AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Pseudohypoaldosteronism (PHA) refers to a heterogeneous group of disorders of electrolyte metabolism characterized by an apparent state of renal tubular unresponsiveness or resistance to the action of aldosterone. The condition is characterized by hyperkalemia, metabolic acidosis, and 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 type I PHA (PHA-I) was first described, it has been further classified (see below) into a classic form of PHA, type I, and PHA type II (PHA-II), which is also referred to as chloride shunt syndrome. Recently, PHA-I has been recognized as a heterogeneous syndrome that includes at least two clinically distinguishable entities with either renal or multiple target organ defects (MTOD). Early childhood hyperkalemia, or renal tubular acidosis (RTA) IV subtype 5, is a variant of the renal form of PHA-I.

PHA-II, also known as Gordon syndrome or chloride shunt syndrome, 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 described PHA-II in 1964, although Gordon described it as a new clinical entity in 1970. The molecular basis for most patients who have PHA-II was recently reported as loss-of-function mutations in WNK1 or WNK4, kinases that regulate chloride cotransporters of the distal nephron and other epithelia.

An acquired or secondary form of PHA has also been described.

A summary of the forms of PHA is as follows:

• Primary pseudohypoaldosteronism
  • Type I (PHA-I)
    • Renal type I (renal PHA-I)
    • Multiple target organ defect type I (MTOD PHA-I)
    • Early childhood hyperkalemia
  • Type II (PHA-II)
    • Gordon syndrome
    • Adolescent hyperkalemic syndrome
• Secondary pseudohypoaldosteronism

Pathophysiology

Renal pseudohypoaldosteronism type I

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

MTOD pseudohypoaldosteronism type I

In this variant, other organs, such as the sweat glands, salivary glands, and colon, are involved. The fundamental abnormality in MTOD PHA-I 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 the ENaC, such as the kidney, lung, colon, and sweat and salivary glands. This amiloride-sensitive member of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels is comprised of 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 Na⁺ 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.

Pseudohypoaldosteronism type II

As first reported in 2003 and confirmed with molecular studies, the defect for PHA-II involves absent WNK1 or WNK4 kinase function in the distal nephron. 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.

Prior studies had implicated both proximal and tubular defects. Enhanced chloride absorption in the distal nephron had been suggested as the primary abnormality, so the name chloride shunt syndrome was proposed. This increased reabsorptive avidity of the distal nephron for chloride, in turn, limits the sodium- and mineralocorticoid-dependent voltage driving force for potassium and hydrogen ion secretion, thus resulting in hyperkalemia and acidosis. The increased reabsorption of sodium chloride results in hyperchloremia with ensuing volume expansion and hypertension. Volume expansion results in secondary hypoaldosteronism and, consequently, in hyporeninemia.

Evidence has been presented to support the conclusion that enhanced sodium chloride reabsorption takes place in several nephron segments proximal to potassium-secreting sites (proximal tubule and thick ascending limb of the loop of Henle). An alternative mechanism to explain 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 Na⁺-Cl^- cotransporter gene have been excluded.

Other authors still speculate that Gordon syndrome could result from a generalized increase in the activity of the bumetanide-sensitive Na⁺-K⁺-2Cl^- cotransporter, but this has not been studied. Based on 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 demonstrated this.

Summary of Pseudohypoaldosteronism

*Plasma renin activity

Frequency

International

Renal PHA-I: More than 70 cases of this salt-wasting syndrome have been reported in the literature since the first description in 1958. Renal PHA-I, 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 type IV RTA in children and is found with equal frequency in males and females. Occasionally, several siblings are affected.

MTOD PHA-I: Multiple target organ resistance has been reported in several kindreds.

PHA-II: This is a rare form of PHA.

Secondary PHA: An acquired form of PHA has been reported rarely but may occur more frequently in clinical practice.

Mortality/Morbidity

• Renal PHA-I: Patients may present with severe symptoms early after birth and throughout the first two weeks of life, or they may be asymptomatic.
• MTOD PHA-I: Patients are prone to developing respiratory symptoms; death may ensue during the neonatal period.
• PHA-II: Most patients are asymptomatic until adolescence when hypertension develops.

Sex

The early childhood hyperkalemia variant of renal PHA-I is found with equal frequency in males and females.

