Phosphate binders: Sevelamer in the prevention and treatment of hyperphosphataemia in chronic renal failure.
ABSTRACT In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Sevelamer, or more precisely 'sevelamer hydrochloride', is a weakly basic anion-exchange resin in the chloride form that was introduced in 1997 for the treatment of the hyperphosphataemia of patients with end-stage renal failure. Sevelamer sequesters phosphate within the gastrointestinal tract, so prevents its absorption and enhances its faecal excretion. Over the succeeding years, large numbers of patients have been treated with sevelamer, and it has fulfilled expectations in helping to control the hyperphosphataemia of end-stage renal failure. Additionally treatment with sevelamer was accompanied with lower incidence of hypercalcemia, decreased incidence of low PTH levels, a 15-31% decrease of LDL-cholesterol both in dialysis and predialysis patients, decreased C-reactive protein, amelioration of hyperuricemia and low fetuin A, decrease of uremic toxins, suggesting an overall anti-inflammatory effect. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact PTH and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a noncalcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations. Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphataemia in CKD patients. Sevelamer carbonate formulated as a powder for oral suspension presents a novel, patient- friendly alternative to tablet phosphate binders. Safety and efficacy of sevelamer carbonate powder compared with sevelamer hydrochloride tablets in CKD patients are equivalent, with Sevelamer carbonate having fewer side effects from gastrointestinal tract.
- Nephrology Dialysis Transplantation 10/1999; 14(9):2085-7. · 3.37 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Epidemiological studies have identified aortic stiffness as an independent predictor of cardiovascular mortality in end-stage renal disease (ESRD) patients. In these patients, aortic pulse wave velocity (PWV) was associated with mediacalcosis, but the influence of arterial calcifications on the viscoelastic properties of large arteries was not well characterized. The purpose of the present study was to analyse the influence of arterial calcifications on arterial stiffness in stable haemodialysed patients. We studied 120 stable ESRD patients on haemodialysis. All patients underwent B-mode ultrasonography of common carotid artery (CCA), aorta, and femoral arteries to determine CCA distensibility, the elastic incremental modulus (Einc), and the presence of vascular calcifications. All patients underwent measurement of aortic PWV and echocardiogram. The presence of calcifications was analysed semiquantitatively as a score (0 to 4) according to the number of arterial sites with calcifications. Our observations indicate that arterial and aortic stiffness is significantly influenced by the presence and extent of arterial calcifications. The extent of arterial calcifications is in part responsible for increased left ventricular afterload, and is inversely correlated with stroke volume. The influence of calcifications is independent of the role of ageing and blood pressure. Arterial calcifications density increases with age, duration of haemodialysis, the fibrinogen level, and the prescribed dose of calcium-based phosphate binders. The results of this study showed that the presence of vascular calcifications in ESRD patients was associated with increased stiffness of large capacity, elastic-type arteries, like the aorta and CCA. The extent of arterial calcifications increased with the use of calcium-based phosphate-binders.Nephrology Dialysis Transplantation 08/2000; 15(7):1014-21. · 3.37 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: In the general population, including those with diabetes mellitus, coronary artery calcification (CAC) correlates with atherosclerotic plaque burden. On the other hand, accumulating evidence suggests that disordered mineral metabolism significantly contributes to the vascular calcification in individuals with end-stage renal disease (ESRD). In order to determine the relative contribution of accelerated atherosclerosis and disordered mineral metabolism to CAC in chronic kidney disease, a pilot study of 90 patients with type 2 diabetes mellitus was done [age, 40-65 years; normoalbuminuria, N= 30; diabetic nephropathy (DN), N= 60]. CAC was more prevalent and severe among individuals with DN compared to diabetic controls (odds ratio for prevalence 8.1, 95% CI 2.3-28.5; median scores, 66 vs. 4, P < 0.001). None of the 4 measures of disordered mineral metabolism evaluated in this study (serum calcium, phosphorus, parathyroid hormone, and 1,25 di-hydroxy vitamin D levels) correlated with the prevalence or severity of CAC, or accounted for the differences seen between DN and diabetic controls. On the other hand, the difference in the severity of hypertension (number of antihypertensive medications) appeared to account for the differences in CAC burden seen between DN and diabetic controls. This first such study of nondialyzed individuals with DN suggests that, unlike ESRD patients, the high CAC burden seen at earlier stages of diabetic chronic kidney disease is probably unrelated to disordered mineral metabolism. The relationship between the severity of hypertension and CAC burden provides a probable target for intervention in the predialysis phase of DN.Kidney International 12/2004; 66(5):2022-31. · 7.92 Impact Factor
HIPPOKRATIA 2011, 15 (Suppl 1): 22-2?
