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

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Presentation on theme: "Hasyim Kasim Syakib Bakri Hasanuddin university METABOLIC BONE DISEASE (HYPERPHOSPHATEMIA) IN CHRONIC KIDNEY DISEASE."— Presentation transcript:

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

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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 1. Foley et al., 1998 Cardiovascular disease in dialysis patients Annual risk of cardiovascular death (%) Haemodialysis patients General population 0.3% 9.2% l Hypertension l Lipid abnormalities l Left ventricular hypertrophy l Glucose intolerance l Cardiovascular and valvular calcification Risk factors include:

9 Clinical manifestations of bone disease Most with CKD and mildly elevated PTH are asymptomatic When present classified as either 1. Musculoskeletal 2. 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)

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13 calciphylaxis 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 Renal bone disease *Unsuppressed as a result of insufficient calcitriol Phosphorus excretion Phosphorus retention Hyperphosphataemia PTH secretion* Parathyroid hyperplasia Secondary hyperparathyroidism

15 – – – – – 16.9 Serum phosphorus quintile (mg/dL) Relative mortality risk * 1.39 † Elevated serum phosphorus increases mortality risk (1) *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 – – – – –10.65 Ca × P quintile (mmol2/L2) Relative mortality risk * 1.00 *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. Elevated serum Ca × P increases mortality risk

17 Coronary-artery calcifications increase with years of dialysis Years of dialysis Proportion with calcification Patients with coronary- artery calcification (n = 39) Estimates by logistic regression analysis Goodman WG et al. N Engl J Med 2000;342:1478 – 83.

18 Calcified Non-calcified Calcification of the lung

19 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; 1. Dietary phosphorous restriction 2. Calcium and non-Ca phosphate binders 3. Calcitriol or other Vit D analogues 4. Calcimimetics 5. Parathyroidectomy

22 Management of Hyperphosphatemia Hyperphosphatemi a Hyperparathyroidism PO4 control Vit D / analog CalcimimeticParathyroidectom y PO4 CONTROL

23  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.)Eknoyan G et al † 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.)Eknoyan G et al † 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.)Eknoyan G et al † 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

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36 TERIMA KASIH


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