Electrolyte disturbances with HIV infection

INTRODUCTION — Hyponatremia and hyperkalemia are the two major electrolyte disorders that may be associated with HIV infection. They are more likely to occur in sicker patients, with the highest rates in those who are hospitalized. In addition, hypokalemia, Fanconi syndrome, lactic acidosis, and hypophosphatemia have been described.

The major electrolyte disorders that occur in patients with HIV infection will be reviewed here. A discussion of the endocrine changes seen in these patients is presented separately. (See "Pituitary and adrenal gland dysfunction in patients with HIV".)

HYPONATREMIA — Hyponatremia occurs in as many as 35 to 55 percent of hospitalized HIV-infected patients, but it can also be seen in ambulatory patients [1-3]. The hyponatremia is usually due to one or more of three disorders, each of which is associated with an impaired ability to excrete water due to increased release of antidiuretic hormone (ADH): syndrome of inappropriate ADH secretion (SIADH), volume depletion, and adrenal insufficiency. Patients with HIV infection may be more susceptible to developing hyponatremia if water intake is high because even stable patients with normal kidney function who are not receiving medications have been shown to have an impaired response to a water load, with free water clearance that is three times lower than in healthy volunteers despite normal osmolar clearance [4].

Syndrome of inappropriate ADH secretion — The syndrome of inappropriate ADH secretion (SIADH) is usually due to pneumonia (with Pneumocystis jirovecii [formerly called Pneumocystis carinii] or other organisms), malignancy, or occult or symptomatic infection of the central nervous system [1-3,5]. Among patients treated with intravenous trimethoprim-sulfamethoxazole, the fluid required to dilute the drug may contribute to the development of hyponatremia. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Volume depletion — Volume depletion in HIV-infected patients is most often caused by gastrointestinal fluid losses, primarily from diarrhea [1,3]. Hypovolemia can be distinguished from the SIADH by a low urine sodium concentration (usually below 15 mEq/L) and correction of the hyponatremia with volume repletion. (See "Diagnostic evaluation of adults with hyponatremia".)

Adrenal insufficiency — Adrenal insufficiency is a much less common cause of hyponatremia than the SIADH or hypovolemia [1,2]. In general, the fall in the plasma sodium concentration is due to cortisol deficiency (which appears to directly enhance hypothalamic ADH release), while the frequently associated hyperkalemia is due to aldosterone deficiency. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)

The adrenal insufficiency seen in acquired immunodeficiency syndrome (AIDS) is often due to adrenalitis that may be induced by infection with cytomegalovirus, Mycobacterium avium intracellulare, or HIV itself. Adrenal hemorrhage and infiltration with Kaposi's sarcoma also may be seen. These issues are discussed in detail elsewhere. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'HIV infection'.)

Pseudohyponatremia — Marked hypertriglyceridemia or hyperproteinemia can produce "pseudohyponatremia" when the serum sodium concentration is measured with certain analytic instruments (eg, flame photometer and indirect ion-selective electrode devices). Patients with HIV may have marked polyclonal hypergammaglobulinemia, which has been reported to cause pseudohyponatremia [6,7]. In affected patients, the serum sodium concentration will be measured as low by autoanalyzers and other analytical instruments that employ a diluting step, while it will be measured as normal by direct sodium-selective electrodes used by blood gas analyzers and some point-of-care devices. (See "Causes of hyponatremia without hypotonicity (including pseudohyponatremia)".)

HYPERNATREMIA — Hypernatremia has been described in up to 31 percent of patients with advanced acquired immunodeficiency syndrome (AIDS). Excessive electrolyte-free water losses can occur in the setting of fever, vomiting, diarrhea, arginine vasopressin deficiency (previously called central diabetes insipidus) caused by encephalitis due to toxoplasmosis or cytomegalovirus, or arginine vasopressin resistance (previously called nephrogenic diabetes insipidus) due to interstitial nephritis or medications [4]. Impaired renal concentrating ability has been reported in stable ambulatory patients with HIV [8].

HYPERKALEMIA — Hyperkalemia has been described in up to 15 to 20 percent of hospitalized patients with HIV [9,10]. The major causes include adrenal insufficiency, hyporeninemic hypoaldosteronism [9], the administration of trimethoprim or pentamidine [11-13], and impaired kidney function due to HIV-induced kidney disease or other disorders. (See "Overview of kidney disease in patients with HIV".)

The mechanism responsible for the low renin release in HIV-infected patients is not known, nor are the relative roles of hyporeninemia and direct adrenal injury in the decreased aldosterone release. Mineralocorticoid replacement (starting with 0.05 to 0.1 mg of fludrocortisone per day) will usually correct the hyperkalemia induced by hypoaldosteronism [9].

Trimethoprim and pentamidine as potassium-sparing diuretics — Trimethoprim is an important cause of hyperkalemia in patients with acquired immunodeficiency syndrome (AIDS). Trimethoprim, which is usually given in combination with sulfamethoxazole or dapsone for Pneumocystis jirovecii pneumonia, causes an average rise in the plasma potassium concentration of 0.5 to 1 mEq/L with occasional cases of severe hyperkalemia [11-13]. Trimethoprim is cationic, like amiloride and triamterene, and appears to act as a potassium-sparing diuretic, reversibly blocking sodium channels in the luminal membrane of the cortical collecting tubule cells [11,13]. The ensuing reduction in sodium reabsorption then minimizes potassium secretion. (See "Causes and evaluation of hyperkalemia in adults", section on 'Reduced urinary potassium excretion'.)