Phosphate binders: Sevelamer in the prevention and treatment
of hyperphosphataemia in chronic renal failure
Nephrology Department,2nd Hospital of IKA,Thessaloniki, Greece
In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality.
Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcifica-
tion, an independent predictor of mortality. Sevelamer, or more precisely ‘sevelamer hydrochloride’, is a weakly basic
anion-exchange resin in the chloride form that was introduced in 1997 for the treatment of the hyperphosphataemia of
patients with end-stage renal failure. Sevelamer sequesters phosphate within the gastrointestinal tract, so prevents its
absorption and enhances its faecal excretion. Over the succeeding years, large numbers of patients have been treated
with sevelamer, and it has fulfilled expectations in helping to control the hyperphosphataemia of end-stage renal failure.
Additionally treatment with sevelamer was accompanied with lower incidence of hypercalcemia, decreased incidence of
low PTH levels, a 15-31% decrease of LDL-cholesterol both in dialysis and predialysis patients, decreased C-reactive
protein, amelioration of hyperuricemia and low fetuin A, decrease of uremic toxins, suggesting an overall anti-inflam-
matory effect. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in
prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2
years. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with
sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact PTH and with progression
of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on
aortic calcifications and stiffening. Sevelamer treatment resulted in no statistically significant changes in bone turn-
over or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture
improved only with sevelamer. In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a
noncalcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification
progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations.
Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyper-
phosphataemia in CKD patients. Sevelamer carbonate formulated as a powder for oral suspension presents a novel, pa-
tient-friendly alternative to tablet phosphate binders. Safety and efficacy of sevelamer carbonate powder compared with
sevelamer hydrochloride tablets in CKD patients are equivalent, with Sevelamer carbonate having fewer side effects
from gastrointestinal tract. Hippokratia 2011; 15 (Suppl 1): 22-26
Key words: sevelamer hydrochloride, sevelamer carbonate, hyperphosphatemia, vascular calcification
Corresponding author: Spaia S, 21 Anapafseos str.,57010 Hortiatis Thessaloniki, Greece, e-mail: email@example.com
According to KDIGO, derangement of metal metabolism
in patients with kidney disease represents a systematic
disease which is not comprised only of disordered me-
tabolism of Ca, P and their product, PTH and bone me-
tabolism but also of vascular calcification and its clini-
cal consequences. This disorder has a critical impact on
patients’ mortality. Hyperphosphatemia indicates ‘‘A si-
lent killer of patients with renal failure’’. Half of patients
with levels of P at the upper limit don’t survive after 4
years. In chronic kidney disease patients, bone and min-
eral abnormalities have a major impact on morbidity and
mortality1. Hyperphosphatemia has been associated with
increased mortality and with the development of cardio-
vascular calcification, an independent predictor of mor-
tality. The pathophysiology of CKD is complex. Events
of underlying disorders of bone and mineral metabolism
have an origin early in kidney disease. Mechanisms of
calcification are triggered very early with derangement of
Na/P transport at the level of vascular smooth muscle cell
and sequential calcified vessel2.
Primary care physicians typically play a key role in the
early treatment and management of patients with CKD.
The most common point of referral to the nephrologist
is usually at stage 4 or even 5, point where most of the
above have already been established and evolved from
latent to apparent symptoms3.
Extra osseous calcifications very early have been as-
sociated with age, time on dialysis, hypecalcemia and
calcium load. Patients receiving > 1, 5 gr elemental Ca/
day, as CaCO3 binder, had a calcification score of 2 in a
scale from 0 to 44. Several published studies show that
the process of vascular calcification begins rather early in
CKD and is particularly severe among elderly and type 2
diabetic patients. Furthermore, among both diabetics and
HIPPOKRATIA 2011, 15 (Suppl 1)
non-diabetics, vascular calcification was seen in patients
who were new to dialysis, in patients with CKD, and in
patients with established disease on dialysis.
Thus, calcification in early CKD is an important
predictor of subsequent progression of CKD. Vascular
calcifications have been associated with low bone turn-
over, low bone volume and lower activation frequency.
In dialysis patients, the treatment of hyperphospathemia
with calcium based compounds is associated with more
frequent episodes of hypercalcemia, suppression of intact
parathyroid hormone and with progression of coronary
calcifications. In the presence of adynamic bone disease,
calcium load has a significantly higher impact on aortic
calcifications and stiffening. Prevalence of CAC is pre-
dominantly higher in diabetics than in non-diabetics5-10.
