Pseudohypoaldosteronism 

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

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.

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.

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.

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.

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.

 

Presentation

History

The clinical expression of renal pseudohypoaldosteronism (PHA) type I (PHA-I) varies widely, even among members of the same family who have the same gene defect. Affected children may have severe symptoms in early infancy (the first 2 weeks 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 is usually the only symptom in those with early childhood hyperkalemia.

In multiple target organ defects (MTOD) PHA-I, salt-wasting episodes develop soon after birth and usually are more severe than in renal PHA-I. Individuals with MTOD PHA-I 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.

With respect to PHA type II (PHA-II), a 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 Examination

In symptomatic individuals with renal PHA-I, failure to thrive, weight loss, vomiting, and dehydration may appear as early as the first 2 weeks of life. Affected individuals experience 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. Affected individuals have a marked tendency to develop low blood volume and hypotension, just like individuals with true hypoaldosteronism.

In children with the early childhood hyperkalemia variant of renal PHA-I, failure to thrive or growth retardation is the only physical finding. Hypertension is absent.

In MTOD PHA-I, the clinical picture is similar to that seen in renal PHA-I, but symptoms may be more severe. These individuals may have recurrent episodes of dyspnea, cyanosis, fever, tachypnea, and intercostal retractions. Crackles may be auscultated over pulmonary fields.

Individuals with PHA-II, in contrast to those with PHA-I, are usually 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. Because hypertension during adolescence or young adulthood is usually the initial sign, 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 years) and an older affected sibling (aged 21 years) 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 have been described in children with Gordon syndrome.

A case study by Korkut et al described dermal findings in a neonatal patient with pseudohypoaldosteronism. Due to the loss of salt, miliaria rubra as well as unusual sebum buildup in the eye as a result of a malfunction in the sodium channels were noted as typical dermal findings.[13]

Complications

Potential complications of PHA include the following:

  • Severe hyperkalemia and even death as a result of cardiac arrhythmia

  • Nephrocalcinosis (in PHA-I)

  • Nephrolithiasis (in PHA-II)

  • Frequent episodes of dehydration

 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Addison disease

  • Chronic renal failure

  • Isolated hypoaldosteronism

  • Nephronophthisis

  • Obstructive uropathy[14]

  • Salt-wasting nephropathies

Differential Diagnoses

 

Workup

Laboratory Studies

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 characteristically normal.

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[15] 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.

Secondary pseudohypoaldosteronism

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.

Other Tests

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.

 

Treatment

Initial Supportive Measures

Patients with pseudohypoaldosteronism (PHA) who are experiencing hypovolemia and shock should receive fluid resuscitation with isotonic sodium chloride solution at 20 mL/kg over 30-60 minutes. Fluid boluses may be repeated until signs of improved perfusion to vital organs are observed.

Patients with severe hyperkalemia should receive intravenous (IV) 10% calcium gluconate 0.5-1 mL/kg to protect the heart muscle and sodium bicarbonate to shift potassium intracellularly until cation exchange resins start to lower the serum potassium level. IV administration of glucose 0.5-1 g/kg and insulin 0.1 U/kg over 30 minutes should also be considered in severe hyperkalemia.

Consultations should include a pediatric endocrinologist and a pediatric nephrologist.

Correction of Hyperkalemia and Acidosis

Agents that may be used in the management of PHA include the following (see Medications):

  • Potassium-binding resins

  • Prostaglandin inhibitors

  • Alkalizing agents

  • Hydrochlorothiazide (in PHA type II [PHA-II])

Angiotensin-converting enzyme (ACE) inhibitors should not be used in patients with PHA-II, because they can aggravate hyperkalemia, which may be life threatening.

No surgical management is needed in most cases. Consultations with an endocrinologist and a nephrologist are appropriate. Genetic counseling should be provided to the patient by a qualified professional.

Renal pseudohypoaldosteronism type I

Patients with renal PHA type I (PHA-I) exhibit 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 extracellular fluid (ECF) increases renal tubular flow and sodium chloride delivery to the distal nephron, thereby creating a favorable gradient for secretion of potassium despite the lack of mineralocorticoid action.

Multiple target organ defects pseudohypoaldosteronism type I

Although administration of exogenous mineralocorticoids is ineffective in correcting the abnormalities in multiple target organ defects (MTOD) PHA-I, ingestion of a high-sodium and low-potassium diet is generally effective in preventing volume depletion and in partially reducing, though not completely correcting, the hyperkalemia. Patients may require oxygen for episodes of dyspnea and cyanosis associated with lower respiratory tract infections.

Pseudohypoaldosteronism type II

In some patients with PHA-II, restriction of dietary sodium has resulted in normalization of blood pressure and of plasma potassium, plasma aldosterone, plasma renin, and urinary calcium levels. However, correction of acidosis with bicarbonate administration does not correct the hyperkalemia.

Diet and Activity

In patients with 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/day) and low-potassium (0.6 mEq/kg/day) diet is generally effective in preventing both volume depletion and hyperkalemia.

After infancy, reduction or discontinuance 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.

For patients with MTOD PHA-I, dietary sodium supplementation (10-15 mEq/kg/day) and a low-potassium diet (0.6 mEq/kg/day) are recommended. Patients typically respond poorly to sodium chloride supplementation alone.

In patients with PHA-II, dietary sodium supplementation and potassium restriction may correct the hyperkalemia and acidosis.

