Aminoaciduria

Aminoaciduria is increased urinary excretion of amino acids. It is caused either by raised plasma levels that exceed the renal threshold (overflow aminoaciduria in metabolic diseases such as phenylketonuria and tyrosinaemia), or by defective renal tubular reabsorption despite normal plasma levels (renal aminoaciduria).

Renal aminoaciduria is selective (a transporter defect for a group of amino acids) or generalised (global proximal tubular dysfunction in Fanconi syndrome).

The principal selective disorders:

• Cystinuria (SLC3A1 and SLC7A9; autosomal recessive and incomplete dominant; about 1 in 7000 people): excess cystine, ornithine, lysine and arginine. It accounts for 1 to 2% of adult stones and 6 to 8% of paediatric stones.
• Hartnup disease (SLC6A19; neutral amino acids; about 1 in 30 000 people).
• Iminoglycinuria (SLC36A2, SLC6A20; benign).
• Lysinuric protein intolerance (SLC7A7; severe).
• Dicarboxylic aminoaciduria.

Generalised aminoaciduria occurs in:

• Inherited Fanconi syndromes (cystinosis, Dent disease, Lowe syndrome, Fanconi-Bickel syndrome, hereditary fructose intolerance, tyrosinaemia type 1, Wilson disease, galactosaemia).
• Acquired Fanconi syndrome (light chain proximal tubulopathy, tenofovir disoproxil, ifosfamide, cisplatin, aminoglycosides, outdated tetracyclines, valproate, aristolochic acid, cadmium and lead).
• Tubulointerstitial disease.

Pathophysiology. Amino acids are filtered freely and about 99% is reabsorbed in the proximal tubule by sodium coupled and exchange transporters. Loss of function of a transporter raises urinary excretion of its substrates. For cystine, poor solubility (about 1 mmol/L at pH 5 to 7) leads to crystallisation and stones.

• Cystinuria: recurrent kidney stones from childhood or young adulthood (cystine stones are radiopaque and often staghorn), renal colic, haematuria, urinary tract infection, obstruction and chronic kidney disease. Up to 70% have some loss of function after repeated stones and surgery. No other features.
• Hartnup disease: usually asymptomatic. Photosensitive pellagra like rash, cerebellar ataxia, psychiatric symptoms, in poor diet or illness.
• Lysinuric protein intolerance: failure to thrive, hepatosplenomegaly, hyperammonaemia after protein meals, osteoporosis, pulmonary alveolar proteinosis, nephropathy.
• Fanconi syndrome: polyuria, polydipsia, dehydration, failure to thrive, rickets or osteomalacia, hypokalaemic weakness, acidosis, with glycosuria, phosphaturia and low molecular weight proteinuria.
• Cystinosis presents with photophobia and renal failure by age 10.
• Isolated aminoaciduria on screening may be benign.

Red flags

• Recurrent stones in a young person, or stones with a family history.
• Growth failure, rickets, polyuria or acidosis (Fanconi syndrome).
• Hyperammonaemia, vomiting or drowsiness after protein feeding.
• New aminoaciduria on tenofovir, ifosfamide or cisplatin.
• Rapid loss of kidney function.

• Urine amino acid chromatography or tandem mass spectrometry (quantitative) on a fresh sample, with plasma amino acids to separate renal from overflow patterns (normal or low plasma amino acids in renal disease).
• Cystinuria: urinary cystine excretion above 1.3 mmol daily (urine cystine above 250 micromol/g creatinine in a spot sample; heterozygotes under 1 mmol daily).
• Cystinuria: cyanide nitroprusside test (positive above 75 mg/g creatinine), hexagonal crystals on microscopy, stone analysis (cystine). Genetic testing (SLC3A1 and SLC7A9) for classification and counselling.
• Fanconi syndrome: serum phosphate, bicarbonate, potassium, urate, glucose, urinary glucose (with normal blood glucose), phosphate wasting, beta-2 microglobulin, urine protein:creatinine ratio, creatinine, eGFR.
• Investigate the cause of Fanconi syndrome: cystine in white cells for cystinosis, slit lamp for corneal cystine crystals, serum free light chains, copper studies, drug history, genetic panel.
• Imaging for stones: non-contrast CT or ultrasound; plain radiograph shows faintly radiodense stones.
• Hartnup disease: urinary neutral amino acids with indolyl compounds in urine; plasma amino acids normal.

Differential diagnosis

• Other causes of kidney stones (calcium oxalate, uric acid, struvite, primary hyperoxaluria), overflow aminoaciduria from metabolic disease, transient neonatal aminoaciduria, hepatic disease, burns, liver failure, acquired Fanconi syndrome from drugs or toxins, tubulointerstitial disease, isolated renal glycosuria.