It is of pivotal importance to maintain very narrow
limits of P, Ca and PXCa product according to more re-
Ideal phosphate binder should not only bind phos-
phate adequately but also protect renal patients from ac-
cumulation of various metals like aluminum or calcium.
In spite our conception that hypocalcaemia accompanies
deterioration of renal function, true hypocalcaemia is
present in less than 5% of patients in stage 3 and in less
than 20% of patients in stage 412.
In 1997 sevelamer hydrochloride (Renagel®) and in
2007 the newer sevelamer carbonate (Renvela) were pre-
sented as nonabsorbable agents that contain neither cal-
cium nor aluminum. These drugs are cationic polymers
that bind phosphate through ion exchange, in the gas-
trointestinal tract. As noted with other phosphate bind-
ing agents, a significant number of trials have found that
sevelamer is effective in lowering serum phosphate lev-
els13-18 (Figure 1). The important issues with respect to the
choice of sevelamer versus other agents are their relative
effects on mortality, vascular calcification, bone disease,
and biochemical effects, particularly hypercalcemia. The
following sections will address some of the evidence
Figure 1: Calcium, Phosphorus and CaXP product through
one year of sevelamer treatment. (Adapted from Chertow
GM. Nephrol Dial Transplant 1999).
evaluating the relative effects of sevelamer on mortality,
vascular calcification, and biochemical indices.
A small number of randomized trials and a meta-
analysis have evaluated mortality with sevelamer versus
calcium-based phosphate binders18,19,20-26. The following
is a brief review of the largest studies:
The three-year Dialysis Clinical Outcomes Revisited
(DCOR) trial evaluated mortality and morbidity outcomes
among 2103 prevalent hemodialysis patients randomly
assigned to either sevelamer or calcium-based phosphate
binders22. A secondary analysis reported no differences
in mortality, but there were benefits with sevelamer on
all cause hospitalizations and hospital days25. DCOR is
the largest prospective outcomes study ever conducted
in dialysis population. This 3-year trial enrolled more
than 2100 patients (50% of patients were diabetic) and
compared the difference in outcomes for patients re-
ceiving sevelamer hydrochloride with those receiv-
ing calcium-based phosphate binders in 75 sites in the
United States. Patients were randomly assigned to either
sevelamer hydrochloride (Renagel®) or calcium-based
binders (PhosLo® [calcium acetate] or TUMS® calcium
carbonate). The median age of patients in the study was
62 years old. Up to 45 months, there was no significant
difference in all-cause mortality (RR 0.93, 95% CI 0.79-
1.11) and cardiovascular mortality (RR 0.93, 95% CI
0.74-1.17) though a 7% reduction in mortality in favor
of sevelamer was noticed p=0.40). However, a clinically
meaningful benefit was associated with sevelamer use
for older patients. In a pre-specified secondary analy-
sis, those 65 years or older achieved a 23% reduction in
all-cause mortality compared with those 65 or older us-
ing calcium-based phosphate binders, a result that was
statistically significant in favor of the sevelamer-treated
patients (p=0.02). The mean number of hospitalizations
per patient per year was lower in the sevelamer-treated
arm (p=0.07), with the biggest difference seen in patients
> 65 years. Additionally, for patients remaining on study
for at least two years (43% of the study population) a
difference in mortality emerged favoring the sevelamer
In the prospective randomized Renagel in New Di-
alysis Patients (RIND) trial, there was relatively less pro-
gression of coronary artery calcification in 127 incident
hemodialysis patients randomly assigned to sevelam-
er versus calcium-based phosphate binders20. In a post-
hoc analysis of this study, mortality at a median follow-
up of 44 months was (borderline) significantly lower
with sevelamer (5.3/100 patient-years versus 10.6/100
patient-years)21. With multivariate analysis, there was
a greater risk for death with calcium-based phosphate
binders (hazard ratio 3.1, CI: 1.23 to 7.61). In addition,
the baseline coronary artery calcium level was a signifi-
cant predictor of mortality. Subjects with no evidence of
CAC (CAC=0) had a significantly lower mortality rate
(3.3/100 patient years, CI: 0.4-6.1) compared to subjects
with a CAC score 1-400 (7.0/100 patient years, CI: 2.7-
11.4) and those with a CAC score >400 (14.7/100 pa-
tient years, CI:8.1-21.4) (p=0.002). After multivariable
adjustment, the presence of a baseline CAC score >400
remained significantly associated with increased mortal-
ity (HR=4.5, p=0.016, CI: 1.33-15.14).
