHA have hyperkalemia and decreased renal potassium excretion in the absence of glomerular insufficiency. Children with the chloride shunt syndrome (Spitzer-Weinstein syndrome) are typically hyperkalemic at presentation. Potassium excretion responds to sodium sulfate infusion but not to sodium chloride infusion.
Serum bicarbonate concentration is typically low, but this is a more variable finding in children and is observed in only one half of cases. Fractional excretion of bicarbonate is normal.
Hypercalciuria has usually been overlooked as a biochemical feature of this disorder, although its presence has occasionally been recognized. Nephrolithiasis is unusual.
Renal concentration and dilution are normal. Urinary acidification after an ammonium chloride load is normal; however, most patients have a marked reduction in urinary acid excretion and in net acid excretion.
The clinical presentation of secondary PHA in children is that of renal tubular resistance to aldosterone (ie, hyponatremia, hyperkalemia, and metabolic acidosis). The plasma aldosterone concentration is elevated, and fractional sodium excretion may be inappropriately high.
Chest radiography may reveal an increased volume of liquid in the airways in patients with MTOD PHA-I, secondary to failure to absorb liquid from airway surfaces. These findings mimic cystic fibrosis.
Renal ultrasonography may show nephrocalcinosis in patients with PHA-I and nephrolithiasis in patients with PHA-II.
Renal biopsy findings in PHA-I are usually normal; however, hypertrophy of the juxtaglomerular apparatus has occasionally been reported.
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|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 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|
|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.