Hypocitraturic Nephrolithiasis

Hypocitraturic nephrolithiasis is calcium stone formation driven by low urinary citrate, defined as under 320 mg (1.67 mmol) daily in adults. It is present in about 20 to 60% of stone formers, and is the sole metabolic abnormality in a minority.

It is easily treated with alkali citrate, which lowers recurrence in properly selected patients.

Pathophysiology. Citrate binds urinary calcium to form soluble calcium citrate and inhibits crystal nucleation, growth and aggregation of calcium oxalate and phosphate.

Proximal tubular reabsorption of citrate rises with intracellular acidosis and falls with alkalosis, so conditions that acidify the proximal cell lower urinary citrate.

Causes:

• Distal renal tubular acidosis.
• Chronic diarrhoea, malabsorption and bariatric surgery (bicarbonate loss).
• High animal protein and low fruit and vegetable intake (acid load).
• Hypokalaemia, high sodium intake, and strenuous exercise.
• Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide).
• Urinary infection (bacterial citrate consumption), and chronic kidney disease.
• Idiopathic, in many patients.

Recurrent calcium oxalate or calcium phosphate stones, colic, haematuria, nephrocalcinosis, and a history of diarrhoea, bariatric surgery or drugs that lower citrate. Distal renal tubular acidosis adds hypokalaemia and bone disease.

• Two 24-hour urine collections at least 6 weeks after a stone event, on the usual diet, for citrate, volume, pH, calcium, oxalate, uric acid, sodium, potassium and creatinine. Severe hypocitraturia is under 150 mg daily.
• Serum bicarbonate, chloride, potassium, calcium, phosphate, creatinine, eGFR and parathyroid hormone when calcium is high.
• Urine pH profile across the day, and urine culture.
• Non-contrast CT or ultrasound for stone burden and nephrocalcinosis.
• Stone analysis. Specialist testing for distal renal tubular acidosis if urine pH stays over 5.3 with acidosis.

Differential diagnosis.

• Hypercalciuric calcium stone disease
• Hyperoxaluric stone disease
• Distal renal tubular acidosis
• Medullary sponge kidney
• Primary hyperparathyroidism
• Enteric hyperoxaluria

• Potassium citrate orally, with meals or within 30 minutes after, in 2 to 3 divided doses. Severe hypocitraturia (under 150 mg daily): 60 mEq daily. Mild to moderate hypocitraturia: 30 mEq daily. Titrate to urine citrate over 320 mg daily (ideal 400 to 500 mg) and urine pH of 6.0 to 7.0. Maximum 100 mEq daily. Extended release tablets are swallowed whole.
• Contraindications: hyperkalaemia, eGFR under 30, untreated adrenal insufficiency, acute dehydration, urease producing urinary infection, peptic ulcer, and delayed gastric emptying or intestinal obstruction.
• Interactions raising potassium: potassium sparing diuretics, ACE inhibitors, angiotensin receptor blockers, trimethoprim, NSAIDs and heparin. Anticholinergics slow gut transit and increase the risk of gastrointestinal injury.
• Adverse effects: nausea, abdominal pain, diarrhoea, hyperkalaemia and metabolic alkalosis.
• Sodium citrate or sodium bicarbonate can be used when potassium is high, but the sodium load raises urinary calcium.
• Lemon juice (about 120 mL daily, diluted) has weaker effect and is an adjunct only.
• Treat the cause: correct diarrhoea and fluid loss, distal renal tubular acidosis (alkali), hypokalaemia, urinary infection, and stop or replace carbonic anhydrase inhibitors.
• Diet: more fruit and vegetables, animal protein 0.8 to 1 g/kg daily, salt under 5 g daily, and fluid for a urine volume over 2.5 L daily.
• Stone removal when active stones are present, directed by size and position.

Special groups. Pregnancy: safety data are limited and treatment needs specialist review. Children need weight based dosing by a paediatric nephrologist.

Monitoring. Serum potassium, bicarbonate and creatinine 1 to 2 weeks after starting, then every 4 to 6 months. 24-hour urine at 3 months for citrate and pH, then yearly. Imaging yearly in recurrent stone formers.

Referral and escalation. Refer to a stone clinic or nephrology for recurrent stones, renal tubular acidosis, bariatric surgery, or eGFR under 45. Urgent referral for hyperkalaemia, acute kidney injury or infection with obstruction.