METABOLIC BONE DISEASE (HYPERPHOSPHATEMIA)
IN CHRONIC KIDNEY DISEASE
Hasyim Kasim
Syakib Bakri
Hasanuddin university
www.kdigo.
Definition of CKD-MBD
A systemic disorder of mineral and bone metabolism
due to CKD manifested by either one or a
combination of the following:
– Abnormalities of calcium, phosphorus, PTH, or
vitamin D metabolism
– Abnormalities in bone turnover, mineralization,
volume, linear growth, or strength
– Vascular or other soft tissue calcification
Moe et al Kidney International June 2
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
Functions of the kidneys
•
•
•
•
•
•
•
Water excretion and balance
Waste excretion – urea, creatinine, etc.
Regulation of Na+, K+ , P + + +, Ca + + and other ions
Regulation of pH
Regulation of blood pressure
Regulation of red-cell production
Production of calcitriol
Bone disease in CKD
• Recent Irish study found 76% of osteoporosis cases in CKD
patients
• Patients with CKD 4&5 had significantly lower BMD at hip &
spine + high bone turnover
• 2 fold increased risk of vertebral fractures
• Statins - known to have beneficial effect in prevention of
osteoporosis as well as decreased incidence of sepsis in
CKD!
CKD  Hyperphosphataemia
• Around 70% of patients with ESRD have
hyperphosphataemia
• Hyperphosphataemia is associated with
– Metastatic calcification
– CVD
– Increased mortality
– Bone disease
• High doses of calcium-based phosphate binders may
contribute to metastatic calcification and adynamic
bone disease
Cardiovascular disease in dialysis
patients1
Annual risk of cardiovascular
death (%)
10
9.2%
8
Risk factors
include:


6


4

2
0.3%
0
General
population
Haemodialysis
patients
1. Foley et al., 1998
Hypertension
Lipid abnormalities
Left ventricular
hypertrophy
Glucose intolerance
Cardiovascular and
valvular calcification
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)
– NB. 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)
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)
Effect of reduced phosphorus
excretion
in the kidney
Phosphorus excretion
Phosphorus retention
Hyperphosphataemia
PTH secretion*
Parathyroid hyperplasia
Secondary hyperparathyroidism
Renal bone disease
*Unsuppressed as a result of insufficient calcitriol
Elevated serum phosphorus
increases mortality risk (1)
Relative mortality risk
1.50
1.39†
1.25
1.18*
1.00
1.00
1.1–4.5
1.00
1.02
4.6–5.5
5.6–6.5
6.6–7.8
7.9–16.9
Serum phosphorus quintile (mg/dL)
*P = 0.03; †P < 0.0001 (n = 6407)
Note: 1 mmol/L = 3.1 mg/dL
Block GA et al. Am J Kidney Dis 1998;31:607–17.
Elevated serum Ca × P increases
mortality risk
Relative mortality risk
1.50
1.34*
1.25
1.13
1.08
1.06
1.00
1.00
1.13–3.39 3.47–4.20 4.28–4.84 4.92–5.81 5.89–10.65
Ca × P quintile (mmol2/L2)
*P = 0.01 (n = 2669)
Note: 1 mmol2/L2 = 12.2 mg2/dL2
Block GA et al. Am J Kidney Dis 1998;31:607–17.
Coronary-artery calcifications
increase with years of dialysis
Proportion with
calcification
1.0
0.8
0.6
0.4
Patients with coronaryartery calcification (n = 39)
0.2
Estimates by logistic
regression analysis
0.0
0
4
8
12
16
Years of dialysis
Goodman WG et al. N Engl J Med 2000;342:1478–83.
20
24
Calcification of the lung
Non-calcified
Calcified
Angulated black eschar with surrounding livedo.
Note the bullous change at the inferior edge of
the eschar. (courtesy Up To Date)
Clinical consequences of
hyperphosphataemia
• Hyperphosphataemia is associated with
– Metastatic calcification
• Hyperphosphataemia is the major cause of calcification
• Results in a number of clinical effects involving different parts of the
body
– CVD
• Calcification is associated with conduction defects, arrhythmias,
cardiac-valve calcification, myocardial fibrosis
• Arterial calcification leads to increased arterial stiffness
– Increased risk of mortality
• Particularly cardiac death
– Renal osteodystrophy
• High- and low-turnover bone disease
Albaaj F et al. Drugs 2003; 63:57796.
Moe S. Calcium and phosphorus balance in ESRD. Cambridge, MA: Genzyme Corporation, 2001.
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
Management of
Hyperphosphatemia
Hyperparathyroidism
Hyperphosphatemi
a
PO4
PO4
CONTROL
control
Vit D /
analog
Calcimimetic
Parathyroidectom
y
PO4 CONTROL

Dietary PO4 restriction

Dialysis

PO4 binders
Dietary PO4 restriction

High PO4 content : meat, milk product, egg, fish

PO4 intake : 600-800 mg/day

Parallel with dietary protein intake

Dialysis patients in diet 1.2-1.4 g of protein/kg BW,
PO4 contain much higher (1200-1400 mg) than be
recommended
 Dilemma (Hyperphosphatemia or Malnutrition)
Nutrition: sources of phosphorus
• High phosphate: cheese, dry fruits, chocolate, fish,
meats, cereals, some legumes
• Substitute different foods within a group
• Phosphate in processed foods > natural foods
• ‘Hidden’ phosphate in food additives can increase
phosphate intake by 1.0 g/day. More fast and
convenience foods = more hidden phosphate
• Nutrient composition tables and software programs
do NOT typically include hidden phosphate
Uribarri J. Semin Dial 2002;15:376.
Dialysis

Has a small role in PO4 excretion

Hemodialysis
: 32,5 mol/4 hrs

CAPD
: 12 mol/ 24 hrs

Dyalisat content (acetate, bicarbonate)
?