Cystinuria (prevent stones; the aim is urine cystine concentration under 1 mmol/L, or under 250 mg/L)

• Hydration: fluid intake 3.5 to 4 litres daily for adults (150 to 200 mL/kg daily in children, or 1.5 litres/m²). Spread it through the day including at night (aim for urine volume above 3 litres daily), with about 500 mL before bed and again at night waking.
• Dietary: sodium under 2 g daily (sodium excretion increases cystine excretion), protein 0.8 to 1 g/kg daily (avoid high methionine intake, which is a precursor of cystine), plenty of fruit and vegetables for alkali.
• Urinary alkalinisation to pH 7.0 to 7.5 (cystine solubility rises sharply once urine pH is over 7.0): potassium citrate 60 to 80 mEq daily in 3 divided doses (adults), sodium bicarbonate 1 to 2 g three times daily, or acetazolamide 250 mg at night.
• Check urine pH with dipsticks 3 times daily and at least once at night. Monitor potassium (especially when eGFR is under 45) and phosphate stones.
• Thiol drugs when stones recur despite these measures, or urinary cystine is above 3 mmol daily:
  • Tiopronin 250 mg daily increasing by 250 mg weekly to 800 to 2000 mg daily in 3 divided doses (adults; children 15 mg/kg daily), taken after meals.
  • D-penicillamine 1 to 2 g daily in 3 to 4 divided doses. It is second line because of rash, nephrotic syndrome, loss of taste, and pyridoxine deficiency. Give pyridoxine 25 mg daily, and monitor full blood count and urine protein monthly for 3 months.
  • Captopril 25 mg three times daily is weaker.
• Stone management: extracorporeal shock wave lithotripsy is often ineffective for cystine stones, so ureteroscopy with laser or percutaneous nephrolithotomy are preferred. Preserve renal function; avoid repeated open surgery; stone analysis; yearly imaging (low dose CT or ultrasound).
• Treat infection promptly (ciprofloxacin 500 mg twice daily for 7 days or co-trimoxazole 960 mg twice daily, adjusted to eGFR).
• Chronic kidney disease: blood pressure below 130/80 mmHg, ramipril 2.5 mg daily increased to 10 mg daily (stop if potassium exceeds 6.0 mmol/L), sodium under 2 g daily.
• Pregnancy: fluids and alkali continue; avoid D-penicillamine and tiopronin where possible.

Hartnup disease. Usually no treatment. High protein diet, sunscreen and avoidance of photosensitising drugs. Nicotinamide 40 to 200 mg daily (and tryptophan ethyl ester) for pellagra like symptoms.

Cystinosis. Cysteamine immediate release 1.3 g/m² daily in 4 divided doses (maximum 1.95 g/m² daily), or delayed release 1.3 g/m² daily in 2 divided doses. Cysteamine eye drops for corneal crystals. Replacement of losses (sodium bicarbonate 1 to 2 mmol/kg, phosphate, potassium, vitamin D, sodium chloride, water). Growth hormone; levothyroxine; kidney transplantation (disease does not recur).

Other Fanconi syndromes

• Treat the cause: stop tenofovir disoproxil, ifosfamide, cisplatin, valproate; chemotherapy for light chain disease; fructose, galactose or tyrosine restriction with nitisinone 1 mg/kg daily for tyrosinaemia type 1; copper chelation for Wilson disease.
• Replace losses: sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L; neutral phosphate 500 to 1000 mg elemental phosphorus daily in divided doses.
• Also potassium chloride 40 to 120 mmol daily in divided doses; cholecalciferol 800 to 2000 units daily; alfacalcidol 0.25 to 0.5 microg daily; fluids to match polyuria.
• Chronic kidney disease: dialysis at eGFR 5 to 10 with symptoms; transplantation.

Lysinuric protein intolerance. Protein restriction (0.8 to 1.5 g/kg daily), citrulline 100 to 150 mg/kg daily in divided doses, sodium benzoate or phenylbutyrate for hyperammonaemia, lysine supplementation, and specialist metabolic care.

Monitoring. Cystinuria: 24-hour urine volume, pH and cystine every 3 to 6 months initially, then yearly. Imaging yearly. Creatinine, eGFR and blood pressure every 6 to 12 months. Fanconi syndrome: electrolytes, phosphate, bicarbonate, creatinine monthly to 3 monthly; growth in children.

Referral and escalation. Nephrology and urology for stones; metabolic and genetic services for children and hereditary Fanconi syndromes; urgent for obstruction, sepsis or hyperammonaemia.

Special groups

• Children: stones appear early; hydration needs are large (nocturnal fluids); weight based thiol dosing under specialist care.
• Pregnancy: continue hydration and alkali; avoid penicillamine; increased risk of urinary tract infection.
• Sub-Saharan Africa: acquired Fanconi syndrome from tenofovir disoproxil and traditional medicines is common; check eGFR, phosphate and urine amino acids in patients on tenofovir.