Age

• Renal PHA-I occurs only in newborns and infants, usually improving with age.
• Early childhood hyperkalemia occurs in infants and young children.
• MTOD PHA-I occurs in newborns and infants but persists into adulthood.
• PHA-II occurs in older children and adults. Even though the defect is present at birth, the disease is not usually diagnosed until adolescence.
• Secondary PHA may occur in people of any age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Renal pseudohypoaldosteronism type I
• • The clinical expression of renal PHA-I is highly variable, even in members of the same family and with the same gene defect. Affected children may have severe symptoms in early infancy (first 2 wk of life) or may be essentially asymptomatic.
  • Salt wasting and polyuria may be present in utero and result in polyhydramnios.
  • Anorexia and vomiting generally develop immediately after birth.
  • Symptoms are similar to those observed in mineralocorticoid deficiency.
  • Salt craving is observed in older children.
  • Vomiting usually is the only symptom in patients with early childhood hyperkalemia.
• Multiple target organ defects pseudohypoaldosteronism type I
• • Salt-wasting episodes develop soon after birth and usually are more severe than in renal PHA-I.
  • These patients have a high incidence of lower respiratory tract involvement secondary to impaired bacterial killing resulting from increased sodium chloride concentration in airway surface fluid, which can mimic cystic fibrosis.
• Pseudohypoaldosteronism type II
• • A similar condition has been described in children (Spitzer-Weinstein syndrome) that is characterized by short stature, hyperkalemic metabolic acidosis, blood pressure within the reference range, and reference range aldosterone levels.
  • Urolithiasis may be present.

Physical

• Renal pseudohypoaldosteronism type I
• • Symptomatic patients have failure to thrive, weight loss, vomiting, and dehydration appearing as early as the first 2 weeks of life.
  • Patients have repeated episodes of dehydration and may appear to be in shock and comatose.
  • Weight loss may occur. If therapy is delayed, patients may become severely undernourished, and failure to thrive becomes evident during infancy.
  • Patients have a marked tendency to develop low blood volume and hypotension just like patients with true hypoaldosteronism.
  • Failure to thrive or growth retardation is the only physical finding in children with early childhood hyperkalemia. Hypertension is absent.
• Multiple target organ defects pseudohypoaldosteronism type I
• • The clinical picture is similar to patients with renal PHA-I, but symptoms may be more severe.
  • These patients may have recurrent episodes of dyspnea, cyanosis, fever, tachypnea, and intercostal retractions. Crackles may be auscultated over pulmonary fields.
• Pseudohypoaldosteronism type II
• • These patients, in contrast to patients with PHA-I, usually are volume expanded and hypertensive.
  • Hypertension is limited to adolescent or adult individuals and is the cardinal feature of adults with this syndrome.
  • Short stature is the cardinal feature in children, who are usually asymptomatic, and hypertension during adolescence or young adulthood usually has been the initial sign. For this reason, this syndrome is often called adolescent hyperkalemic syndrome.
  • Children with the chloride shunt syndrome have blood pressure within the reference range (Spitzer-Weinstein syndrome). A finding of 2 affected normotensive children (aged 4 and 11 y) and an older affected sibling (aged 21 y) in the same family suggests that Gordon syndrome and Spitzer-Weinstein syndrome are the same genetic entity. In fact, hypertension may be absent in adults and present in children.
  • Muscular weakness and periodic paralysis has been described in children with Gordon syndrome.

Causes

• Renal pseudohypoaldosteronism type I
• • The renal limited form 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 (MLR).
  • Even though many cases appear to be sporadic, elevated plasma aldosterone levels were found in some of the apparently asymptomatic parents.
• Multiple target organ defects pseudohypoaldosteronism type I
• • MTOD PHA-I is most likely inherited as an autosomal recessive disorder and has a high incidence of consanguinity among parents. The degree of penetrance is variable. Most studied kindreds have had a loss-of-function mutation in one of the subunits of the epithelial Na⁺ channel (ENaC).
  • Sporadic cases have also been suggested.
• Pseudohypoaldosteronism type II
• • An autosomal dominant form of inheritance has been suggested. Analysis of 8 affected families showed linkage to chromosome arms 1q31-42 and 17p11-q21. The genetic defect has not yet been characterized.
  • Sporadic instances also occur.
• Secondary pseudohypoaldosteronism
• • 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, neonatal medullary necrosis, and in some infants after unilateral renal vein thrombosis. Cases have also been reported in patients with multiple myeloma and renal transplantation. Tubular injury is presumed responsible for the diminished response to aldosterone in these disorders.
  • Drugs can impair renin or aldosterone synthesis or cause mineralocorticoid resistance. Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause hyperkalemia and metabolic acidosis as a result of inhibition of renin release. Beta-adrenergic antagonists alter potassium distribution and interfere with the renin-aldosterone system, resulting in hyperkalemia. Heparin inhibits aldosterone synthetase and causes hyperkalemia because of impaired aldosterone synthesis. Angiotensin-converting enzyme (ACE) inhibitors can result in hypoaldosteronism with hyperkalemic acidosis by inhibiting angiotensin II formation. The potassium-sparing diuretics impair distal potassium secretion; spironolactone antagonizes the effects of aldosterone, amiloride, and triamterene by directly closing the sodium channel in the luminal membrane of the collecting tubular cell. Cyclosporine inhibits basolateral sodium- and potassium-activated adenosine triphosphatase, thereby decreasing intracellular potassium. These drugs shouldbeusedwithcaution in patients with tubulointerstitial nephritis, mild-to-moderate renal function impairment, and diabetic nephropathy because of the risk of hyperkalemia. Drugs that can cause PHA are as follows:
    • Cyclooxygenase inhibitors (NSAIDs)
    • Beta-adrenergic antagonists
    • Heparin
    • ACE inhibitors
    • Potassium-sparing diuretics (ie, amiloride, triamterene, spironolactone)
    • Trimethoprim
    • Cyclosporine A

