Transcript MANAGEMENT OF CHRONIC KIDNEY DISEASE PROGRESSION

DIAGNOSIS AND TREATMENT
OF BONE DISEASE IN
RENAL
FAILURE
Dr.Shahram Sajjadieh
Nephrologist

The management of progression of CKD is
aimed at addressing a multiplicity of factors
known to be associated with progression.
DIAGNOSIS AND TREATMENT
OF BONE DISEASE IN
RENAL FAILURE
Dr.Shahram Sajjadieh
Nephrologist
CKD Metabolic Bone Disease

All stages of chronic kidney disease (CKD) are
associated with increased mortality; patients who
require dialysis have a particularly poor prognosis.

Without the benefits of a kidney transplant, 5-year
survival for patients aged ~60 years who are on
dialysis is only just better than 5-year survival for
sufferers of ovarian carcinoma (46% versus 44%,
respectively) and much worse than the 5-year
survival for patients with breast or colon cancer
Changes in bone mineral metabolism and alterations in
calcium and phosphate homeostasis occur early in
the course of CKD and progress as kidney function
declines
These changes are grouped under the umbrella term
Chronic Kidney Disease-Mineral and Bone Disorder
(CKD-MBD) which includes renal osteodystrophy
and extraskeletal (vascular) calcification related to
abnormalities of bone mineral metabolism
Pathogenesis


Kidney failure disrupts systemic calcium and
phosphate homeostasis and affects the bone, GIT
and parathyroid glands.
In kidney failure there is decreased renal excretion
of phosphate and diminished production of
calcitriol (1,25-dihydroxyvitamin D)
 Calitriol increases serum calcium levels

The increased phosphate and reduced calcium,
feedback and lead to secondary
hyperparathyroidism, metabolic bone disease, soft
tissue calcifications and other metabolic
abnormalities
PO4
Ca
GFR
1,25 DHCC
Calcitriol
PTH

Although bone disease and abnormal
PTH are a major feature, CVD and
excess calcification (extra-skeletal) are
important causes of morbidity and
mortality
Normal Bone
Remodelling Cycle
Resorption
osteoclasts
Quiescence
Formation
osteoblasts 
matrix
Mineralisation
Hyperparathyroidism
Increase PTH is hallmark of secondary
hyperparathyroidism
 The major factors leading to it’s increase
are;

 Decreased production of Vit D3 (calcitriol)
 Decreased serum calcium
 Increased serum phosphorous
Role of PTH


Responsible for maintaining serum
calcium in a narrow range (8.5-10.3)
Does this by;
1. acting directly on the distal tubule of the
kidney to increase calcium reabsorption
–
–
Increases calcitriol production (D3)
D3 increases GIT absorption of Ca and
Phos and promotes osteoclast formation.
2. Acting on bone to increase calcium and
phosphate efflux
The net effect of PTH is to create
positive calcium balance necessary to
maintain homeostasis.
 To balance out the increased phos from
skeletal effects, and GIT effects of
calcitriol, PTH acts secondarily to
increase renal phos excretion

 By decreasing activity of sodium phosphate
co-transporter in prox renal tubule.
Uremic Secondary
Hyperparathyroidism
Cause
PO4 retention
Low 1,25 Vit D synthesis
Effects
(late)
Proximal weakness, Bone pain
Alk Phos, bone erosions
Rx
Diet, PO4 binders
Calcitriol, PTHx (usually for 3o)
hyperPTH in CKD





In CKD is a progressive disorder.
Involves both increased secretion PTH &
hyperplasia
Can occur once eGFR < 60
PTH levels increase progressively as renal
function declines and by CKD stage 5(<15)
most pt’s expected to have this.
Usually the 1st sign and occurs before lab
tests pick up  phosphatemia, ↓ Vit D3 and ↓
calcium
 Presumably as PTH is maintaining homeostasis.

Unless treated, progresses and frequency of
parathyroidectomy proportional to yrs on
dialysis
Classification of
Bone Disease in CKD


The circulating level of PTH is primary
determinant of bone turnover in CKD
Type of bone disease depends upon





Age of pt
Duration of kidney failure
Severity of hyperPTH
Type of dialysis
PTH & Vit D receptors, as well as
calcium sensors are present on
osteoblasts
Types of Renal Bone Disease
Traditionally classified according to degree
of abnormal bone turnover
High Turnover (osteitis fibrosa)

 Hyperparathyroidism
Low turnover
 Adynamic
- Osteomalacia
Beta 2 MG amyloidosis
Osteoporosis
 Post-menopausal
- Post-transplant
High turn over bone disease
Due to excess PTH
 Increased bone turnover activity
(greater number of osteoclasts and
osteoblasts) and defective
mineralization.
 Associated with bone pain and
increased risk of fractures.
 Severe symptomatic disease is currently
uncommon with modern therapy.

