Department Internal Medicine, Heidelberg, Germany
Keywords: hyperphosphataemia; phosphate binders; uraemia
The consequences of hyperphosphataemia
In the past nephrologists were aware that the hyperphosphataemia of advanced renal failure triggered hyperparathyroidism, but because only few patients die from skeletal problems, hyperphosphataemia was treated with benign neglect. The panorama has abruptly changed after evidence accrued suggesting that hyperphosphataemia has adverse cardiovascular consequences. In some observational studies [1], but not consistently in all [2], pre-dialysis serum P concentrations >6.5 mg/dl were associated with a higher relative risk of cardiovascular death. Furthermore, with the availability of electronbeam-CT, a high prevalence of vascular, particularly coronary, calcification was noted in dialysed patients, which was progressive with time [3,4]. Furthermore, the group of London has shown that active wall stiffness is correlated to vascular calcification [5]. Vascular calcifications are presumably more than the result of passive precipitation of Ca and P, and under certain conditions vascular smooth muscle cells can even acquire, at least partially, an osteoblastic phenotype.
Against this background, the control of serum phosphate concentration has obvious clinical importance. This issue has recently generated much interest, but problems persist both with respect to understanding the underlying pathomechanisms and translating novel insights into clinical practice.
This brief editorial comment provides some background information and reflects our admittedly subjective thoughts on the principles guiding the selection of phosphate binders.
The phosphate balance
A mid-European diet contains approximately 8001000 mg phosphorus per day (in the calculations the reader should avoid confounding elemental P and phosphate) of which approximately 60% is absorbed. Consequently haemodialysis patients are in positive P balance because per dialysis session only 8001000 mg P are removed. The difference between net intestinal absorption and removal with thrice weekly haemodialysis (i.e. up to 1800 mg/week approximately) has to be taken care of by administration of P binders.
Classical P binders
Aluminium-containing phosphate binders
In the distant past, aluminium-containing phosphate binders were used. This has certainly resulted in a true medical catastrophe [6], but even at present, Al-containing P chelators are still widely used, although this probably varies much from centre to centre and from country to country. The past epidemic should be a warning, however, to nephrologists looking for alternative phosphate binders. It must be avoided that (to paraphrase St Matthew) the Satan of hyperphosphataemia is cast out and the Beelzebub of trace element intoxication is admitted.
But what are the alternatives?
Calcium-containing P binders
Calcium carbonate, calcium acetate or other calcium-containing P binders (except citrate; [7]) are widely used because they are effective P binders. In the past they had very vocal advocates [8,9], although more sceptical nephrologists (modesty prevents us from stating whether the authors were amongst them) were always concerned about the possibility of inducing a positive calcium balance. This is more than an academic consideration. These concerns have recently been justified by observations that in dialysis patients both coronary [3,4] and aortic calcifications [5] are related, amongst others, to the total dose of oral calcium binders used.
This issue requires a more detailed discussion of the determinants of the calcium balance. The calcium balance is the net result of intestinal calcium absorption (which depends on dietary calcium intake and on potential ancillary treatment with active vitamin D) on the one hand and dialysate calcium concentration on the other hand. In theory, a positive calcium balance can be avoided if the dialysate calcium concentrations are adjusted, but this presents two problems.
First, prolonged use of dialysate calcium concentrations below 6 mg/dl [10] is associated with the risk of aggravating secondary hyperparathyroidism. Second, this strategy would require individualization of dialysate calcium concentration. This is therefore laborious and not easily carried out. Experience tells that such sophisticated procedures are not followed. Similarly, HIV could be easily prevented by chastity, but such advise will never be heeded as every astute clinician will know.
A further confounder is patient compliance: if dialysate calcium concentration is reduced and the patient does not take his calcium-containing phosphate binders, he will certainly be in negative calcium balance and be at risk of bone mineral loss.
Finally, considering just the calcium balance is an oversimplified approach. An important further variable to consider is bone turnover. Patients with low bone turnover are at risk of developing hypercalcaemia even if the calcium balance is only slightly positive [11]. The link between bone and vascular calcification has recently been nicely illustrated by osteoprotegerin knock-out mice who develop both bone osteopenia and vascular calcification [12], reversible with the administration of osteoprotegerin.
Since calcium-containing P binders are to some extent problematic, what are the alternatives?
Novel P binders
Sevelamer
First, the use of Sevelamer, a polyallylamine-hydrochloride. There is now firm evidence from a controlled prospective trial comparing Sevelamer and calcium carbonate [13] that effective P lowering with Sevelamer is associated with less coronary and aortic calcification. The data are somewhat difficult to interpret mechanistically becausesimilar to cholestyraminthe compound also lowers plasma lipid concentration (which by itself is not unwanted). Furthermore, the sceptic may still raise the point that so far no evidence is available that more coronary or aortic calcium content implies higher cardiovascular mortality, although this has admittedly been shown at least in non-renal patients [14].
Sevelamer does have several problems, however. In past studies [15,16] the target serum P concentration of 5.5 mg/dl [17] has not been reached in the majority of patients and the compound was associated with gastrointestinal side effects, particularly in elderly patients. This is presumably a problem of the galenic preparation, since the tolerance and acceptability have been substantially improved with the new 800-mg tablets.
