Caroline Ashley MSc BPharm MRPharmS
Lead Pharmacist, Renal Services
Royal Free Hampstead NHS Trust, London
Patients with chronic kidney disease are prone to developing multiple complications, of which renal bone disease or ‘renal osteodystrophy’ is one of the most common. The normal physiological mechanisms regulating blood levels of phosphate, calcium, vitamin D and parathyroid hormone are disrupted in renal bone disease, and this has important implications for the structural integrity and long-term health of bone. However, in recent years it has become clear that the complex pathophysiology associated with this condition is not restricted just to bone, but is also linked to the increased risk of calcification, especially of the cardiovascular system, with the associated risks of morbidity and mortality. Therefore, the term ‘renal bone disease’ has now been changed to ‘chronic kidney disease – mineral and bone disorder’ (CKD-MBD).
CKD-MBD is a breakdown in the homeostatic mechanisms that control bone biochemistry, and is triggered by a decline in renal function. The kidneys play a vital role in controlling serum phosphate, serum calcium, the calcium–phosphate product, vitamin D and parathyroid hormone (PTH) levels, so as renal function declines, the kidneys become progressively deranged in line with the development of secondary hyperparathyroidism.
Chronic kidney disease (CKD) is now classified by stages 1–5, with abnormalities in serum calcium, phosphate and PTH starting to be identified by stage 3 CKD. Patients that reach stages 4 and 5 CKD will almost certainly be exhibiting symptoms of CKD-MBD.
Approximately 85% of all the phosphate in the body is stored in bones, whilst the remaining 15% is stored in other tissues throughout the body. Phosphate is excreted by the renal tubules, so in the presence of a reduced glomerular filtration rate (GFR), urinary clearance is reduced leading to the development of hyperphosphataemia. High phosphate levels can cause severe generalised itching, and the deposition of calcium phosphate in tissues around the body.
Vitamin D is crucial for good bone health as it promotes the gastrointestinal absorption of calcium, influences the renal tubular reabsorption of calcium and aids the mineralisation process within bones. Vitamin D is present in the body because of the action of sunlight on the skin and also through dietary absorption. This form of vitamin D (cholecalciferol) is inactive and requires enzymatic hydroxylation in both the kidney and the liver to become the active form of vitamin D, (calcitriol, 1-α, 25-dihydroxycholecalciferol). The renal activation occurs via 1-α hydroxylase and, as renal function falls there is reduced enzymatic capacity, so activated vitamin D levels fall.
In total, the average body contains approximately 1kg of calcium, 99% of which is stored in bone tissue. Hypocalcaemia can cause muscle twitching and spasms, especially in the face and arms, whereas hypercalcaemia can cause agitation, gritty eyes and abdominal pain. The vitamin D deficiency and hyperphosphataemia associated with CKD can initially result in a fall in serum calcium below the normal range.
If the abnormal levels of phosphate, calcium and vitamin D are left uncorrected, the parathyroid glands begin to respond. Parathyroid hormone (PTH) is fundamentally important for the maintenance of normal bone turnover, and regulation of bone biochemistry. In response to hypocalcaemia, vitamin D deficiency and/or hyperphosphataemia, PTH secretion rises above the basal level in an attempt to restore normality. In CKD this is not possible, so PTH secretion continues to rise well above the normal range. Parathyroid tissue hyperplasia will eventually occur and secondary hyperparathyroidism (HPT) then develops.
Progression of renal bone disease
In the early stages of CKD-MBD, patients will exhibit decreased serum vitamin D levels, low serum calcium, high serum phosphate, as well as a high PTH. Many patients will also exhibit bone damage secondary to both low and high bone turnover. The clinical consequences of the effects of CKD and HPT on bone include an increase in the risk of pathological fractures (for example, vertebral fractures), bone pain, muscle pain, micro fractures and even skeletal deformities.
Treatment with vitamin D analogues and phosphate binders can be beneficial, but increasing doses of both will be required with time.
As vitamin D doses increase, this will facilitate the absorption of more calcium from the gastrointestinal tract, and result in both serum phosphate and serum calcium becoming elevated. This in turn increases the calcium–phosphate product (serum calcium level x serum phosphate level), leading to the extraskeletal manifestations of CKD-MBD.
In recent years it has become increasingly apparent that there are further consequences of CKD–MBD. The most important of these are ectopic calcification (the calcification of soft tissues) and peripheral vasculature, and their effects on the cardiovascular system. Under normal physiological conditions, calcium and phosphate remain soluble in the blood. However, if serum levels of each rise beyond a certain point, there is a risk of precipitation of calcium phosphate, resulting in extraskeletal calcification.
Calcification of the cardiovascular system (for example, myocardium, coronary arteries, aorta and cardiac valves) is an extremely important concern for patients with CKD. It is well established that the cardiovascular mortality of dialysis patients is on average thirty times that of the general population, and nearly half of all deaths in dialysis patients can be attributed to cardiovascular disease. CKD–MBD is increasingly being implicated in these high mortality rates.
Management of CKD–MBD
Conventional therapy for CKD–MBD includes dietary modification to reduce phosphate intake, the modification of the dialysis regimen, and the use of phosphate binders, hydroxylated vitamin D sterols (calcitriol, alfacalcidol) or the synthetic vitamin D analogue: paricalcitol. In severe HPT, total or partial surgical removal of the parathyroid glands may be required.
