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Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)

Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)
Literature review current through: Sep 2023.
This topic last updated: Oct 17, 2022.

INTRODUCTION — Hypoaldosteronism should be considered in any patient with persistent hyperkalemia in whom there is no obvious cause such as kidney failure or the use of potassium supplements or a potassium-sparing diuretic [1-3]. The rise in the plasma potassium in this disorder reflects the major role played by aldosterone in urinary potassium excretion. In addition to hyperkalemia, hypoaldosteronism is usually associated with a mild metabolic acidosis with a normal anion gap (ie, a hyperchloremic acidosis) that has been called type 4 renal tubular acidosis.

The pathophysiology, clinical manifestations, etiology, diagnosis, and treatment of hypoaldosteronism will be presented here. The evaluation of patients with hyperkalemia in general is discussed separately. (See "Causes and evaluation of hyperkalemia in adults".)

PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS — The major clinical manifestations in patients with hypoaldosteronism are hyperkalemia and a mild hyperchloremic metabolic acidosis. Hypoaldosteronism should be considered in any patient with persistent hyperkalemia in whom there is no obvious cause such as kidney failure or the use of potassium supplements or a potassium-sparing diuretic [1-3].

Although aldosterone also promotes sodium retention, hypoaldosteronism is not typically associated with prominent sodium wasting (except in young children) because of the compensatory action of other sodium-retaining factors (such as angiotensin II and norepinephrine) [1]. Hyponatremia is also uncommon in patients with isolated aldosterone deficiency since there is no hypovolemia-induced stimulation of antidiuretic hormone (ADH) release and because plasma cortisol, a tonic inhibitor of ADH release, is normal [1]. When hyponatremia is present, primary adrenal insufficiency should be suspected. In this disorder, the concurrent lack of cortisol is a potent stimulus to ADH secretion, leading to water retention and a fall in the plasma sodium concentration. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)

Hyperkalemia — Aldosterone acts by increasing the number of open sodium channels in the luminal membrane of the principal cells in the cortical collecting tubule, leading to increased sodium reabsorption. The ensuing removal of sodium from the tubular fluid makes the lumen electronegative, thereby creating an electrical gradient that favors the secretion of cellular potassium into the lumen through potassium channels in the luminal membrane (figure 1).

Most patients with hypoaldosteronism have only a moderate decrease in aldosterone release or effect, with a small increase in plasma potassium concentration. The development of overt hyperkalemia is most common in aldosterone-deficient patients with other risk factors that further impair the efficiency of potassium excretion, such as kidney function impairment, reduced kidney perfusion, or the use of medications that interfere with potassium handling such as spironolactone, eplerenone, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or renin inhibitors.

Metabolic acidosis — Hyperkalemia in hypoaldosteronism is usually associated with a mild metabolic acidosis; the anion gap is typically normal (ie, a hyperchloremic acidosis) unless there is concurrent kidney function impairment. This condition has been called type 4 renal tubular acidosis and appears to be due primarily to decreased urinary ammonium excretion.

Three mechanisms have been proposed to explain decreased ammonium excretion in this disorder:

When urinary potassium excretion is impaired, some of the excess potassium enters the cells, with electroneutrality being maintained in part by the movement of cellular sodium and hydrogen ions into the extracellular fluid. The ensuing intracellular alkalosis in the kidney would then diminish ammonium production in the proximal tubule [2].

Ammonium is normally reabsorbed into the medullary interstitium and is then resecreted into the medullary collecting tubule [4]. Hyperkalemia decreases medullary cycling by inhibiting ammonium reabsorption in the thick ascending limb. Potassium and ammonium compete for a common transporter in the luminal membrane, which can function as an Na-K-2Cl or an Na-NH4-2Cl transporter. A review of loop transport mechanisms can be found elsewhere. (See "Diuretics and calcium balance".)

In the collecting duct, the basolateral Na-K-ATPase can also function as an Na-NH4 exchanger, permitting uptake of ammonium from the interstitium and subsequent secretion into the urine [5,6]. However, potassium competes with ammonium for this exchanger, and therefore hyperkalemia impairs the capacity of the pump to carry ammonium into the cell.

