2 Clinical need and practice
2.1 The parathyroid glands produce parathyroid hormone (PTH), which controls the levels of calcium in the blood. Excessive production of this hormone is called hyperparathyroidism. When this is caused by another condition, it is called secondary hyperparathyroidism. Secondary hyperparathyroidism is a common complication of impaired renal function. Almost all people with end-stage renal disease (ESRD) have secondary hyperparathyroidism. Two UK studies have estimated the annual incidence of ESRD to be 132 and 148 per million population. A high proportion of people with ESRD receive dialysis; it is estimated that approximately 100 people per million population begin dialysis each year.
2.2 The development of secondary hyperparathyroidism in people with impaired renal function is complex. It occurs as a result of failure of the excretory function of the kidney (impaired excretion of phosphate and impaired reabsorption of calcium) and of the endocrine function of the kidney (reduced hydroxylation of inactive forms of vitamin D to the active form, calcitriol [1,25-dihydroxyvitamin D]). In the early stages of renal impairment, phosphate excretion is reduced. Initially, this does not lead to high levels of phosphate in the blood (hyperphosphataemia) because increased secretion of PTH stimulates the kidneys to excrete more phosphate. When renal impairment progresses to the moderate stage, the kidneys can no longer eliminate more phosphate in response to increased PTH secretion, and phosphate levels begin to rise. Hyperphosphataemia suppresses the renal hydroxylation of inactive calcidiol (25‑hydroxyvitamin D) to calcitriol. Low levels of calcitriol lead to reduced intestinal absorption of calcium, leading in turn to hypocalcaemia. Hypocalcaemia, low calcitriol levels and hyperphosphataemia all independently stimulate PTH synthesis and secretion. As these chronic stimuli persist, the parathyroid glands become enlarged and begin to function autonomously, continuing to secrete PTH even if hypocalcaemia is corrected. This condition is referred to as 'refractory' hyperparathyroidism and is also sometimes called 'tertiary' hyperparathyroidism. PTH levels become extremely elevated and this causes calcium and phosphate to be released from bone. Hyperphosphataemia is exacerbated and hypercalcaemia may occur.
2.3 Secondary hyperparathyroidism is associated with clinical complications involving the bones and other tissues. Bone disease (renal osteodystrophy) is present in about 70% of people starting dialysis. It is a multifactorial disease but secondary hyperparathyroidism is an important contributor to its development. Renal osteodystrophy manifests as bone pain, bone deformity and pathological fracture, and is a major cause of disability in people with ESRD. A study conducted in the USA including 40,538 people on haemodialysis found that the serum phosphorous concentration was statistically significantly related to the rate of hospitalisation for fracture. Time on dialysis was also strongly associated with hospitalisation for fracture.
2.4 People with kidney disease have a much higher risk of cardiovascular disease and associated mortality compared with the general population. This is a result of multiple factors, but derangements in calcium and phosphate homoeostasis appear to contribute. Hyperphosphataemia and elevated calcium–phosphorus product (Ca x P; the multiple of the serum levels of calcium and phosphorus) are associated with cardiovascular calcification affecting the aorta, the carotid and coronary arteries, the cardiac valves and myocardial muscle.
2.5 Calcification can also occur in other soft tissues including the lung, the conjunctiva, periarticular tissues and the breast. Calciphylaxis (calcific uraemic arteriolopathy) is a rare but serious complication that can occur in people with ESRD. It appears as painful, red/purple cutaneous nodules (singular or numerous), and often progresses rapidly to ulceration, necrosis and sepsis of the skin and subcutaneous tissues. On biopsy, arteriolar calcification of the subcutaneous fat and dermis is seen. Mortality is high; rates of between 45% and 65% have been reported in people with this complication.
2.6 The aim of treatment in secondary hyperparathyroidism is to manage levels of phosphate, PTH and calcium. Conventional therapy includes dietary modification to reduce phosphate intake, the use of phosphate binders, hydroxylated vitamin D sterols (calcitriol, alfacalcidol) or the synthetic vitamin D analogue paricalcitol, and modification of the dialysis regimen. In severe hyperparathyroidism, total or partial surgical removal of the parathyroid glands may be needed.
2.7 Reducing phosphate levels in the diet while maintaining adequate nutritional intake is difficult, because many sources of protein are also high in phosphate. Phosphate binders can be taken with meals to reduce phosphate absorption from the gut. In the past aluminium hydroxide was commonly used as a phosphate binder, but concern about aluminium toxicity in people receiving dialysis means that it is no longer widely used for this purpose. Calcium acetate and calcium carbonate are the most commonly used phosphate binders, but calcium salts are contraindicated in hypercalcaemia. Sevelamer is a non-calcium-containing phosphate-binding agent.
2.8 Vitamin D compounds that do not need renal hydroxylation for activation have been used in the treatment of secondary hyperparathyroidism in patients with ESRD. However, doses that are capable of suppressing PTH secretion may lead to hypercalcaemia and a decline in renal function. Vitamin D compounds are contraindicated in hypercalcaemia. By increasing intestinal absorption of calcium and phosphate, the risk of vascular calcification may be increased.
2.9 Phosphate clearance can be improved by intensifying the dialysis regimen. The most usual haemodialysis prescription is for 4 hours three times per week. Slow prolonged dialysis (over the course of 8 hours or more at night) or more frequent (daily) dialysis increases phosphate removal. Limitations on the availability of dialysis facilities mean that this option may be feasible only for some patients on home dialysis.
2.10 Surgical parathyroidectomy can be subtotal, total, or total with some parathyroid tissue reimplanted in a site such as the arm. Perioperative risk is greater in people with renal failure than in people with normal renal function, and there is the additional risk that any remaining parathyroid tissue will become hyperplastic and require repeat surgery.