Material of dialyzer
(cellulose diacetate > polysulfone)
Phosphate binders
• Factors influencing choice of phosphate binder
– Long-term control of serum phosphorus
– Reducing risk of cardiovascular disease and
metastatic calcification
– Lack of toxic effects on bone and the central nervous
system
– Cost in relation to other products (particularly calcium
salts) – relative pricing was considered a major factor
in the USA and EU. The extent of calcium carbonate
use in the Pacific Rim suggests that cost is also a
prime consideration there
– Compliance – pill burden and general acceptability of
formulations
to patients
Aluminium-based phosphate binders
• Highly effective
• Usually in the form of aluminium hydroxide
gels or capsules
• Important side effects
– Known to cause bone disease
– Associated with dialysis encephalopathy
• Use is in decline, but still used on a short-term,
second- or
third-line basis
• Aluminium accumulates in the body, so even
short-term pulsed treatment is potentially
damaging
Aluminium
Safety issues
• Aluminium is absorbed from the GI tract – increased
plasma aluminium levels seen in trials
• Aluminium is toxic to the brain
– Concentrated in the neocortex and hippocampus, areas that are selectively
vulnerable in Alzheimer’s disease
– Neurotoxic effects and encephalopathy
• Aluminium is toxic to bone
– Mineralization defects and direct toxic effects on bone cells
– Reduced bone turnover and osteomalacia
• Few data on GI tolerability
– Poor GI tolerability reported in some patients
Clarkson EM et al. Clin Sci 1972;43:519–31.
Nordal KP et al. Pharmacol Toxicol 1988;63:351–4.
Biswas CK et al. Br Med J (Clin Res Ed) 1982;284:776–8.
Andress DL et al. J Bone Min Res 1986;1:391–8.
Parkinson IS et al. J Clin Pathol 1981;34:1285–94.
Kates DM et al. Semin Dial 1996;6:310–5.
Boyce BF et al. Scan Electron Microsc 1981;(Pt 3):329–37.
Alfrey AC et al. N Engl J Med 1976;294:184–8.
Evaluation of serum phosphorus
levels
• In patients with CKD (stages 3 or 4), the serum level
of phosphorus should be maintained at or above 2.7
mg/dL (0.87 mmol/L)† and no higher than 4.6 mg/dL
(1.49 mmol/L)†
• In CKD patients with kidney failure (stage 5) and
those treated with haemodialysis or peritoneal
dialysis, the serum levels of phosphorus should be
maintained between 3.5 and 5.5 mg/dL (1.13 and
1.78 mmol/L)*
*Evidence-based guideline (Eknoyan G et al. Am J Kidney Dis 2003;42[Suppl. 3]:S1–201.)
†Opinion-based guideline
Use of phosphate binders in
patients with end-stage renal
disease (ESRD) (1)
• Calcium-based and other non-calcium-, non-aluminium-,
non-magnesium-containing agents are effective* and
may be used
as the primary therapy†
• In dialysis patients who remain hyperphosphataemic, a
combination
of calcium-based or other non-calcium-, non-aluminium-,
non-magnesium-containing agents should be used†
• The total dose of elemental calcium provided by
phosphate binders should not exceed 1500 mg/day.†
Total intake of elemental calcium should not exceed
2000 mg/day†
*Evidence-based guideline (Eknoyan G et al. Am J Kidney Dis 2003;42[Suppl. 3]:S1–201.)
†Opinion-based guideline
Use of phosphate binders in
patients with ESRD (2)
• Calcium-based binders should not be used in
patients who are hypercalcaemic or whose plasma
PTH levels are <150 pg/mL (16.5 pmol/L) on two
consecutive measurements*
• Non-calcium-containing binders are preferred in
patients with severe soft-tissue calcifications†
• In patients with serum phosphorus >7.0 mg/dL
(2.26 mmol/L), aluminium-based binders may be
used as a short-term therapy (4 weeks), and for one
course only.† In such patients, more frequent dialysis
should also be considered*
*Evidence-based guideline (Eknoyan G et al. Am J Kidney Dis 2003;42[Suppl. 3]:S1–201.)
†Opinion-based guideline
Lanthanum
• Discovered in 1839 by Mosander
• ‘Rare earth’ element – widely found in the
environment
• Present in drinking water at 0.01–0.13-ng/mL levels
• Measurable plasma concentrations in healthy
subjects and patients with impaired renal function
• Exists in solution as a trivalent acid cation
• Various salts bind phosphate avidly
– Lanthanum phosphate very insoluble
– Lanthanum carbonate least soluble salt
Safety – summary
• Lanthanum carbonate taken with meals appears to be
generally
well tolerated
• GI effects are the most common adverse events and are
typically mild
• The incidence of hypercalcaemia was greatly reduced by
lanthanum carbonate (<1%) compared with calcium
carbonate (22%)
• Withdrawal rates were similar in both treatment groups
(lanthanum carbonate 20%, calcium carbonate 26%)
• Lanthanum carbonate was well tolerated in clinical
studies for periods of up to 104 weeks
TERIMA
KASIH