Hyperphosphatemia el-menya

Hyperphosphatemia in CKD Patients;
The Magnitude of The Problem?
By
Alaa Sabry., MD, FACP
Mansoura University, Egypt

Five objectives
• To explain Phosphate hemostasis and
disturbance that happen in CKD patients.
•Why should we control hyperphosphatemia ?
•Is phosphorus a cardiac toxin?
Are we achieving a target serum phosphorus
recommendations?
Different treatment strategies .

Phosphorus balance and tissue distribution in human.
(In healthy human or CKD patients in stage 3 or milder)

Ritter CS, Slatopolsky E. Clin J Am Soc Nephrol. 2016
Phosphate Homeostasis

FGF23/iPTH and Phsophorus levels
Wolf M. J Am Soc Nephrol. 2010;21:1427-35.

• Only 1% of the body’s phosphate is contained in
the blood .
(McMillan et al. 1968).
• Serum phosphate remains within the normal
laboratory range until eGFR drops below 30
ml/min, despite derangements in other
parameters of mineral homeostasis by this stage .
(Levin et al. 2007).
Wolf M. J Am Soc Nephrol. 2010;21:1427-35.

Serum phosphate is a NOT
sensitive measure of whole
body phosphate?

Circadian variation of serum phosphate levels in healthy individuals
on a normal diet.

Five objectives
1
• To explain Phosphate hemostasis and disturbance that happen
in CKD patients.
2
•Why should we control
hyperphosphatemia l?
3
4
4-Are we achieving a target serum phosphorus
recommendations?
5
Different treatment strategies ?.

Higher levels of serum phosphate were associated with an increased risk of
All cause of death, CAD, MI and new heart failure after adjustment for age, sex, and race .
Each 2.7mg/dl increase in phosphate was associated with 22% increased risk of all cause
mortality.
Tonelli et al. 2005
4127 Patients With a recent myocardial infarction
Normal kidney function
94% of the subjects had a phosphate within the
normal laboratory range (2.5-4.5 mg/dl).

Framingham Offspring Study
3368 participants
Follow up 16.1 years
Higher serum phosphorus levels are associated with an increased CVD risk in
individuals free of CKD and CVD in the community.
Dhingra, R, Sullivan LM, Fox CS, et al. Arch Intern Med. 2007.

Serum phosphate level is associated with all-cause and cardiovascular
mortality in the general population.
Chang, A.R. & Grams M.E. Am. J. Kidney
Dis. 64, 567–573 (2014)

Serum Phosphorus is Associated With Increased Mortality in Observational
Studies
• Observational studies have been published over the
last decade - and longer than that - and have shown
that the serum phosphorous is associated with
increased mortality in observational studies, both
• in dialysis patients - the first three studies - and in
nondialysis patients with CKD stages III to IV.
• AndI think that’s an important observation, but you see
here - and we’ll talk about, really, what should the
normal serum phosphorous be?
• You see that in Kestenbaum’s study, there’s an increase
in mortality risk with serum phosphorous above 3.5.

Prospective cohort study.
466 non-dialysis chronic kidney disease
stage 2–4 patients.
Adjusted survival curves of mineral parameters and the outcome of ESRD

Patients (1203) of nondialysis chronic kidney disease
(CKD)
Mean (SD) eGFR was 32 (15) ml/min per 1.73 m2
Survival according to phosphate levels relative to KDOQI guidelines.

A systematic search yielded 47
eligible studies (N = 327 644)
in 49 cohorts of adults with
chronic kidney disease
• The risk of death was higher with
increasing levels of serum
phosphorus (5.5 mg/dL).
• For every 1-mg/dL increase in
serum phosphorus, the risk of
mortality increased by 18% .

3-year, multicentre, open-cohort, prospective
study
6797 adult chronic haemodialysis patients randomly
selected from 20 European countries.

All-cause and cardiovascular mortality risk associated
with baseline serum phosphorous
Tentori F, et al. Am J Kidney Dis. 2008;52(3):519-30.