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Addison disease
Chronic renal failure
Isolated hypoaldosteronism
Nephronophthisis
Obstructive uropathy
Salt-wasting nephropathies

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Renal pseudohypoaldosteronism type I
• • The clinical characteristics of PHA-I are those of hypoaldosteronism, ie, hyponatremia, hyperkalemic metabolic acidosis, hyperreninemia, and renal salt wasting.
  • Diagnosis is made by demonstrating inappropriately high urinary sodium losses in the presence of hyponatremia, decreased urinary potassium excretion, normal GFR, normal adrenal function, and increased levels of aldosterone and renin.
  • Hyponatremia is usually present but may be masked by hemoconcentration.
  • Hyperkalemia and metabolic acidosis are typically present despite a normal GFR. Plasma potassium concentration varies from moderately to greatly increased values.
  • Occasionally, hypercalciuria and nephrocalcinosis have also been described.
  • The only biochemical abnormality in patients with early childhood hyperkalemia is the presence of hyperkalemia and hyperchloremic (nonanion gap) metabolic acidosis. Azotemia and sodium chloride wasting notably are absent.
• Multiple target organ defects pseudohypoaldosteronism type I
• • Urinary salt wastage, as in renal PHA-I, is characteristic of MTOD PHA-I.
  • Salt wastage can occur from the salivary glands, sweat glands, and colon.
  • A variant of MTOD PHA-I has been described in the literature with salt wastage limited to sweat and salivary glands without associated renal salt wasting.
• Pseudohypoaldosteronism type II
• • Hyperkalemia, hyperchloremic metabolic acidosis, and normal GFR are present with low aldosterone and renin levels.
  • 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) typically are hyperkalemic at presentation. Potassium excretion responds to sodium sulfate infusion but not to sodium chloride infusion.
  • Serum bicarbonate concentration typically is low, but this is a more variable finding in children and is observed in only one half of cases.
  • Hypercalciuria has usually been overlooked as a biochemical feature of this disorder, although its presence has been recognized occasionally.
  • Nephrolithiasis is unusual.
• Secondary pseudohypoaldosteronism: The clinical presentation in children is that of renal tubular resistance to aldosterone, ie, hyponatremia, hyperkalemia, and metabolic acidosis.

Imaging Studies

• Chest radiography may show 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.

Other Tests

• Renal pseudohypoaldosteronism type I
• • Overall renal function is normal.
  • Plasma aldosterone concentration, urinary aldosterone excretion, and PRA are usually elevated.
  • 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.
  • Sweat and salivary sodium and chloride determinations characteristically are normal.
  • Children with the early childhood hyperkalemia variant of renal PHA-I have consistently normal or elevated PRA and 24-hour urinary aldosterone excretion. Functional evaluation reveals a normal ability to acidify the urine, low ammonium and potassium excretion, and a mild defect in bicarbonate reabsorption (ie, functional markers of type IV RTA). Renal bicarbonate wasting can be observed with high-dose alkali therapy, but, in contrast to type II proximal RTA, associated kaluria is not observed. In contrast to type I and II RTA, this subtype has no hypercalciuria but, rather, a relative hyperreabsorption of calcium and a high urinary citrate excretion; thus, nephrocalcinosis is absent.
• Multiple target organ defects pseudohypoaldosteronism type I
• • 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
• • Renin and aldosterone levels are low to normal; renin and aldosterone levels increase if volume expansion is corrected by diuretics or salt restriction. Even though aldosterone levels may be within the reference range in some cases, they are probably not elevated appropriately for the degree of hyperkalemia.
  • Renal concentration and dilution are normal.
  • Fractional excretion of bicarbonate (FE HCO₃) is 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.
• Secondary pseudohypoaldosteronism: Plasma aldosterone concentration is elevated, and fractional sodium excretion may be inappropriately high.