The use of trimethoprim doses in HIV-infected patients that are often five to 10 times higher than that given for conventional infections probably explains the more frequent development of hyperkalemia among HIV-infected patients. A retrospective, single-center study of 100 HIV-infected patients treated with trimethoprim found that hyperkalemia requiring a therapeutic intervention was more common among patients treated with ≥10 mg/kg/day of trimethoprim than among those receiving lower doses [14]. However, conventional doses of trimethoprim can also raise the plasma potassium concentration. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

An elevation in the plasma potassium concentration is also a common complication of pentamidine therapy [15-17]. Pentamidine appears to act by the same mechanism as trimethoprim, blocking distal potassium secretion. (See "Overview of kidney disease in patients with HIV", section on 'Electrolyte disorders'.)

HYPOKALEMIA — Hypokalemia (serum potassium <3.5 mEq/L) is common in hospitalized patients with acquired immunodeficiency syndrome (AIDS), usually because of infectious diarrhea, AIDS-associated enteropathy, or vomiting [4]. Urinary potassium wasting can occur because of tubular injury from nephrotoxic drugs. Cases of profound hypokalemia with paralysis have been reported due to potassium wasting caused by drug-induced tubulopathies associated with tenofovir [18,19]. (See 'Fanconi syndrome' below.)

FANCONI SYNDROME — Tenofovir disoproxil fumarate (TDF) has been associated with renal proximal tubulopathy with the Fanconi syndrome (proximal renal tubular acidosis with a normal anion gap metabolic acidosis, hypophosphatemia and osteomalacia with renal phosphate wasting, hypokalemia, hypouricemia, glycosuria with normal blood glucose, and aminoaciduria) [18,20-22]. Risk factors for developing the syndrome include use of concomitant protease inhibitors or didanosine, genetic polymorphisms of renal transporters of tenofovir, low glomerular filtration rate (GFR), and greater circulating tenofovir levels. The tubulopathy typically resolves within two months of discontinuing the drug.

LACTIC ACIDOSIS — Because of the increased propensity to serious infection, sepsis-induced lactic acidosis can occur in patients with acquired immunodeficiency syndrome (AIDS) [23]. In addition, there are cases in which lactic acidosis appears to result from drug-induced mitochondrial dysfunction in the absence of sepsis or hypoperfusion (type B lactic acidosis). This issue is discussed in detail elsewhere. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors", section on 'Hyperlactatemia and lactic acidosis'.)

OTHER ABNORMALITIES — Hyperuricemia and hypophosphatemia have been described with increased frequency in the era of potent antiretroviral therapy (ART). In a single-center study from France of 1232 consecutive HIV patients, hyperuricemia was present in 41 percent and hypophosphatemia in 17 percent [24]. Protease inhibitor and non-nucleoside reverse transcriptase inhibitor therapy were significantly associated with hyperuricemia and hypophosphatemia, respectively.

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

●Overview – Hyponatremia (35 to 55 percent of patients), hyperkalemia (15 to 20 percent), hyperuricemia (41 percent), and hypophosphatemia (17 percent) are commonly observed among hospitalized patients with HIV infection. (See 'Introduction' above.)

●Hyponatremia – Hyponatremia may be caused by one of three mechanisms: the syndrome of inappropriate antidiuretic hormone secretion (SIADH), usually resulting from Pneumocystis or other pneumonia or CNS disease; adrenal insufficiency; or hypovolemia resulting from infectious diarrhea. (See 'Hyponatremia' above.)

●Hyperkalemia – Hyperkalemia may be caused by adrenal insufficiency, hyporeninemic hypoaldosteronism, or the administration of trimethoprim or pentamidine; mineralocorticoid replacement (starting with 0.05 to 0.1 mg of fludrocortisone per day) will usually correct the hyperkalemia induced by hypoaldosteronism. (See 'Hyperkalemia' above.)

●Hypokalemia – Hypokalemia is common in hospitalized patients with acquired immunodeficiency syndrome (AIDS), usually because of infectious diarrhea, AIDS-associated enteropathy, or vomiting. Urinary potassium wasting can occur because of tubular injury from nephrotoxic drugs. (See 'Hypokalemia' above.)

●Fanconi syndrome – Tenofovir disoproxil fumarate (TDF) has been associated with renal proximal tubulopathy with the Fanconi syndrome. Risk factors for developing the syndrome include use of concomitant protease inhibitors or didanosine, genetic polymorphisms of renal transporters of tenofovir, low glomerular filtration rate (GFR), and greater circulating tenofovir levels. (See 'Fanconi syndrome' above.)

●Lactic acidosis – Lactic acidosis can occur in HIV-infected patients as a complication of sepsis or from drug-induced mitochondrial dysfunction in the absence of sepsis or hypoperfusion. (See 'Lactic acidosis' above.)

●Other abnormalities – Protease inhibitor and non-nucleoside reverse transcriptase inhibitor therapies are significantly associated with hyperuricemia and hypophosphatemia respectively. (See 'Other abnormalities' above.)