Dialysis Patients
• Phosphate was initially identified as a CV risk factor in
haemodialysis patients in 1998 in a population of 6,407 Patients .
(Block et al. 1998)
• Subsequently corroborated in 2004 in 40,538 from the US Renal
Data System (USRDS) .
• Serum phosphate levels >4.6 mg/dl were associated with a
stepwise increase in all-cause and CV mortality, even after
adjustment for confounding variables.
(Block et al. 2004)
Cannata-Andia JB, et al. Kidney Int. 2013;84:998-1008.

Five objectives
in CKD patients.
•Why should we control hyperphosphatemia l?
4-Are we achieving a target serum phosphorus
recommendations?

Calcification of Coronary Arteries is Highly
Prevalent Among CKD Patient Populations
23
CKD = chronic kidney disease; RIND=Renagel in New Dialysis; TTG=treat-to-goal.
1. Russo D et al. Am J Nephrol. 2007;27:152-158.
2. Spiegel DM et al. Hemodial Int. 2004;8:265-272.
3. Chertow GM et al. Kidney Int. 2002;62:245-252.
Percentage of CKD Patients With Coronary Artery Calcification Across 3 Studies in
Different CKD Populations
51
64
83
0
20
40
60
80
100
CKD Patients Not on
Dialysis
Incident Dialysis Prevalent Dialysis
Patients(%)
(Russo1)
(Spiegel,
RIND2)
(Chertow,
TTG3)

Massy, Z. A. & Drüeke, T. B. Nat. Rev. Nephrol. 2015

Does Hyperphosphatemia
accelerates the progression of CKD
?

Association between plasma phosphate concentration at the start of pre-dialysis
care and subsequent decline in renal function during follow-up.
448 patients
Median follow-
up time was 337
days
Each milligram/dl higher plasma phosphate was associated
with 0.154 ml/min/month steeper slope of the renal function .

Five objectives
in CKD patients.
•Why should we control hyperphosphatemia l?
4-Are we achieving a target serum
phosphorus recommendations?

Management
1- Dietary interventions.
2-Phosphate binders.
3- Dialysis

3 main Important Issues
Phosphorus content
Bioavailability.
Protein / Phosphorus … Ratio

The Phosphorus Content
Phosphorus Pyramid

Animal Origin
More bioavailable
inorganic salts or as
part of organic
compounds.
cleaved by hydrolases
in the intestinal tract
releasing inorganic P,
which is finally
absorbed.
Plant origin
largely in the form of
phytate in cereals and
legumes.
In humans, the phytase
enzyme is not
expressed
Reduced bioavailability
of P of plant origin,
remaining below 50%.
Phosphorus Bioavailability
Plant Vs Animal

predominantly polyphosphates,
pyrophosphates and lecithins.
100% bioavilability

Bioavailability
The bioavailability of phosphate differs according to the protein source.

Egg
The yolk contains most of
the P (largely as
phospholipids) with a small
amount of protein, while
the white part of the egg
contains protein (3.7 g for
one egg white) with a nearly
absent P content.
The egg white is, therefore, a
natural source of protein of
high biological value, almost
free of P.

Boiling for 30 min reduced phosphorus
content up to ;
 42% in beef
 63 % in chicken breast
 65% in potato
 93% in pasta
 77% in rice
Method of processing :
 Frying
 Roasting
 Grilling
 Baking
 Reheating
reduced phosphorus digestibility and
increases fecal excretion of phosphorus in
men.

Boiling of Food
Effect of different directions of cut on
phosphorus content of meat
Effect of different boiling fluids on
phosphorus content
of meat

DIETARY INTERVENTIONS
4 Strategies
1- Restricting phosphorus-rich
foods.
2-Preferring phosphorus sourced
from plant origin.
3- Boiling as the preferred cooking
procedure .
4- Avoiding foods with phosphorus-
containing additives.
.

DIETARY INTERVENTIONS
Dietary Restrictions : is there
anything left to Eat?