ETIOLOGY — The causes of hypoaldosteronism include both acquired and, less often, inherited disorders, which can affect adrenal aldosterone synthesis or kidney (and perhaps adrenal) secretion of renin (table 1) [2]. Plasma renin activity is usually increased in those disorders in which there is diminished aldosterone action with the exception of the different forms of hyporeninemic hypoaldosteronism.

The most common acquired causes of hypoaldosteronism are hyporeninemic hypoaldosteronism, pharmacologic inhibition of angiotensin II, and heparin therapy. Primary adrenal insufficiency is an infrequent cause.

In addition, the clinical features of aldosterone deficiency can be mimicked by disorders that reduce the renal response to aldosterone, the most common being pharmacologic inhibition of the epithelial sodium channel in the cortical collecting tubule with potassium-sparing diuretics. The following discussion is divided according to the primary mechanism: reduced aldosterone production or aldosterone resistance.

Reduced aldosterone production

Hyporeninemic hypoaldosteronism — The syndrome of hyporeninemic hypoaldosteronism is characterized by both diminished renin release and an intraadrenal defect, which in concert, result in decreased systemic and intraadrenal angiotensin II production. Reduced angiotensin II production contributes to the decline in aldosterone secretion [1,2]. The intraadrenal defect may involve the local renin-angiotensin system since there is evidence that angiotensin II produced locally within the adrenal gland may stimulate the release of aldosterone [7]. Many of these patients also have diminished responsiveness to aldosterone as evidenced by the need for a higher physiologic replacement mineralocorticoid dose [1].

Hyporeninemic hypoaldosteronism is most common in patients with mild to moderate kidney function impairment due to diabetic nephropathy or chronic interstitial nephritis but can also occur with acute glomerulonephritis and in patients taking nonsteroidal antiinflammatory drugs (NSAIDs) or calcineurin inhibitors.

Diabetes and kidney function impairment — Low plasma renin activity is common in diabetic patients due, in part, to a defect in the conversion of the precursor prorenin to active renin [8] (see "Diabetic kidney disease: Pathogenesis and epidemiology"). Volume expansion induced by diabetic and other chronic kidney diseases also may play a contributory role; the increase in atrial natriuretic peptide release in these patients can suppress both the release of renin and hyperkalemia-induced secretion of aldosterone [9].

Similar hemodynamic and humoral changes occur in acute glomerulonephritis (such as postinfectious glomerulonephritis) [10]. These changes can lead to hyperkalemia that responds to mineralocorticoid replacement [11]. Recovery of kidney function within one to two weeks is associated with restoration of normal potassium balance [11].

Nonsteroidal antiinflammatory drugs — NSAIDs have two effects that promote the development of hyperkalemia: They reduce kidney secretion of renin, which is normally mediated in part by locally produced prostaglandins, and they impair angiotensin II-induced release of aldosterone. An NSAID-induced reduction in glomerular filtration rate can also contribute to the rise in plasma potassium. The magnitude of the effect of NSAIDs on the plasma potassium was evaluated in a study of 50 hospitalized patients in whom indomethacin therapy was initiated [12]. The serum potassium rose by 0.5 to 0.9 mEq/L in 34 percent and by 1 mEq/L or more in 26 percent. (See "NSAIDs: Electrolyte complications", section on 'Hyperkalemia'.)

Calcineurin inhibitors — Cyclosporine leads to hyperkalemia in 15 to 25 percent of kidney transplant recipients due in part to diminished secretion of, as well as responsiveness to, aldosterone [13-15]. The latter effect may be mediated by reduced mineralocorticoid receptor expression [15]. Approximately 75 percent of transplant recipients who receive immunosuppressive therapy with cyclosporine and tacrolimus develop hyperkalemia [16]. (See "Cyclosporine and tacrolimus nephrotoxicity", section on 'Hyperkalemia'.)

Angiotensin inhibitors — Similar considerations apply to angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors, which diminish aldosterone release by impairing the conversion of angiotensin I to angiotensin II both systemically and perhaps within the adrenal zona glomerulosa, by blocking angiotensin II action at the receptor and by inhibiting renin activity, respectively. In addition, the normal stimulatory effect of an elevation in the plasma potassium concentration on aldosterone release may be mediated in part by the adrenal generation of angiotensin II [7]. Thus, an ACE inhibitor may decrease both angiotensin II- and potassium-mediated aldosterone release [7,17,18].

