1. Hasyim Kasim Syakib Bakri Hasanuddin university
METABOLIC BONE DISEASE (HYPERPHOSPHATEMIA) IN CHRONIC KIDNEY DISEASE
Hasyim Kasim
Syakib Bakri
Hasanuddin university

3. 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 2006

4. 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

5. 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

6. 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!

7. 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

8. Cardiovascular disease in dialysis patients110
9.2%
Hypertension
Lipid abnormalities
Left ventricular hypertrophy
Glucose intolerance
Cardiovascular and valvular calcification
Risk factors include: 8 6
Annual risk of cardiovascular
death (%) 4
Mortality in dialysis patients
This graph shows that the incidence of death due to cardiovascular disease is dramatically higher in ESRD dialysis patients than in the general population. The risk of cardiovascular death in dialysis patients is, on average, more than 30 times greater than that in the general population.1
Dialysis is associated with high cardiovascular mortality. Uraemia, anaemia, fluid overload, hypertension and hyperlipidaemia all contribute to the cardiovascular risk. Survival is increased if blood pressure is well controlled.2
Risk factors for cardiovascular disease include hypertension, lipid abnormalities, left ventricular hypertrophy, cardiovascular and valvular calcification. Many of these will present before the patient receives dialysis.
Cardiovascular disease is the leading cause of death in dialysis patients, accounting for half of the deaths in this population.3 This percentage has been slowly rising in recent years.
Death due to cardiovascular disease may occur as a result of arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, stroke, atherosclerotic heart disease and pulmonary oedema.
References:
1. Foley RN et al. Am J Kidney Dis 1998;32:S112–9.
2. Mallick NP, Gokal R. Lancet 1999;353:737–42.
3. US Renal Data System (USRDS). USRDS 2003 Annual Data Report 2
0.3%
General
Haemodialysis
population
patients
1. Foley et al., 1998

9. Clinical manifestations of bone disease
Most with CKD and mildly elevated PTH are asymptomatic
When present classified as either
Musculoskeletal
Extra-skeletal

10. 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.

11. 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)

13. 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)

14. Effect of reduced phosphorus excretion in the kidney
Phosphorus retention
Hyperphosphataemia
PTH secretion*
Parathyroid hyperplasia
Secondary hyperparathyroidism
Renal bone disease
*Unsuppressed as a result of insufficient calcitriol

15. Elevated serum phosphorus increases mortality risk (1)
1.50
1.39†
Relative mortality risk
1.25
1.18*
1.02
1.00
1.00
1.00
1.1–4.5
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 < (n = 6407)
Note: 1 mmol/L = 3.1 mg/dL
Block GA et al. Am J Kidney Dis 1998;31:607–17.

16. Elevated serum Ca × P increases mortality risk
1.50
1.34*
Relative mortality risk
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.

17. Coronary-artery calcifications increase with years of dialysis
1.0
0.8
0.6
Proportion with calcification
Patients with coronary- artery calcification (n = 39)
Estimates by logistic regression analysis
0.4
0.2
0.0 4 8 12 16 20 24
Years of dialysis
Goodman WG et al. N Engl J Med 2000;342:1478–83.

18. Calcification of the lung
Non-calcified
Calcified

19. Angulated black eschar with surrounding livedo
Angulated black eschar with surrounding livedo. Note the bullous change at the inferior edge of the eschar. (courtesy Up To Date)

20. 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.

21. Treatment of CKD bone disease
Various Rx for secondary hyperPTH and hyperphosphataemia include;
Dietary phosphorous restriction
Calcium and non-Ca phosphate binders
Calcitriol or other Vit D analogues
Calcimimetics
Parathyroidectomy

22. Management of Hyperphosphatemia
Hyperparathyroidism
PO4 CONTROL
PO4 control
Vit D / analog
Calcimimetic
Parathyroidectomy

23. PO4 CONTROL
Dietary PO4 restriction
Dialysis
PO4 binders

24. Dietary PO4 restriction
High PO4 content : meat, milk product, egg, fish
PO4 intake : mg/day
Parallel with dietary protein intake
Dialysis patients in diet g of protein/kg BW, PO4 contain much higher ( mg) than be recommended
 Dilemma (Hyperphosphatemia or Malnutrition)

25. 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.

26. 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)

27. 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

28. 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

29. 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.

30. 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

31. 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

32. 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

33. 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

34. 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

36. TERIMA KASIH