Drugs
Another vastly understudied element of
phosphate intake is the content within
prescription medications.
An Italian study estimated that 70% of patients
with CKD were prescribed medications that
contain absorbable phosphate, although the
phosphate quantity was unknown45
 (10 mg of amlodipine contained 8.6–40.1 mg of
phosphate)

Which phosphate binder for which
patient?
High phosphate-binding capacity (translating into
low pill burden and good patient adherence).
Few adverse effects.
 No safety concerns.
Negligible interactions with other drugs .
All this at a
low cost.

No currently available phosphate binder fulfills all these criteria,
although some come close.

Serum phosphorus 24-hour urine phosphorus, C-terminal FGF23
over the study period among all active- and placebo-treated patients.
148 patients -Estimated GFR=20–45 ml/min per 1.73 m2
calcium acetate, lanthanum carbonate,
sevelamer carbonate, or placebo.

Coronary artery Abdominal aorta
Thoracic aorta BMD

Treart to
Goal
RIND
Vascular Calcification

• Although the data are not consistent.
• There appears to be relatively less
progression of vascular calcification with
sevelamer versus calcium-containing
phosphate binders among patients with CKD.
Vascular Calcification

2013 patients were randomized to Sevelamer
or CBPB

The all-cause mortality rate was
significantly higher (P,0.05) among
patients receiving calcium carbonate.
12 nephrology clinics in South Italy were
evaluated.
(n=212; stage 3–4 CKD) were randomized to
either sevelamer (n=107) or calcium carbonate
(n=105).

All-cause mortality by phosphate binder:
randomized trials (11 Trials 4622 patients )
Published online July 19, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60897-1
Study or Subgroup
1.12.1 RCT
Barreto 2008
Block 2007
Chertow 2002
Di Iorio 2012
Kakuta 2011
Qunibi 2008
Russo 2007
Sadek 2003
Suki 2008
Takei 2008
Wilson 2009
Subtotal (95% CI)
Total events
Heterogeneity: Tau² = 0.03; Chi² = 12.35, df = 7 (P = 0.09); I² = 43%
Test for overall effect: Z = 2.09 (P = 0.04)
1.12.2 Non-Randomized Studies
Borzecki 2007
Jean 2011
Panichi 2010
Subtotal (95% CI)
Total events
Total (95% CI)
Total events
Test for subgroup differences: Chi² = 0.92, df = 1 (P = 0.34), I² = 0%
Events
1
11
6
12
0
3
0
1
267
0
135
436
148
62
74
284
720
Total
52
60
99
107
91
100
27
21
1053
22
680
2312
608
247
242
1097
3409
Events
8
23
5
22
0
7
0
3
275
0
157
500
228
109
170
507
1007
Total
49
67
101
105
92
103
28
21
1050
20
674
2310
769
432
515
1716
4026
Weight
0.3%
3.2%
1.0%
3.0%
0.8%
0.3%
24.5%
17.9%
50.9%
20.6%
12.7%
15.9%
49.1%
100.0%
M-H, Random, 95% CI
0.12 [0.02, 0.91]
0.53 [0.28, 1.00]
1.22 [0.39, 3.88]
0.54 [0.28, 1.03]
Not estimable
0.44 [0.12, 1.66]
Not estimable
0.33 [0.04, 2.95]
0.97 [0.84, 1.12]
Not estimable
0.85 [0.70, 1.05]
0.78 [0.61, 0.98]
0.82 [0.69, 0.98]
0.99 [0.76, 1.30]
0.93 [0.74, 1.16]
0.89 [0.78, 1.00]
0.87 [0.77, 0.97]
Non-Calcium Binders Calcium Binders Risk Ratio Risk Ratio
M-H, Random, 95% CI
0.02 0.1 1 10 50
Favours Non-Calcium Favours Calcium
22 % reduction in moratlity in favor of non-CBBs

• There are insufficient data to establish the
comparative superiority of novel non-calcium
binding agents over calcium-containing
phosphate binders for patient-level outcomes
such as all-cause mortality and cardiovascular
end-points in CKD.
Mortality