Unlike some of the other drugs discussed in this section, renin secretion is increased with ACE inhibitors. ACE inhibitors usually raise the plasma potassium concentration by less than 0.5 mEq/L in patients with relatively normal kidney function [18]. However, more prominent hyperkalemia can occur in patients with kidney function impairment or those taking a potassium-sparing diuretic [18]. Similar considerations apply to patients treated with ARBs. The hyperkalemic effect can also be seen in patients on maintenance hemodialysis [19]. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Hyperkalemia'.)

The latter interaction is becoming an increasingly common problem because ACE inhibitors, ARBs, and the potassium-sparing diuretics that block the mineralocorticoid receptor (spironolactone and eplerenone) improve survival in patients with heart failure. The frequency and magnitude of the combined effect on plasma potassium are described elsewhere.

Heparin and low-molecular-weight heparin — Heparin has a direct toxic effect on the adrenal zona glomerulosa cells, which may be mediated by a reduction in the number and affinity of adrenal angiotensin II receptors [2,20]. Even low-dose heparin (5000 units administered subcutaneously twice daily) can lead to a substantial reduction in plasma aldosterone concentrations [21]. It has been estimated that a greater than normal plasma potassium concentration occurs in 7 percent of patients. Severe hyperkalemia occurs only if some other impairment in potassium excretion is present, such as kidney function impairment or use of an ACE inhibitor, ARB, or potassium-sparing diuretic [20].

It appears that low-molecular-weight heparin has a similar effect on potassium balance. In one report of 81 patients treated with low-molecular-weight heparin as prophylaxis for venous thromboembolism, the plasma potassium concentration increased slightly (a mean of 5 to 10 percent); the highest rise (from 5.11 to 5.70 mmol/L) was recorded in a patient with kidney failure [22]. A similar increase in plasma potassium concentration was noted in another series, with the value exceeding 5 mEq/L in 9 percent of patients [23].

Primary adrenal insufficiency — Primary adrenal insufficiency is associated with lack of cortisol as well as aldosterone. Pituitary disease, by comparison, does not lead to hypoaldosteronism since corticotropin (ACTH) does not have a major role in the regulation of aldosterone release. Primary adrenal insufficiency can result from autoimmune adrenalitis, infectious adrenalitis (eg, HIV), and other disorders. Primary adrenal insufficiency is discussed in detail elsewhere. (See "Causes of primary adrenal insufficiency (Addison disease)".)

Transient hypoaldosteronism following surgical cure of hyperaldosteronism — Following resection of a unilateral aldosterone-producing adenoma, there is a risk of transient but clinically important hyperkalemia due to hypoaldosteronism [24]. The degree of contralateral suppression of aldosterone at adrenal venous sampling predicts hyperkalemia following adrenalectomy for primary aldosteronism [25]. Short-term mineralocorticoid replacement with fludrocortisone may be required.

Severe illness — Hypoaldosteronism due to decreased adrenal production can occur in critically ill patients. Volume expansion may play a contributory role in some patients. In addition, the stress-induced hypersecretion of ACTH may diminish aldosterone synthesis by diverting substrate to the production of cortisol [26]. (See "Adrenal steroid biosynthesis".)

Inherited disorders — Inherited forms of hypoaldosteronism due to reduced aldosterone production include congenital isolated hypoaldosteronism and pseudohypoaldosteronism type 2. By contrast, pseudohypoaldosteronism type 1 is associated with aldosterone resistance. (See 'Pseudohypoaldosteronism type 1' below.)

Congenital isolated hypoaldosteronism — In children, hypoaldosteronism can result from a deficiency of enzymes required for aldosterone synthesis, which may or may not be associated with concurrent abnormalities in cortisol and androgen production. Examples include genetic defects in aldosterone synthase (P450c11as, pure hypoaldosteronism) and P450c21 (21-hydroxylase, hypocortisolism with variable virilizing) (figure 2) [2,27,28]. (See "Adrenal steroid biosynthesis".)

