3 Definition of CKD-MBDA 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 metabolismAbnormalities in bone turnover, mineralization, volume, linear growth, or strengthVascular or other soft tissue calcificationMoe et al Kidney International June 2006
4 Diagnosis of CKD bone disease BloodPTHRandom circulating PTH (1/2 life 2-4 mins)Excreted renally so present for longer in RFCalciumPhosphateBone biopsyno longer frequently performedImagingIn general not indicated
5 Functions of the kidneys Water excretion and balanceWaste excretion – urea, creatinine, etc.Regulation of Na+, K+ , P + + +, Ca + + and other ionsRegulation of pHRegulation of blood pressureRegulation of red-cell productionProduction of calcitriol
6 Bone disease in CKDRecent Irish study found 76% of osteoporosis cases in CKD patientsPatients with CKD 4&5 had significantly lower BMD at hip & spine + high bone turnover2 fold increased risk of vertebral fracturesStatins - 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 hyperphosphataemiaHyperphosphataemia is associated withMetastatic calcificationCVDIncreased mortalityBone diseaseHigh doses of calcium-based phosphate binders may contribute to metastatic calcification and adynamic bone disease
8 Cardiovascular disease in dialysis patients1 109.2%HypertensionLipid abnormalitiesLeft ventricular hypertrophyGlucose intoleranceCardiovascular and valvular calcificationRisk factors include:86Annual risk of cardiovasculardeath (%)4Mortality in dialysis patientsThis 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.1Dialysis 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.2Risk 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 Report20.3%GeneralHaemodialysispopulationpatients1. Foley et al., 1998
9 Clinical manifestations of bone disease Most with CKD and mildly elevated PTH are asymptomaticWhen present classified as eitherMusculoskeletalExtra-skeletal
10 MusculoskeletalFractures, 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-skeletalImportant 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 calciphylaxisA, 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 retentionHyperphosphataemiaPTH secretion*Parathyroid hyperplasiaSecondary hyperparathyroidismRenal bone disease*Unsuppressed as a result of insufficient calcitriol
16 Elevated serum Ca × P increases mortality risk 1.501.34*Relative mortality risk1.251.131.081.061.001.001.13–3.393.47–4.204.28–4.844.92–5.815.89–10.65Ca × P quintile (mmol2/L2)*P = 0.01 (n = 2669)Note: 1 mmol2/L2 = 12.2 mg2/dL2Block GA et al. Am J Kidney Dis 1998;31:607–17.
17 Coronary-artery calcifications increase with years of dialysis 1.00.80.6Proportion with calcificationPatients with coronary- artery calcification (n = 39)Estimates by logistic regression analysis0.40.20.04812162024Years of dialysisGoodman WG et al. N Engl J Med 2000;342:1478–83.
18 Calcification of the lung Non-calcifiedCalcified
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 withMetastatic calcificationHyperphosphataemia is the major cause of calcificationResults in a number of clinical effects involving different parts of the bodyCVDCalcification is associated with conduction defects, arrhythmias, cardiac-valve calcification, myocardial fibrosisArterial calcification leads to increased arterial stiffnessIncreased risk of mortalityParticularly cardiac deathRenal osteodystrophyHigh- and low-turnover bone diseaseAlbaaj F et al. Drugs 2003; 63:57796.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 restrictionCalcium and non-Ca phosphate bindersCalcitriol or other Vit D analoguesCalcimimeticsParathyroidectomy
22 Management of Hyperphosphatemia HyperparathyroidismPO4 CONTROLPO4 controlVit D / analogCalcimimeticParathyroidectomy
24 Dietary PO4 restriction High PO4 content : meat, milk product, egg, fishPO4 intake : mg/dayParallel with dietary protein intakeDialysis 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 legumesSubstitute different foods within a groupPhosphate 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 phosphateNutrient composition tables and software programs do NOT typically include hidden phosphateUribarri J. Semin Dial 2002;15:376.
26 Dialysis Has a small role in PO4 excretion Hemodialysis : 32,5 mol/4 hrsCAPD : 12 mol/ 24 hrsDyalisat content (acetate, bicarbonate) ?Material of dialyzer (cellulose diacetate > polysulfone)
27 Phosphate binders Factors influencing choice of phosphate binder Long-term control of serum phosphorusReducing risk of cardiovascular disease and metastatic calcificationLack of toxic effects on bone and the central nervous systemCost 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 thereCompliance – pill burden and general acceptability of formulations to patients
28 Aluminium-based phosphate binders Highly effectiveUsually in the form of aluminium hydroxide gels or capsulesImportant side effectsKnown to cause bone diseaseAssociated with dialysis encephalopathyUse is in decline, but still used on a short-term, second- or third-line basisAluminium 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 trialsAluminium is toxic to the brainConcentrated in the neocortex and hippocampus, areas that are selectively vulnerable in Alzheimer’s diseaseNeurotoxic effects and encephalopathyAluminium is toxic to boneMineralization defects and direct toxic effects on bone cellsReduced bone turnover and osteomalaciaFew data on GI tolerabilityPoor GI tolerability reported in some patientsClarkson 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 environmentPresent in drinking water at 0.01–0.13-ng/mL levelsMeasurable plasma concentrations in healthy subjects and patients with impaired renal functionExists in solution as a trivalent acid cationVarious salts bind phosphate avidlyLanthanum phosphate very insolubleLanthanum carbonate least soluble salt
34 Safety – summaryLanthanum carbonate taken with meals appears to be generally well toleratedGI effects are the most common adverse events and are typically mildThe 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