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Phosphorus Control in Chronic Kidney Disease
analysis of the Treat-to-Goal study after two years, haemodialysis In order to achieve highly effective P binding with SEV the pill burden is
patients who were treated with Ca-containing P binders were shown to high, and there were concerns about an increased incidence of intestinal
develop both increases in their coronary calcification scores and obstruction with SEV treatment. The prospective pivotal trials had
decreases in their computed tomography (CT)-measured bone mineral indeed demonstrated some gastrointestinal side effects, but not to a
densities (BMDs), associated with relative drops in their PTH levels.
9
degree that would have caused safety concerns. Finally, SEV is limited in
These results were in direct contrast to those observed with the Ca-free its use against hyperphosphataemia in pre-dialysis CKD stages 3 and 4
P binder SEV. Although the CT-generated BMD measurements were not because of the hydrochloride (HCL) content potentially aggravating
appropriately standardised to give absolute values comparable to dual metabolic acidosis. The new development in this area may be sevelamer
energy X-ray absorptiometry (DXA) scans, the individually observed
changes from baseline to follow up after two years seemed valid in both
treatment groups.
Sevelamer hydrochloride is limited in
According to K/DOQI 2003, the maximum daily Ca intake by P binders is
recommended to be ≤1,500mg/day. However, this is clearly an opinion-
its use against hyperphosphataemia in
based recommendation, tolerable and optimal Ca intakes may vary
pre-dialysis chronic kidney disease
significantly among patients on dialysis and the minimal requirements of
daily Ca intake in order to facilitate optimal bone turnover are currently
stages 3 and 4 because of the
not defined at all in this patient group.
hydrochloride content potentially
aggravating metabolic acidosis.
Sevelamer Hydrochloride
SEV is a synthetic ion-exchange polymer that lowers serum P
concentration in dialysis patients, while significantly reducing coronary
artery and aortic calcification progression in incident (Renagel in New
Dialysis (RIND) study) as well as in prevalent (Treat-to-Goal study) carbonate, which avoids acid-base side effects and is currently being
haemodialysis patients.
10,11
It is currently a matter of debate whether tested in appropriate cohorts.
16
these beneficial effects of SEV were due only to the lower Ca intake
compared with the comparator drugs in these studies – i.e. Ca Lanthanum Carbonate
carbonate and Ca acetate – or due to ‘pleitropic’ effects on lipids, Lanthanum carbonate (La) entered the European market in 2006 as
inflammation or gut-related uraemic toxins. Indeed, there are reports the second Ca- and aluminum-free P binder.
17,18
La is a rare earth with
suggesting that SEV may possess anti-inflammatory properties or may strong P-binding properties, and was shown to be highly effective in
upregulate serum levels of fetuin-A, a calcification inhibitory many sufficiently large phase II and III studies. The adverse event
protein.
12,13
Furthermore, the intestinal binding of cholesterol may profile was similar in treated and placebo-controlled patient groups in
reduce the plaque burden and, therefore, the calcification matrix in the studies covering up to six years. Special care was taken to judge the
atherosclerotic transformation process of arteries. potential of La accumulation in the bone, as this had previously
occurred with aluminum, but neither a negative influence on an over-
In addition to the studies in which the surrogate outcome ‘vascular representation of adynamic bone nor a significant deposition of La
calcification’ was evaluated, the Dialysis Clinical Outcomes Revisited in the bone could be demonstrated in experimental as well as in
(DCOR) trial was launched to determine the hard outcome of ‘all-cause clinical studies.
19
mortality’, investigating more than 2,000 haemodialysis patients stratified
to either Ca-based or SEV-based P binder treatment for up to three years. Two experimental studies in rats with renal insufficiency had raised
Unfortunately, the results are available only in abstract form and must thus concerns of hepatic accumulation of La after high-dose exposure.
20,21
be regarded as preliminary.
14
The presentations so far indicated a negative Follow-up reports, however, emphasised the probability that La is not
result concerning the primary end-point all-cause mortality, while specific depositing in the liver tissues, but is ‘shuttled’ through the liver for
benefits for older patients (according to a higher event rate in this excretion in an enterohepatic circulation.
22
La binds to the transferrin
population) and for patients on long-term treatment with SEV (>two receptor and is subsequently taken up by lysosomes and transported
years) were observed, but the final full publication will have to be through liver cells in a granular form for biliary excretion. The final
considered for definite interpretation of the study results. However, hard proof negating the safety concern of hepatic accumulation would be
outcome data were recently published from the RIND cohort.
15
Observing to demonstrate complete La washout out of hepatic tissue following
survival of the patients had been a pre-specified secondary end-point withdrawal of La in, for example, experimental rats; such studies are
when the study was started, and after a median follow-up of 44 months probably underway. In clinical studies there was no evidence of any
the multivariable adjusted hazard ratio for mortality risk was 3.1 functional or biochemical hepatic alterations including elevations
(1.23–7.61) for patients treated with Ca-containing phosphate binders of transaminase enzymes, disturbances of coagulation factors or
versus SEV during the initial protocol. On the one hand, the study size bilirubin elevations.
(n=127) was much smaller than in the DCOR study, while on the other
hand the observation period was much longer, potentially indicating that The safety and efficacy data on La are thus very comprehensive, but
treatments such as prevention of Ca ingestion or direct ‘pleoitropic’ SEV outcome data unfortunately are still missing. Although it is likely that the
effects, respectively, may take years to show biologically relevant effects Ca-free nature of La could cause benefits comparable to those shown
on processes such as unwanted vascular calcification. with SEV, it is still possible that SEV acts quite differently because of its
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