Histologic Findings

Renal biopsy findings in PHA-I are usually normal; however, hypertrophy of the juxtaglomerular apparatus has been reported occasionally.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Patients with hypovolemia and shock should receive fluid resuscitation with isotonic sodium chloride solution at 20 mL/kg over 30-60 minutes. Fluid bolus may be repeated until signs of improved perfusion to vital organs are observed. Patients with severe hyperkalemia should receive intravenous calcium gluconate 10% (0.5-1 mL/kg) to protect the heart muscle and sodium bicarbonate to shift potassium intracellularly until cation exchange resins start to lower serum potassium. The use of glucose (0.5-1 g/kg) and insulin (0.1 U/kg) intravenously over 30 minutes should also be considered in severe hyperkalemia.

• Renal PHA-I: Patients with renal PHA-I have a characteristic lack of improvement despite administration of large doses of mineralocorticoids. Therapy consists of fluid and sodium supplementation, with requirements being higher early in infancy and tending to diminish over time. Large doses may be necessary to correct serum electrolyte abnormalities. Sodium chloride supplementation is followed by significant clinical improvement and correction of electrolyte abnormalities. Expansion of ECF increases the renal tubular flow and sodium chloride delivery to the distal nephron, thus creating a favorable gradient for secretion of potassium despite the lack of mineralocorticoid action.
• MTOD PHA-I: Although administration of exogenous mineralocorticoids is ineffective in correcting the abnormalities in this disorder, ingestion of a high-sodium and low-potassium diet generally is effective in preventing volume depletion and in partially reducing, but not completely correcting, the hyperkalemia. Patients may require oxygen for episodes of dyspnea and cyanosis associated with lower respiratory tract infections.
• PHA-II: Restriction of dietary sodium in some patients has resulted in normalization of blood pressure, plasma potassium, aldosterone, renin, and urinary calcium levels. However, correction of acidosis with bicarbonate does not correct the hyperkalemia.

Surgical Care

No surgical management is needed in most cases.

Consultations

• Endocrinologist
• Nephrologist

Diet

• Renal PHA-I: Sodium chloride supplementation during infancy can reverse hyponatremia and hyperkalemia, improve symptoms, and permit improved growth. Ingestion of a high-sodium (10-15 mEq/kg/d) and low-potassium (0.6 mEq/kg/d) diet generally is effective in preventing both volume depletion and hyperkalemia. After infancy, reduction or discontinuation of sodium chloride supplementation is possible when patients develop an appetite for salt and are asymptomatic while eating a normal diet. Symptoms may recur with salt restriction in older children and adults.
• MTOD PHA-I: Dietary sodium supplementation (10-15 mEq/kg/d) and a low-potassium (0.6 mEq/kg/d) diet are recommended. Patients have a poor response to sodium chloride supplementation alone.
• PHA-II: Dietary sodium and potassium restriction may correct the hyperkalemia and acidosis.

Activity

No restrictions are necessary once adequate replacement therapy is instituted.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Alkalinizing agents

Used for correcting acidosis in children with early childhood hyperkalemia during the first few years of life. Correction of acidosis in PHA-II does not correct the hyperkalemia.

Drug Category: Potassium-binding resins

May be used in patients with pseudohypoaldosteronism to successfully control hyperkalemia.

Drug Category: Prostaglandin inhibitors

Inhibit the production of prostaglandin by blocking the action of cyclooxygenase (also called prostaglandin synthetase).

Drug Category: Diuretic agents

Used to increase the rate of urine formation and output, thus eradicating fluid overload and controlling hypertension.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients should be closely monitored; they require frequent reevaluations.
• No potassium should be contained in intravenous fluids.
• Once fluid and sodium deficits are corrected, administer maintenance fluids at 120-160 mL/kg/d and sodium supplementation at 20-40 mEq/kg/d.
• If differentiating adrenal insufficiency from PHA-I is impossible at presentation, treat patients with glucocorticoids once electrolytes, blood sugar, cortisol, and adrenocorticotropic hormone (ACTH) concentrations are obtained until the diagnosis of PHA-I is confirmed.
• Monitor weight and fluid intake and output every 12 hours and recalculate infusion rate if fluid balance becomes negative.
• Monitor blood pressure and serum and urine electrolytes closely, watching for normalization of blood pressure as well as of serum electrolytes.
• Electrocardiographic monitoring is warranted.

Further Outpatient Care

• Maintain fluids at 120-160 mL/kg/d.
• A high-sodium and low-potassium diet should be followed.
• Sodium supplementation at 20-40 mEq/kg/d until patients are aged 1-2 years may be provided as 20% NaCl (at 3 mEq/mL) every 6 hours and added to patients' feedings.
• Monitor serum electrolytes, blood pressure, weight, and height closely.
• Watch for dehydration and hypovolemia.
• Patients with MTOD PHA-I should be observed for episodes of respiratory distress.