The remaining problem is obviously the price of the substance. The average dose of 4800 mg as capsules per day currently costs approximately 20 DM/day amounting to 7200 DM (or approximately 3600 Euro) per year.
Sevelamer as a lipid-binding compound might, in principle, also sequester fat soluble vitamins and micronutrients. So far no problems in this respect have emerged, but more information on long-term safety is certainly welcome.
Lanthanum
A second alternative is lanthanum. In preliminary studies, lanthanum has been administered to volunteers and to haemodialysis patients [18,19]. These studies showed some gastrointestinal side effects, but otherwise reasonable short-term tolerability and efficacy. There are, however, some concerns from animal studies which showed a dose-dependent decrease in bone formation rate and osteomalacia [20], and studies showing cytotoxicity for pulmonary alveolar macrophages in vitro [21], as well as neurodevelopmental abnormalities [22] and neurotoxicity [23]. Certainly, any substance that is absorbed and cumulates is suspicious in view of the aluminium experience and data on long-term safety are necessary before such a compound can unhesitatingly be recommended.
Polynuclear iron preparations
A third development is polynuclear iron preparations. The principle is based on the observation that the solubility product of trivalent iron and phosphate is extremely low, as shown by the mineral vivianit. The use of trivalent iron has recently generated much interest [24,25]: it is effective and well tolerated, but is still in the early stages of clinical development.
In 13 patients with stable preterminal renal failure (endogenous creatinine clearance <20 ml/min) we performed a short-term study using stabilized polynuclear iron hydroxide [26]. Stabilized polynuclear iron III hydroxide is an insoluble compound that acts by iron-phosphate complex formation (one can learn from nature, which sequesters iron as insoluble polynuclear hydroxy iron III oxide phosphate).
Hyperphosphataemic patients with preterminal renal failure and a median fasting plasma phosphate of 2.2 mmol/l (range 1.953.0 mmol/l) were given daily 3x2.5 g stabilized polynuclear iron hydroxide as a powder suspended in 50 ml water with meals for a total of 4 weeks. This caused a median per cent decrease of plasma phosphate concentration of 20%. And a median per cent decrease of urinary phosphate excretion of 37%. Ferritin and serum iron levels did not differ significantly during the study. The tolerability of the compound in this short-term study was excellent and no significant side effects were observed.
Based on ongoing studies in haemodialysis patients a dose of approximately 15 g/day is necessary to bring the elevated serum phosphate concentrations of dialysed patients back into the range proposed by Block [17].
The production process would potentially allow a relatively low selling price. Fe III-bound P traps calcium and tends to lower serum calcium, which may be a benefit in disguise in view of the relation between serum calcium concentration and vascular calcification. It is currently also under investigation whether calcium carbonate can be co-administered.
Points to consider when selecting P binders
After all these learned discussions, what P binders should be practising nephrologists select? There is still much uncertainty and need for further data, so that today dogmatic statements cannot be made. The following thoughts reflect the personal opinion of the authors.
If (i) the plasma P concentration is in the desired range, (ii) with relatively low doses of calcium carbonate, (iii) if the serum calcium concentration is in the normal range, and (iv) if there is no evidence of soft tissue calcification, it is wise to continue according to the wisdom don't change a winning horse.
If the plasma P concentration is above the desired range, the nephrologist should first verify whether the patient is compliant with prescribed medications (and in the authors' experience this check often yields amazing and sobering results). One should also verify that calcium carbonate is taken with meals rather than between meals. It is also wise to check whether the dialysis procedure is efficacious. Particularly one should exclude low blood flow and recirculation of the arteriovenous fistula with consecutive inadequate dialytic P removal.
If the plasma P concentration continues to be high (or if unacceptably high doses of more than 34 g/day of calcium carbonate are required), Sevelamer is a sensible option particularly for patients with long life expectancy and little chance of early transplantation. The presumed (but still unproven) benefit on patient survival must be balanced against the cost, however, although we do not want to enter the discussionwell known for cardiological interventionsof how much money can be spent to prolong the patient's life by 1 year. It would certainly be welcome to have information whether a combination of calcium carbonate and Sevelamer in an effort to save cost is feasible and safe.
How about the alternative novel compounds?
Particularly in view of the past tragic experience with aluminium in renal patients, it is in the opinion of the authors that lanthanum is currently not acceptable without information on long-term safety. In view of the aluminium history nephrologists must disprove the cynical statement of the philosopher Hegel What history teaches is this: that people have never learned anything from history or acted on principles deduced from it [27].
The polynuclear trivalent iron compound is theoretically attractive, but currently not available [25] and data on long-term efficacy are necessary.
One further dark horse as an ancillary agent in the difficult to handle hyperphosphataemic patients might be calcimimetic drugs [28] which lower serum Ca and serum P by lowering serum PTH concentration and reducing efflux of Ca and P from the skeleton.
These considerations may seem unsatisfactory on scientific grounds, but the nephrologist must make pragmatic decisions based on incomplete evidenceto quote Sir William Osler: Medicine is an art of uncertainty and a science of probability.
Notes
Correspondence and offprint requests to: Eberhard Ritz, Department of Internal Medicine, Bergheimer Strasse 56a, D-69115 Heidelberg, Germany. Email: Prof.E.Ritz{at}t\|[hyphen]\|online.de
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