Hyperphosphatemia in CKD patients; The Magnitude of The Problem - Prof. Alaa Sabry

Hyperphosphatemia in CKD Patients;
The Magnitude of The Problem.
By
Alaa Sabry., MD, FACP,FASN
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.

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 ?.

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 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.

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.

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
16
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)

Schematic representation of intimal and medial calcification.

The Role of Phosphorus in the
Development and Progression of VC

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
( 40-60%)
inorganic salts or as
part of organic
compounds.
cleaved by hydrolases
in the intestinal tract
releasing inorganic P,
which is finally
absorbed.
Plant origin
Reduced
bioavailability
(20-40%)
largely in the form
of phytate in cereals
and legumes.
In humans, the
phytase enzyme is
not expressed
Phosphorus Bioavailability
Plant Vs Animal

predominantly polyphosphates,
pyrophosphates and lecithins.
100% bioavilability

• 1 can of cola contains 65 mg of phosphate,
equivalent to 20 grams of cooked chicken filet

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
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?

Comprehensive Clinical Nephrology. 5th
Edition 2.15

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.

Treart to
Goal
RIND
Vascular Calcification
Calcium Acetate
Renagel Evaluation

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

• 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
1-Ferric Citrate
2-Sucroferric oxyhydroxide

Phase III study, 644
patients (HD/PD).
384 sucroferric
oxyhydroxide;
n = 260 sevelamer

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.

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

DailyNocturnal Trial
8% of participants.73% of participantsPhosphate 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
312 dialysis patients;
Daily trial (1.5-2.75 hours)
Nocturonal Trial (6-8 hours)

Convective hemodialysis techniques
Online-HDF

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

Phosphate content of the prescribed
Medications

200 of the most widely prescribed
medications in Dialysis Clinic centers in the
United States Was examined , found that 23
(11.5%) contained phosphorus.
The phosphorus content of a generic 10 mg
lisinopril (32.6 mg) and a generic 10 mg
amlodipine (40.1 mg).

An Italian study estimated that 70% of patients with CKD were prescribed
medications that contain absorbable phosphate.

• 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.

 Phosphorus is a cardiac killer.
 Serum phosphate concentration has a circadian rhythm .
 Detailed understanding of dietary sources of phosphate,
including food additives, can enable phosphate restriction
without risking protein malnutrition.
• Frequent hemodialysis with extended session lengths
• Therapeutic approaches to lower serum phosphate will
improve patient-centered outcomes ???.
Conclusion

Hyperphosphatemia in CKD patients; The Magnitude of The Problem - Prof. Alaa Sabry

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