In 1377 new to dialysis patients concerning veterans,
use of sevelamer was associated with 33% advantage in
mortality rate compared to the use of calcium containing
phosphate binders (p< 0,001)26. It seems that sevelamer
hydrochloride is associated with with a survival benefit
in some hemodialysis patients populations.
A meta-analysis of five trials consisting of 2429 pa-
tients (2103 from the DCOR study) reported a similar
risk difference for all-cause mortality between sevelam-
er and calcium-based phosphate binders (-2 percent, 95%
CI: -6 to +2 percent). Tonelli et al state that there was
no evidence that sevelamer reduced all-cause mortality,
cardiovascular mortality, the frequency of symptomatic
bone disease or health-related quality of life23. In respond
Frazao and Adragao27 in a systematic review argue that
three of the studies included in the mortality analysis of
Tonelli et al involved a small number of patients (20 to 42
patients), had a short follow-up (18 weeks to 5 months),
and mortality was not an end point to most of them.
These studies18,19,24 were not powered in terms of follow-
up time, number of patients, and end points to evaluate
mortality. It is impossible to withdraw any mortality in-
formation in studies with 42 patients and a 5-month fol-
low-up, or a crossover study with 20 patients and a total
follow-up of 18 weeks. The Chertow study’s primary end
point was vascular calcification; mortality was not even
an end point and received 24% weight in the analysis.
Regarding the RIND study21, with a long follow-up for
the secondary end point mortality and evidence of sur-
vival benefit in the sevelamer-treated group, the weight
attributed was only 4.26%.
It is critical to cultivate a balanced approach to un-
derstanding results generated by meta-analysis of data
from small trials.It is important to accept the limitations
implicit in this method.’ Meta-analysis only generates
hypotheses and certainly should be carefully interpreted.
One should always keep in mind that well designed;
randomized controlled trials are the strong bases for evi-
Effect on calcification
There appears to be relatively less progression of
vascular calcification with sevelamer versus calcium-
containing phosphate binders among patients with
CKD. The prospective and randomized “Treat-to-Goal”
and RIND trials both reported relatively less progres-
sion of coronary artery calcification with sevelamer ver-
sus calcium-containing phosphate binders18,19-21,29. By
comparison, the Calcium Acetate Renagel Evaluation
(CARE)-2 trial found similar progression of coronary
artery calcification with sevelamer and calcium acetate
after intensive lipid control30. The differences observed
between the “Treat-to-Goal”, RIND, and the CARE-2
trial may be due, in part, to study limitations of CARE-
2. Treatment assignment was not blinded in CARE-2,
the 1.8 a priori margin for drug equivalence in favor
of calcium acetate was large, CAC is only a surrogate
outcome, duration of treatment was short(1-year), and
dropout rate was high.
In incident dialysis patients, treatment with sevelamer
has been associated with better survival, while in preva-
lent patients a clear benefit could only be demonstrated
in older patients and in patients treated for more than 2
years. In conclusion, the treatment of hyperphosphatemia
with sevelamer hydrochloride, a noncalcium and non-
metal containing phosphate binder, is associated with a
beneficial effect on vascular calcification progression,
bone disease and most likely with a survival benefit in
some hemodialysis patients populations27.
Given these findings, the risk of long-term calcium
exposure remains a concern. Limiting calcium-contain-
ing phosphate binder use and the early use of sevelam-
er in patients with persistent hyperphosphatemia, even
in combination with calcium-containing binders, may be
There appears to be no major difference between
sevelamer and calcium-based phosphate binders in terms
of bone histology. A few randomized prospective studies
have been performed that found varying outcomes in dif-
ferent patients, with a consistent finding of improved bone
volume with calcium therapy31,32,33. A small randomized,
prospective, open label study, evaluated patients with
bone biopsies at the beginning and after 1 year treatment
period with sevelamer hydrochloride or calcium carbon-
ate. Sevelamer treatment resulted in no statistically sig-
nificant changes in bone turnover or mineralization com-
pared with calcium carbonate, but bone formation rate
increased and trabecular architecture improved only with
Although the evidence is somewhat inconsistent, there
appears to be a correlation between increased calcium in-
take and an increased incidence of both adynamic bone
disease and vascular calcification31,34,35. The increased
calcium intake was most commonly the result of the use
of calcium-containing phosphate binders compared with
either sevelamer or lanthanum.
Effects on biochemical parameters
A number of randomized prospective studies have
found that sevelamer compared with calcium-based
phosphate binders is associated with lower serum calcium
levels and higher phosphate and PTH levels18,20,21,27,28,36.