No activity restrictions are necessary once adequate replacement therapy is instituted.

Prevention

The rare occasions on which 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 (eg, a MedicAlert necklace or bracelet) is imperative as another means of alerting healthcare professionals who may be unfamiliar with the patient’s rare medical condition.

Long-Term Monitoring

Ensure that the IV fluids the patient is receiving contain no potassium. Once fluid and sodium deficits are corrected, administer maintenance fluids at 120-160 mL/kg/day, and provide sodium supplementation at 20-40 mEq/kg/day. 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.

While in the hospital, patients should be closely monitored and frequently reevaluated. Monitor weight and fluid intake and output every 12 hours, and recalculate the 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 electrolyte levels. Electrocardiographic (ECG) monitoring is warranted.

In the outpatient setting, maintain fluids at 120-160 mL/kg/day. Ensure that the patient follows a high-sodium and low-potassium diet. Sodium supplementation at 20-40 mEq/kg/day until patients are aged 1-2 years may be provided as 20% sodium chloride (at 3 mEq/mL) every 6 hours and added to patients’ feedings.

Closely monitor serum electrolytes, blood pressure, weight, and height. Watch for dehydration and hypovolemia. Observe patients with MTOD PHA-I for episodes of respiratory distress.

 

Medication

Medication Summary

Drugs used in the management of pseudohypoaldosteronism (PHA) include alkalizing agents, potassium-binding resins, prostaglandin inhibitors, and diuretics.

Alkalinizing agents

Class Summary

These agents are used for correcting acidosis in children with early childhood hyperkalemia during the first few years of life. Correction of acidosis in pseudohypoaldosteronism type II (PHA-II) does not correct the hyperkalemia.

Sodium bicarbonate (Neut, Brioschi)

Sodium bicarbonate is preferred for alkali therapy because it is inexpensive and easy to prepare and does not have to be metabolized by the liver. Unfortunately, sodium bicarbonate is commercially available for oral use only in 325-mg (ie, 5-grain) and 650-mg (ie, 10-grain) tablets, which provide 4 mEq and 8 mEq per tablet, respectively. These tabs can be crushed and added to food or diluted in water to yield a bicarbonate concentration of 1 mEq/mL.

An alternative is to mix an 8-oz box of baking soda in 2.88 L of distilled water to produce a concentration of 1 mEq/mL. It is also feasible to administer an appropriate concentration of the intravenous (IV) product orally.

Citric acid and sodium citrate (Bicitra, Oracit)

Citric acid and sodium citrate are systemic alkalinizing agents that have been used to correct the acidosis in PHA; however, they are metabolized by the liver to bicarbonate. Bicitra is extensively used rather than Shohl solution because it does not require mixing by the pharmacist. It provides 1 mEq of sodium bicarbonate per milliliter. Potassium citrate solutions such as Polycitra and Polycitra-K have no use in PHA and should be avoided.

Antidotes, Other

Class Summary

Potassium-binding resins may be used to control hyperkalemia in patients with PHA.

Sodium polystyrene sulfonate (Kayexalate, Kalexate, Kionex, SPS)

Sodium polystyrene sulfonate may be required for control of hyperkalemia in patients with multiple target organ defects (MTOD) PHA type I (PHA-I). The resin partially releases the sodium ions in the large intestine, and these are replaced mole for mole by potassium ions.

NSAIDs

Class Summary

Prostaglandin inhibitors, like NSAIDs, inhibit the production of prostaglandin by blocking the action of cyclooxygenase (also called prostaglandin synthetase).

Indomethacin (Indocin)

Indomethacin has been used in selected cases of MTOD PHA-I and is thought to decrease urinary volume and sodium excretion. Response to indomethacin varies, and some patients may not benefit. Most patients with MTOD PHA-I continue to require sodium supplementation.

Diuretics, Loop

Class Summary

Diuretics are used to increase the rate of urine formation and output, thereby eradicating fluid overload and controlling hypertension.

Furosemide (Lasix)

Furosemide is a loop diuretic that has been effective in the treatment of PHA-II.

Hydrochlorothiazide (Esidrix, HydroDIURIL, Microzide)

Thiazide diuretic that has been used occasionally to correct hyperkalemia and hypercalciuria in MTOD PHA-I; however, thiazides should be used with caution because they can exacerbate hypovolemia and salt wastage. Preferred treatment in patients with PHA-II because it can correct hyperkalemia, metabolic acidosis, hypertension, and plasma aldosterone and plasma renin levels. Unlike furosemide, it can also correct hypercalciuria. Does not result in catch-up growth in patients with PHA-II.

Diuretics, Thiazide

Class Summary

Diuretics are used to increase the rate of urine formation and output, thereby eradicating fluid overload and controlling hypertension.

In general, thiazides should be used with caution, because they can exacerbate hypovolemia and salt wastage.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide is a thiazide diuretic that has occasionally been used to correct hyperkalemia and hypercalciuria in patients with MTOD PHA-I.

Hydrochlorothiazide is the preferred treatment in patients with PHA-II because it can correct hyperkalemia, metabolic acidosis, hypertension, and plasma renin and aldosterone levels. Unlike furosemide, it can also correct hypercalciuria. It does not result in catch-up growth in patients with PHA-II.

Chlorothiazide (Diuril)

Chlorothiazide inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions.