Diapositiva 1

Marina Di Luca
A.O.Osp.Riuniti Marche Nord
Presidio San Salvatore
Phosphorus and outcome:
serum phosphorus links with a poor prognosis
Causative role ?
Epiphenomenon ?
numerous epidemiological studies, but data are far from being conclusive
Lowering and maintaining phosphorus levels is accepted as an
important therapeutic goal to improve outcomes of CKD MBD
in CKD patients
Unresolved questions
Active measures should be taken in early stages of CKD when
serum phosphorus is still in the normal or near normal range?
 What serum phosphorus levels should be targeted or
maintained in CKD stage 3-4 ?
 When to Start Treating Phosphate Retention in CKD?
 Which binder is more appropriate in CKD ?
Treatment Target Ranges for
Target PO4
KDIGO: Maintain Normal
KDOQI: 2.7-4.6 mg/dL
KDIGO: Maintain Normal
KDOQI: 2.7-4.6 mg/dL
KDIGO: Towards Normal
KDOQI: 3.5-5.5 mg/dL
KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130
K/DOQI clinical practice guidelines for bone metabolism and disease in
chronic kidney disease. Am J Kidney Dis. 2003(suppl 3)
How treating Phosphate Retention in CKD?
Diet ?
Binders ?
Or Both ?
Protein restriction
reducing FGF 23
and is associated
with a very modest
decrease in serum
phosphate levels.
Britt Newsome
How treating Phosphate Retention in CKD?
Diet ?
Binders ?
Or Both ?
Mean serum phosphorus declined from
4.2 to 3.9 mg/dl in pts treated.
Daily urine phosphorus was
reduced by 22% in pts treated.
Median duration of follow-up: 249 days.
Mean doses of study medication:
Ca acetate 5.9 g/d (1.5 g elementalcalcium)
Lanthanum carbonate 2.7 g/d
Sevelamer carbonate 6.3 g/d
This randomized placebo-controlled pilot clinical trial shows that the use of
phosphate binders in patients with nondialysis requiring CKD reduces urinary
phosphorus excretion (a surrogate of intestinal phosphate absorption) and
attenuates progressive secondary hyperparathyroidism.
The effect on serum phosphorus, although statistically significant, was modest,
despite relatively high-dose therapy and a significant effect on urinary phosphorus
Active therapy resulted in progression of vascular calcification, particularly
among patients randomized to calcium acetate.
Caution regarding the type of statistical
analysis selected by the authors. The
choice to compare all treatment groups
together (90 patients) with only one
placebo group(58 patients) constitutes in
our view a major problem.
The three phosphate binders considered together greatly differ from each other in
several aspects.
The assessment of changes in arterial calcium scores in the study by Block et al.
was possible only in a subset of 90 patients (60 active and 36 placebo) and was
effectively performed only in those with non-zero calcium scores at baseline (n 81;
55% of the original cohort).
Moreover, the baseline characteristics of this subgroup of 81 patients have not
been reported separately in the manuscript, and lack of perfect matching between
active treatment and placebo groups therefore remains possible; insufficient
sample size, with large standard deviations.
Clearly, additional RCTs in larger CKD patient cohorts both before and after
the initiation of dialysis therapy are required to answer the question of
whether phosphate binders should be given early.
Ca Acetato
CAC calcification (p=0.02)
= Non Calcium based
FGF-23 (p= 0.02)
1,25 dihydroxyvitamin D levels
(P =0.004)
(P =0.0002)
These data, in concert with calcium and
phosphate balance study,from Hill et al .,
argue against the nearly universal practice
of providing calcium-containing phosphate
binders to patients with CKD.
Hyperphosphataemia in
chronic kidney disease
Calcium based phosphate binders:
a case for change
March 2013
NICE clinical guideline 157
First-line phosphate binders:
For both people ‘on’ and ‘not on’ dialysis
•For adults, offer calcium acetate as the first-line
phosphate binder to control serum phosphate in addition
to dietary management. [1.1.8]
•For adults, consider calcium carbonate if calcium acetate
is not tolerated or patients find it unpalatable. [1.1.9]
Sequencing of phosphate
binders for patients not on
dialysis: recommendations
Adults with stage 4 or 5 CKD not on dialysis
and taking a calcium-based binder
binders are not
• Hypercalcaemia develops (account
for other causes of raised calcium)
• Serum PTH hormone levels are low
Consider switching to a
Consider either combining with,
or switching to, a
non-calcium-based binder
First-line phosphate binders:
the savings
Depending upon practice locally, prescription of calcium
acetate as first line phosphate binder is likely to reduce the
number of people prescribed sevelamer hydrochloride and
lanthanum carbonate
• Changing from sevelamer hydrochloride to either calcium
carbonate or calcium acetate will result in savings of
£2186 or £2096 per person respectively.
• Changing from lanthanum carbonate to either calcium
carbonate or calcium acetate will result in savings
of £1806 or £1716 per person respectively.
The primary outcome, all-cause mortality, was based on the 11 randomised trials
that reported an outcome of mortality, and consisted of 4622 patients with 936
deaths.Patients randomly assigned to non-calcium-based phosphate binders had a
statistically significant 22% reduction in all-cause mortality compared with those
randomly assigned to calcium-based phosphate binders.
The reduction in vascular calcification in patients assigned to non-calcium- based
phosphate binders vs those assigned to calcium binders was statistically significant
when we analysed data from the longest follow-up point for each study (mean diff
erence in Agatston score −95·26, 95% CI −146·68 to −43·84)
We suggest that the first-line therapy for phosphate lowering should be non-calciumbased binders — specifically sevelamer or lanthanum. One potential explanation for
the decrease in mortality associated with the use of non-calcium-based binders might
be related to slowing of vascular calcifi cation.
Final remarks
Our current approaches to treatment, which are focused on dietary restriction
and the prescription of intestinal binders to prevent phosphate absorption, are
based on principles and assumptions that need to be examined more
rigorously. Recent clinical trials involving phosphate binders have failed to
show the expected impact on serum phosphate levels.
Future clinical studies comparing effective phosphorus-lowering interventions
(i.e., diet and phosphate binders) vs. placebo should provide some definitive
evidence on when in the course of CKD these should be used and how low
serum phosphorus should be kept in chronic renal failure.
Uncertainty remains as to whether the clinical benefits of targeting phosphate
homeostasis require a change in serum phosphate level or whether modification
of intestinal phosphate load is sufficient : a decrease in urine phosphate
excretion might represent a useful treatment target??
It is likely that as our understanding of phosphate metabolism in early CKD
advances, our therapeutic approaches will change, our therapies will be more
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Grazie per l’attenzione !!!

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