Iron Based Phosphate Binders
Ferric Citrate
Sucroferric oxyhydroxide

New Phosphate Bonders
1- Chitosan-loaded chewing gum:
• A natural glucosamine polymer binding phosphate.
• Can reduce serum phosphate in dialysis patients by more than 2 mg/dl within just 2 weeks .
2- Phosphate transport
inhibitors
• A- Nicotinamide :
• A sodium phosphate transport inhibitor.
• French study that’s comparing it as a phosphate-reducing agent to sevelamer, and there’s also an
NIH study looking at nicotinamide and comparing it to lanthanum, which is expected to be
completed in 2018.
• B–Tenapanor (phase 2b study now recruiting)
• Affects on intestinal phosphate transport.
• 3-Colestilan
• This nonmetallic and noncalcium P binder acts as an anion exchange resin, and it is not absorbed
after oral administration.
• Preliminary studies have demonstrated its capability to bind dietary P within the intestinal tract.

Comprehensive Clinical Nephrology. 5th
Edition 2.15

A series of variables may be present:
 Patient predialysis P levels.
 Membrane surface .
Permeability characteristics.
Session duration – currently one of the most
relevant factors.
Diffusive hemodialysis techniques

• 1- Mass transfer of P is hindered :
Coated with water particles that bind strongly to P, thus
transforming an originally small molecule into a molecule
of medium dimension.
• Thus, its increased hydrated radius renders the
passage through the pores of the dialysis
membrane more difficult.
Pribil AB J Comput Chem. 2008;29(14):2330–2334.
• 2- The multicompartmental distribution of P.
• 3- Slow shift from the intracellular to the extracellular
compartment and to plasma.
Dialysis

Ranges of phosphate removal (grams per
week) by different dialysis strategies

• .
Daily or Nocturnal dialysis

312 dialysis patients;
Daily trial (1.5-2.75 hours); 125 ( 3 sessions /wk)-120 (6 /wk)
Nocturonal Trial (6-8 hours): 40 (3 sessions/wk- 45 ( 6/w)
Adjusted mean levels of Monthly predialysis serum phosphorus

DailyNocturnal Trial
8% of participants assigned
to treatment three times
per week .
73% of participants had
their PBD reduced to 0 at
month 12
Phosphate Binder Dose
Reduction
((0 at month 12
28.4%51.4%Normal predialysis serum
phosphorus levels
(4.5mg/dl) at month 12:
42%Phosphorus added into the
dialysate to prevent
hypophosphatemia

Convective hemodialysis techniques
Online-HDF

5366 adult patients,
4515 (84%) haemodialysis .
851 (16%) by haemodiafiltration.
P=0.001

• 1-Increased cardiac output and thus increased blood
flow to lower extremities and open capillary surface area
would increase the flux of toxins from tissue to vascular
compartment .
• 2- Significant decrease in inter-compartmental resistance
owing to capillary endothelium or cellular membrane.
• 3- Increase the body core temperature which will
probably further dilate the vasculature ,it will result in
increased toxin removal from remote inaccessible
compartments.

Systematic Reviews Go Out of Date? A Survival Analysis
Ann Intern Med. 2007;147(4):224-233
Survival of the original systematic review by clinical topic area.

 There is a substantial body of evidence in literature that describes
an association between high serum phosphate ( even within the
normal biological range) and adverse outcomes in general
population , non-dialysis CKD and dialysis patients.
 Serum phosphate concentration has a circadian rhythm that must
be considered when interpreting patient phosphate levels.
 The choice of phosphate binder takes into account CKD stage, the
presence of other components of CKD-mineral and bone
disorders, concomitant therapies and drug side-effect profile.
Conclusion

• Detailed understanding of dietary sources of phosphate,
including food additives, can enable phosphate restriction
without risking protein malnutrition.
• However, there is still a lack of trial data demonstrating that
therapeutic approaches to lower serum phosphate will
improve patient-centered outcomes.
• Frequent hemodialysisextended session lengths clearly
facilitates control of hyperphosphatemia and could afford
Patients the option of more liberal diets and freedom from
phosphorus binders.
Conclusion

Do we Need an new guidelines?
Change the Target of serum phosphorus ?
Change the starting time to check s.
Phosphorus?
To confirm the safety of CBB ?
Advise to use new markers of CKD-MBD
Diagnosis…..FGF23- kolotho ?????

