Pseudohypoaldosteronism

Pseudohypoaldosteronism 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 ¹. Pseudohypoaldosteronism 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 pseudohypoaldosteronism was first described, it has been further subclassified into pseudohypoaldosteronism type 1 (pseudohypoaldosteronism-1), which is the classic form, and pseudohypoaldosteronism type 2 (pseudohypoaldosteronism-2), which is also referred to as Gordon syndrome or chloride shunt syndrome. Pseudohypoaldosteronism type 1 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 pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1

Pseudohypoaldosteronism type 1 is a condition characterized by problems regulating the amount of sodium in the body. Sodium regulation, which is important for blood pressure and fluid balance, primarily occurs in the kidneys. However, sodium can also be removed from the body through other tissues, such as the sweat glands and colon. Pseudohypoaldosteronism type 1 is named for its characteristic signs and symptoms, which mimic (pseudo) low levels (hypo) of a hormone called aldosterone that helps regulate sodium levels. However, people with pseudohypoaldosteronism type 1 have high levels of aldosterone.

There are two types of pseudohypoaldosteronism type 1 distinguished by their severity, the genes involved, and how they are inherited.

1. Autosomal dominant pseudohypoaldosteronism type 1 also known as renal pseudohypoaldosteronism type 1, is characterized by excessive sodium loss from the kidneys. This form of the condition is relatively mild and often improves in early childhood.
2. Autosomal recessive pseudohypoaldosteronism type 1 also known as generalized or multiple target organ defects (MTOD) pseudohypoaldosteronism type 1, is characterized by sodium loss from the kidneys and other organs, including the sweat glands, salivary glands, and colon. This type of pseudohypoaldosteronism type 1 is more severe and does not improve with age.
3. Early Childhood Hyperkalemia or Renal Tubular Acidosis type 4 subtype 5, is a variant of the renal form of pseudohypoaldosteronism type 1.

The earliest signs of both types of pseudohypoaldosteronism type 1 are usually the inability to gain weight and grow at the expected rate (failure to thrive) and dehydration, which are typically seen in infants. The characteristic features of both types of pseudohypoaldosteronism type 1 are excessive amounts of sodium released in the urine (salt wasting), which leads to low levels of sodium in the blood (hyponatremia), and high levels of potassium in the blood (hyperkalemia). Infants with pseudohypoaldosteronism type 1 can also have high levels of acid in the blood (metabolic acidosis). Hyponatremia, hyperkalemia, or metabolic acidosis can cause nonspecific symptoms such as nausea, vomiting, extreme tiredness (fatigue), and muscle weakness in infants with pseudohypoaldosteronism type 1.

Infants with autosomal recessive pseudohypoaldosteronism type 1 can have additional signs and symptoms due to the involvement of multiple organs. Affected individuals may experience episodes of abnormal heartbeat (cardiac arrhythmia) or shock because of the imbalance of salts in the body. They may also have recurrent lung infections or lesions on the skin. Although adults with autosomal recessive pseudohypoaldosteronism type 1 can have repeated episodes of salt wasting, they do not usually have other signs and symptoms of the condition.

Pseudohypoaldosteronism type 1 is a rare condition that has been estimated to affect 1 in 80,000 newborns ².

Pseudohypoaldosteronism type 1 causes

Mutations in one of four different genes involved in sodium regulation cause autosomal dominant or autosomal recessive pseudohypoaldosteronism type 1 ². Mutations in the NR3C2 gene cause autosomal dominant pseudohypoaldosteronism type 1. This gene provides instructions for making the mineralocorticoid receptor protein. Mutations in the SCNN1A, SCNN1B, or SCNN1G genes cause autosomal recessive pseudohypoaldosteronism type 1. Each of these three genes provides instructions for making one of the pieces (subunits) of a protein complex called the epithelial sodium channel (ENaC).

