Secondary Hyperparathyroidism

Secondary hyperparathyroidism in chronic kidney disease is an adaptive parathyroid response to phosphate retention, low calcitriol and low or low normal ionised calcium, leading first to hypersecretion and then to polyclonal then nodular parathyroid hyperplasia. Parathyroid hormone begins to rise at eGFR below 60 mL/min/1.73 m² and is present in over 80% of patients at stage G5. Fibroblast growth factor 23 rises years before parathyroid hormone.

Persistently elevated parathyroid hormone drives high turnover bone disease, bone loss, fractures, vascular calcification, anaemia (resistance to erythropoiesis stimulating agents), cardiomyopathy, pruritus and calciphylaxis.

Risk factors for progression: hyperphosphataemia, vitamin D deficiency, hypocalcaemia, metabolic acidosis, low dietary calcium intake, long dialysis vintage.

• Frequently asymptomatic; diagnosis rests on biochemistry.
• Bone and joint pain, fractures, proximal myopathy, tendon rupture, pruritus, muscle weakness, growth failure and bone deformity in children.
• Soft tissue and vascular calcification; red eye; calcific uraemic arteriolopathy; hypercalcaemia complicating therapy.
• Brown tumours (osteoclastomas) in jaw or long bones, with osteitis fibrosa on radiograph.
• Anaemia that responds poorly to erythropoietin.

Red flags

• Parathyroid hormone above 85 pmol/L (800 pg/mL), or rising by more than 50% within 6 months despite treatment.
• Hypercalcaemia (above 2.6 mmol/L) with high parathyroid hormone: suggests autonomous hyperplasia or an adenoma.
• Painful skin ulcers (calciphylaxis) and severe bone pain with fractures.

• Intact parathyroid hormone (use one assay throughout; plasma in EDTA is more stable than serum), corrected calcium (and ionised calcium where available), phosphate, magnesium, alkaline phosphatase, bicarbonate, 25-hydroxyvitamin D. Take samples before dialysis and not from the same arm used for dialysis; allow for the day of the dialysis week. Judge the trend over several results rather than a single value.
• Targets: dialysis, parathyroid hormone 2 to 9 times the upper limit of normal. Non-dialysis, treat when parathyroid hormone is progressively rising or persistently over the upper limit after correcting phosphate, calcium and vitamin D.
• Radiographs: subperiosteal resorption (radial side middle phalanges), terminal phalangeal tufting, salt-and-pepper skull, rugger jersey spine, brown tumours. DXA of the distal one third radius shows cortical loss.
• Parathyroid ultrasound and sestamibi scan with SPECT-CT before surgery to identify nodular hyperplasia and ectopic glands.
• Bone biopsy when parathyroid hormone is intermediate (2 to 9 times the upper limit) and fractures or hypercalcaemia raise doubt about turnover.

Differential diagnosis

• Primary hyperparathyroidism in chronic kidney disease (hypercalcaemia with normal phosphate and earlier in course); tertiary hyperparathyroidism; familial hypocalciuric hypercalcaemia; lithium effect; vitamin D deficiency alone; hypomagnesaemia related parathyroid hormone suppression; sample handling errors and assay differences; adynamic bone disease (low parathyroid hormone).

First line: address the drivers in this order

1. Control phosphate: diet of 800 to 1000 mg daily, binders (sevelamer carbonate 800 mg three times daily with meals titrated to phosphate 1.1 to 1.7 mmol/L, or calcium carbonate 500 mg elemental calcium with meals up to 1.5 g elemental calcium daily), and dialysis intensification.

2. Correct hypocalcaemia and vitamin D deficiency: cholecalciferol 50 000 units weekly for 6 to 8 weeks when 25-hydroxyvitamin D is below 25 nmol/L, then 800 to 2000 units daily; target at least 50 nmol/L.

3. Correct acidosis to bicarbonate at least 22 mmol/L and avoid hypomagnesaemia.

4. Set dialysate calcium at 1.25 to 1.5 mmol/L according to parathyroid hormone and calcium.

Alternative and escalation

• Active vitamin D (reserved for stage G4 to G5 with severe, progressive disease, and for dialysis): alfacalcidol 0.25 to 0.5 microg daily or calcitriol 0.25 microg daily; paricalcitol 1 microg daily. Stop or reduce if calcium exceeds 2.6 mmol/L or phosphate exceeds 1.7 mmol/L.
• Calcimimetics (calcium above 2.2 mmol/L): cinacalcet 30 mg daily with food, titrated every 2 to 4 weeks (60, 90, 120, 180 mg) to a maximum of 180 mg daily. Check calcium within 1 week and after each dose change, and parathyroid hormone 1 to 4 weeks later. Reduce the dose or stop when calcium is below 2.2 mmol/L; hold if below 1.9 mmol/L or symptomatic. Nausea and vomiting often respond to dividing the dose or taking with food. Etelcalcetide 5 mg intravenously at the end of each dialysis, increased in 2.5 to 5 mg steps every 4 weeks to a maximum of 15 mg; omit if calcium is below 1.9 mmol/L.
• Combine calcimimetic with low dose active vitamin D in persistent disease.

Surgical management

• Parathyroidectomy when parathyroid hormone is persistently more than 85 pmol/L (800 pg/mL) with hypercalcaemia or hyperphosphataemia refractory to medical therapy, severe bone disease, fractures, calciphylaxis or intractable pruritus. Options: subtotal (3.5 gland) or total parathyroidectomy with autotransplantation into forearm or sternocleidomastoid.
• Preoperative: optimise calcium and vitamin D; start alfacalcidol 1 microg daily and calcium carbonate beforehand when alkaline phosphatase is raised (high risk of hungry bone).
• Postoperative: measure calcium every 6 hours for 48 hours, then daily. For hungry bone syndrome (calcium below 2.0 mmol/L with low phosphate and magnesium), give calcium gluconate 10% 10 to 20 mL intravenously over 10 minutes for symptoms, then an infusion of calcium gluconate 10% 100 mL in 1 litre of 5% glucose at 50 mL/hour titrated to calcium 2.0 to 2.2 mmol/L; start oral calcium carbonate to give 2 to 4 g elemental calcium daily and alfacalcidol 1 to 3 microg daily. Replace magnesium. Expect needs to continue for weeks.
• Recurrence of hyperparathyroidism after total parathyroidectomy with autograft occurs in about 10 to 15% over years.

Referral and escalation. Refer to nephrology when parathyroid hormone is rising despite normal calcium, phosphate and vitamin D, to endocrine surgery for refractory disease, and urgently for calciphylaxis.

Special groups

• Children: calcitriol 0.25 microg daily or alfacalcidol 0.25 to 0.5 microg daily; cinacalcet is used in selected older children.
• Pregnancy: calcimimetics are avoided; manage with phosphate control and cautious calcitriol.
• Dialysis patients: reduce dialysate calcium for hypercalcaemia (1.0 to 1.25 mmol/L), raise for hypocalcaemia on calcimimetics.