Phosphaturia

Phosphaturia is increased renal excretion of phosphate. In the pathological form, renal phosphate wasting causes hypophosphataemia, osteomalacia or rickets, muscle weakness and growth impairment.

The proximal tubule reabsorbs about 80 to 90% of filtered phosphate through the sodium phosphate cotransporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3). Fibroblast growth factor 23 and parathyroid hormone raise phosphate excretion.

Causes include:

• FGF23 mediated disease. This covers X-linked hypophosphataemia from PHEX variants, the commonest inherited cause, with a prevalence of about 1 in 20 000 people. It also covers autosomal dominant and recessive hypophosphataemic rickets from FGF23, DMP1 and ENPP1 variants, tumour induced osteomalacia from phosphaturic mesenchymal tumours, fibrous dysplasia, and iron infusions such as ferric carboxymaltose.
• FGF23 independent disease: hereditary hypophosphataemic rickets with hypercalciuria from SLC34A3, Fanconi syndrome, primary hyperparathyroidism, Dent disease, vitamin D deficiency.
• Drugs: tenofovir disoproxil, ifosfamide, cisplatin, aminoglycosides, valproate, aristolochic acid.

Pathophysiology. Reduced NaPi-IIa and NaPi-IIc at the brush border membrane increases urinary phosphate loss. FGF23 also suppresses 1-alpha-hydroxylase, lowering calcitriol, so intestinal phosphate absorption falls. Low phosphate impairs mineralisation of growth plate and bone.

• Children: rickets (bowed legs, widened wrists, rachitic rosary), short stature, delayed walking, dental abscesses (poorly mineralised dentine), craniosynostosis, delayed dentition.
• Adults: bone pain, osteomalacia, pseudofractures, fractures, muscle weakness, enthesopathy, hearing loss, dental abscesses, difficulty climbing stairs.
• Tumour induced osteomalacia: progressive severe bone pain and weakness, often over years, with a small hidden tumour (tumours of bone or soft tissue).
• Severe hypophosphataemia (under 0.3 mmol/L): rhabdomyolysis, respiratory failure, haemolysis, cardiac dysfunction, encephalopathy.
• Nephrocalcinosis and kidney stones (hypercalciuria in hereditary hypophosphataemic rickets with hypercalciuria and with treatment).
• Associated features: glycosuria, aminoaciduria, acidosis (Fanconi); family history.

Red flags

• Phosphate under 0.5 mmol/L with weakness or respiratory difficulty.
• Adult onset osteomalacia with no family history (tumour induced osteomalacia).
• Fractures or pseudofractures with a high alkaline phosphatase.
• Kidney failure, nephrocalcinosis or hyperparathyroidism during treatment.
• Pregnancy in X-linked hypophosphataemia.

• Fasting serum phosphate (age specific ranges; adults 0.8 to 1.5 mmol/L), calcium, albumin, magnesium, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, bicarbonate, glucose, potassium, creatinine, eGFR.
• 1,25-dihydroxyvitamin D is low or inappropriately normal in FGF23 disease. It is high in hereditary hypophosphataemic rickets with hypercalciuria.
• Renal phosphate handling: tubular maximum reabsorption of phosphate relative to glomerular filtration rate (TmP/GFR) under 0.8 mmol/L (0.7 to 1.2 normal) with hypophosphataemia confirms renal wasting.
• Urinary phosphate excretion above 0.1 mmol/kg daily despite low serum phosphate. Fractional excretion of phosphate above 5% when the serum phosphate is low.
• Intact FGF23 (raised or inappropriately normal in FGF23 mediated disease). Genetic testing (PHEX, FGF23, DMP1, ENPP1, SLC34A3, SLC34A1, CLCN5).
• Urinary calcium (hypercalciuria in hereditary hypophosphataemic rickets with hypercalciuria and Fanconi), urinary amino acids, glucose, beta-2 microglobulin (Fanconi).
• Imaging: skeletal radiographs, ultrasound for nephrocalcinosis.
• In tumour induced osteomalacia, localise the tumour with functional imaging (68Ga-DOTATATE positron emission tomography, whole body MRI), with venous sampling for FGF23 where needed.
• Drug and toxin review.

Differential diagnosis

• Vitamin D deficiency and dependent rickets, primary hyperparathyroidism, Fanconi syndrome (cystinosis, Dent disease, Lowe syndrome, light chain, drugs), refeeding syndrome and other non-renal causes of hypophosphataemia (malabsorption, alcohol, hyperventilation, insulin, antacids), fibrous dysplasia, hypophosphatasia.