Congenital isolated hypoaldosteronism is a rare inherited disorder that is transmitted as an autosomal recessive trait [29]. The clinical presentation is typical of aldosterone deficiency; affected infants have recurrent hypovolemia, salt wasting, and failure to thrive [27,28]. The usual defect in this disorder is in the activity of the terminal enzyme in the aldosterone biosynthetic pathway, aldosterone synthase (CYP11B2) [30,31]. Two types of aldosterone synthase defects can occur, reflecting its two enzymatic functions: CYP11B2 type I, characterized by impaired hydroxylation of corticosterone at the 18-carbon position, and CYP11B2 type II, characterized by impaired conversion of the 18-hydroxyl group to an aldehyde [30].

Aldosterone synthase type I deficiency would be expected to produce low plasma concentrations of products derived from corticosterone (18-hydroxycorticosterone and aldosterone) and low urinary excretion of their metabolites [32]; by contrast, aldosterone synthase type II deficiency should be associated with hypoaldosteronism but high plasma concentrations of 18-hydroxycorticosterone and increased urinary excretion of the major metabolite of 18-hydroxycorticosterone, tetrahydro-18-hydroxy,11-dehydrocorticosterone [32,33]. Thus, the ratio of plasma 18-hydroxycorticosterone to plasma aldosterone can be used to differentiate between the two disorders: <10 in type I and >100 in type II [34].

Many of the cases originally thought to be caused by aldosterone synthase type I defects have been shown to represent type II deficiency [32,33]. This finding is not surprising, because mitochondrial P450c11, as the product of a single gene, catalyzes 11-beta-hydroxylation and both of the reactions convert deoxycorticosterone to aldosterone [35]. The CYP11B2 gene is located on chromosome 8q24.3 [36] and is the site of mutations causing both types I and type II aldosterone synthase deficiency. CYP11B2 is located adjacent to CYP11B1, which encodes P-450c11, the enzyme that converts deoxycortisol to cortisol (figure 2).

Some patients with aldosterone synthase type I deficiency have a 5-nucleotide deletion in exon 1 leading to a frameshift and premature stop codon; as a result they produce no functional aldosterone synthase [28,37]. Other patients have a point mutation causing an R384P substitution; the arginine (R) is highly conserved and presumably important for enzyme activity [38]. An L461P and a nonsense E255X mutation have also been described [39,40]. Twin boys with type I deficiency had simultaneous E198D and V386A mutations [41].

Patients with aldosterone synthase type II deficiency have one of two point mutations resulting in R181W and V386A substitutions that do not affect 11-beta-hydroxylase activity but reduce 18-hydroxylase activity and abolish 18-oxidase activity [28,42]. A mutation that greatly reduces the activity of the enzyme in vitro is associated with normal aldosterone secretion [42]; thus, only the most severe enzyme deficiencies are manifested clinically.

A number of kindreds with a similar presentation of familial hyperreninemic hypoaldosteronism have no mutation in CYP11B2 [31]. The genetic abnormality in these families is not known.

Pseudohypoaldosteronism type 2 (Gordon's syndrome) — Pseudohypoaldosteronism type 2 (MIM #145260), also called Gordon's syndrome or familial hyperkalemic hypertension, is characterized by hypertension, hyperkalemia, metabolic acidosis, normal kidney function, and low or low-normal plasma renin activity and aldosterone concentrations [43-47]. By contrast, pseudohypoaldosteronism type 1 produces aldosterone resistance. (See 'Pseudohypoaldosteronism type 1' below.)

Hyperkalemia and hypertension in pseudohypoaldosteronism type 2 are caused by abnormalities in two serine/threonine kinases, WNK1 and WNK4, proteins that localize to the distal nephron and affect the thiazide-sensitive Na-Cl cotransporter (figure 3) [43,48-50]. Mutations affecting WNK4 or WNK1, or mutations affecting the proteins that degrade WNK4 or WNK1, result in increased chloride reabsorption in the distal nephron, thereby reducing lumen electronegativity and lowering the force for potassium secretion. These mutations also result in decreased expression of the potassium channels through which potassium enters the collecting duct.

Such mutations can result in similar phenotypes:

Disruptions in WNK4 are transmitted as an autosomal dominant trait. Wild-type (normal) WNK4 inhibits the surface expression of the thiazide-sensitive Na-Cl cotransporter in the luminal membrane of the distal tubule by 50 to 85 percent [51-54]. Missense mutations in the WNK4 gene result in a mutant protein with decreased inhibitor activity [55], resulting in increased expression of the Na-Cl cotransporter and hyperplasia of the distal convoluted tubule [49].