Mixed uremic bone disease

Mixture of high turn over bone disease
and osteomalacia
Osteomalacia

Formally linked to aluminium toxicity
 From aluminium based phosphate binders
 From contamination of water in diasylate
solutions
Adynamic bone disease





Characterized by low osteoblastic activity and
bone formation rates
Seen in up to 40% HD and 50% PD
May be due to excess suppression of the
parathyroid gland with therapies, particularly
calcium-containing phosphate binders and vitamin
D analogues.
Typically maintain a low serum intact PTH
concentration, which is frequently accompanied by
an elevated serum calcium level.
Felt to represent a state of relative
hypoparathyroidism
Clinical manifestations of bone
disease


Most with CKD and mildly elevated
PTH are asymptomatic
When present classified as either
1. Musculoskeletal
2. Extra-skeletal
Musculoskeletal
Fractures, tendon rupture and bone pain
from metabolic bone disease, muscular
pain and weakness.
 Most clinically significant is hip fracture,
seen in CKD 5 (and is associated with
increase risk of death)

 In dialysis pts there is already a 4.4 x
increase risk of hip fracture.
Extra-skeletal
Important to recognise disordered bone
and mineral metabolism is a systemic
disorder affecting soft tissues,
particularly vessels, heart valves and
skin.
 CVD accounts for around half of all
deaths of dialysis patients.
 Coronary artery and vascular
calcifications occur frequently in CKD 5
(and increase each year on dialysis)

Types of calcification
1. Focal calcification associated with lipid
laden atherosclerotic plaques
•
Increases fragility and risk of plaque rupture
2. Diffuse calcification
•
•
•
not in atherosclerotic plaques and occurs in
media of vessels
Called “Monckeberg’s sclerosis”
Increases blood vessel stiffness and reduces
vascular compliance
○
○
○
Results in widened pulse pressure
Increased afterload
LVH
•
Contributing to CVD morbidity
Types of calcification

Calciphylaxis or calcemic uremic
arteriopathy
 Seen primarily in CKD 5
 Occurs in 1-4% of dialysis patients
 Presents with extensive calcification of the skin,
muscles and SC tissues.
○ Extensive medial calcification of small arteries,
arterioles, capillaries and venules.
○ Clinically they may have skin nodules, skin
firmness, eschars, livedo reticularis and painful
hyperesthesia of the skin.
○ May lead to non healing ulcers and gangrene
calciphylaxis
A, Confluent calf plaques •
(borders shown with arrows).
Parts of the skin are
erythematous, which is easily
confused with simple cellulitis.
B, Gross ulceration in the
same patient 3 months later.
The black eschar has been
surgically débrided. C,
Calciphylactic plaques, a few
of which are beginning to
ulcerate. (Photographs courtesy
of Dr. Adrian Fine. Up To Date)
Angulated black eschar with surrounding livedo.
Note the bullous change at the inferior edge of the eschar.
(courtesy Up To Date)
Diagnosis of CKD bone disease

Blood
 PTH
○ Random circulating PTH (1/2 life 2-4 mins)
○ Excreted renally so present for longer in RF
 Calcium
 Phosphate

Bone biopsy
 no longer frequently performed

Imaging
 In general not indicated
PTH levels
Normal (Pathwest) 0.7 – 7.0 pmol/L
 In CKD there is end-organ resistance
 Hence, recommended levels are 2 – 3 x
normal.

Treatment of CKD bone disease

Directed towards normalizing serum
calcium, phosphate and PTH, while
minimizing the risks associated with
Rx
Treatment of CKD bone disease
Various Rx for secondary hyperPTH and
hyperphosphataemia include;
1. Dietary phosphorous restriction
2. Calcium and non-Ca phosphate binders
3. Calcitriol or other Vit D analogues
4. Calcimimetics
5. Parathyroidectomy

Phosphorus (oxidized form is phosphate)







80% in the bone
Food products include; nuts, beer,
chocolate, coca-cola
Normal level 0.8 – 1.5mmol/L (Pathwest)
Passes into glomerular filtrate and 90%
reabsorbed
Reabsorption decreased by PTH and by
calcitonin and increased if PTH is absent
Low levels if hyperparathyroidism with
excessive losses in urine
High levels in hypoparathyroidism or renal
failure
Phosphate binders

