Clinical Tests> Renal>

DESCRIPTION

• State of aldosterone deficiency or resistance, often associated with hyperkalemia and mild non-anion gap metabolic acidosis.
• Associated with type 4 renal tubular acidosis (RTA) in patients with diabetic nephropathy.
• May also be seen in patients with diabetes and hypertension treated with ACE-inhibitors, ARBs, or potassium-sparing diuretics.
• In autoimmune conditions such as type 1 diabetes, may be associated with primary adrenal insufficiency.

ASSAYS

• Plasma renin activity (PRA) measured by radioimmunoassay (RIA) for angiotensin I after plasma incubation at 37 degrees Celsius.
• Serum aldosterone and cortisol measured by RIA or chemiluminescence immunoassay (CLIA).
• Serum and urine potassium and osmolality should be checked to calculate transtubular potassium gradient (TTKG).
• TTKG = (urine potassium X serum osmolality) / (serum potassium X urine osmolality). For Interpretation, see below.

INDICATIONS

• Persistent or recurrent hyperkalemia without apparent cause such as acute renal failure and/or severe illness with marked intravascular volume depletion (e.g. severe CHF, dehydration).

DIFFERENTIAL DIAGNOSIS

• In general, 3 causes of hypoaldosteronism (hyporeninemic hypoaldosteronism, primary aldosterone deficiency, aldosterone resistance). 
• Hyporeninemic hypoaldosteronism: causes include diabetic nephropathy, chronic interstitial nephritis, medication use (NSAID, ACE-I, ARB, cyclosporine), and HIV.
• Primary aldosterone deficiency: causes include primary adrenal insufficiency (Addison's disease), some forms of congenital adrenal hyperplasia (CAH, most commonly 21-hydroxylase deficiency), aldosterone synthase deficiency (rare), or heparin use.
• Aldosterone resistance: causes include K-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene), trimethoprim, pentamidine, pseudohypoaldosteronism (rare).

INTERPRETATION

• In hyperkalemia, aldosterone action should increase potassium excretion causing TTKG > 10.  
• TTKG < 6 with hyperkalemia suggests hypoaldosteronism (Choi). Further interpretation is then based on upright PRA, serum aldosterone, serum cortisol
• Low PRA, low aldosterone, and normal cortisol suggests hyporeninemic hypoaldosteronism.
• Low cortisol, low aldosterone, and high PRA suggests primary adrenal insufficiency or CAH.
• Low aldosterone, normal cortisol, and high PRA is consistent with aldosterone synthase deficiency (seen in infants with recurrent hypovolemia, failure to thrive).
• High PRA and high aldosterone is consistent with pseudohypoaldosteronism.

LIMITATIONS OR CONFOUNDERS

• TTKG is unreliable with urine sodium concentration < 25 mEq/L, as sodium delivery to distal nephron may become rate limiting for potassium excretion.
• TTKG also unreliable with urine osmolality < plasma osmolality since ADH is needed for optimal potassium excretion.

EXPERT COMMENTS

• Hyporeninemic hypoaldosteronism is a common cause of hyperkalemia in diabetic patients age > 50, with mild-moderate nephropathy and exacerbating medications (eg, ACE-I) or acute illness (e.g. dehydration).
• Patients with hyperkalemia due to hypoaldosteronism often have renal insufficiency with associated volume expansion that may be exacerbated by mineralocorticoid therapy (fludrocortisone).
• Most patients with hyporeninemic hypoaldosteronism respond well to low potassium diet and, if necessary, a loop or thiazide diuretic to enhance potassium excretion.

REFERENCES