BPharm DipClinPharm MSc
Lead Pharmacist for Nephrology and Renal Transplantation
University Hospital of Wales
E: [email protected]
Hyperphosphataemia is a component of the bone biochemistry abnormalities seen in patients with chronic kidney disease (CKD), leading to renal bone disease (or renal osteodystrophy: ROD). The underlying pathophysiology is a breakdown in homoeostatic mechanisms controlling phosphate, calcium, vitamin D and parathyroid hormone (PTH) triggered by decline in renal function (the glomerular filtration rate [GFR]). This generally becomes apparent at CKD stage 3 and is almost inevitable for patients at CKD stage 5 − end-stage renal disease (ESRD) − on long-term dialysis therapies. Each biochemical parameter is important, but it is the complex interaction between them that can be used to describe why ROD occurs and to direct effective drug management such as treatment with phosphate binders.
Reduced urinary clearance of phosphate means the normal serum level (eg, 0.8-1.45 mmol/l) is exceeded, and values well in excess of 2 mmol/l are regularly seen, particularly in ESRD patients.
Hyperphosphataemia also directly impacts on secretion of PTH from the parathyroid glands. PTH is fundamentally important for bones (for maintenance of normal bone turnover) and regulation of bone biochemistry (through homoeostatic processes). CKD triggers increased secretion of PTH through the �following mechanisms:
- Vitamin D deficiency (the kidneys are vital in the enzymatic activation of vitamin D to calcitriol).
- Hypocalcaemia (related to vitamin D deficit and hyperphosphataemia).
Eventually, hyperplasia of the parathyroid gland tissue occurs. The response of the glands is now regarded as pathological, and secondary hyperparathyroidism (HPT) is present.
Complications for the skeleton
There are a variety of bone diseases that can be present in a CKD patient, for example:
- Osteitis fibrosa:
- Related to elevated PTH levels.
- High turnover state, triggering increased bone remodelling.
- Many causes: for example, vitamin D deficiency.
- Causes low bone turnover and defective mineralisation.
The clinical consequences for the skeleton are increased risk of pathological fractures (for example, HPT has been associated with an increase in the rate of vertebral fractures), bone pain, muscle pain, microfractures and even skeletal deformities.(1,2)
It is becoming increasingly clear that there are other consequences of hyperphosphataemia (and other bone biochemistry disruptions) that are extremely important, and renal bone disease is too narrow a description. Other potential complications include:
- Red, sore eyes.
- Soft tissue calcification.
- Peripheral vascular calcification.
- Cardiovascular calcification.
Calcification disorders are very important, and evidence is emerging about the pathophysiology and cell biology in the CKD population.(3) The serum is supersaturated with calcium and phosphate, but homoeostatic mechanisms ensure they remain soluble under normal physiological conditions. This situation changes in CKD, and there are various risk factors for calcification. For example, if serum levels of calcium, phosphate or both are elevated, there is a risk of precipitation, resulting in extraskeletal calcification.
Calcification in the cardiovascular system (eg, myocardium, coronary arteries, aorta and cardiac valves) is an extremely serious issue for patients with CKD. It is well established that, particularly in the ESRD population, the most common cause of death is of cardiovascular origin. For example, on average, the cardiovascular mortality of dialysis patients is 30 times that of the general population.(4) Nearly half of all deaths in dialysis patients can be attributed to cardiovascular disease.(5) The aetiology behind these facts is complex and multifactorial, but disturbances to bone mineral homoeostasis, particularly hyperphosphataemia, are frequently implicated. These new data have raised the profile of phosphate binders in nephrology.
There is also supporting epidemiological evidence for the significance of hyperphosphataemia as an independent risk factor for death in ESRD patients. A retrospective study demonstrated a 27% higher mortality risk, adjusted for age and co-morbidities, in haemodialysis (HD) patients with a phosphate level over 2.10 mmol/l.(6)
Treatment with phosphate binders
Managing hyperphosphataemia can be extremely difficult in CKD patients. The pharmacological therapies used are poorly tolerated and, unlike most other drugs, efficacy is totally reliant on the patient taking the prescribed agent at specific times so that this class of drugs is plagued by compliance problems, both deliberate and unintentional. The latter are often due to gaps in the patient’s knowledge of CKD.
Phosphate binder drugs act to reduce the absorption of dietary phosphate, so they must be taken either with or just before meals, depending on the particular agent. Their action is indirect and relatively slow – dietary phosphate binds to the drug, and the resulting complex is not absorbed systemically.
Taking phosphate binders inappropriately (for example, between meals) will have little effect on phosphate levels, so a patient can be compliant with therapy at a basic level but see no benefits. This can lead to doses of binders being increased to address the elevated phosphate levels when simple patient education would address the problem while maintaining the same dose.
