Decreased Aldosterone Synthesis

Inherited Disorders

  • Congenital Isolated Hypoaldosteronism
    • 21 Hydroxylase Deficiency
    • Other Defects
  • Pseudohypoaldosteronism Type 2 (Gordon’s Syndrome)
    • Physiology: defects in WKNK1 or WNK4 kinases
    • Clinical
      • Familial Hypertension (see Hypertension)
      • Hyperkalemia (see Hyperkalemia)
      • Low or Low-Normal Plasma Renin Activity and Aldosterone Level
      • Metabolic Acidosis
      • Normal Renal Function

Hyporeninemic Hypoaldosteronism

  • General Comments
    • Hyporeninemic Hypoaldosteronism is Characterized by a Combination of Decreased Renin Release and an Intra-Adrenal Defect, Resulting in Decreased Systemic and Intra-Adrenal Angiotensin II Synthesis, Culminating in Decreased Aldosterone Secretion
      • The intra-adrenal defect may be related to the local renin-angiotensin system: this is supported by the fact that angiotensin II produced locally within the adrenal gland may stimulate the release of aldosterone
      • Many of these patients may also have decreased aldosterone responsiveness, since they require a higher mineralocorticoid dose for physiologic replacement
  • Advanced Age
  • Drug-Induced Hyporeninemic Hypoaldosteronism
    • Beta Blockers (see β-Adrenergic Receptor Antagonists)
    • Calcineurin Inhibitors (see Calcineurin Inhibitors)
      • Physiology: due to decreased secretion of aldosterone and decreased responsiveness to aldosterone (likely due to decreased mineralocorticoid receptor expression)
      • Cyclosporine A (see Cyclosporine A)
      • Tacrolimus (see Tacrolimus)
    • Nonsteroidal Anti-Inflammatory Drug (NSAID) (see Nonsteroidal Anti-Inflammatory Drug)
      • Physiology: dose-dependent COX-inhibition -> decreased renal prostaglandin synthesis -> decreased renal renin secretion
        • Additionally, impaired angiotensin II-induced release of aldosterone occurs
        • NSAID-induced decrease in glomerular filtration rate may also contribute to the development of hyperkalemia
  • Intrinsic Renal Disease
    • Acute Glomerulonephritis with Volume Expansion (see Acute Glomerulonephritis)
      • Treatment: responds to mineralocorticoid replacement
      • Prognosis: recovery of renal function (typically within 1-2 wks) leads to resolution of hyperkalemia
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease): with chronic interstitial nephritis
    • Diabetic Nephropathy (see Diabetes Mellitus)
      • Epidemiology: diabetic nephropathy accounts for approximately 50% of cases of hyporeninemic hypoaldosteronism
      • Physiology
        • Defect in the conversion of the precursor pro-renin to active renin -> low plasma renin activity
        • Volume expansion (due to diabetic and other chronic renal disease) may contribute
        • Increased atrial natriuretic peptide -> suppresses both the release of renin and hyperkalemia-induced secretion of aldosterone


  • Angiotensin Converting Enzyme (ACE) Inhibitors (see Angiotensin Converting Enzyme Inhibitors)
    • Physiology: impair the conversion of angiotensin I to angiotensin II systemically (and possibly within the adrenal zona glomerulosa) -> since the normal stimulatory effect of hyperkalemia on aldosterone release may be mediated in part by the adrenal generation of angiotensin II, ACE inhibitors can decrease both angiotensin II-mediated and potassium-mediated aldosterone release
      • In contrast to ARB’s and renin inhibitors, ACE inhibitors increase renin levels
    • Captopril (Capoten) (see Captopril)
    • Enalapril (Vasotec, Enalaprilat) (see Enalapril)
    • Fosinopril (Monopril) (see Fosinopril)
    • Lisinopril (Zestril) (see Lisinopril)
    • Moexipril (Univasc) (see Moexipril)
    • Perindopril (Coversyl, Coversum, Preterax, Aceon) (see Perindopril)
    • Quinapril (Accupril) (see Quinapril)
    • Ramipril (Altace) (see Ramipril)
    • Trandolapril (Mavik) (see Trandolapril)
  • Angiotensin II Receptor Blockers (see Angiotensin II Receptor Blockers)
    • Physiology: block angiotensin II activity at its receptor
    • Candesartan (Atacand) (see Candesartan)
    • Fimasartan (Kanarb) (see Fimasartan)
    • Irbesartan (Avapro, Aprovel, Karvea) (see Irbesartan)
    • Losartan (Cozaar) (see Losartan)
    • Olmesartan (Benicar, Olmecip) (see Olmesartan)
    • Telmisartan (Micardis) (see Telmisartan)
    • Valsartan (Diovan) (see Valsartan)
  • Heparins
    • Physiology: heparins have a direct toxic effect on the adrenal zona glomerulosa cells (this may be mediated by a decrease in the number and affinity of adrenal angiotensin II receptors)
      • May occur even with the low doses of heparin used for deep venous thrombosis prophylaxis
    • Enoxaparin (Lovenox) (see Enoxaparin)
    • Heparin (see Heparin)
  • Renin Inhibitors
    • Physiology: directly inhibit renin activity
    • Aliskiren (Tekturna, Rasilez) (see Aliskiren): renin inhibitor (may cause hyperkalemia when used in combination with ACE inhibitors or ARB’s)