In/Out Patient Meds

• Potassium-binding resins
• Prostaglandin inhibitors
• Alkalinizing agents
• Hydrochlorothiazide in PHA-II

Deterrence/Prevention

• The rare occasions when unintentional salt or fluid restriction is most likely to occur include hospitalization, surgery, major accidental trauma, and life-threatening emergency. Thus, wearing lifelong medical identification (such as a MedicAlert necklace or bracelet) is imperative to provide another way to alert healthcare professionals who are unfamiliar with the patient's rare medical condition.

Complications

• Severe hyperkalemia and even death may occur as a result of cardiac arrhythmia.
• Nephrocalcinosis may occur in PHA-I.
• Nephrolithiasis may occur in PHA-II.
• Frequent episodes of dehydration may occur.

Prognosis

• Renal pseudohypoaldosteronism type I
• • 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. 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 possess a lifetime higher 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.
• MTOD PHA-I: Salt wasting is more severe in this form of PHA. MTOD PHA-I has a poorer outcome than the renal form, and death may ensue during the neonatal period. Improvement with advancing age does not occur as in the isolated renal form. Therapy must be maintained throughout childhood and probably throughout life.
• PHA-II: Patients with PHA-II require lifelong therapy.
• Secondary pseudohypoaldosteronism
• • 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 following discontinuation of drugs that can impair renin or aldosterone synthesis or cause mineralocorticoid resistance.