For this reason, renal healthcare professionals, including pharmacists, have a vital role to play in talking to CKD patients about the benefits of phosphate binders and how to take them correctly. In addition, although phosphate binders are generally prescribed as a three times a day dosage, patients should be encouraged to adjust their doses according to their diet and number of meals per day.
Dietetic input is important at this stage when phosphate binder regimens are tailored to the individual.
Calcium-based phosphate binders
- Calcium carbonate (eg, Calcichew(R), 500 mg elemental calcium per tablet, chew 5-10 minutes before meals).
- Calcium acetate (eg, Phosex(R), 250 mg elemental calcium per tablet, swallow whole with meals).
These binders, which are the most widely �prescribed, will be first-line agents for most patients and are cheap and relatively efficacious. Some calcium will be absorbed, which is desirable in the hypocalcaemic patients but limits or contraindicates their use in patients with more severe forms of hyperparathyroidism if hypercalcaemia is present, and in those with evidence of vascular or soft tissue calcification.
The starting dose of calcium-based phosphate binders is one or two tablets at mealtimes, before or with meals depending on the calcium salt chosen. It is important that patients understand that binders are not calcium supplements, particularly as this may lead to doses being taken between meals to maximise gastrointestinal calcium absorption. Aside from risk of hypercalcaemia, other important problems are gastrointestinal disturbances such as nausea and the cumulative effect of poor palatability (for example, the chewable formulations have a chalky texture).
Aluminium-based phosphate binders
- Aluminium hydroxide (eg, Alucaps(R), 475 mg capsules, swallow whole with meals).
These agents were formerly widely prescribed and are the most potent phosphate binders currently available.(7) Concerns over toxicity of absorbed aluminium (especially dementia) led to a �reduction in their use, although the elevated serum aluminium levels seen in haemodialysis patients that guided this decision were more likely to be related to absorption of the metal from the water used in the haemodialysis process. Water purification now removes aluminium before it reaches the haemodialysis machine, and aluminium-based phosphate binders are now more readily prescribed. However, there are other significant potential adverse reactions linked to aluminium. It is a toxin to the bone marrow, so it may worsen renal anaemia and it is a toxin to bone cells, so it may cause greatly reduced bone turnover – another form of ROD called adynamic bone disease.
The starting dose of these agents is one capsule with meals, and their main indication is as a second- or third-line agent or as an add-on therapy when a single agent has provided insufficient reductions in phosphate levels. To minimise toxicity, aluminium-based binders are ideally used only on a short-term basis. As with all phosphate binders, gastrointestinal intolerance, in this case constipation, is a problem.
Calcium-/aluminium-free phosphate binders
- Sevelamer hydrochloride (Renagel(R), 800 mg tablets, swallow whole with meals).
Sevelamer, the newest phosphate binder available to nephrologists, belongs to a completely new pharmacological class – a hydrogel of poly(allylamine hydrochloride), a polymer molecule with partially protonated amine groups that bind to intestinal phosphate via ionic and hydrogen bonds. Its advantages are that it is safer to prescribe for patients who are hypercalcaemic or those with evidence of calcification. Sevelamer has been shown to have lower incidence of hypercalcaemia than calcium-based binders.(8) Unbound sevelamer is not absorbed from the gut, so it has no systemic side-effects, but still leads to gastrointestinal tolerability problems, such as nausea, to compare with the other phosphate binders. It is also probably the least potent of the current range of drugs, which can cause a problem with high tablet burden. Cost is also an issue because sevelamer is much more expensive than traditional therapies (for example, in the UK, Renagel tablets are currently around 10 times more expensive than Calcichew tablets), so it is important to be able to justify prescription on sound clinical grounds so that sevelamer can be utilised in a cost-effective manner. An interesting effect of sevelamer is an action to bind bile acids in the gut, leading to a reduction in serum LDL (low-density lipoprotein)-cholesterol by up to 20%, which may have benefits in terms of reducing cardiovascular risk factors in CKD patients.(9)
The starting dose of sevelamer is one or two tablets with meals, and it is generally prescribed as a second- or third-line agent, when other binders are contraindicated or not tolerated, or as an additional therapy in combination with calcium- or aluminium-based binders.
Combination therapy with phosphate binders and causes of poor response to treatment
Combination therapy with different phosphate binders is increasingly seen in clinical practice. This could be indicated in cases of recalcitrant
hyperphosphataemia, but the strategy is often intended to be short term, in order to gain better control of phosphate. It is important to review such patients regularly to avoid polypharmacy.
Persistently elevated phosphate may be the result of:
- Poor concordance.
- Lack of understanding of how to take phosphate binders.
- Severe hyperparathyroidism � high bone turnover releases phosphate from bones into the blood to exacerbate hyperphosphataemia.
Unfortunately, due to the difficulties in managing phosphate, around 50% of dialysis patients worldwide are estimated to have serum phosphate levels above 1.8 mmol/l.(10) Prescribing phosphate binders is a crucial component of preventing complications of ROD, but it is generally not done in isolation. Many CKD patients will also take vitamin D, for example alfacacidol.