Calcium-based phosphate binders
 Calcium carbonate (Cal-Sup/Caltrate)
 Only Cal-Sup i PBS/S100
 Varies, eg. 1 BD, 1-4 TDS
 Must be chewed with food to maximize
binding of ingested phosphorous.
Phosphate binders
Non-calcium phos binder
 Sevelamer

 Often used in conjunction with Cal-sup
 Used when phos still high despite max Cal-
Sup (2 TDS)
 More costly
Phosphate binders

Aluminium-containing phos binders
 Alu-tabs/aluminium hydroxide
 Most effective, but ceaesd use when
sevelamer and cinacalcet available.
 Systemic absorption with subsequent
neurological, hematological and bone
toxicity.
Calcitriol

1,25-(OH)2 Vitamin D3 or other
analogues bind to receptor on PT tissue
and suppress PTH production
Calcimimetics
Calcium receptor-sensing agonists
 Act on PT gland and increase sensitivity
of receptor to calcium
 Cinacalcet (Sensipar)

 Significant decrease PTH, w/o  Ca or phos
 Avoids calcification
Parathyroidectomy
Last option
 Considered when other methods fail to ↓
PTH
 Either total or sub-total

 Used to re-implant in forearm.
We recommend measuring serum levels of calcium,
phosphate, PTH, and alkaline phosphatase activity
at least once in adults with GFR <45 mL/min/1.73 m2
in order to determine baseline values and inform
prediction equations if used
As kidney function declines abnormalities of serum
calcium, phosphate and circulating hormones
related to CKD-MBD progress.
These include parathyroid hormone (PTH), 25hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin
D (1,25(OH)2D), and other vitamin D metabolites,
fibroblast growth factor-23 (FGF-23), and growth
hormone.
At the tissue level there is down regulation of vitamin
D receptors and resistance to the actions of PTH.
abnormalities of calcium and phosphate appear
to occur relatively later in the course of CKD,
than do abnormalities in values of 1,25 (OH)
and 25 (OH) Vitamin D and PTH. Thus, the
recommendation is to evaluate these
parameters in relatively early stages of CKD,

In dialysis patients the highest risks for
mortality have been reported with
combinations of high serum phosphate and
calcium together with either high PTH or low
PTH compared with the combination of high
PTH with normal serum calcium and
phosphate
We suggest not to perform bone mineral density
testing routinely in those with eGFR <60
mL/min/1.73 m2, as information may be misleading
or unhelpful.
bone densitometry does not reliably predict
fracture risk in patients with GFR <60
mL/min/1.73 m2,neither does it predict the type
of renal osteodystrophy.
Thus, BMD measurements do not provide the
information usually sought from such testing
In people with GFR <60 mL/min/1.73 m2, we suggest
maintaining serum phosphate concentrations in the
normal range
In people with GFR <60 mL/min/1.73 m2, the optimal
PTH level is not known.
We suggest that people with levels of intact PTH (iPTH)
above the upper normal limit of the assay are first
evaluated for hyperphosphatemia, hypocalcemia,
and vitamin D deficiency
Higher serum phosphate concentrations are
associated with mortality and experimental
data suggests that serum phosphate
concentration is directly related to bone
disease, vascular
calcification and cardiovascular disease.
earlier phosphate control may help reduce the
early clinical consequences of CKD-MBD
the risk of death increased 18% for every 1mg/dL
increase in serum phosphate concentration
There was no association seen with either PTH or
serum calcium and all cause mortality
Each 1 mg/dL increase in serum phosphate
concentration was associated with a 21% ,33% .,25%
,and 62% greater prevalence of coronary artery,
thoracic, aortic valve, and mitral valve calcification,
Sources of dietary phosphate are proteinrich foods, including dairy products,
meat, and fish as well as legumes, nuts,
chocolates and inorganic phosphate
additives such as are found in
carbonated drinks.
There are a number of agents available
for phosphate binding
In the absence of hypercalcemia there is no
indication to prescribe phosphate-binders less
cost effective than calcium-based agents.
Current data are insufficient to make
recommendations about target levels of serum
calcium or PTH concentrations in people with
CKD
We suggest to not routinely prescribe vitamin D
supplements, in the absence of documented
deficiency, to suppress elevated PTH
concentrations in people with CKD not on
dialysis
In the absence of deficiency treatment with vitamin D
and related compounds has not been shown to
improve either mortality or cardiovascular
outcomes.
Of particular note a higher urinary albumin creatinine
ratio was associated with lower levels of 1,25(OH)2D
at GFR values of <60 mL/min/1.73 m2.
We suggest not to prescribe
bisphosphonate treatment in people
with GFR <30 mL/min/1.73 m2
their safety and efficacy below GFRs of 30 mL/min
have not been well validated and intravenous
bisphosphonates have been implicated in
nephrotoxicity, especially when rapidly infused
History

