- State of aldosterone deficiency or resistance, which is often associated with hyperkalemia and mild non-anion gap metabolic acidosis.
- In normal states within the kidney, aldosterone increases sodium reabsorption through opening epithelial sodium channels within the principal cells of the cortical collecting tubule causing the development of an electronegative lumen. This resulting electrical gradient favors secretion of cellular potassium through potassium channels (i.e. potassium excretion develops). In hypoaldosterone states, there is reduced sodium reabsorption in the cortical collecting tubules; therefore a lesser electrical gradient to facilitate secretion of cellular potassium, which results in hyperkalemia.  
- The resulting mild non-anion gap metabolic acidosis is known as type 4 renal tubular acidosis (RTA). It is primarily due to reduced urinary ammonium excretion through various proposed mechanisms.  
- Causes of hypoaldosteroinism can be both acquired and inherited (less common).
- Hyperaldosteronism is divided into aldosterone deficiency and aldosterone resistance. 
- Causes of aldosterone deficiency include hyporeninemic hypoaldosteronism (due to diabetic kidney disease , non-steroidal anti-inflammatory drugs, calcineurin inhibitors), angiotensin inhibitors, heparin therapy, primary adrenal insufficiency, critical illness, congenital isolated hypoaldosteronism, and pseudohypoaldosteronism type 2.
- Causes of aldosterone resistance include inhibitors of the epithelial sodium channel (potassium-sparing diuretics, trimethoprim, pentamidine) and pseudohypoaldosteronism type 1.
- Differentiating between the different causes of hypoaldosteronism is done by measurement of the plasma renin activity (PRA), serum aldosterone, and serum cortisol.
- The PRA is measured by radioimmunoassay (RIA) for angiotensin I after plasma incubation at 37 degrees Celsius. Expressed as the amount of angiotensin I generated per unit of time.
- The PRA is preferred over the direct active renin concentration. 
- Serum aldosterone and cortisol measured by RIA or chemiluminescence immunoassay (CLIA).  
- The transtubular potassium gradient (TTKG) was historically recommend for assessing hyperkalemia    but the original studies’s assumptions were proven invalid. It has been concluded that the TTKG is not a reliable test to help differentiate the causes of hyperkalemia. It’s use is not recommended. 
- Persistent or recurrent hyperkalemia without apparent cause such as renal failure, severe illness, intravascular volume depletion, or use of potassium supplements or potassium-sparing diuretics.
- Aldosterone Deficiency:
- Hyporeninemic hypoaldosteronism - Commonly seen in patients with renal insufficiency (diabetic kidney disease, chronic tubulointerstitial disease, or glomerulonephritis) and those that take certain medications (non-steroidal anti-inflammatory drugs, calcineurin inhibitors). 
- Angiotensin inhibitors - angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), direct renin inhibitors
- Heparin therapy (including low molecular weight heparin) - Heparin has a direct toxic effect on the adrenal zona glomerulosa cells which leads to a reduction in plasma aldosterone concentration. 
- Primary adrenal insufficiency (Addison’s disease) - Associated with the lack of cortisol and aldosterone. This can result from autoimmune adrenalitis, infectious adrenalitis, and other disorders. 
- Critical illness - There is decreased adrenal production of aldosterone and stress-induced hypersecretion of ACTH which can diminish aldosterone synthesis by diverting substrate to the production of cortisol.
- Congenital isolated hypoaldosteronism - Deficiency of enzymes required for aldosterone synthesis. 
- Pseudohypoaldosteronism type 2 (Gordon’s syndrome or familial hyperkalemic hypertension) - Abnormalities in WNK kinases in the distal nephron increase chloride reabsorption leading to reduced renal potassium secretion. Characterized by hypertension, hyperkalemia, metabolic acidosis, normal renal function, and low or low-normal plasma renin activity and aldosterone concentrations.  
- Aldosterone Resistance:
- Inhibitors of the epithelial sodium channel - Most commonly associated with the administation of potassium-sparing diuretics (spironolactone, eplerenone, amiloride) and certain antibiotics (trimethoprim, pentamidine).
- Pseudohypoaldosteronism type 1 - Characterized by marked elevations of plasma aldosterone levels. There is an autosomal recessive form, and an autosomal dominant or sporadic form. The autosomal dominant form tends to be associated with milder symptoms.  