Patient Education

• Watch for dehydration.
• Avoid foods high in potassium content.
• Genetic counseling should be provided by a qualified professional.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• ACE inhibitors should not be used in patients with PHA-II because these drugs may aggravate hyperkalemia, which may be life threatening.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Abramson O, Zmora E, Mazor M, Shinwell ES. Pseudohypoaldosteronism in a preterm infant: intrauterine presentation as hydramnios. J Pediatr. Jan 1992;120(1):129-32. [Medline].
• Alon U, Kodroff MB, Broecker BH, et al. Renal tubular acidosis type 4 in neonatal unilateral kidney diseases. J Pediatr. Jun 1984;104(6):855-60. [Medline].
• Anand SK, Froberg L, Northway JD, et al. Pseudohypoaldosteronism due to sweat gland dysfunction. Pediatr Res. Jul 1976;10(7):677-82. [Medline].
• Arai K, Tsigos C, Suzuki Y, et al. Physiological and molecular aspects of mineralocorticoid receptor action in pseudohypoaldosteronism: a responsiveness test and therapy. J Clin Endocrinol Metab. Oct 1994;79(4):1019-23. [Medline].
• Arai K, Tsigos C, Suzuki Y, et al. No apparent mineralocorticoid receptor defect in a series of sporadic cases of pseudohypoaldosteronism. J Clin Endocrinol Metab. Mar 1995;80(3):814-7. [Medline].
• Armanini D, Kuhnle U, Strasser T, et al. Aldosterone-receptor deficiency in pseudohypoaldosteronism. N Engl J Med. Nov 7 1985;313(19):1178-81. [Medline].
• Armanini D, Strasser T, Weber PC. Characterization of aldosterone binding sites in circulating human mononuclear leukocytes. Am J Physiol. Mar 1985;248(3 Pt 1):E388-90. [Medline].
• Ballauff A, Wendel U, Kupke I, Kuhnle U. A partial form of hypoaldosteronism type I without sodium wasting. J Pediatr Endocrinol. 1994;7:57-60. [Medline].
• Bierich JR, Schmidt U. Tubular Na, K-ATPase deficiency, the cause of the congenital renal salt-losing syndrome. Eur J Pediatr. Jan 2 1976;121(2):81-7. [Medline].
• Bistritzer T, Evans S, Cotariu D, et al. Reduced Na+, K(+)-ATPase activity in patients with pseudohypoaldosteronism. Pediatr Res. Mar 1994;35(3):372-5. [Medline].
• Blachar Y, Kaplan BS, Griffel B, Levin S. Pseudohypoaldosteronism. Clin Nephrol. Jun 1979;11(6):281-8. [Medline].
• Brautbar N, Levi J, Rosler A, et al. Familial hyperkalemia, hypertension, and hyporeninemia with normal aldosterone levels. A tubular defect in potassium handling. Arch Intern Med. Apr 1978;138(4):607-10. [Medline].
• Chang S, Muller J, Rosler A. Molecular analysis of epithelial sodium channel subunits in pseudohypoaldosteronism type 1. J Am Soc Nephrol. 1996;7:1611.
• Chang SS, Grunder S, Hanukoglu A, et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. Mar 1996;12(3):248-53. [Medline].
• Cheek DB, Perry JA. A salt wasting syndrome in infancy. Arch Dis Child. 1958;33:252-256.
• Chitayat D, Spirer Z, Ayalon D, Golander A. Pseudohypoaldosteronism in a female infant and her family: diversity of clinical expression and mode of inheritance. Acta Paediatr Scand. Jul 1985;74(4):619-22. [Medline].
• Choate KA, Kahle KT, Wilson FH, et al. WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia. Proc Natl Acad Sci USA. 2003;100:663-668. [Medline]. [Full Text].
• Claris Appiani A, Marra G, Tirelli SA, et al. Early childhood hyperkalemia: variety of pseudohypoaldosteronism. Acta Paediatr Scand. Nov 1986;75(6):970-4. [Medline].
• Cogan MC, Arieff AI. Sodium wasting, acidosis and hyperkalemia induced by methicillin interstitial nephritis. Evidence for selective distal tubular dysfunction. Am J Med. Mar 1978;64(3):500-7. [Medline].
• Cugini P, Natoli G, Gerlini G, et al. Erythrocyte transmembrane Na and K fluxes in pseudohypoaldosteronism. Biochem Med Metab Biol. Dec 1992;48(3):241-54. [Medline].
• Daughaday WH, Rendleman D. Severe symptomatic hyperkalemia in an adrenalectomized woman due to enhanced mineralocorticoid requirement. Ann Intern Med. Jun 1967;66(6):1197-203. [Medline].
• DuBose TD Jr. Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int. Feb 1997;51(2):591-602. [Medline].
• Farfel Z, Iaina A, Levi J, Gafni J. Proximal renal tubular acidosis: association with familial normaldosteronemic hyperpotassemia and hypertension. Arch Intern Med. Dec 1978;138(12):1837-40. [Medline].
• Fuller PJ, Lim-Tio S. Aldosterone action, sodium channels and inherited disease. J Endocrinol. Mar 1996;148(3):387-90. [Medline].
• Geller DS, Rodriguez-Soriano J, Vallo Boado A, et al. Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I. Nat Genet. Jul 1998;19(3):279-81. [Medline].
• Geller DS, Zhang J, Zennaro MC, et al. Autosomal dominant pseudohypoaldosteronism type 1: mechanisms, evidence for neonatal lethality, and phenotypic expression in adults. J Am Soc Nephrol. 2006;17:1429-1436. [Medline].