The mineralocorticoid receptor regulates specialized proteins in the cell membrane that control the transport of sodium or potassium into cells. In response to signals that sodium levels are low, such as the presence of the hormone aldosterone, the mineralocorticoid receptor increases the number and activity of these proteins at the cell membrane of certain kidney cells. One of these proteins is ENaC, which transports sodium into the cell; another protein simultaneously transports sodium out of the cell and potassium into the cell. These proteins help keep sodium in the body through a process called reabsorption and remove potassium from the body through a process called secretion.

Mutations in the NR3C2 gene lead to a nonfunctional or abnormally functioning mineralocorticoid receptor protein that cannot properly regulate the specialized proteins that transport sodium and potassium. As a result, sodium reabsorption and potassium secretion are both decreased, causing hyponatremia and hyperkalemia.

Mutations in the SCNN1A, SCNN1B, and SCNN1G genes result in reduced functioning or nonfunctioning ENaC channels. As in autosomal dominant pseudohypoaldosteronism type 1, the reduction or absence of ENaC function in the kidneys leads to hyponatremia and hyperkalemia. In addition, nonfunctional ENaC channels in other body systems lead to additional signs and symptoms of autosomal recessive pseudohypoaldosteronism type 1, including lung infections and skin lesions.

Pseudohypoaldosteronism type 1 inheritance pattern

Pseudohypoaldosteronism type 1 can have different inheritance patterns. When the condition is caused by mutations in the NR3C2 gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. When pseudohypoaldosteronism type 1 is caused by mutations in the SCNN1A, SCNN1B, or SCNN1G genes, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Pseudohypoaldosteronism type 2

Pseudohypoaldosteronism type 2 also called familial hyperkalemic hypertension, Gordon’s syndrome or Gordon hyperkalemia-hypertension syndrome, is caused by problems that affect regulation of the amount of sodium and potassium in the body. Sodium and potassium are important in the control of blood pressure, and their regulation occurs primarily in the kidneys.

People with pseudohypoaldosteronism type 2 have high blood pressure (hypertension) and high levels of potassium in their blood (hyperkalemia) despite having normal kidney function. The age of onset of pseudohypoaldosteronism type 2 is variable and difficult to pinpoint; some affected individuals are diagnosed in infancy or childhood, and others are diagnosed in adulthood. Hyperkalemia usually occurs first, and hypertension develops later in life. Affected individuals also have high levels of chloride (hyperchloremia) and acid (metabolic acidosis) in their blood (together, referred to as hyperchloremic metabolic acidosis). People with hyperkalemia, hyperchloremia, and metabolic acidosis can have nonspecific symptoms like nausea, vomiting, extreme tiredness (fatigue), and muscle weakness. People with pseudohypoaldosteronism type 2 may also have high levels of calcium in their urine (hypercalciuria).

Pseudohypoaldosteronism type 2 is a rare condition; however, the prevalence is unknown ².

Electrolyte and blood pressure abnormalities of pseudohypoaldosteronism type 2 in children and adults are often corrected with thiazide diuretics.

Pseudohypoaldosteronism type 2 causes

Pseudohypoaldosteronism type 2 can be caused by mutations in the WNK1, WNK4, CUL3, or KLHL3 gene. These genes play a role in the regulation of blood pressure.

The proteins produced from the WNK1 and WNK4 genes help control the amount of sodium and potassium in the body by regulating channels in the cell membrane that control the transport of sodium or potassium into and out of cells. This process primarily occurs in the kidneys. Mutations in either of these genes disrupt control of these channels, leading to abnormal levels of sodium and potassium in the body. As a result, affected individuals develop hypertension and hyperkalemia.