Wild-type WNK4 also stimulates clathrin-dependent endocytosis of potassium channels in the collecting duct [56], thereby decreasing the surface expression of potassium channels. Endocytosis of potassium channels is enhanced by defective WNK4 proteins, resulting in fewer functioning potassium channels.

Thus, mutant WNK4 increases sodium chloride reabsorption in the distal tubule and decreases potassium secretion in the collecting tubule.

WNK1 is expressed in many tissues including the distal tubule and collecting tubule [57]. Wild-type WNK1 inhibits the function of WNK4 [52,53]. Thus, a gain-of-function mutation in WNK1 would further inhibit WNK4 activity, resulting in increased expression of the Na-Cl cotransporter in the distal tubule and reduced expression of potassium channels in the collecting tubule. In addition to inhibiting WNK4, WNK1 may have direct effects on potassium channel expression in the collecting duct [58].

Disease-causing mutations in both WNK1 and WNK4 also increase chloride permeability via the paracellular pathway [59].

Mutations in genes (CUL3 and KLHL3) encoding the Cullin-3 and Kelch-3 proteins impair degradation of WNK kinases, causing their accumulation in the cell [50,60,61]. These mutations are responsible for pseudohypoaldosteronism type 2 (Gordon's syndrome) in 80 percent of kindreds and are associated with an earlier age at diagnosis and more severe hyperkalemia and metabolic acidosis [43].

Genotype-phenotype correlations — Increased sodium chloride reabsorption in the distal tubule leads to volume expansion, hypertension, and diminished renin secretion. In addition, increased distal sodium chloride reabsorption decreases sodium and water delivery to the potassium and hydrogen secreting cells in the cortical collecting tubule, thereby reducing potassium and hydrogen excretion. The ability of collecting tubule cells to secrete potassium is also impaired by increased chloride permeability in the distal tubule, which reduces lumen electronegativity and lowers the driving force for potassium secretion [45]. The defect in potassium secretion is compounded by reduced expression of potassium channels in the collecting tubule [56,62].

Consistent with this hypothesis is the observation that, in the presence of persistent mineralocorticoid excess, the administration of sodium chloride does not increase potassium excretion as it does in patients without this disorder; however, giving sodium with a non-reabsorbable anion, such as sulfate or bicarbonate, produced a marked increase in potassium excretion [45]. An alternative hypothesis is that the principal cause of hyperkalemia, at least with WNK4 mutations, is impaired cortical collecting potassium channel activity via enhanced cell surface retrieval [56,62].

In a mouse model of pseudohypoaldosteronism type 2, both hydrochlorothiazide and knockout of the Na-Cl cotransporter reversed the abnormal phenotype induced by WNK4 mutations [49]. Thus, pseudohypoaldosteronism type 2 due to WNK4 and WNK1 mutations is the mirror image of Gitelman syndrome. The latter disorder is due to a loss-of-function mutation in the distal Na-Cl cotransporter resulting in hypokalemia and metabolic alkalosis. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

Aldosterone resistance — Aldosterone resistance is most often due to the administration of potassium-sparing diuretics and certain antibiotics that inhibit the collecting tubule sodium channel. A rare cause is the inherited disorder, pseudohypoaldosteronism type 1.

Inhibition of the epithelial sodium channel — Pharmacologic inhibition of the epithelial sodium channel in the collecting tubule, which is the site of action of aldosterone (figure 1), may be induced by potassium-sparing diuretics and certain antibiotics. The net effect is aldosterone resistance rather than reduced aldosterone production.

Potassium-sparing diuretics — Potassium-sparing diuretics act by either antagonizing the action of aldosterone on the collecting tubule cells by competing for the aldosterone receptor (spironolactone and eplerenone) or closing the sodium channels in the luminal membrane (amiloride and probably triamterene) (figure 1) [2].

Antibiotics — Two antibiotics, trimethoprim (usually given as trimethoprim-sulfamethoxazole) and pentamidine, can also cause hyperkalemia by closing the epithelial sodium channels in the collecting tubule [63-68]. Trimethoprim-induced hyperkalemia is dose dependent, seen primarily at the very high doses used in patients with AIDS [63-65].