In the prospective “Treat-to-Goal” trial, 200 patients
undergoing maintenance hemodialysis were randomly
assigned to sevelamer or calcium-based phosphate bind-
ers16. At one year, although serum phosphate control was
similar with both agents, sevelamer was associated with
HIPPOKRATIA 2011, 15 (Suppl 1)
Lower incidence of hypercalcemia (5 versus 16 per-
A minimal decrease in the serum calcium concentra-
tion (9.5 versus 9.7 mg/dL [2.35 and 2.43 mmol/L])
Decreased incidence of low PTH levels (30 versus
Sevelamer causes 15-31% decrease of LDL-choles-
terol both in dialysis and predialysis patients37.
C-reactive protein levels decreased significantly after
52 weeks in sevelamer receiving patients while remained
unchanged in calcium binder arm, suggesting an antiath-
eromatous, anti-inflammatory action of the drug38.
Additionally use of sevelamer has been associated
with amelioration of hyperuricemia, low fetuin A, de-
crease of uremic toxins, suggesting an anti-inflamma-
tory action39. Although conventional dosing of sevelamer
is effective, compliance with the requirement for thrice
daily dosing with any phosphate binder can be problem-
atic. A small crossover study found that thrice daily and
once daily dosing were equally effective40. Although fur-
ther study is required, once daily dosing may simplify the
dosing regimen, thereby resulting in increased compli-
ance and overall efficacy.
One problem associated with sevelamer hydrochlo-
ride is the possible induction of metabolic acidosis. As
a result, a buffered form of sevelamer, sevelamer car-
bonate (Renvela®), has been developed. It is associated
with higher serum bicarbonate levels than sevelamer
hydrochloride (Renagel®), but these agents appear to be
equivalent in their ability to control phosphate levels.
This was shown in a double-blind randomized trial of
79 hemodialysis patients in which patients were admin-
istered eight weeks of sevelamer carbonate or sevelamer
hydrochloride and then crossed-over to the other agent
for eight weeks41. Both agents similarly controlled mean
serum phosphate levels, while bicarbonate levels were
significantly higher with sevelamer carbonate (+1.3
mEq/L). Additional advantages of sevelamer carbon-
ate (Renvela®) over sevelamer hydrochloride would be
multiple dose forms of sevelamer carbonate, not only in
tablet, but also in a powder that will be able to be mixed
with a liquid and then have taken as an emulsion, that
is, alternative dose forms. Also, the ability to lessen or
eliminate acidosis with the carbonate moiety of Renve-
la® compared with the hydrochloride in Renagel® is a
big benefit. (Figure 2) Overall adverse reactions among
those treated with sevelamer hydrochloride occurring
in > 5% of patients included: vomiting (22%), nausea
(20%), diarrhea (19%), dyspepsia (16%), abdominal
pain (9%), flatulence (8%) and constipation (8%). If the
clinical trial and cross-over design is held out in larger
use, then it looks like the GI side effects won’t even be
an issue at all with sevelamer carbonate.
Another potential weakness of sevelamer is that it
may have an effect on concomitant vitamin D treat-
ment. Pre-clinical studies suggest that high doses of
sevelamer may reduce absorption of fat-soluble vita-
mins, including vitamin D. Sevelamer carbonate has
been studied in human drug to drug interaction studies
with warfarin and digoxin. Sevelamer hydrochloride,
which contains the same active moiety as sevelamer
carbonate, has been studied in human drug to drug in-
teraction studies with ciprofloxacin. In a study of 15
healthy subjects, a co-administered single dose of 2.8
grams of sevelamer hydrochloride decreased the bio-
availability of ciprofloxacin by approximately 50%. No
interaction was noticed with digoxin, warfarin, enala-
pril, metoprolol and iron.
Though there is a large difference in cost between
sevelamer and calcium based phosphate
binders, with sevelamer being much more
expensive, we must have also in mind that
there is mounting evidence from basic
science, observational studies, and ran-
domized trials with surrogate end points
such as cardiovascular calcification and
mortality that calcium can be toxic for
dialysis patients. So, with this level of
information, the nephrology community
should be asking what level of scientific
evidence is needed to convince us to dis-
continue, or at least to be extremely cau-
tious with the use of calcium-containing
phosphate binders, a potentially harmful
Table 1: Sevelamer presents a benefit in survival in certain patient groups.
Figure 3: Treatment with sevelamer carbonate powder im-
proves serum bicarbonate in chronic kidney disease patients
on haemodialysis. (Adapted from Delmez J. Clin Nephrol.
2007; 68: 386-391).
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