Hypocalcaemia in Chronic Kidney Disease

Hypocalcaemia in chronic kidney disease is albumin corrected serum calcium below 2.2 mmol/L (ionised calcium below 1.15 mmol/L). It occurs in advanced disease through failure of renal 1-alpha-hydroxylation (low calcitriol), phosphate retention, skeletal resistance to parathyroid hormone, and low calcium intake and absorption. Drug induced causes are calcimimetics, bisphosphonates and denosumab. Marked hypocalcaemia also follows parathyroidectomy (hungry bone syndrome).

Other causes

• Hypomagnesaemia (impaired parathyroid hormone release and action), acute pancreatitis, rhabdomyolysis, sepsis, tumour lysis, citrate anticoagulation, large transfusions, proton pump inhibitors, loop diuretics, foscarnet, phosphate binders taken between meals (calcium chelation), low dialysate calcium, hypoparathyroidism, and alkalosis (ionised fraction falls).

• Perioral and fingertip paraesthesia, muscle cramps, carpopedal spasm, tetany, Chvostek sign (facial twitch on tapping the facial nerve) and Trousseau sign (carpal spasm with a blood pressure cuff inflated to over systolic pressure for 3 minutes).
• Laryngospasm, stridor and bronchospasm, seizures, irritability, depression, psychosis, cataracts, papilloedema, basal ganglia calcification.
• Prolonged QT interval, ventricular arrhythmia, reduced contractility and hypotension, heart failure.
• Chronic hypocalcaemia: dry skin, brittle nails, alopecia, dental defects in childhood.

Red flags

• Corrected calcium below 1.9 mmol/L (or ionised calcium below 0.8 mmol/L), QTc above 500 ms, seizure, laryngospasm, or arrhythmia.
• Severe hypocalcaemia after parathyroidectomy, denosumab, or in a patient on digoxin.
• Hypocalcaemia with hyperphosphataemia above 2.5 mmol/L (acute phosphate load or tumour lysis).

• Corrected calcium = measured calcium + 0.02 x (40 minus albumin in g/L) (mmol/L), unreliable in critical illness and dialysis; measure ionised calcium on a blood gas analyser where available (also required with citrate anticoagulation).
• Phosphate, magnesium, parathyroid hormone, 25-hydroxyvitamin D, alkaline phosphatase, bicarbonate (alkalosis reduces ionised calcium), creatinine, amylase, creatine kinase.
• ECG: prolonged QT, T wave abnormality. Review drugs (cinacalcet, etelcalcetide, denosumab, bisphosphonates, loop diuretics, phenytoin, phenobarbital), dialysate calcium concentration, and recent neck surgery.

Differential diagnosis

• Pseudohypocalcaemia from low albumin (corrected calcium normal); hypoparathyroidism (low or inappropriately normal parathyroid hormone with high phosphate); pseudohypoparathyroidism (high parathyroid hormone, high phosphate); vitamin D deficiency or resistance; hypomagnesaemia; hungry bone syndrome.

Emergency (symptomatic, corrected calcium below 1.9 mmol/L, or QTc above 500 ms)

• Continuous ECG monitoring. Calcium gluconate 10% 10 mL (2.25 mmol) intravenously over 10 minutes, repeated if symptoms persist.
• Follow with an infusion of calcium gluconate 10% 100 mL in 1 litre of 5% glucose or 0.9% sodium chloride at 50 mL/hour, titrated to corrected calcium 2.0 to 2.2 mmol/L (check every 4 to 6 hours). Peripheral extravasation causes tissue necrosis; use a large vein or central access.
• Correct magnesium: magnesium sulphate 2 g (8 mmol) intravenously over 15 to 20 minutes, repeated as needed (monitor reflexes and respiration); in hypermagnesaemia risk (eGFR under 30) halve the dose and check levels.
• If phosphate is above 2.5 mmol/L, give calcium only for symptoms and arrange dialysis for the phosphate load.
• Seizures: treat with intravenous calcium; use anticonvulsants as well; digoxin patients need calcium infused slowly with continuous ECG.

Chronic hypocalcaemia

• Replace 25-hydroxyvitamin D: cholecalciferol 50 000 units weekly for 6 to 8 weeks, then 800 to 2000 units daily.
• Active vitamin D (needed in advanced chronic kidney disease): alfacalcidol 0.25 to 0.5 microg daily (maximum 2 microg daily) or calcitriol 0.25 to 0.5 microg daily; check calcium and phosphate 1 week after starting and after each change. Reduce or stop if calcium exceeds 2.5 mmol/L.
• Oral calcium: calcium carbonate 500 mg elemental calcium three times daily, taken away from meals when phosphate is normal, or with meals as a binder when phosphate is high (total elemental calcium from binders up to 1.5 g daily).
• Dialysate calcium 1.5 mmol/L for persistent hypocalcaemia on dialysis.
• Calcimimetic therapy: if corrected calcium falls below 2.2 mmol/L, reduce or stop cinacalcet; hold etelcalcetide if below 1.9 mmol/L or symptomatic and restart at a lower dose when calcium is at least 2.3 mmol/L and symptoms have resolved.
• After parathyroidectomy (hungry bone syndrome): calcium gluconate 10% 10 mL intravenously over 10 minutes then an infusion of 100 mL of 10% in 1 litre of 5% glucose at 50 mL/hour, oral calcium to 2 to 4 g elemental daily, alfacalcidol 1 to 3 microg daily, magnesium replacement.
• Denosumab associated hypocalcaemia: calcium carbonate 500 mg elemental calcium three times daily and alfacalcidol 0.25 to 0.5 microg daily, with calcium monitored weekly for the first month.

Monitoring. Calcium every 4 to 6 hours in the emergency; at 1 week after dose changes of vitamin D or calcimimetics; every 1 to 3 months in stable dialysis.

Referral and escalation. Intensive care or high dependency monitoring for calcium below 1.9 mmol/L with arrhythmia or seizures. Endocrine review when parathyroid hormone is low (hypoparathyroidism).

Special groups

• Children and neonates: calcium gluconate 10% 0.5 mL/kg (maximum 20 mL) intravenously over 10 to 30 minutes, followed by an infusion; watch for rickets.
• Pregnancy: use calcitriol and calcium; avoid high dose vitamin D analogues without monitoring.
• Critical illness and citrate dialysis: monitor ionised calcium every 4 to 6 hours.