- High clinical suspicion for hypoaldosteronism if hyperkalemia and mild non-anion gap metabolic acidosis are present.
- Low PRA, low aldosterone, and normal cortisol suggests hyporeninemic hypoaldosteronism.
- Low cortisol, low aldosterone, and high PRA suggests primary adrenal insufficiency or congenital adrenal hyperplasia.
- 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 type 1.
Plasma Renin Activity
Low to normal
Primary adrenal insufficiency
Pseudohypoaldosteronism type 1
Pseudohypoaldosteronism type 2
Low to normal
Low to normal
LIMITATIONS OR CONFOUNDERS
- Factors that affect renin levels include sodium intake, age, gender, menstrual phase, pregnancy, time of day, posture, chronic kidney disease, race, and medication use.
- Factors that affect aldosterone levels include time of day, volume status, menstrual phase, race and posture.
- Due to these factors, most centers will draw labs in the morning (preferably 8 am) while in the upright position, with paired sampling (plasma aldosterone and plasma renin activity (or plasma renin concentration)).
- Hyporeninemic hypoaldosteronism, angiotensin inhibition (i.e. ACE inhibitors or ARBs), and heparin therapy are the most common acquired causes of hypoaldosteronism.
- Hyporeninemic hypoaldosteronism is a common cause of hyperkalemia in diabetic patients with an age > 50, mild to moderate nephropathy and exacerbating medications (e.g. ACE inhibitor, ARB, NSAIDs) or acute illness (e.g. dehydration).
- Primary adrenal insufficiency is an infrequent cause, but should be considered in patients with other autoimmune conditions such as type 1 diabetes.
- Most patients with hypoaldosteronism have only have a small increase in plasma potassium concentration.
- Overt hyperkalemia is most commonly seen in hypoaldosteronism patients with other risk factors that further impair potassium excretion, such as renal insufficiency, decreased renal perfusion, or the use of medications that interfere with potassium handling.
- Most patients with hyporeninemic hypoaldosteronism respond well to low potassium diet and, if necessary, a loop or thiazide diuretic to enhance potassium excretion.
- Fludrocortisone is sometimes needed with dosing affected by the cause of hormone deficiency.
- Liamis G et al: Diabetes mellitus and electrolyte disorders. World J Clin Cases 2:488, 2014 [PMID:25325058]
- Jain G, Ong S, Warnock DG: Genetic disorders of potassium homeostasis. Semin Nephrol 33:300, 2013 [PMID:23953807]
- Kamel KS, Halperin ML: Intrarenal urea recycling leads to a higher rate of renal excretion of potassium: an hypothesis with clinical implications. Curr Opin Nephrol Hypertens 20:547, 2011 [PMID:21788894]
- Karet FE: Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol 20:251, 2009 [PMID:19193780]
- Nyirenda MJ et al: Hyperkalaemia. BMJ 339:, 2009 [PMID:19854840]
Comment: Clinical review of hyperkalemic disorders.
- Choi MJ, Ziyadeh FN: The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol 19:424, 2008 [PMID:18216310]
Comment: TTKG < 6 indicates impaired aldosterone action as a cause of hyperkalemia.
- Perschel FH et al: Rapid screening test for primary hyperaldosteronism: ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays. Clin Chem 50:1650, 2004 [PMID:15247156]
- Ferrari P et al: Active renin versus plasma renin activity to define aldosterone-to-renin ratio for primary aldosteronism. J Hypertens 22:377, 2004 [PMID:15076197]
- Oster JR, Singer I, Fishman LM: Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 98:575, 1995 [PMID:7778574]
- White PC: Disorders of aldosterone biosynthesis and action. N Engl J Med 331:250, 1994 [PMID:8015573]
Comment: Review of disorders of mineralocorticoid deficiency and resistance including CAH, aldosterone synthase deficiency, and pseudohypoaldosteronism.
- Ethier JH et al: The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J Kidney Dis 15:309, 1990 [PMID:2321642]
Comment: Defined expected values for TTKG in hypokalemia and hyperkalemia.
- West ML et al: New clinical approach to evaluate disorders of potassium excretion. Miner Electrolyte Metab 12:234, 1986 [PMID:3762510]
Comment: Described the use of TTKG in assessing renal mineralocorticoid action.
- Mayes D et al: A radioimmunoassay for plasma aldosterone. J Clin Endocrinol Metab 30:682, 1970 [PMID:5444558]
- Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001.
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