Vascular Calcification in Chronic Kidney Disease

Vascular calcification in chronic kidney disease is deposition of calcium phosphate crystals in the arterial wall and heart valves.

Two forms coexist: intimal calcification within atherosclerotic plaques, and medial calcification (Mönckeberg sclerosis) of the elastic and muscular arteries, which stiffens vessels independently of lumen narrowing.

Calcification begins at stage G3, is present in over half of dialysis patients, and predicts cardiovascular death. Valvular calcification (aortic and mitral) and calcific uraemic arteriolopathy (calciphylaxis) are related lesions.

Pathophysiology

• Vascular smooth muscle cells transdifferentiate into osteoblast like cells under the influence of high phosphate, calcium load, FGF23 and uraemic toxins. Inhibitors of calcification fall: fetuin-A, matrix Gla protein (needs vitamin K), pyrophosphate, magnesium and osteopontin.
• Contributors: hyperphosphataemia, calcium based binders, active vitamin D, hypercalcaemia, adynamic bone (reduced calcium buffering), inflammation, diabetes, hypertension, warfarin, dyslipidaemia, smoking, long dialysis vintage.

• Usually asymptomatic; consequences are arterial stiffness (systolic hypertension, wide pulse pressure), left ventricular hypertrophy, diastolic dysfunction and heart failure.
• Coronary calcification with angina, myocardial infarction and sudden cardiac death; aortic stenosis with exertional dyspnoea, syncope and angina; mitral annular calcification with regurgitation or conduction block.
• Peripheral arterial disease: claudication, rest pain, non-healing ulcers, non-compressible ankle vessels.
• Calciphylaxis: severe pain, livedo reticularis, then violaceous plaques and ulcers with black eschar on thighs, abdomen and buttocks, and distal digital gangrene.

Red flags

• Painful skin necrosis (calciphylaxis): mortality of 40 to 60% within a year.
• Symptomatic aortic stenosis, angina or syncope.
• Critical limb ischaemia.
• Rapidly rising coronary calcium score on serial scans.

• Lateral abdominal radiograph with Kauppila score (0 to 24; above 6 is severe) for aortic calcification; hand and pelvic radiographs for medial calcification.
• Echocardiography for aortic and mitral valve calcification, stenosis (peak velocity above 4 m/s is severe), and ventricular function.
• CT coronary artery calcium score (Agatston score above 400 is severe); not needed routinely but used before transplantation or if results change management.
• Pulse wave velocity (above 10 m/s indicates stiffness); ankle brachial index above 1.3 indicates non-compressible vessels, so use toe brachial index (abnormal below 0.7).
• Biochemistry: calcium, phosphate, parathyroid hormone, alkaline phosphatase, 25-hydroxyvitamin D, lipids, HbA1c.
• Calciphylaxis: skin biopsy only when the diagnosis is uncertain (risk of non-healing wound); plain radiographs show net like calcification.

Differential diagnosis

• Atherosclerotic occlusive disease, vasculitis, warfarin necrosis, cholesterol emboli, pyoderma gangrenosum, vasculopathy of antiphospholipid syndrome, cryoglobulinaemia.

Prevent progression

• Control phosphate to 1.1 to 1.7 mmol/L in dialysis (towards the normal range in earlier stages): dietary phosphorus 800 to 1000 mg daily, sevelamer carbonate 800 mg three times daily with meals, lanthanum carbonate 500 mg with meals, or sucroferric oxyhydroxide 500 mg with meals. Limit elemental calcium from binders to 1.5 g daily, or avoid if calcification is progressive.
• Avoid calcium and active vitamin D excess: stop alfacalcidol and calcitriol when calcium exceeds 2.6 mmol/L; dialysate calcium 1.25 mmol/L. Avoid hypercalcaemia.
• Control parathyroid hormone to 2 to 9 times the upper limit of normal; cinacalcet 30 mg daily (maximum 180 mg) or etelcalcetide 5 mg after dialysis (maximum 15 mg) when calcium is above 2.2 mmol/L may slow progression.
• Correct acidosis (bicarbonate at least 22 mmol/L), longer or more frequent dialysis, and avoid vitamin K antagonists where an alternative anticoagulant is suitable, because warfarin impairs matrix Gla protein activation.

Cardiovascular risk reduction

• Blood pressure target below 130/80 mmHg.
• Statin: atorvastatin 20 mg daily in non-dialysis chronic kidney disease aged over 50 (continue if already taking it on dialysis).
• SGLT2 inhibitor: dapagliflozin 10 mg daily with eGFR at least 25, or empagliflozin 10 mg daily with eGFR at least 20.
• Stop smoking, glycaemic control, weight management, exercise.

Calciphylaxis (specialist led, urgent)

• Wound care and surgical debridement only after specialist advice; opioid analgesia (fentanyl or oxycodone at reduced doses); treat infection promptly.
• Stop warfarin and calcium based binders and active vitamin D; correct phosphate and calcium.
• Sodium thiosulphate 12.5 to 25 g intravenously after each dialysis session for at least 3 months; dialysis intensification to 5 to 6 sessions weekly if feasible; hyperbaric oxygen in selected patients; parathyroidectomy if hyperparathyroid.

Valve disease and coronary disease. Cardiology review; aortic valve replacement for severe symptomatic stenosis (transcatheter route often preferred in dialysis); revascularisation by usual criteria.

Referral and escalation. Nephrology for rising calcification scores, hypercalcaemia or adynamic bone; urgent referral for suspected calciphylaxis to a team with wound and dialysis expertise.

Special groups

• Children and young adults with long standing chronic kidney disease have calcification disproportionate to age; prevention starts early.
• Kidney transplant candidates: assess iliac artery calcification by CT or ultrasound before surgery.