Chronic Kidney Disease Mineral and Bone Disorder

Chronic kidney disease mineral and bone disorder is a systemic disorder of mineral and bone metabolism caused by chronic kidney disease. It is defined by one or more of three components: abnormal calcium, phosphate, parathyroid hormone or vitamin D metabolism; abnormal bone turnover, mineralisation, volume, linear growth or strength; and calcification of vessels or other soft tissue. It begins at stage G2 to G3 and progresses with declining eGFR.

Pathophysiology

• Early phosphate retention is offset by raised fibroblast growth factor 23 (FGF23), which increases phosphaturia and suppresses 1-alpha-hydroxylase, so calcitriol falls. Klotho deficiency in the kidney causes FGF23 resistance.
• Low calcitriol and phosphate retention reduce intestinal calcium absorption and cause hypocalcaemia, stimulating parathyroid hormone release and parathyroid hyperplasia with reduced calcium sensing and vitamin D receptors.
• Late disease features high phosphate, low calcium, high parathyroid hormone, skeletal resistance to parathyroid hormone, metabolic acidosis (bone buffering), and uraemic toxins.
• Therapy contributes: calcium based binders and vitamin D analogues can cause calcium overload, vascular calcification and adynamic bone.

Clinical significance. Fractures, cardiovascular calcification, calcific uraemic arteriolopathy (calciphylaxis), growth failure in children, and increased mortality.

• Asymptomatic in early stages; biochemical abnormalities precede symptoms.
• Bone pain (hips, back, lower limbs), proximal muscle weakness and waddling gait, fractures after minor trauma, tendon rupture, height loss, bone deformity, and in children rickets, growth failure, slipped epiphyses and genu valgum.
• Pruritus, red eyes (conjunctival calcification), periarticular calcification, tumoral calcinosis.
• Hypocalcaemia: perioral paraesthesia, carpopedal spasm, tetany, prolonged QT. Hypercalcaemia: constipation, polyuria, confusion.
• Calciphylaxis: painful violaceous plaques and ulcers with black eschar on thighs, abdomen and buttocks.

Red flags

• Painful skin lesions with necrosis (calciphylaxis): high mortality, needs urgent specialist care.
• Hip or vertebral fracture, or new bone pain with a rising alkaline phosphatase.
• Corrected calcium above 2.6 mmol/L or below 1.9 mmol/L, or QTc above 500 ms.
• Parathyroid hormone persistently more than 9 times the upper limit of normal.

Monitoring schedule (adults)

• Calcium and phosphate: every 6 to 12 months at stage G3a to G3b, every 3 to 6 months at G4, every 1 to 3 months at G5 and on dialysis.
• Parathyroid hormone: baseline at G3 and repeated according to the level and rate of change; every 6 to 12 months at G4; every 3 to 6 months at G5 and on dialysis.
• Alkaline phosphatase: annually from G4, more often if parathyroid hormone is high. 25-hydroxyvitamin D: baseline and repeated after treatment and annually.
• Bicarbonate monthly in dialysis; magnesium, albumin.

Targets

• Corrected calcium within the normal range 2.2 to 2.6 mmol/L, avoiding hypercalcaemia.
• Phosphate: in non-dialysis disease towards the normal range of 0.8 to 1.5 mmol/L; in dialysis 1.1 to 1.7 mmol/L.
• Parathyroid hormone: in dialysis 2 to 9 times the upper limit of normal for the assay. In non-dialysis disease, treat progressive rise or persistent values outside the normal range after correcting modifiable factors.

Imaging and bone assessment

• Lateral abdominal radiograph or echocardiography for vascular and valvular calcification (Kauppila score).
• Dual energy X-ray absorptiometry when results will change treatment (predicts fracture in G3 to G5D).
• Hand and pelvic radiographs: subperiosteal resorption of the radial aspect of the middle phalanges, rugger jersey spine, salt-and-pepper skull, pseudofractures.
• Bone biopsy with double tetracycline labelling is the reference test and is indicated before bisphosphonates in G4 to G5D with biochemical abnormalities, for unexplained fractures, hypercalcaemia, suspected aluminium, or when the result would change uncertain therapy.