X-linked and other FGF23 mediated hypophosphataemia

• Burosumab (anti-FGF23 antibody), children 1 year and over: 0.8 mg/kg subcutaneously every 2 weeks (start 0.4 mg/kg, increase to 0.8; maximum 90 mg each dose).
• Burosumab, adults: 1 mg/kg every 4 weeks (maximum 90 mg).
• Target fasting serum phosphate at the lower end of normal. Stop phosphate and active vitamin D supplements 1 week before starting.
• Monitor phosphate fortnightly for the first month. Monitor calcium, parathyroid hormone, alkaline phosphatase and nephrocalcinosis. Burosumab is contraindicated when phosphate is high or eGFR is under 30.
• Conventional therapy when burosumab is not available: oral phosphate 20 to 60 mg/kg elemental phosphorus daily in 4 to 5 divided doses (adults 750 to 1600 mg elemental phosphorus daily in 3 to 5 doses; start low to limit diarrhoea).
• Add calcitriol 20 to 30 ng/kg daily in 2 divided doses (adults 0.5 to 1.5 microg daily) or alfacalcidol 30 to 50 ng/kg daily (adults 1 to 3 microg daily).
• Titrate to alkaline phosphatase, parathyroid hormone and radiographic healing, not to normal phosphate.
• Monitor calcium, phosphate, parathyroid hormone and urinary calcium every 3 months, and ultrasound for nephrocalcinosis yearly.
• Reduce doses for hypercalciuria (above 0.1 mmol/kg daily), hypercalcaemia or secondary hyperparathyroidism.
• Orthopaedic correction of deformity after medical control; dental care.

Tumour induced osteomalacia. Locate and resect the tumour (cure in most). When unresectable, use burosumab 0.5 to 2 mg/kg every 4 weeks, or oral phosphate 750 to 1600 mg elemental phosphorus daily in 3 to 5 doses with calcitriol 0.5 to 1.5 microg daily in 2 divided doses. Radiofrequency ablation or radiotherapy are options.

Hereditary hypophosphataemic rickets with hypercalciuria. Phosphate alone: 1 to 2.5 g elemental phosphorus daily (children 20 to 40 mg/kg daily) in 4 to 5 divided doses. Avoid calcitriol, which raises urinary calcium. Monitor urinary calcium, parathyroid hormone and nephrocalcinosis.

Fanconi syndrome and secondary causes

• Treat the cause (stop tenofovir disoproxil, ifosfamide or other drugs; chemotherapy for light chain disease; cysteamine for cystinosis).
• Replace losses: phosphate 500 to 1000 mg elemental phosphorus daily in divided doses (maximum 3 g).
• Sodium bicarbonate 500 mg to 1 g two to three times daily, to bicarbonate at least 22 mmol/L.
• Potassium chloride 40 to 120 mmol daily in divided doses.
• Cholecalciferol 800 to 2000 units daily (50 000 units weekly for 6 to 8 weeks when 25-hydroxyvitamin D is under 25 nmol/L).
• Alfacalcidol 0.25 to 0.5 microg daily.

Acute severe hypophosphataemia (under 0.4 mmol/L, or symptomatic)

• Intravenous sodium glycerophosphate 20 mmol over 8 to 12 hours (or potassium phosphate 10 to 20 mmol over 6 hours in a monitored setting; reduce dose by 50% when eGFR is under 30).
• Repeat until phosphate is over 0.8 mmol/L. Check phosphate, calcium, magnesium and potassium every 6 to 12 hours. Give oral phosphate 500 to 1000 mg daily when able.
• Stop and treat the cause (refeeding, drugs, insulin, alcohol).

Complications. Hypertension, hyperparathyroidism (cinacalcet 30 mg daily, maximum 180 mg) and nephrocalcinosis (stop excessive vitamin D, reduce phosphate, fluids above 2.5 litres daily, thiazide for hypercalciuria). Chronic kidney disease: sodium under 2 g daily, ramipril for proteinuria, dialysis at eGFR 5 to 10 with symptoms.

Monitoring. Children: growth, radiographs and biochemistry every 3 months. Adults: every 6 to 12 months. Blood pressure and kidney ultrasound yearly. DEXA when adult.

Referral and escalation. Paediatric or adult metabolic bone and nephrology service. Endocrinology and nuclear medicine for tumour localisation. Urgent for symptomatic severe hypophosphataemia.

Special groups

• Pregnancy in X-linked hypophosphataemia: continue conventional therapy at lower doses. Burosumab is not used in pregnancy unless necessary. Monitor phosphate, calcium and urinary calcium. Risk of hypertension and pre-eclampsia.
• Children: early treatment prevents deformity; growth hormone is not routine.
• Adults: treat symptomatic osteomalacia and enthesopathy; avoid bisphosphonates in untreated osteomalacia.