Secondary hyperparathyroidism
 Patients with secondary
hyperparathyroidism usually present with a
history of underlying disease such as renal
or intestinal conditions.
 Symptoms are musculoskeletal in nature,
including bone pain, muscle weakness, and
previous fracture.
Physical Exam.
 Secondary
hyperparathyroidism
 Skeletal deformity
 Decreased muscle tone
 Bone pain on palpation
 Short stature
Medical Care

For secondary hyperparathyroidism that occurs with chronic
renal failure, parenteral administration of calcitriol is helpful;
however, this manner of administration is feasible only for
those patients receiving hemodialysis.

For those individuals receiving therapy with peritoneal
dialysis, oral administration of calcitriol is the only alternative.
This route of administration may not be as effective as the
intravenous route; however, some preliminary clinical trials
have been conducted for calcimimetics in this condition, as
well as in primary hyperparathyroidism. Early results are
encouraging.
Medical Care

For other forms of secondary hyperparathyroidism,
such as that resulting from chronic cholestatic liver
disease, no standard treatment guidelines exist.

Therefore, treatment should be aimed at ameliorating
the underlying condition and supplying sufficient dietary
calcium, phosphorus, vitamin D, and magnesium.

This ensures that hyperparathyroidism is not
exacerbated by nutritional insufficiency.
over the past four decades it has been suggested that the
accumulation of various ‘uremic toxins’ contribute to this
increased mortality.
urea
 parathyroid hormone (PTH)
 β2-microglobulin
 homocysteine
 leptin
 advanced glycation end products, asymmetric
dimethylarginine and advanced oxidation protein
products.
 phosphate

Pathophysiology of
hyperphosphatemia


A normal diet contains ~1,500 mg per day of phosphate.
However, modern practices of food processing
frequently include the addition of sodium
polyphosphates, and have appreciably increased this
daily intake.
Depending on individual food choices, phosphate intake
can be increased by as much as 1,000 mg per day by
increasing the percentage of processed foods in the
diet.
Pathophysiology...

Serum levels of phosphate do not generally rise in patients with
stage 3 CKD, as a result of compensatory reduction in tubular
resorption mediated by increased serum levels of PTH, fibroblast
growth factor 23 (FGF23) and phosphate itself.

In patients with stage 4 and 5 CKD, the dietary intake of phosphate
exceeds the excretion of phosphate (Figure 1), and serum levels of
phosphate begin to rise to the point that hyperphosphatemia is
usual in patients with advanced CKD.
Pathophysiology...


As intestinal phosphate absorption is linearly related to
intake over the range 4–30 mg/kg per day
the main determinants of absorption are the amount of
phosphate present in the diet, its bioavailability and the
presence or absence of natural dietary phosphate
binders.
Pathophysiology...

Standard dialysis plus dietary restriction of phosphate are
moderately effective control measures, but are unable to normalize
serum levels in the majority of patients

Consequently, oral phosphate-binding agents are generally
required to bind phosphate in the gut lumen and thereby reduce its
absorption.

the only dialysis modality shown to normalize, or even deplete,
serum levels of phosphate is DAILY, NOCTURNAL HOME
HEMODIALYSIS, which is only practical for a small percentage of
patients who are physically and psychologically able.
Phosphate transport

Following renal filtration, the majority of phosphate in
the serum is reabsorbed across the kidney proximal
tubule epithelium.

Several humoral factors impinge on these transport
systems to differing degrees to modulate the amount of
phosphate that is reabsorbed. For example, FGF23
inhibits reabsorption of renal phosphate and decreases
the synthesis of 1,25-dihydroxyvitamin D3.
Clinical impact of
hyperphosphatemia

a statistical association between serum levels of phosphate and allcause (but not cardiovascular) mortality.

the degree of hyperphosphatemia is statistically associated with
vascular calcification, and vascular calcification is in turn
associated with mortality.

control of hyperphosphatemia in patients with stage 3–5D CKD is
now regarded as a high priority and most patients on dialysis are
eventually prescribed phosphate binders
Pharmacology of oral phosphate
binders

All currently available oral phosphate binders work in a
similar way—binding phosphate in the gastrointestinal
tract, either by forming an insoluble complex or by
binding it into a resin.