Monitoring, dose adjustment and therapeutic targets
The benefits of pharmacological intervention to �control hyperphosphataemia are not obvious to patients, and it is important that they understand that phosphate binders are long-term treatments that will protect the bones, and possibly the heart and blood vessels, against future damage.
It is essential that the target ranges for serum phosphate and best therapeutic practice are clearly defined. Unfortunately, the evidence base in the field of ROD is inconclusive and controversial – nonetheless, guidance on hyperphosphataemia is published by nephrology groups such as the Renal Association in the UK(11) and the National Kidney Foundation in the USA.(12)
A very important point to consider is that for the majority of ESRD patients it is extremely unlikely that a normalised phosphate level will be achieved with binder drugs. A more realistic, though still difficult, objective is to bring serum phosphate down below 1.7 or 1.8 mmol/l. Achieving this level of phosphate will assist in normalisation of calcium and reduction of PTH. Phosphate binder dose adjustments are usually not made more frequently than every two to four weeks during the initiation phase of treatment, and every four to eight weeks thereafter.
New management strategies and new therapeutic agents for managing hyperphosphataemia
The current controversy in hyperphosphataemia management is the role of calcium intake in the pathogenesis of extraskeletal, especially cardiovascular, calcification. Does utilisation of exogenous calcium (for example, as phosphate binders) in CKD patients become pathological, contributing to extra-skeletal calcification? If confirmed, this fact would have major implications for how phosphate binder drugs are selected for patients, and techniques for assessing a patient’s calcification risk will be required to guide choice of phosphate binders.
Many renal units already have increasing patient numbers on sevelamer at an earlier stage. After years of widespread use of calcium carbonate and calcium acetate this is a major change in practice, and one with a significant financial implication for renal units, particularly if sevelamer is adopted as first-line phosphate binder. Research is ongoing to compare sevelamer and calcium-based binders with respect to risk of developing cardiovascular calcification, rate of progression of cardiovascular calcification and, crucially, cardiovascular morbidity and mortality.
Lanthanum carbonate (Fosrenol(R)) is a new agent that is currently awaiting European licence. Lanthanum is a rare-earth element that appears to be a potent binder of dietary phosphate. It will add new options for the nephrologist in the control of hyperphosphataemia, but, like sevelamer, it will be a high-cost drug for hospital pharmacists, especially those specialising in nephrology, to manage the entry into clinical practice and ensure that it is prescribed in a cost-effective manner.
Drug therapy for hyperphosphataemia will continue to be an evolving area as the evidence base accumulates related to its negative impact on survival of ESRD patients. Elucidation of the disease processes underpinning this risk, for example cardiovascular calcification, is essential, as will be the role of phosphate binder drugs, in modifying these risks and improving patient outcomes. Pharmacological intervention is likely to become more aggressive, and there may even be a shift away from calcium-based agents as standard first-line therapy. Changes to clinical practice will be implemented in the tertiary setting, so hospital pharmacists working with CKD patients are well placed to play a proactive role implementing and monitoring advancements in the pharmacological management of hyperphosphataemia.
- Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone disease in end-stage renal failure an evolving disorder. Kidney Int 1993;43:436-42.
- Malluche H, Faugere MC. Renal bone disease 1990: an unmet challenge for the nephrologists. Kidney Int 1990;38:193-211.
- Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end stage renal disease. Kidney Int 2001;60:472-9.
- Foley RN, Palfrey PS, Saran MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease.Am J Kidney Dis 1998;32:S112-9.
- Causes of death. In: Renal Data System. USRDS Annual data report 1998. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; 1999. p. 79-90.
- Block GA, Hulbert-Sheron TE, Levin NW, Port FK. Association of serum phosphate and calcium x phosphate product with mortality risk in chronic haemodialysis patients: a national study.Am J Kidney Dis 1998;31:607-17.
- Janssen MJA, van de Kuy A, ter Wee PM, van Boven WP. Aluminium hydroxide, calcium carbonate and calcium acetate in chronic intermittent haemodialysis patients. Clin Nephrol 1996;45(2):111-9.
- Bleyer AJ, Burke SK, Dillon MA, et al. A comparison of the calcium free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphataemia in haemodialysis patients.Am J Kidney Dis 1999;33(4):694-701.
- Slatopolsky EA, Burke SK, Dillon MA. Renagel, a nonabsorbed calcium and aluminium free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int 1999;55:299-307.
- Young E, Satayathum S, et al. Prevalence of values on mineral metabolism being outside the targets from the proposed new draft NKF-K/DOQI and European Best Practice Guidelines in countries of the dialysis outcomes and practice patterns study (DOPPS). Nephrol Dial Transplant 2003;18 Suppl 4:677-8.
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UK Renal Registry
Renal Association Standards