Not on Dialysis
• The 2009 Guideline1 suggested maintaining serum phosphate in the normal range for patients with
CKD G3a to G3b and G4. On reevaluating the evidence for the 2017 Update,3 the Work Group drew
several conclusions:
• (i) The association between serum phosphate and clinical outcome is not monotonic;
• (ii) Evidence is lacking to demonstrate the efficacy of phosphate binders for lowering serum phosphate
in patients with CKD G3a to G4 .
• (iii) The safety of phosphate binders in this population is unproven .
• (iv) There is an absence of data showing that dietary phosphate restriction improves clinical
outcomes.
• Consequently, the Work Group has abandoned the previous suggestion to maintain phosphate in the
normal range, instead suggesting that treatment be focused on patients with hyperphosphatemia.
• The Work Group recognizes that preventing, rather than treating, hyperphosphatemia may be of value
in patients with CKD G3a to G5D, but acknowledges that current data are inadequate to support the
safety or efficacy of such an approach.
• Particularly in the case of CKD patients not on dialysis, the 2017 Update Work Group clarified that
phosphate-lowering therapies may only be indicated in the event of “progressive or persistent
hyperphosphatemia,” and not to prevent hyperphosphatemia.

The efficacy of phosphate-binder therapy in patients with chronic kidney
disease, including those on dialysis.
a | Data from placebo-controlled studies in populations without overt
hyperphosphatemia do not support the use of any phosphate
binder in the absence of hyperphosphataemia.
b | In patients with hyperphosphataemia,
only relative effects can be estimated owing to an absence of placebo-controlled data.
The available studies suggest that non-calcium-based phosphate binders might be more
beneficial than calcium-based phosphate binders.

Introduction
• It’s one of seven major essential minerals in the body.
• 1- Avery important component of cell membrane phospholipid content and
function. When somebody has cell lysis, like rhabdomyolysis, a lot of phosphorous
is released into the body
• 3- Participates in cell signaling and platelet aggregation, and it also produces
energy production in cells.
• ATP is really catalyzed to ATP and phosphorous. And the phosphorous that’s
released by cells really drives the engine of a lot of these cells to continue to
function appropriately.
• 4- It’s an essential component of daily life and cell signaling, not just skeletal
health.
• atomic number 15
• As an element, phosphorus exists in two major forms—white phosphorus and red
phosphorus—but because it is highly reactive, phosphorus is never found as a free
element on Earth.
• As an element, phosphorus exists in two major forms—white phosphorus and red
phosphorus—but because it is highly reactive, phosphorus is never found as a free
element on Earth.

Chitosan-loaded chewing gum
• In 2009, a small uncontrolled trial reported that
twice daily treatment with a chewing gum loaded
with chitosan, a natural glucosamine polymer
binding phosphate, can reduce serum phosphate
in dialysis patients by more than 2 mg/dl within
just 2 weeks [107].
• Subsequent studies reported much smaller
effects, well below 0.3 mg/dl serum phosphate
reductions or even absent effects under similar
conditions [106, 108].

Serum phosphate concentrations follow a circadian rhythm that reaches a nadir
between 7 and 10 am
Bringhust FR, et al. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, editors. Harrison's Principles of Internal
Medicine. 18th ed. 2012. pp. 3082–95.

Phosphate
Reference Range:
2.5 – 4.5 mg/L

Fractional Excretion of Pi
• FE-Pi > 15% Non-renal :
Massive phosphate ingestion
(eg, laxative [Phospho-soda] abuse)
Lysis of tissue and resulting release of
intracellular phosphate
• FE-Pi < 15%  Renal:
Renal failure
Hypoparathyroidism

Above GFR ~35, Compensatory Pathways Maintain
Serum Phosphate Balance

Hyperphosphatemia el-menya

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