In both cases less phosphate is available to be
absorbed and more passes through the gastrointestinal
tract to be excreted in the feces than when no
phosphate binder is administered
Aluminum salts

these binders are highly effective but associated with cognitive
disturbances, osteomalacia and anemia.

Aluminum successfully reduces serum levels of phosphate via two
mechanisms. First, aluminum ions in the gut form aluminum
phosphate precipitates that are insoluble and cannot be absorbed.
Second, aluminum hydroxide is able to form coordination
compounds with phosphate ions and thus ‘trap and mask’
phosphate ions in the blood.

No safe dose of aluminum has been identified.
Aluminum salts

an important tool in the treatment of hyperphosphatemia in most
developing countries

used as short-term ‘salvage’ therapy to achieve acute control of
high levels of phosphate in most Western countries.

sometimes used in patients whose prognosis is felt to be so short,
because of other comorbidities

a low dose of aluminum (2 g daily) probably does not cause
toxicity in patients with a reduced life expectancy (such as patients
aged >75 years receiving dialysis)
Calcium and magnesium salts

Binders that have a calcium or magnesium base bind phosphate
ionically and are effective and inexpensive.

Calcium carbonate and calcium acetate are the most widely used,
but their administration results in hypercalcemia in up to 50% of
patients, especially when coadministered with vitamin D
analogues.
Calcium and magnesium salts

Calcium carbonate has a fairly long disintegration time and is not a
particularly effective binder at low pH values because hydrogen
ions compete with calcium for phosphate. Calcium carbonate
dissociates best in an acid milieu and therefore a noteworthy
problem with calcium carbonate is the opposing effects of pH on
solubility and on the calcium–phosphate reaction—acidity is best
for solubility, but alkalinity is best for binding.

its performance as a phosphate binder can be inhibited by other
medications such as gastric proton pump inhibitors.
Calcium and magnesium salts


Other binders that contain calcium but are much less
widely used include calcium alginate (25% elemental
calcium)and calcium lactate (12% elemental calcium).
Calcium ketoglutarate is also reported to have
phosphate-binding properties, without inducing notable
hypercalcemia.
Lanthanum carbonate
Lanthanum carbonate retains binding activity across the full
range of pH 1–7, but binds phosphate optimally at pH 3–5 Thus,
lanthanum carbonate is able to bind phosphate efficiently in the
low pH environment of the stomach, as well as at the higher pH
values found in the duodenum and jejunum.
 Unlike calcium carbonate, lanthanum carbonate is highly
insoluble and therefore has a low potential for accumulation,
with only 0.001% of an oral dose being absorbed in the
gastrointestinal tract, compared with 0.1% for aluminum. As
expected for a minimally absorbed drug, the majority of an oral
dose of lanthanum carbonate is excreted in the feces
lanthanum does not seem to cross the blood–brain barrier and
therefore the potential for neurological adverse events is
extremely low.

Sevelamer hydrochloride and
carbonate



Sevelamer (molecular weight 1016 Da) is a cationic hydrogel that is
hydrophilic but insoluble in water
Peak binding occurs in vitro in the physiological pH range (~pH 7)
and is appreciably affected by changes in gastric acidity.
sevelamer hydrochloride binds bile acids and reduces serum
levels of LDL cholesterol at the expense of previously bound
phosphate ions, which are released. Sevelamer hydrochloride,
therefore, might also bind lipophilic drugs, such as
immunosuppressants and the fat-soluble vitamins D, E and K.
Reduced levels of 25-hydroxyvitamin D have been reported in a
12-month study in healthy volunteers.
Sevelamer hydrochloride and
carbonate

evelamSer had little effect on ciclosporin levels, but further studies
looking at the metabolites of ciclosporin demonstrated that the area
under the curve and peak concentration of one of the metabolites,
were significantly reduced by approximately 30% and 25%,
respectively, 4 days after commencing sevelamer treatment.

concomitant administration of sevelamer hydrochloride and
mycophenolate mofetil reduced the immunosuppressant’s area
under the curve by 25% even after a single dose.
Sevelamer hydrochloride and
carbonate

Sevelamer carbonate has a similar structure to sevelamer
hydrochloride. Both are marketed as 800 mg tablets, but a
powdered form of sevelamer carbonate is also available in many
countries in foil packets containing 800 mg or 2,400 mg.