• Gereda JE, Bonilla-Felix M, Kalil B, Dewitt SJ. Neonatal presentation of Gordon syndrome. J Pediatr. Oct 1996;129(4):615-7. [Medline].
• Gordon R, Geddes R, Pawsey C, O''Halloran M. Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction. Australas Ann Med. Nov 1970;19(4):287-94. [Medline].
• Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension. Feb 1986;8(2):93-102. [Medline].
• Greenberg D, Abramson O, Phillip M. Fetal pseudohypoaldosteronism: another cause of hydramnios. Acta Paediatr. May 1995;84(5):582-4. [Medline].
• Hanukoglu A, Bistritzer T, Rakover Y, Mandelberg A. Pseudohypoaldosteronism with increased sweat and saliva electrolyte values and frequent lower respiratory tract infections mimicking cystic fibrosis. J Pediatr. Nov 1994;125(5 Pt 1):752-5. [Medline].
• Hanukoglu A, Fried D, Gotlieb A. Inheritance of pseudohypoaldosteronism. Lancet. Jun 24 1978;1(8078):1359. [Medline].
• Hanukoglu A. Type I pseudohypoaldosteronism includes two clinically and genetically distinct entities with either renal or multiple target organ defects. J Clin Endocrinol Metab. Nov 1991;73(5):936-44. [Medline].
• Hogg R, Marks J, Marver D, Frolich J. Long-term observation in a patient with pseudohypoaldosteronism. Pediatr Nephrol. 1991;5:205-210. [Medline].
• Honour JW, Dillon MJ, Shackleton CH. Analysis of steroids in urine for differentiation of pseudohypoaldosteronism and aldosterone biosynthetic defect. J Clin Endocrinol Metab. Feb 1982;54(2):325-31. [Medline].
• Hummler E, Barker P, Gatzy J, et al. Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice. Nat Genet. Mar 1996;12(3):325-8. [Medline].
• Kahle KT, Wilson FH, Leng Q, et al. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat Genet. Dec 2003;35(4):372-6. [Medline].
• Klemm SA, Gordon RD, Tunny TJ, Finn WL. Biochemical correction in the syndrome of hypertension and hyperkalaemia by severe dietary salt restriction suggests renin-aldosterone suppression critical in pathophysiology. Clin Exp Pharmacol Physiol. Mar 1990;17(3):191-5. [Medline].
• Komesaroff PA, Verity K, Fuller PJ. Pseudohypoaldosteronism: molecular characterization of the mineralocorticoid receptor. J Clin Endocrinol Metab. Jul 1994;79(1):27-31. [Medline].
• Kotchen TA, Welch WJ, Lorenz JN, Ott CE. Renal tubular chloride and renin release. J Lab Clin Med. Nov 1987;110(5):533-40. [Medline].
• Kuhnle U, Nielsen MD, Tietze HU, et al. Pseudohypoaldosteronism in eight families: different forms of inheritance are evidence for various genetic defects. J Clin Endocrinol Metab. Mar 1990;70(3):638-41. [Medline].
• Kuhnle U, Keller U, Armanini D. Immunofluorescence of mineralocorticoid receptors in peripheral lymphocytes: presence of receptor-like activity in patients with the autosomal dominant form of pseudohypoaldosteronism, and its absence in the recessive form. J Steroid Biochem Mol Biol. Dec 1994;51(5-6):267-73. [Medline].
• Kuhnle U, Hinkel GK, Akkurt HI, Krozowski Z. Familial pseudohypoaldosteronism: a review on the heterogeneity of the syndrome. Steroids. Jan 1995;60(1):157-60. [Medline].
• Landau D. Potassium handling in health and disease: lessons from inherited tubulopathies. Pediatr Endocrinol Rev. 2004;2:203-208. [Medline].
• Levin TL, Abramson SJ, Burbige KA, et al. Salt losing nephropathy simulating congenital adrenal hyperplasia in infants with obstructive uropathy and/or vesicoureteral reflux--value of ultrasonography in diagnosis. Pediatr Radiol. 1991;21(6):413-5. [Medline].
• Limal JM, Rappaport R, Dechaux M, Morin C. Familial dominant pseudohypoaldosteronism. Lancet. Jan 7 1978;1(8054):51. [Medline].
• Luke RG, Allison ME, Davidson JF, Duguid WP. Hyperkalemia and renal tubular acidosis due to renal amyloidosis. Ann Intern Med. Jun 1969;70(6):1211-7. [Medline].
• Mansfield TA, Simon DB, Farfel Z, et al. Multilocus linkage of familial hyperkalaemia and hypertension, pseudohypoaldosteronism type II, to chromosomes 1q31-42 and 17p11-q21. Nat Genet. Jun 1997;16(2):202-5. [Medline].
• Marra G, Goj V, Appiani AC, et al. Persistent tubular resistance to aldosterone in infants with congenital hydronephrosis corrected neonatally. J Pediatr. Jun 1987;110(6):868-72. [Medline].
• Mastrandrea LD, Martin DJ, Springate JE. Clinical and biochemical similarities between reflux/obstructive uropathy and salt-wasting congenital adrenal hyperplasia. Clin Pediatr (Phila). 2005;44:809-812. [Medline].
• Matthew PM, Manasra KB, Hamdan JA. Indomethacin and cation-exchange resin in the management of pseudohypoaldosteronism. Clin Pediatr (Phila). 1993;32:58-60. [Medline].
• McSherry E. Renal tubular acidosis in childhood. Kidney Int. Dec 1981;20(6):799-809. [Medline].