However, trimethoprim can raise the plasma potassium concentration even when used in conventional doses, particularly in older adults [66,67,69,70]. As an example, one study reviewed the course of 80 patients without kidney function impairment or another cause of altered potassium homeostasis who were treated for at least five days with conventional doses of trimethoprim-sulfamethoxazole [66]. Plasma potassium concentration rose by a mean of 1.2 mEq/L, from 3.9 to 5.1 mEq/L; 21 percent of patients had a plasma potassium concentration ≥5.5 mEq/L. The peak effect was at four to five days. Patients with mild kidney function impairment may be at risk for more severe hyperkalemia [67]. As previously mentioned, ammonia production is inhibited with the increased potassium concentration, thereby resulting in type 4 renal tubular acidosis.

Older adult patients who are on ACE inhibitors or ARBs are at particularly high risk of developing hyperkalemia when treated with trimethoprim. This was shown in a case control study of 371 individuals 66 years or older who were receiving continuous therapy with ACE inhibitors or ARBs and were hospitalized with hyperkalemia within 14 days after starting an antibiotic [71]. Compared with amoxicillin, the use of trimethoprim-sulfamethoxazole was associated with an almost sevenfold increased risk of hyperkalemia-associated hospitalization. Although fewer than 15 percent of the cases in the cohort had a documented history of kidney disease, approximately one-half had diabetes, suggesting that hyporeninemic hypoaldosteronism due to undiagnosed diabetic nephropathy may have contributed to hyperkalemia. In addition, other drugs may have contributed to hyperkalemia in this study since approximately one-third were also taking NSAIDs, beta-adrenergic blockers, or potassium-sparing diuretics. (See 'Hyporeninemic hypoaldosteronism' above.)

Pseudohypoaldosteronism type 1 — Pseudohypoaldosteronism type 1 is a rare hereditary disorder characterized by resistance to the actions of aldosterone. By contrast, pseudohypoaldosteronism type 2 is associated with reduced aldosterone production because of volume expansion associated with the disorder. (See 'Pseudohypoaldosteronism type 2 (Gordon's syndrome)' above.)

Two different modes of inheritance with different mechanisms and clinical manifestations have been described in pseudohypoaldosteronism type 1:

Autosomal recessive pseudohypoaldosteronism type 1 (MIM #264350) affects the collecting tubule sodium channel (also called the epithelial sodium channel or ENaC). The defect is permanent and affects all aldosterone target organs (including the renal collecting tubule, colon, and salivary glands). This disorder is discussed in detail separately. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1", section on 'Pseudohypoaldosteronism type 1'.)

Autosomal dominant or sporadic pseudohypoaldosteronism type 1 (MIM #177735) affects the mineralocorticoid receptor in most patients. The defect is limited to the kidney, produces milder salt wasting than the autosomal recessive form of pseudohypoaldosteronism type 1 disease, and often improves with age. More than 50 different loss-of-function mutations in the gene encoding (NR3C2) the mineralocorticoid receptor have been reported including nonsense, frameshift, and splice site mutations as well as deletions, all leading to an abnormal protein [72-79]. Other mutations affect binding of aldosterone to the receptor [79].

Compared with the recessive form, autosomal dominant pseudohypoaldosteronism type 1 is typically associated with milder clinical symptoms that may remit over time [72-74]. However, severe neonatal manifestations (hyperkalemia, hyponatremia, and failure to thrive) have been described [74]. The clinical presentation does not correlate well with the specific genotype. Some patients with autosomal dominant pseudohypoaldosteronism type 1 do not have mutations in the mineralocorticoid receptor gene [76-78,80]. In two series, such mutations were not found in 15 to 30 percent of patients [76,78]. The causative genes have not been identified [80].

DIAGNOSIS OF HYPOALDOSTERONISM — Patients suspected to have hypoaldosteronism should be questioned about the use of any drug or the presence of a disease that can impair aldosterone release, such as a nonsteroidal antiinflammatory drug (NSAID), an angiotensin inhibitor, a calcineurin inhibitor, heparin, beta-adrenergic blockers, or HIV infection [2]. As discussed above, other causes include hyporeninemic hypoaldosteronism (most often associated with diabetes and chronic kidney disease), primary adrenal insufficiency, an adrenal enzyme defect (most often CYP11B2 [aldosterone synthase, P450c11as] deficiency), or the rare genetic disorders pseudohypoaldosteronism type 1 and type 2.

