Hyperphosphataemia

Also known as: Hyperphosphatemia, High phosphate

Hyperphosphataemia is an elevated serum phosphate, and because phosphate is renally excreted, chronic kidney disease is by far the commonest cause. It is a central component of chronic kidney disease-mineral and bone disorder, driving secondary hyperparathyroidism, vascular calcification and increased cardiovascular mortality.

Other causes fall into three groups: reduced excretion (acute kidney injury, hypoparathyroidism), massive cellular release (tumour lysis syndrome, rhabdomyolysis, haemolysis, severe catabolic states), and increased intake or absorption (phosphate-containing enemas and laxatives, excessive vitamin D, intravenous phosphate).

Acutely, the main hazard is not phosphate itself but the hypocalcaemia it produces through calcium-phosphate precipitation, and the acute kidney injury that follows deposition in renal tissue.

Serum phosphate, interpreted alongside calcium, PTH, magnesium and renal function, since phosphate in isolation says little
The calcium-phosphate product is a useful indicator of precipitation risk, with a markedly raised product carrying a risk of metastatic calcification
Renal function to identify acute or chronic kidney disease as the underlying driver
Where phosphate is high and renal function is normal, consider hypoparathyroidism (low calcium, low PTH), tumour lysis syndrome or rhabdomyolysis (check LDH, urate, potassium, creatine kinase), and exogenous phosphate load — phosphate-containing bowel preparations and enemas are a recognised and preventable cause of severe hyperphosphataemia, particularly in older patients and those with renal impairment
Pseudohyperphosphataemia can occur with haemolysed samples, paraproteinaemia or hyperbilirubinaemia
In chronic kidney disease, phosphate is monitored serially as part of routine bone mineral management rather than investigated afresh each time

Acute severe hyperphosphataemia:

Treat the underlying cause, which is usually the definitive action
Intravenous saline promotes phosphaturia where renal function permits
Haemodialysis for severe hyperphosphataemia with renal failure, symptomatic hypocalcaemia, or tumour lysis syndrome
Manage the associated hypocalcaemia cautiously: giving calcium while phosphate is very high risks precipitating calcium-phosphate in tissues, so calcium is generally reserved for symptomatic hypocalcaemia rather than given to normalise the number

Chronic kidney disease:

Dietary phosphate restriction, with dietitian input, focusing particularly on processed foods containing inorganic phosphate additives, which are far more readily absorbed than the organic phosphate in natural foods and are frequently the largest modifiable contributor
Phosphate binders, taken with meals so they bind dietary phosphate in the gut rather than being given between meals, which is a common and consequential administration error:

Calcium-based binders (calcium carbonate, calcium acetate), effective but contribute to calcium load and vascular calcification
Non-calcium binders (sevelamer, lanthanum), preferred where calcium load or vascular calcification is a concern
Iron-based binders (sucroferric oxyhydroxide, ferric citrate), which also provide iron

Manage secondary hyperparathyroidism alongside, with activated vitamin D analogues and calcimimetics as indicated
Adequate dialysis in dialysis-dependent patients

Prevention: avoid phosphate-containing bowel preparations and enemas in renal impairment and in older patients.

Referral: nephrology for chronic kidney disease-mineral and bone disorder management and for dialysis decisions.

Hypercalcaemia

Also known as: Hypercalcemia, High calcium

Hypercalcaemia is a raised corrected serum calcium, graded broadly as mild (up to about 3.0 mmol/L), moderate (3.0–3.4 mmol/L) and severe (≥3.4 mmol/L, or any level with significant symptoms).

Because roughly 40% of calcium is albumin-bound, the corrected value must be used, or hypercalcaemia will be missed in hypoalbuminaemic patients and over-diagnosed in others.

Primary hyperparathyroidism and malignancy together account for around 90% of cases, and the distinction is usually straightforward: primary hyperparathyroidism tends to be chronic, mild and asymptomatic in an outpatient, while malignancy-associated hypercalcaemia is usually higher, symptomatic and of shorter history.