  • Severe Illness
    • Physiology: decreased adrenal aldosterone synthesis (perhaps complicated by volume expansion)
      • Additionally, stress-induced ACTH hypersecretion may decrease aldosterone synthesis by diverting substrate to the synthesis of cortisol
  • Primary Adrenal Insufficiency (see Adrenal Insufficiency)
    • Physiology: decreased cortisol and aldosterone
      • Note: in contrast, pituitary disease does not result in hypoaldosteronism, since corticotropin (ACTH) does not play a major role in the regulation of aldosterone release

Aldosterone Resistance

Inherited Disorders

  • Pseudohypoaldosteronism Type 1
    • Subtypes
      • Autosomal Recessive Pseudohypoaldosteronism Type 1
      • Autosomal Dominant/Sporadic Pseudohypoaldosteronism Type 1
    • Physiology: resistance to action of aldosterone


  • Aldosterone Antagonists: antagonize the activity of aldosterone on the collecting tubule cells by competition for the aldosterone receptor
    • Drospirenone (Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, Angeliq) (see Drospirenone): synthetic hormone used in birth control pills
    • Eplerenone (Inspra) (see Eplerenone)
    • Spironolactone (Aldactone) (see Spironolactone)
  • Epithelial Sodium Channel (ENaC) Antagonists (see Epithelial Sodium Channel Antagonists): these agents act to close sodium channels on the luminal membrane of cells in the collecting tubule (collecting tubule is the site of action of aldosterone)




Plasma Renin

  • Technique: should be performed after the administration of a loop diuretic or 3 hrs in the upright position (as these will increase renin and aldosterone release in normal individuals)
  • Conditions
    • Hyporeninemic Hypoaldosteronism: usually low
    • Primary Adrenal Insufficiency: high (due to volume depletion and/or hypotension)

Serum Aldosterone

  • Technique: should be performed after the administration of a loop diuretic or 3 hrs in the upright position (as these will increase renin and aldosterone release in normal individuals)
  • Conditions
    • Hyporeninemic Hypoaldosteronism: low
    • Primary Adrenal Insufficiency: low

Serum Cortisol

  • Technique: should be performed after the administration of a loop diuretic or 3 hrs in the upright position (as these will increase renin and aldosterone release in normal individuals)
  • Conditions
    • Hyporeninemic Hypoaldosteronism: normal
    • Primary Adrenal Insufficiency: low

Clinical Manifestations

Renal Manifestations

Hyperkalemia (see Hyperkalemia)

  • Clinical: hyperkalemia is usually mild-moderate (except in the setting of other risk factors for hyperkalemia, such as ACE inhibitors, renal insufficiency, etc)

Type 4 Renal Tubular Acidosis (RTA) (see Type 4 Renal Tubular Acidosis)

  • Mechanisms of Decreased Urinary Ammonium Excretion
    • Impaired Potassium Excretion with Potassium Entry into Cells -> Consequent Movement of Sodium and Hydrogen Ion into the Extracellular Fluid (to Maintain Electroneutrality) -> Alkalosis in Kidney Decreases Ammonium Synthesis in the Proximal Tubule
    • Hyperkalemia Decreases Medullary Cycling by Inhibiting Ammonium Reabsorption in Thick Ascending Limb: ammonium is normally reabsorbed into the medullary interstitium and then is re-secreted into the medullary collecting tubule
    • Potassium Competition for the Collecting Duct Na-NH4 Exchanger (i.e. the Basolateral Na-K-ATPase) Which Functions to Permit Uptake of Ammonium from the Interstitium and Allow Its Secretion into the Urine: potassium impairs the capacity of this pump to carry ammonium into the cell
  • Clinical

Absence of Sodium-Wasting and Hyponatremia

  • Physiology
    • Although aldosterone normally acts to increase sodium retention, hypoaldosteronism is not usually associated with significant sodium wasting (except in young children)
      • This is due to the compensatory action of other sodium-retaining stimuli (such as angiotensin II and norepinephrine)
    • In the absence of hypovolemia-induced stimulation of ADH release (with normal plasma cortisol, which is an inhibitor of ADH release), hyponatremia is uncommon
      • When hyponatremia is present, primary adrenal insufficiency should be suspected: in primary adrenal insufficiency, the concurrent lack of cortisol potently stimulates secretion of ADH secretion, resulting in water retention and hyponatremia


Primary Adrenal Insufficiency

  • Fludrocortisone (Florinef) (see Fludrocortisone): dose of 0.05 to 0.2 mg/day
    • Rationale: to correct the hyperkalemia
  • Normal Saline (see Normal Saline)
    • Rationale: to correct the hypovolemia
  • Glucocorticoid

Hyporeninemic Hypoaldosteronism

  • Fludrocortisone (Florinef) (see Fludrocortisone): dose of 0.2 to 1 mg/day
    • Dose Considerations: note that this replacement dose is higher than that required in primary adrenal insufficiency, as these patients have some degree of aldosterone resistance (due to their underlying renal disease)
    • Rationale: to correct the hyperkalemia
    • Contraindications: these are commonly present and may be exacerbated by fludrocortisone
  • Low Potassium Diet: indicated
  • Loop Diuretic: may be useful to control the hyperkalemia