The different causes of hypoaldosteronism can be differentiated by measurement of plasma renin activity, serum aldosterone, and serum cortisol [2]. These tests should be performed after the administration of a loop diuretic or three hours in the upright position, which will increase renin and aldosterone release in patients without hypoaldosteronism [1,2]. (See "Assays of the renin-angiotensin-aldosterone system in adrenal disease" and "Measurement of cortisol in serum and saliva".)

Hyporeninemic hypoaldosteronism most often occurs in patients 50 to 70 years of age with diabetic nephropathy or chronic tubulointerstitial disease who have mild to moderate kidney function impairment [1]. It is associated with a low plasma renin activity in most but not all cases, low serum aldosterone concentration, and normal serum cortisol concentration.

Patients with primary adrenal insufficiency have low serum aldosterone and cortisol concentrations but high plasma renin activity due to volume depletion and/or hypotension.

Children with an adrenal enzyme deficiency fall into one of two categories. Those with one of the forms of congenital adrenal hyperplasia (ie, CYP21A2 [21-hydroxylase], CYP17 [17-hydroxylase] or 3-beta-hydroxysteroid dehydrogenase deficiency, or congenital lipoid hyperplasia) have a concurrent defect in cortisol synthesis. Thus, their serum values are similar to those in primary adrenal insufficiency, but adrenal androgen synthesis may be increased, leading to virilization [81]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

By comparison, children with congenital isolated (primary) hypoaldosteronism have a defect in one of the two steps (both of which are mediated by the same enzyme, CYP11B2) that are involved in the production of aldosterone: the addition of a hydroxyl group at the 18-carbon position and the subsequent oxidation of this hydroxyl group to an aldehyde group [30]. In a study of 62 patients with congenital hypoaldosteronism, CYP11B2 gene sequencing revealed 12 different pathogenic variants; however, 96 percent of the patients carried the p.T185I variant, either in homozygosity or in compound heterozygosity with another variant [29].

In both congenital adrenal hyperplasia and congenital isolated hypoaldosteronism, the serum aldosterone concentration is low, the serum cortisol concentration is normal, and the plasma renin activity is high. The diagnosis of congenital isolated hypoaldosteronism can be confirmed by measurement of serum 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, 18-hydroxydeoxycorticosterone, and aldosterone [34]. (See 'Congenital isolated hypoaldosteronism' above.)

Children with the rare syndrome of pseudohypoaldosteronism type 1 have high plasma renin activity and serum aldosterone concentrations [82]. Infants with the autosomal recessive variant, in which the epithelial sodium channel is abnormal, may present with a miliaria papular rash due presumably to a high sodium concentration in sweat [83]. This is not seen in patients with the autosomal dominant form, who usually have loss-of-function mutations in the mineralocorticoid receptor [78]. In this condition, therapy with conventional doses of a mineralocorticoid is usually ineffective. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1", section on 'Autosomal recessive disease' and 'Inherited disorders' above.)

Hyperkalemic patients in whom all of the above disorders have been excluded and in whom kidney function is not markedly impaired probably have a selective potassium secretory defect or the hyperkalemic form of distal renal tubular acidosis [2]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

TREATMENT — Appropriate therapy for hypoaldosteronism varies with the cause of the hormone deficiency. Patients with primary adrenal insufficiency, for example, should receive mineralocorticoid replacement therapy (with fludrocortisone at a dose of 0.05 to 0.2 mg/day) to correct the hyperkalemia and with 0.9 percent saline to correct symptomatic hypovolemia. Primary adrenal insufficiency should also be treated with a glucocorticoid, such as hydrocortisone or prednisone, to correct the cortisol deficiency. (See "Treatment of adrenal insufficiency in adults".)

Fludrocortisone is also effective in patients with hyporeninemic hypoaldosteronism [1]. The typical dose required to normalize the serum potassium is 0.2 to 1 mg/day, substantially higher than the dose in primary adrenal insufficiency. It is therefore likely that these patients have some component of aldosterone resistance, presumably due to the underlying kidney disease.