The proteins produced from the CUL3 gene (called cullin-3) and the KLHL3 gene help control the amount of WNK1 and WNK4 protein available. Cullin-3 and KLHL3 are two pieces of a complex, called an E3 ubiquitin ligase, that tags certain other proteins with molecules called ubiquitin. This molecule acts as a signal for the tagged protein to be broken down when it is no longer needed. E3 ubiquitin ligases containing cullin-3 and KLHL3 are able to tag the WNK1 and WNK4 proteins with ubiquitin, leading to their breakdown. Mutations in either the CUL3 or KLHL3 gene impair breakdown of the WNK4 protein. (The effect of these mutations on the WNK1 protein is unclear.) An excess of WNK4 likely disrupts control of sodium and potassium levels, resulting in hypertension and hyperkalemia.

Pseudohypoaldosteronism type 2 inheritance pattern

Pseudohypoaldosteronism type 2 is usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases caused by mutations in the WNK1, WNK4, or KLHL3 gene, an affected person inherits the mutation from one affected parent. While some cases caused by CUL3 gene mutations can be inherited from an affected parent, many result from new mutations in the gene and occur in people with no history of the disorder in their family.

Some cases caused by mutations in the KLHL3 gene are inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Pseudohypoaldosteronism causes

Renal pseudohypoaldosteronism type 1 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 pseudohypoaldosteronism type 1 is caused by heterozygous mutation in the mineralocorticoid receptor gene (NR3C2). The renal pseudohypoaldosteronism phenotype is due to either haploinsufficiency (loss of 1 of the 2 functional alleles) of the mineralocorticoid receptor or a negative dominant effect of the mutated mineralocorticoid receptor on the activity of the wild-type mineralocorticoid receptor ³. Even though many cases appear to be sporadic, elevated plasma aldosterone levels were found in some of the apparently asymptomatic parents.

MTOD pseudohypoaldosteronism type 1 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 pseudohypoaldosteronism-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 pseudohypoaldosteronism 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.

Pseudohypoaldosteronism type 2 is a genetically heterogenous group of disorders. It is grouped into types pseudohypoaldosteronism type 2 A thru E that represent various inheritance patterns and differing affected genes. Pseudohypoaldosteronism type 2A has been mapped to 1q31-q42, pseudohypoaldosteronism type 2B is caused by mutations in the WNK4 gene on 17q21, pseudohypoaldosteronism type 2C is caused by mutations in the WNK1 gene on 12p13, pseudohypoaldosteronism type 2D is caused by mutations in the KLHL3 gene on 5q31, and pseudohypoaldosteronism type 2E is caused by mutations in the CUL3 gene ⁴.

Secondary pseudohypoaldosteronism 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 pseudohypoaldosteronism 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.

Pseudohypoaldosteronism pathophysiology

Renal pseudohypoaldosteronism type 1 (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 pseudohypoaldosteronism type 1, 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) ⁵.

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 2 pseudohypoaldosteronism 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 pseudohypoaldosteronism-2B and 2C, the defect involves absent WNK1 or WNK4 kinase function in the distal nephron ⁶. 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 pseudohypoaldosteronism type 2.

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 ⁷. 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.

Pseudohypoaldosteronism symptoms

Pseudohypoaldosteronism type 1 symptoms

The clinical expression of renal pseudohypoaldosteronism type 1 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.

In symptomatic individuals with renal pseudohypoaldosteronism type 1, anorexia, 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 pseudohypoaldosteronism type 1, vomiting, failure to thrive or growth retardation is the only physical finding. Hypertension is absent.

Salt craving is observed in older children.

In multiple target organ defects (MTOD) pseudohypoaldosteronism type 1, salt-wasting episodes develop soon after birth and usually are more severe than in renal pseudohypoaldosteronism type 1. Individuals with MTOD pseudohypoaldosteronism  type 1 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. These individuals may have recurrent episodes of dyspnea, cyanosis, fever, tachypnea, and intercostal retractions. Crackles may be auscultated over pulmonary fields.

Pseudohypoaldosteronism type 2 symptoms

Individuals with pseudohypoaldosteronism type 2, in contrast to those with pseudohypoaldosteronism type 1, 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 ⁸ 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.