Phosphate binders act to reduce the absorption of dietary phosphate by forming a complex with phosphate in the gut; this complex is not absorbed systemically and is cleared from the body via the faecal route. Phosphate binders are generally prescribed to be taken three times daily, either with or just before meals. Gastrointestinal intolerance and patient adherence are the most problematic issues with the phosphate binders.
A variety of these preparations are commercially available, but any di- or tri-valent cation will bind phosphate.
Calcium-based phosphate binders
Calcium carbonate or calcium acetate
These agents are the most widely prescribed, and will be first-line therapy for most patients as they are inexpensive and relatively efficacious.
Calcium binds to phosphate in the gut and the resulting complex is not absorbed, yet the remaining unbound calcium will be absorbed. While this is desirable in hypocalcaemic patients, it limits or contraindicates the use of calcium-based phosphate binders in patients with severe secondary HPT.
Aluminium-based phosphate binders
Historically, aluminium is the most potent phosphate binder, but there have been concerns over the toxicity of systemically absorbed aluminium (especially concerned with dementia), which have led to a reduction in its use. Other significant adverse reactions linked to aluminium include bone marrow toxicity (so may worsen renal anaemia) and reduced bone turnover (for example, adynamic bone disease is an adverse reaction that can be linked to aluminium).
Calcium/aluminium-free phosphate binders
Calcium-free phosphate binders are safer to prescribe for patients who have hypercalcaemia or in those with evidence of ectopic calcification.
Sevelamer hydrochloride or sevelamer carbonate
Sevelamer is a hydrogel of polyallylamine hydrochloride, a polymer molecule with partially protonated amine groups, which bind to intestinal phosphate. Sevelamer has been shown to have a lower incidence of hypercalcaemia than calcium based binders, although it is probably the least effective of the current range of binders and is generally prescribed as a second- or third-line agent. The hydrochloride salt has been associated with a risk of exacerbating metabolic acidosis in CKD patients, although this does not appear to be a problem with the carbonate. An interesting effect of sevelamer is its ability to bind bile acids in the gut, leading to a reduction in serum low-density lipoprotein cholesterol by up to 20%.
This may have benefits in terms of reducing cardiovascular risk factors in CKD patients.
Lanthanum is a trivalent ion, and as such has a similar phosphate-binding capacity to aluminium and has been shown to have a much lower incidence of hypercalcaemia compared with calcium-based binders. Because of its similarity to aluminium, there have been concerns over its long-term safety, however studies comparing lanthanum with calcium carbonate (with four-year follow-up data) have shown no clinically relevant adverse effects, and far more patients on lanthanum move towards normal bone cell activity compared to calcium-treated patients. Lanthanum is usually reserved for when patients’ calcium-phosphate product is high, or their hyperparathyroidism is not adequately controlled on standard therapy.
Magnesium is a divalent ion, so it has similar phosphate binding capacity to calcium. It has a lower incidence of hypercalcaemia compared with calcium-based binders, although there is the risk of hypermagnesaemia. A combined preparation containing magnesium carbonate and calcium acetate is now commercially available.
Vitamin D analogues
As CKD progresses, plasma levels of activated vitamin D continue to fall, necessitating therapeutic intervention. Vitamin D therapy promotes gastrointestinal absorption of calcium, thereby increasing serum calcium levels, and this in turn stimulates the calcium-sensing receptors on the surface of the parathyroid gland, inducing a drop in PTH secretion. Vitamin D also directly suppresses the hormone by inhibiting PTH gene transcription in the parathyroid gland cells.
- Calcitriol (1-α,25-dihydroxychole- calciferol) is active form vitamin D.
- Alfacalcidol (1-α-hydroxychole-calciferol) is rapidly converted in the liver to calcitriol.
- The clinical effects of alfacalcidol and calcitriol are therefore very similar.
- Paricalcitol is a synthetic, biologically active vitamin D analogue of calcitriol, which selectively upregulates the vitamin D receptor in the parathyroid glands. Paricalcitol also upregulates the calcium-sensing receptor in the parathyroid glands, thereby inhibiting parathyroid proliferation and PTH synthesis and secretion.
The clinically significant side effects of
vitamin D therapy relate to inappropriate changes to the bone biochemistry:
- Exacerbation of hyperphosphataemia (via promotion of phosphate absorption from the gut)
- Oversuppression of the parathyroid glands (PTH is essential for normal bone turnover, so over-zealous treatment with vitamin D can reduce PTH to a level linked to risk of adynamic bone disease. This in turn reduces the buffering action of bone on phosphate and calcium levels, as the bones will no longer absorb these minerals, thereby increasing the risk of calcium phosphate deposition)
Cinacalcet is a calcimimetic agent that increases the sensitivity of calcium-sensing receptors to extracellular calcium ions, thereby inhibiting the release of PTH. As a consequence, PTH levels fall independently of disease severity or changes in vitamin D dose. In addition, serum calcium and phosphate levels both fall, leading to a significant reduction in the calcium-phosphate product. Cinacalcet is generally used as part of a therapeutic regimen including phosphate binders and/or vitamin D, as appropriate.
The past ten years have seen both a much greater understanding of the pathophysiology of CKD-MBD and an increase in the pharmacological armoury associated with it. New international standards for the management of this complex condition were published recently, but successful therapy remains a challenge to clinicians and pharmacists alike