Renal Tubular Dysfunction

Renal tubular dysfunction is impaired function of one or more tubular segments, causing wasting of solutes, defective urinary acidification or concentration, and electrolyte disturbance, with relative preservation of glomerular filtration. It may be inherited or acquired.

Segment based syndromes:

• Proximal tubule: Fanconi syndrome (glycosuria with normal blood glucose, phosphaturia, aminoaciduria, bicarbonate wasting, uricosuria, tubular proteinuria) and isolated proximal renal tubular acidosis (type 2)
• Thick ascending limb: Bartter syndrome (hypokalaemic alkalosis, hypercalciuria, salt wasting)
• Distal convoluted tubule: Gitelman syndrome (hypokalaemic alkalosis, hypomagnesaemia, hypocalciuria)
• Collecting duct: distal renal tubular acidosis (type 1), nephrogenic diabetes insipidus, Liddle syndrome (hypertension, hypokalaemia), pseudohypoaldosteronism (salt wasting, hyperkalaemia)

Acquired causes include drugs (tenofovir, ifosfamide, cisplatin, aminoglycosides, amphotericin B, lithium, expired tetracycline, valproate), heavy metals, paraproteinaemias (light chain proximal tubulopathy), Sjögren syndrome, interstitial nephritis, obstruction, sickle cell disease and kidney transplantation.

Inherited causes include cystinosis, Dent disease, Lowe syndrome, galactosaemia, Wilson disease and hereditary fructose intolerance.

• Polyuria, polydipsia and dehydration; salt craving
• Muscle weakness, cramps and tetany; paralysis in severe hypokalaemia
• Growth failure, rickets, bone pain and pathological fractures from phosphate wasting
• Nephrocalcinosis and calculi in distal renal tubular acidosis
• Hypertension in Liddle syndrome; normal or low blood pressure in Bartter, Gitelman
• Hearing loss in distal renal tubular acidosis (ATP6V1B1 variants) and Bartter type IV
• Photophobia and hypothyroidism in cystinosis

Red flags: life threatening hypokalaemia (below 2.5 mmol/L) with arrhythmia, severe acidosis (bicarbonate below 12 mmol/L), failure to thrive, rickets, rapidly progressing eGFR decline, ongoing exposure to a nephrotoxin.

• Blood: sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate, urate, glucose, creatinine, venous blood gas
• Urine: pH, glucose, amino acids, phosphate, calcium, magnesium, protein electrophoresis (low molecular weight proteins), osmolality
• Fractional excretion of phosphate and uric acid; tubular reabsorption of phosphate (TmP/GFR)
• Urine anion gap (sodium + potassium minus chloride): positive in distal renal tubular acidosis, negative in gastrointestinal bicarbonate loss
• Distal renal tubular acidosis: urine pH above 5.5 despite systemic acidosis; confirm with oral furosemide 40 mg and fludrocortisone 1 mg if uncertain
• Proximal renal tubular acidosis: urine pH falling to 5.5 or less once serum bicarbonate drops under the proximal reabsorptive threshold; fractional bicarbonate excretion above 15% after bicarbonate loading
• Renal ultrasound for nephrocalcinosis
• Genetic testing for Bartter, Gitelman, Dent, cystinosis, Liddle and others

Differentials: gastrointestinal bicarbonate loss, hypokalaemia from vomiting or diuretics (urine chloride below 20 mmol/L in vomiting), diabetic ketoacidosis, diuretic use, primary hyperaldosteronism, hypercalcaemia, nephrogenic diabetes insipidus.

Remove the cause

• Stop tenofovir (switch to alternatives), aminoglycosides, ifosfamide or lithium where possible.
• Treat paraproteinaemia or Sjögren syndrome.

Electrolyte replacement

• Hypokalaemia: potassium chloride 40 to 80 mmol daily orally in divided doses; intravenous potassium chloride 10 mmol/h (20 mmol/h with monitoring in severe arrhythmia), maximum 40 mmol/L concentration peripherally.
• Hypomagnesaemia: magnesium sulphate 8 mmol intravenously over 1 hour acutely; magnesium glycerophosphate 4 mmol orally two to three times daily.
• Hypophosphataemia: oral phosphate 250 to 500 mg elemental phosphorus (8 to 16 mmol) two to four times daily; reduce for diarrhoea.
• Acidosis (proximal): sodium bicarbonate or potassium citrate in large doses, often 5 to 15 mmol/kg daily in children and adults, divided into 4 to 6 doses.
• Acidosis (distal): alkali 1 to 2 mmol/kg daily (sodium bicarbonate 500 mg to 1 g orally three times daily or potassium citrate 10 mEq three times daily), titrated to serum bicarbonate at least 22 mmol/L.

Disease specific

• Bartter and Gitelman syndromes: high salt intake, potassium and magnesium supplements, spironolactone 25 to 100 mg daily or amiloride 5 to 20 mg daily; indomethacin 25 to 50 mg two to three times daily in Bartter (with proton pump inhibitor).
• Liddle syndrome: amiloride 5 to 10 mg twice daily and salt restriction.
• Fanconi syndrome: alfacalcidol 0.25 to 1 microg daily, phosphate, bicarbonate and potassium; cysteamine for cystinosis.
• Nephrogenic diabetes insipidus: hydrochlorothiazide 25 to 50 mg daily with amiloride 5 to 10 mg.
• Dent disease: thiazide for hypercalciuria; stone prevention.

Monitoring. Potassium, bicarbonate, calcium, phosphate and magnesium at 2 to 4 weeks after dose change, then every 3 to 6 months; annual renal ultrasound for nephrocalcinosis.

Refer to nephrology and, for children, paediatric nephrology and genetics.

Special groups. Children need early, aggressive alkali and phosphate replacement to protect growth and prevent rickets; dose by weight and review every 3 months.