Apart from the absence of induction of metabolic acidosis,
sevelamer carbonate seems to be equivalent to sevelamer
hydrochloride in terms of efficacy and tolerability.
Efficacy of oral phosphate binders

traditionally efficacy has been judged simply by the criterion of
serum levels of phosphate.

with phosphate binders was independently associated with
decreased mortality compared with no treatment, but the results
were independent of baseline and follow-up serum levels of
phosphate

lack of correlation with serum levels of phosphate, might be
attributable to an effect on circulating levels of FGF23
Efficacy of oral phosphate binders

all phosphate binders decreased serum levels of phosphate
compared with placebo.

calcium salts were superior to sevelamer for reduction of serum
levels of phosphate.

Compared with calcium salts, however, sevelamer and lanthanum
carbonate were associated with considerably reduced rates of
hypercalcemia, which might result in decreased vascular
calcification.

increased PTH suppression by treatment with calcium salts
compared with sevelamer
Patient preference for phosphate binders



Phosphate binders have to be taken with food, and their
interference with an individual’s lifestyle and social habits is known
to affect treatment concordance.
all phosphate binders are of similar efficacy, and none is ideal.
the choice of binder will depend to some extent on the prescriber’s
and the patient’s individual habits and behavior as well as their
expectations, beliefs and preferences.
Safety and tolerability

Gastrointestinal adverse events and tablet burden are the main
tolerability issues that are common to all currently available oral
phosphate binders.

no statistically significant difference in the risk of gastrointestinal
adverse events with calcium acetate compared with calcium
carbonate, or with lanthanum carbonate compared with placebo or
calcium carbonate. However, sevelamer was associated with an
increased risk of gastrointestinal adverse events compared with
calcium salts
Calcium salts

calcium overload might contribute to vascular calcification in
patients with advanced CKD or on dialysis continues to
accumulate.

The KDIGO Clinical Practice Guidelines recommend restricting the
dose of calcium-based phosphate binders in patients on dialysis in
the presence of persistent or recurrent hypercalcemia, and in
patients with arterial calcification and/or adynamic bone disease
and/or if serum levels of PTH are persistently low, but the extent to
which doses should be restricted is not specified.
Magnesium salts



Magnesium-containing phosphate binders are associated with
raised serum levels of magnesium and diarrhea.
A combination of calcium acetate and magnesium carbonate is
available under the trade name OsvaRen®.
OsvaRen® was equivalent to sevelamer in lowering serum levels
of phosphate.A small increase in total serum calcium and no
change in ionized calcium were reported. OsvaRen® was
associated with an asymptomatic increase in serum levels of
magnesium, but had a good tolerability profile.
Lanthanum carbonate

Avoidance of hypercalcemia is the major advantage cited for use of
both lanthanum and sevelamer

trace deposition of lanthanum occurred in some tissues, particularly
in the liver, and tissue levels seemed to be increased under uremic
conditions.

a satisfactory long-term safety profile, with no evidence of harmful
adverse events. Subsequent studies have demonstrated the
absence of adverse effects on liver function, bone and the central
nervous system.
Sevelamer hydrochloride and
carbonate

the most important of its is association with metabolic acidosis.
sevelamer’s amine content causing a dietary acid overload, and
also the withdrawal of other phosphate-binding agents, which are
often alkalinizing agents such as carbonates and acetates.

Apart from the absence of induction of metabolic acidosis,
sevelamer carbonate seems to be equivalent to sevelamer
hydrochloride in terms of safety and tolerability.
Sevelamer hydrochloride and
carbonate

Isolated cases of fecal impaction, ileus, bowel obstruction and
perforation have been reported with sevelamer, possibly
attributable to the large increase in the size of the tablet as the
sevelamer molecules hydrate in the gastrointestinal tract

Sevelamer binds various other molecules apart from phosphate,
including folic acid (which results in a rise in levels of
homocysteine) and vitamin D.

In vitro, sevelamer binds vitamins C and K as well as copper and
zinc.
Alternatives to current phosphate
binders

Nicotinamide:inhibit sodium-dependent phosphate cotransport
activity in the rat small intestine. The nicotinamide had no effect on serum
levels of calcium, and resulted in a possibly beneficial rise in serum levels
of HDL cholesterol plus a fall in levels of LDL cholesterol. Gastrointestinal
adverse events will probably limit the dosage of nicotinamide to between 1
g per day and 2 g per day, and doses above 3 g per day are associated
with hepatoxicity.
Thanks for your attention