Mineralocorticoid Resistance

Mineralocorticoid resistance is reduced tissue response to aldosterone, causing salt loss, hyperkalaemia, metabolic acidosis and raised renin and aldosterone. It is either primary (pseudohypoaldosteronism) or secondary to another renal condition or drug.

The inherited form results from loss-of-function variants in the mineralocorticoid receptor (NR3C2, autosomal dominant renal pseudohypoaldosteronism type 1) or in the epithelial sodium channel (SCNN1A, SCNN1B, SCNN1G, autosomal recessive systemic form).

Secondary resistance is more common. Causes include obstructive uropathy, urinary infection in infants, kidney transplantation, interstitial nephritis, sickle cell disease, diabetes (type 4 renal tubular acidosis), and drugs.

Pathophysiology.

Aldosterone cannot promote sodium reabsorption and potassium and hydrogen secretion in the collecting duct. Sodium wasting causes volume depletion and raised renin and aldosterone, while potassium and acid are retained.

Drugs acting at different sites are spironolactone, eplerenone, amiloride, trimethoprim, heparin, calcineurin inhibitors and ACE inhibitors.

• Infants: vomiting, poor feeding, failure to thrive, dehydration and hypotension, with sodium low and potassium high.
• Older children and adults: often asymptomatic with mild hyperkalaemia, muscle weakness or arrhythmia.
• Features of the underlying cause such as urinary tract obstruction.

Red flags.

• Potassium over 6.5 mmol/L or ECG changes.
• Shock or dehydration in an infant.

• Sodium low, potassium high, bicarbonate low, urea normal or raised, with plasma renin and aldosterone markedly raised and urinary sodium inappropriately high.
• Exclude adrenal insufficiency and congenital adrenal hyperplasia (cortisol and 17-hydroxyprogesterone normal), and a drug or renal cause (renal tract ultrasound, urine culture, medicines review).
• Sweat chloride is high in the systemic form (and the chest disease can mimic cystic fibrosis).
• NR3C2, SCNN1A, SCNN1B and SCNN1G sequencing. Fludrocortisone gives no response.

Differential diagnosis.

• Primary adrenal insufficiency and congenital adrenal hyperplasia (salt wasting form).
• Secondary pseudohypoaldosteronism (urinary tract infection or obstruction).
• Gordon syndrome (hypertension, low renin) and hyporeninaemic hypoaldosteronism.

• Treat hyperkalaemia with potassium over 6.5 mmol/L or ECG changes: calcium gluconate 10% 10 mL intravenously over 10 minutes, soluble insulin 10 units with glucose 25 g over 15 minutes, and nebulised salbutamol 10 to 20 mg. Add a potassium binder.
• Sodium chloride supplements: 3 to 10 mmol/kg daily in infants with renal disease, up to 20 mmol/kg or more in the severe systemic form, in several doses.
• Potassium binders (calcium polystyrene sulphonate or sodium zirconium cyclosilicate), a low potassium diet, and bicarbonate for acidosis.
• Treat the secondary cause: relieve obstruction, treat infection and stop causative drugs. Fludrocortisone does not help.
• Genetic counselling: 50% risk for children in dominant disease and 25% recurrence risk in siblings in recessive disease.

Special groups. Infants: avoid dehydration, with frequent feeding. Adults with renal disease: review all drugs that raise potassium.

Monitoring. Sodium, potassium and acid base every 1 to 3 months in infants, then every 6 months, and growth, and renal ultrasound as indicated.

Referral and escalation. Paediatric endocrinology and nephrology; emergency admission for hyperkalaemia.