Pseudohypoaldosteronism complications

Potential complications of pseudohypoaldosteronism include the following:

• Severe hyperkalemia and even death as a result of cardiac arrhythmia
• Nephrocalcinosis (in pseudohypoaldosteronism type 1)
• Nephrolithiasis (in pseudohypoaldosteronism type 2)
• Frequent episodes of dehydration

Pseudohypoaldosteronism diagnosis

Laboratory studies

Renal pseudohypoaldosteronism type 1

The clinical characteristics of pseudohypoaldosteronism type 1 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 pseudohypoaldosteronism type 1 (renal tubular acidosis type 4 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 renal tubular acidosis type 4). Renal bicarbonate wasting can be observed with high-dose alkali therapy, but unlike proximal renal tubular acidosis type 2, early childhood hyperkalemia is not associated with kaliuria. Unlike renal tubular acidosis type 1 and 2, 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 1

Like renal pseudohypoaldosteronism type 1, multiple target organ defects (MTOD) pseudohypoaldosteronism type 1 is characterized by urinary salt wastage, which can occur from the salivary glands, sweat glands, respiratory tract, and colon. A variant of MTOD pseudohypoaldosteronism type 1 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 2

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 pseudohypoaldosteronism type 1 and mineralocorticoid deficient states.

Patients with pseudohypoaldosteronism 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 ⁹ 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 pseudohypoaldosteronism 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 multiple target organ defects (MTOD) pseudohypoaldosteronism type 1, secondary to failure to absorb liquid from airway surfaces. These findings mimic cystic fibrosis.

Renal ultrasonography may show nephrocalcinosis in patients with pseudohypoaldosteronism type 1 and nephrolithiasis in patients with pseudohypoaldosteronism type 2.

Renal biopsy findings in pseudohypoaldosteronism type 1 are usually normal; however, hypertrophy of the juxtaglomerular apparatus has occasionally been reported.

Pseudohypoaldosteronism treatment

Patients with pseudohypoaldosteronism 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 pseudohypoaldosteronism include the following:

• Potassium-binding resins
• Prostaglandin inhibitors
• Alkalizing agents
• Hydrochlorothiazide (in pseudohypoaldosteronism type 2)

Angiotensin-converting enzyme (ACE) inhibitors should not be used in patients with pseudohypoaldosteronism type 2, 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 1

Patients with renal pseudohypoaldosteronism type 1 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 1

Although administration of exogenous mineralocorticoids is ineffective in correcting the abnormalities in multiple target organ defects (MTOD) pseudohypoaldosteronism type 1, 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 2

In some patients with pseudohypoaldosteronism type 2, 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.

Physical activity

In patients with renal pseudohypoaldosteronism type 1, 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 pseudohypoaldosteronism type 1, 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 pseudohypoaldosteronism type 2, dietary sodium supplementation and potassium restriction may correct the hyperkalemia and acidosis.

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

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 pseudohypoaldosteronism type 1 is impossible at presentation, treat patients with glucocorticoids once electrolytes, blood sugar, cortisol, and adrenocorticotropic hormone (ACTH) concentrations are obtained until the diagnosis of pseudohypoaldosteronism type 1 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 pseudohypoaldosteronism type 1 for episodes of respiratory distress.

Pseudohypoaldosteronism prognosis

Individuals with renal pseudohypoaldosteronism type 1 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 pseudohypoaldosteronism type 1 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 multiple target organ defects (MTOD) pseudohypoaldosteronism type 1, salt wasting is more severe. This form of pseudohypoaldosteronism 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 pseudohypoaldosteronism. Therapy must be maintained throughout childhood and probably throughout life.

Most individuals with pseudohypoaldosteronism type 2 are asymptomatic until adolescence, when hypertension develops. These patients require lifelong therapy.

In patients with 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 after discontinuance of drugs that can impair renin or aldosterone synthesis or cause mineralocorticoid resistance.

References

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