Hyporeninaemic Hypoaldosteronism

Hyporeninaemic hypoaldosteronism is a disorder in which low renin secretion from damaged juxtaglomerular cells leads to low aldosterone. It causes hyperkalaemia and non-anion gap metabolic acidosis out of proportion to the reduction in glomerular filtration (type 4 renal tubular acidosis).

It is the commonest cause of persistent hyperkalaemia with acidosis in adults. It occurs mostly in people aged over 50 years with diabetes (the cause in 50 to 70%) and mild to moderate chronic kidney disease (eGFR 20 to 60). It also complicates chronic tubulointerstitial nephritis, HIV nephropathy, obstructive uropathy, myeloma, amyloid, sickle cell nephropathy and lupus nephritis.

Drugs increase the risk:

• NSAIDs and cyclo oxygenase 2 inhibitors (reduce prostaglandin driven renin release).
• Calcineurin inhibitors.
• Beta blockers, ACE inhibitors and angiotensin receptor blockers.
• Heparin and trimethoprim.

Volume expansion (diabetes and tubular sodium retention) suppresses renin further.

Pathophysiology. Damage to the juxtaglomerular apparatus and autonomic neuropathy reduce renin release. Low angiotensin II and aldosterone reduce potassium and hydrogen ion secretion by the collecting duct. Hyperkalaemia suppresses ammonium production and aggravates acidosis.

• Frequently asymptomatic: potassium 5.5 to 6.5 mmol/L, bicarbonate 15 to 20 mmol/L, chronic course.
• Weakness, palpitations, bradycardia, heart block, occasional paralysis.
• Hypertension, mild volume expansion and oedema (renin is low, so sodium is retained rather than lost).
• Diabetes with autonomic neuropathy and postural hypotension.
• Kidney function mildly or moderately reduced; hyperkalaemia is greater than expected from eGFR.

Red flags

• Potassium over 6.0 mmol/L or ECG changes.
• Rapid worsening after starting ACE inhibitor, NSAID, trimethoprim or potassium supplements.
• Severe acidosis (bicarbonate under 15 mmol/L).
• Hyperkalaemia with syncope or bradycardia (beta blocker, conduction disease).

• Potassium (non-haemolysed), sodium, bicarbonate, chloride, anion gap (normal), creatinine, eGFR, glucose, HbA1c, venous blood gas, ECG.
• Plasma renin (low) and aldosterone (low) after exclusion of drug effects; a rise in aldosterone after furosemide 40 mg and 3 hours upright is impaired.
• Urine pH (under 5.5 in most; acidification is intact), urinary ammonium (low), urine potassium, transtubular potassium gradient (under 7), urine anion gap (positive).
• Urine protein:creatinine ratio, urine microscopy, kidney ultrasound; serum protein electrophoresis and free light chains when interstitial disease or myeloma is suspected.
• Cortisol and synacthen test when adrenal insufficiency is possible.

Differential diagnosis

• Adrenal insufficiency, aldosterone synthase deficiency, pseudohypoaldosteronism, Gordon syndrome, advanced chronic kidney disease, drug induced hyperkalaemia, obstructive uropathy, rhabdomyolysis, insulin deficiency, pseudohyperkalaemia.

First line: remove causes and reduce potassium

• Stop or substitute NSAIDs, trimethoprim, heparin, potassium supplements and salt substitutes containing potassium.
• Review beta blockers, calcineurin inhibitors, ACE inhibitors and angiotensin receptor blockers (reduce rather than stop when the benefit is high).
• Dietary potassium 50 to 70 mmol (2 to 2.7 g) daily; avoid salt substitutes; sodium under 2 g daily.
• Loop diuretic: furosemide 40 to 80 mg once or twice daily (higher doses when eGFR is under 30). Check sodium, potassium, magnesium and creatinine at 1 week.
• Alternatively, a thiazide such as hydrochlorothiazide 12.5 to 25 mg daily while eGFR is at least 30. Chlortalidone 12.5 to 25 mg daily is also effective when eGFR is under 30.
• Sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L (watch fluid overload; avoid in heart failure).
• Glucose control, blood pressure below 130/80 mmHg.

Alternative and specialist

• Fludrocortisone 0.05 to 0.2 mg daily when hypertension and oedema are absent (monitor blood pressure, weight, potassium at 1 week; avoid in heart failure).
• Potassium binders to allow continued renin angiotensin blockade:
  • Sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours, then 5 to 10 g daily (maximum 15 g, with oedema watched).
  • Patiromer 8.4 g daily increasing to 25.2 g (separate from other drugs by 3 hours).
• Renoprotection: ramipril 2.5 to 10 mg daily (check creatinine and potassium at 1 to 2 weeks; accept a rise up to 30%; stop if potassium exceeds 6.0 mmol/L).
• Finerenone 10 mg daily (20 mg when eGFR is at least 60) only with potassium under 5.0 mmol/L.
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) lowers hyperkalaemia risk.

Emergency: potassium over 6.5 mmol/L or ECG changes

• Calcium gluconate 10% 10 mL intravenously over 10 minutes.
• Insulin 10 units with glucose 25 g.
• Salbutamol 10 to 20 mg nebulised.
• Sodium zirconium cyclosilicate 10 g three times daily for up to 48 hours, then 5 to 10 g daily (maximum 15 g).
• Dialysis if refractory, oliguric or pH under 7.15.

Monitoring. Potassium and bicarbonate at 1 week after any change, then every 3 months. Creatinine, eGFR, glucose, blood pressure and weight at each visit.

Referral and escalation. Nephrology for persistent potassium over 5.5 mmol/L despite treatment; endocrinology when adrenal disease is possible; urgent for ECG changes or potassium over 6.5 mmol/L.

Special groups

• Older adults with diabetes: higher risk of drug precipitated hyperkalaemia; check potassium within 1 week of any new drug.
• Kidney transplant recipients: calcineurin inhibitor induced hyperkalaemia responds to dose reduction, fludrocortisone and loop diuretics.
• Pregnancy: avoid ACE inhibitors and mineralocorticoid antagonists; manage with diet, loop diuretics and bicarbonate.