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, [[Hypertension]])
      • Hyperkalemia (see Hyperkalemia, [[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 -> these result in decreased systemic and intra-adrenal angiotensin II synthesis -> results 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, [[β-Adrenergic Receptor Antagonists]])
    • Calcineurin Inhibitors (see Calcineurin Inhibitors, [[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, [[Cyclosporine A]])
      • Tacrolimus (see Tacrolimus, [[Tacrolimus]])
    • Non-Steroidal Anti-Inflammatory Drug (NSAID) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal 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, [[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, [[Chronic Kidney Disease]]): with chronic interstitial nephritis
    • Diabetic Nephropathy (see Diabetes Mellitus, [[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, [[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, [[Captopril]])
    • Enalapril (Vasotec, Enalaprilat) (see Enalapril, [[Enalapril]])
    • Fosinopril (Monopril) (see Fosinopril, [[Fosinopril]])
    • Lisinopril (Zestril) (see Lisinopril, [[Lisinopril]])
    • Moexipril (Univasc) (see Moexipril, [[Moexipril]])
    • Perindopril (Coversyl, Coversum, Preterax, Aceon) (see Perindopril, [[Perindopril]])
    • Quinapril (Accupril) (see Quinapril, [[Quinapril]])
    • Ramipril (Altace) (see Ramipril, [[Ramipril]])
    • Trandolapril (Mavik) (see Trandolapril, [[Trandolapril]])
  • Angiotensin II Receptor Blockers (see Angiotensin II Receptor Blockers, [[Angiotensin II Receptor Blockers]])
    • Physiology: block angiotensin II activity at its receptor
    • Candesartan (Atacand) (see Candesartan, [[Candesartan]])
    • Fimasartan (Kanarb) (see Fimasartan, [[Fimasartan]])
    • Irbesartan (Avapro, Aprovel, Karvea) (see Irbesartan, [[Irbesartan]])
    • Losartan (Cozaar) (see Losartan, [[Losartan]])
    • Olmesartan (Benicar, Olmecip) (see Olmesartan, [[Olmesartan]])
    • Telmisartan (Micardis) (see Telmisartan, [[Telmisartan]])
    • Valsartan (Diovan) (see Valsartan, [[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, [[Enoxaparin]])
    • Heparin (see Heparin, [[Heparin]])
  • Renin Inhibitors
    • Physiology: directly inhibit renin activity
    • Aliskiren (Tekturna, Rasilez) (see Aliskiren, [[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, [[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, [[Drospirenone]]): synthetic hormone used in birth control pills
    • Eplerenone (Inspra) (see Eplerenone, [[Eplerenone]])
    • Spironolactone (Aldactone) (see Spironolactone, [[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)


  • Tubulointerstitial Renal Disease: defect in sodium reabsorption by distal tubule


  • Normal Physiologic Action of Aldosterone: aldosterone increases the number of open sodium channels on the luminal membrane of the principal cells in the cortical collecting tubule -> results in sodium reabsorption
    • The removal of sodium from the tubular fluid makes the lumen electronegative, creating an electrical gradient that favors the secretion of cellular potassium into the lumen through potassium channels on the luminal membrane


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, [[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, [[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, [[Fludrocortisone]]): dose of 0.05 to 0.2 mg/day
    • Rationale: to correct the hyperkalemia
  • Normal Saline (see Normal Saline, [[Normal Saline]])
    • Rationale: to correct the hypovolemia
  • Glucocorticoid
    • Rationale: to correct the cortisol deficiency
    • Hydrocortisone (see Hydrocortisone, [[Hydrocortisone]])
    • Prednisone (see Prednisone, [[Prednisone]])

Hyporeninemic Hypoaldosteronism

  • Fludrocortisone (Florinef) (see Fludrocortisone, [[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


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