• Melzi ML, Guez S, Sersale G, et al. Acute pyelonephritis as a cause of hyponatremia/hyperkalemia in young infants with urinary tract malformations. Pediatr Infect Dis J. Jan 1995;14(1):56-9. [Medline].
• Muhammad S, Mamish ZM, Tucci JR. Type II pseudohypoaldosteronism. Report of a case and review of the literature. J Endocrinol Invest. Jun 1994;17(6):453-7. [Medline].
• Oberfield SE, Levine LS, Carey RM, et al. Pseudohypoaldosteronism: multiple target organ unresponsiveness to mineralocorticoid hormones. J Clin Endocrinol Metab. Feb 1979;48(2):228-34. [Medline].
• Paver WKA, Pauline GJ. Hypertension and hyperpotassemia without renal disease in a young male. Med J Austr. 1964;2:305-306.
• Perimenis P, Wemeau JL, Vantyghem MC. Hypercalciuria [French]. Ann Endocrinol (Paris). 2005;66:532-539. [Medline].
• Peters TA, Levtchenko E, Cremers CW, et al. No evidence of hearing loss in pseudohypoaldosteronism type 1 patients. Acta Otolaryngol. 2006;126:237-239. [Medline].
• Proesmans W, Muaka B, Corbeel L, Eeckels R. Pseudohypoaldosteronism, a proximal tubular sodium wasting disease. J Pediatr. Apr 1978;92(4):678-9. [Medline].
• Rodriguez-Soriano J, Vallo A, Oliveros R, Castillo G. Transient pseudohypoaldosteronism secondary to obstructive uropathy in infancy. J Pediatr. 1983;103:375-380. [Medline].
• Rodriguez-Soriano J, Vallo A, Dominguez MJ. "Chloride-shunt" syndrome: an overlooked cause of renal hypercalciuria. Pediatr Nephrol. Apr 1989;3(2):113-21. [Medline].
• Roessler A. The natural history of salt-wasting disorders of adrenal and renal origin. J Clin Endocrinol Metab. 1984;59:689-700. [Medline].
• Sanderson IR, Carter EP, Dillon MJ, et al. Familial salivary gland insensitivity to aldosterone: a variant of pseudohypoaldosteronism. Horm Res. 1989;32(4):145-7. [Medline].
• Sanjad SA, Keenan BS, Hill LL. Renal hypoprostaglandism, hypertension, and type IV renal tubular acidosis reversed by furosemide. Ann Intern Med. Nov 1983;99(5):624-7. [Medline].
• Savage MO, Jefferson IG, Dillon MJ, et al. Pseudohypoaldosteronism: severe salt wasting in infancy caused by generalized mineralocorticoid unresponsiveness. J Pediatr. Aug 1982;101(2):239-42. [Medline].
• Schambelan M, Sebastian A, Rector FC Jr. Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): role of increased renal chloride reabsorption. Kidney Int. May 1981;19(5):716-27. [Medline].
• Schindler AM, Bergman GE. Prospective diagnosis of pseudohypoaldosteronism. Pediatrics. Sep 1986;78(3):516-8. [Medline].
• Semmekrot B, Monnens L, Theelen BG, et al. The syndrome of hypertension and hyperkalaemia with normal glomerular function (Gordon''s syndrome). A pathophysiological study. Pediatr Nephrol. Jul 1987;1(3):473-8. [Medline].
• Shalev H, Ohali M, Abramson O. Nephrocalcinosis in pseudohypoaldosteronism and the effect of indomethacin therapy. J Pediatr. Aug 1994;125(2):246-8. [Medline].
• Sheridan MB, Fong P, Groman JD, et al. Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome. Hum Mol Genet. 2005;14:3493-3498. [Medline].
• Shimkets RA, Warnock DG, Bositis CM, et al. Liddle''s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. Nov 4 1994;79(3):407-14. [Medline].
• Shoker A, Morris G, Skomro R, Laxdal V. Pseudohypoaldosteronism with normal blood pressure. Clin Nephrol. Aug 1996;46(2):105-11. [Medline].
• Spitzer A, Edelmann CM Jr, Goldberg LD, Henneman PH. Short stature, hyperkalemia and acidosis: A defect in renal transport of potassium. Kidney Int. Apr 1973;3(4):251-7. [Medline].
• Stone RC, Vale P, Rosa FC. Effect of hydrochlorothiazide in pseudohypoaldosteronism with hypercalciuria and severe hyperkalemia. Pediatr Nephrol. Aug 1996;10(4):501-3. [Medline].
• Tobias JD, Brock JW III, Lynch A. Pseudohypoaldosteronism following operative correction of unilateral obstructive nephropathy. Clin Pediatr (Phila). Jun 1995;34(6):327-30. [Medline].
• Valimaki M, Pelkonen R, Tikkanem I, Fyhriquist F. Normal renin sensitivity to atril natriuretic peptide in Gordon''s syndrome. Pediatr Nephrol. 1992;6:44-45. [Medline].
• Weinstein SF, Allan DM, Mendoza SA. Hyperkalemia, acidosis, and short stature associated with a defect in renal potassium excretion. J Pediatr. Sep 1974;85(3):355-8. [Medline].
• Wilson FH, Kahle KT, Sabath E, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003;100:680-684. [Medline]. [Full Text].
• Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest. 2003;111:1039-1045. [Medline]. [Full Text].
• Zennaro MC, Borensztein P, Jeunemaitre X, et al. No alteration in the primary structure of the mineralocorticoid receptor in a family with pseudohypoaldosteronism. J Clin Endocrinol Metab. Jul 1994;79(1):32-8. [Medline].
• Zennaro MC, Borensztein P, Soubrier F, et al. The enigma of pseudohypoaldosteronism. Steroids. Feb 1994;59(2):96-9. [Medline].

Article Last Updated: Jul 27, 2006