Differential diagnosis

• Primary hyperparathyroidism, vitamin D deficiency osteomalacia, myeloma, metastatic bone disease, Paget disease, age related osteoporosis, hypophosphataemic rickets, hypophosphatasia, aluminium bone disease.

Step 1: correct modifiable abnormalities

• Replace vitamin D: 25-hydroxyvitamin D below 25 nmol/L, give cholecalciferol 50 000 units weekly for 6 to 8 weeks, then 800 to 2000 units daily; repeat level after 3 months and maintain at least 50 nmol/L.
• Control phosphate with diet (800 to 1000 mg daily; avoid inorganic phosphate additives), binders with meals, and dialysis intensity.
• Treat metabolic acidosis: sodium bicarbonate 500 mg to 1 g orally two to three times daily to bicarbonate at least 22 mmol/L.

Phosphate binders

• Sevelamer carbonate 800 mg three times daily with meals, titrated to phosphate 1.1 to 1.7 mmol/L (maximum about 13 g daily).
• Calcium carbonate 500 mg elemental calcium with meals, limiting total elemental calcium from binders to 1.5 g daily; avoid when calcium is high or vascular calcification is present.
• Lanthanum carbonate 500 mg chewed with meals, increasing by 750 mg daily every 2 to 3 weeks to a maximum of 3750 mg daily; sucroferric oxyhydroxide 500 mg chewed three times daily; ferric citrate 1 g with each meal.

Treating parathyroid hormone

• Active vitamin D: alfacalcidol 0.25 to 0.5 microg daily or calcitriol 0.25 microg daily (G4 to G5 with severe progressive hyperparathyroidism only; hypercalcaemia and hyperphosphataemia limit use). Paricalcitol 1 microg daily or 2 microg on alternate days.
• Calcimimetics (dialysis, and calcium above 2.2 mmol/L): cinacalcet 30 mg daily, titrated every 2 to 4 weeks to a maximum of 180 mg daily. Etelcalcetide 5 mg intravenously after each haemodialysis, increasing by 2.5 to 5 mg every 4 weeks to a maximum of 15 mg.
• Dialysate calcium 1.25 mmol/L (range 1.25 to 1.5), adjusted to the calcium balance.
• Parathyroidectomy when parathyroid hormone is persistently above 85 pmol/L (800 pg/mL) with hypercalcaemia, hyperphosphataemia, bone disease, calciphylaxis or refractory symptoms despite medical therapy.

Osteoporosis and fractures. In G3a to G3b, treat osteoporosis on the basis of fracture risk alone, using the usual agents for people with normal kidney function. In G4 to G5D, individualise: alendronate 70 mg weekly if eGFR is at least 35, risedronate 35 mg weekly if eGFR is at least 30; denosumab 60 mg subcutaneously every 6 months with calcium and vitamin D cover and calcium checked at 1 and 2 weeks (severe hypocalcaemia is a risk in dialysis); consider bone biopsy first.

Calciphylaxis. Wound care, analgesia, stop warfarin and calcium based binders, correct phosphate and calcium, sodium thiosulphate 12.5 to 25 g intravenously after each dialysis, intensify dialysis, parathyroidectomy if hyperparathyroid. Refer to a specialist centre.

Referral and escalation. Nephrology for parathyroid hormone more than 9 times the upper limit or rising, hypercalcaemia, bone pain, fractures or calciphylaxis. Endocrine surgery for parathyroidectomy.

Special groups

• Children: monitor growth, calcium, phosphate, alkaline phosphatase and parathyroid hormone from G2; somatropin 0.045 to 0.05 mg/kg daily subcutaneously when height is under the 3rd centile and mineral control is achieved.
• Transplant recipients: persistent hyperparathyroidism and hypophosphataemia; bone loss from glucocorticoids.
• Pregnancy: avoid calcimimetics and bisphosphonates; use calcitriol cautiously.