Other causes include granulomatous disease (sarcoidosis, tuberculosis), vitamin D toxicity, thiazides, lithium, thyrotoxicosis, immobilisation, milk-alkali syndrome and familial hypocalciuric hypercalcaemia.

The classic summary of "bones, stones, abdominal groans and psychic moans" remains a useful memory aid.

Renal: polyuria and polydipsia (nephrogenic diabetes insipidus), nephrolithiasis, nephrocalcinosis, and acute kidney injury from volume depletion
Gastrointestinal: anorexia, nausea, vomiting, constipation, abdominal pain, peptic ulceration and pancreatitis
Neuropsychiatric: fatigue, poor concentration, depression, confusion, and in severe hypercalcaemia drowsiness, stupor and coma
Musculoskeletal: bone pain, proximal muscle weakness, and in longstanding hyperparathyroidism osteitis fibrosa cystica
Cardiac: shortened QT interval, bradycardia, and arrhythmia in severe cases, with increased digoxin sensitivity

Volume depletion is central to the pathophysiology and drives a vicious cycle: hypercalcaemia causes polyuria and vomiting, which cause dehydration, which reduces renal calcium excretion, which raises calcium further. Breaking that cycle with fluid is the first therapeutic priority.

Corrected calcium, repeated to confirm, alongside albumin. Ionised calcium is preferable where available and where the correction is unreliable, as in critical illness or acid-base disturbance
PTH is the single most useful discriminating test: an inappropriately normal or raised PTH indicates primary (or tertiary) hyperparathyroidism, while a suppressed PTH points to a non-parathyroid cause, principally malignancy
If PTH is suppressed: PTHrP (humoral hypercalcaemia of malignancy), vitamin D metabolites (raised 1,25-dihydroxyvitamin D suggests granulomatous disease or lymphoma), myeloma screen, and imaging directed by the clinical picture
Renal function, phosphate, magnesium, alkaline phosphatase
ECG for QT shortening
24-hour urinary calcium and the calcium-creatinine clearance ratio to identify familial hypocalciuric hypercalcaemia, an important benign mimic in which parathyroidectomy is inappropriate and which is otherwise easily mistaken for mild primary hyperparathyroidism
Review medications, particularly thiazides, lithium, calcium and vitamin D supplements

Differentials: as above, with the practical task usually being to separate parathyroid-driven from non-parathyroid causes and then to identify the specific underlying disease.

Severe or symptomatic hypercalcaemia:

Intravenous isotonic saline is the first and most important step, typically several litres over the first 24 hours, correcting volume depletion and promoting calciuresis. This alone often produces a substantial fall
Loop diuretics are no longer recommended routinely and should be used only once the patient is genuinely volume replete and where fluid overload is a concern; giving furosemide to a dehydrated hypercalcaemic patient worsens the problem
Intravenous bisphosphonate (zoledronic acid or pamidronate) for malignancy-associated hypercalcaemia, with the important caveat that the effect takes 2–4 days, so it does not substitute for fluid in the acute phase. Dose adjustment is needed in renal impairment
Calcitonin works within hours and is useful as a bridge while awaiting bisphosphonate effect, though tachyphylaxis limits it to a few days
Denosumab is an option in bisphosphonate-refractory hypercalcaemia or significant renal impairment
Corticosteroids are effective specifically in granulomatous disease, lymphoma and vitamin D toxicity, where the mechanism is excess 1,25-dihydroxyvitamin D
Haemodialysis for severe hypercalcaemia with renal failure or where the patient is unable to tolerate fluid loading
Stop contributing drugs and mobilise the patient where possible

Underlying cause:

Primary hyperparathyroidism: parathyroidectomy where criteria are met; cinacalcet where surgery is not appropriate
Malignancy: treat the underlying disease, recognising that hypercalcaemia of malignancy carries a poor prognosis and that discussion of goals of care is often appropriate alongside treatment

Referral: endocrinology for parathyroid disease; oncology or palliative care for malignancy-associated hypercalcaemia; nephrology for dialysis or severe renal impairment.

Hyperphosphataemia

Overview

Diagnosis

Management

Overview

Clinical Features

Diagnosis

Management