Despite its efficacy, fludrocortisone is often not used in hyporeninemic hypoaldosteronism because many patients with this disorder have hypertension and/or edema, problems that can be exacerbated by mineralocorticoid replacement. In this setting, use of a low-potassium diet and, if necessary, a loop or thiazide-type diuretic will usually control the hyperkalemia [84,85]. (See "Patient education: Low-potassium diet (Beyond the Basics)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

Hypoaldosteronism should be considered in any patient with persistent hyperkalemia in whom there is no obvious cause such as kidney failure or the use of potassium supplements or a potassium-sparing diuretic. In addition to hyperkalemia, hypoaldosteronism is usually associated with a mild metabolic acidosis with a normal anion gap (ie, a hyperchloremic acidosis). This condition has been called type 4 renal tubular acidosis. (See 'Pathophysiology and clinical manifestations' above.)

Aldosterone acts by increasing the number of open sodium channels in the luminal membrane of the principal cells in the cortical collecting tubule, leading to increased sodium reabsorption. The ensuing removal of sodium from the tubular fluid makes the lumen electronegative, thereby creating an electrical gradient that favors the secretion of cellular potassium into the lumen through potassium channels in the luminal membrane (figure 1). Decreased aldosterone effect leads to retention of potassium. (See 'Hyperkalemia' above.)

The type 4 renal tubular acidosis appears to be due primarily to a hyperkalemia-induced decreased urinary ammonium excretion. (See 'Metabolic acidosis' above.)

The causes of hypoaldosteronism include both disorders that can reduce aldosterone synthesis, and the syndrome can be mimicked by disorders that impair the renal response to aldosterone (aldosterone resistance) (table 1). (See 'Etiology' above.)

Major causes of impaired aldosterone production include hyporeninemic hypoaldosteronism, pharmacologic inhibition of renin or angiotensin II, heparin therapy, and primary adrenal insufficiency (see 'Reduced aldosterone production' above):

Hyporeninemic hypoaldosteronism is most common in patients with mild to moderate kidney function impairment due to diabetic nephropathy or chronic interstitial nephritis but can also occur with acute glomerulonephritis and in patients taking nonsteroidal antiinflammatory drugs (NSAIDs) or calcineurin inhibitors. (See 'Hyporeninemic hypoaldosteronism' above.)

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors diminish aldosterone release by impairing the conversion of angiotensin I to angiotensin II both systemically and perhaps within the adrenal zona glomerulosa, by blocking angiotensin II action at the receptor and inhibiting renin activity, respectively. (See 'Angiotensin inhibitors' above.)

Heparin therapy, which has a direct toxic effect on the adrenal zona glomerulosa cells, can lead to a substantial reduction in plasma aldosterone concentrations. (See 'Heparin and low-molecular-weight heparin' above.)

Primary adrenal insufficiency is associated with lack of both aldosterone and cortisol. (See 'Primary adrenal insufficiency' above.)

Inherited disorders, which are less common, include congenital isolated hypoaldosteronism and pseudohypoaldosteronism type 2 (Gordon's syndrome). (See 'Inherited disorders' above.)

The major cause of aldosterone resistance is pharmacologic inhibition of the epithelial sodium channel in the collecting tubule due either to potassium-sparing diuretics or antibiotics (especially trimethoprim). Pseudohypoaldosteronism type 1 is a rare genetic disorder characterized by resistance to the actions of aldosterone. (See 'Aldosterone resistance' above.)

Patients suspected to have hypoaldosteronism should be questioned about the use of any drug or the presence of a disease that can impair aldosterone release, such as an NSAID, an angiotensin inhibitor, a calcineurin inhibitor, heparin, or HIV infection. The different causes of hypoaldosteronism can be differentiated by measurement of plasma renin activity, serum aldosterone, and serum cortisol. These tests should be performed after the administration of a loop diuretic or three hours in the upright position, which will increase renin and aldosterone release in patients without hypoaldosteronism. (See 'Diagnosis of hypoaldosteronism' above.)

Appropriate therapy for hypoaldosteronism usually includes fludrocortisone, but the dose varies with the cause of the hormone deficiency. (See 'Treatment' above.)

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Topic 2306 Version 29.0

References

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