UPDATE ON RENAL BONE DISEASE

UPDATE ON RENAL BONE DISEASE Dr Jo Taylor July, 2006 Normal Bone • • • • Production of organic matrix by osteoblasts Matrix maturation Mineralisation of mature matrix Osteoclastic resorption of mineralised bone Normal bone undergoes constant remodelling Bone disease in patients with renal failure • Osteoporosis (post-transplant, vasculitis) • Osteomalacia – Aluminium related, or Vitamin D deficiency (CRF, Dialysis) • Hyperparathyroidism (CRF, Dialysis) • Adynamic bone disease (low or suppressed PTH) Bone disease in patients with renal failure • Osteoporosis (post-transplant, vasculitis) • Osteomalacia – Aluminium related, or Vitamin D deficiency (CRF, Dialysis) • Hyperparathyroidism (CRF, Dialysis) • Adynamic bone disease (low or suppressed PTH) Osteoporosis • 200 million world wide • USA – 25 million – costing over 10 billion to treat! • Decreased bone mass with disruption of normal architecture • Primary and Secondary Changes with Age Secondary Osteoporosis • Corticosteroids – second commonest cause of osteoporosis • Cumulative dose correlates with severity and incidence of fracture • Trabecular bone more sensitive than cortical bone • Rib and vertebral fractures Osteoporosis – Inx/Rx • Laboratory values normal • Bone densitometry more sensitive than x-rays • • • • Exercise, avoid alcohol and smoking Calcium and Vitamin D Bisphosphonates Others (calcitonin, fluoride, raloxifine, PTH) Bone disease in patients with renal failure • Osteoporosis (post-transplant, vasculitis) • Osteomalacia – Aluminium related, or Vitamin D deficiency (CRF, Dialysis) • Hyperparathyroidism (CRF, Dialysis) • Adynamic bone disease (low or suppressed PTH) Osteomalacia • Disorder of mineralisation of newly formed bone matrix • Vitamin D deficiency • Hypophosphatemia (Fanconi syndrome, X-linked hypophosphatemic rickets) • Bone matrix disorders (Fibrogenesis imperfecta, Hypophosphatasia) • Aluminium Vitamin D Metabolism Osteomalacia • Skeletal pain, proximal muscle weakness • X-ray – Looser’s zones • Laboratory – low PO4-, (vitamin D deficiency: low Ca2+, increased alkaline phosphatase) • Treat underlying deficiency Osteomalacia • Skeletal pain, proximal muscle weakness • X-ray – Looser’s zones • Laboratory – low PO4-, (vitamin D deficiency: low Ca2+, increased alkaline phosphatase) • Treat underlying deficiency Aluminium toxicity • Aluminium absorption from diet enhanced by citrate and iron deficiency • Other sources – dialysate, aluminium hydroxide • Effects: 1.Anaemia (microcytic) 2.Encephalopathy (apraxia, dementia) 3.PTH suppression (adynamic bone) 4.Bone (impaired mineralisation osteomalacia; impaired cell proliferation – adynamic bone) Aluminium toxicity • Normal: less than 20 mcg/l • Desferioxamine test: 5mg/kg in 100 ml saline over last hour of dialysis; measure aluminium levels pre-dialysis, and 40 hours later • Aluminium toxicity: increase in aluminium level of > 50 mcg/l • Desferioxamine infusions – note side effects • High flux dialysis if level > 200 mcg/l • Care with parathyroidectomy! Aluminium toxicity • Post-DFO test Al rise: 50 – 299 mcg/l: DFO infusion (5mg/kg) during last hour of dialysis, weekly for 2 months • Post DFO test Al rise: > 300 mcg/l: DFO infusion 5 hours pre-dialysis, weekly for 4 months (also if side effects with DFO) • Follow DFO infusion with High Flux Dialysis session Bone disease in patients with renal failure • Osteoporosis (post-transplant, vasculitis) • Osteomalacia – Aluminium related, or Vitamin D deficiency (CRF, Dialysis) • Hyperparathyroidism (CRF, Dialysis) • Adynamic bone disease (low or suppressed PTH) Hyperparathyroidism • Osteitis Fibrosa Cystica • Excess of Parathyroid Hormone causing marrow fibrosis, expansion of osteoid surfaces, and numerous osteoclasts with resorptive surfaces Effect of Renal Failure • PHOSPHATE RETENTION • Reduced synthesis of 1,25-dihydroxy-D3 (also, suppression of 1-hydroxylase enzyme by hyperphosphataemia, uric acid, ?uraemic toxins) • Stimulation of parathyroid glands (low calcium, low vitamin D, raised phosphate) Parathyroid Hormone • • • • • • Increases tubular reabsorption of calcium Increases renal phosphate excretion Increases renal synthesis of 1,25-dihydroxy-D3 Increases intestinal calcium absorption Increases osteoclastic reabsorption of bone Stimulates osteoblast maturation • Parathyroid glands have calcium and vitamin D sensing receptors Hyperparathyroidism • Primary: High Ca2+, Low PO4(Adenoma, normal U&Es) Low Ca2+, High PO4(Early CRF) High Ca2+, High PO4(Late CRF) • Secondary: • Tertiary: Adynamic bone disease • Lack or suppression of PTH • Aluminium toxicity • Reduced trabecular bone formation and resorption • Unlike osteomalacia – no increase in osteoid formation or unmineralised bone Adynamic Bone Disease Risk factors: • Calcium and Vitamin D • Parathyroidectomy • Age • Diabetes • Aluminium Fractures, hypercalcaemia (following calcium load) Other factors in Renal Bone Disease • Metabolic acidosis – bone carbonate buffer • Strontium? • Bone morphogenetic protein 7 (induces osteoblast growth and differentiation – high levels in normal kidneys) Monitoring of Acidosis • CKD 3: 12 monthly • CKD 4: • CKD 5: • Dialysis: 3 monthly 3 monthly Monthly • Aim for Bicarbonate > 22 mmol/l Prevalence of Bone Disease in Dialysis Patients • • • • • Thai Study – 56 patients, bone biopsy 41% adynamic bone disease 29% hyperparathyoidism 20% mixed 4% osteomalacia Changsirikulchai S et al, J Med Assoc Thai 2000; 83: 1223 Consequences of Elevated Serum Phosphorus1 • Increased Ca  P product • Parathyroid gland hyperplasia • Increased intact PTH levels (direct and indirect) • Coronary artery calcification – Morbidity and mortality – Conduction defects, arrhythmias – Mitral and aortic valve calcification • Other calcification, eg, pulmonary, periarticular • Myocardial fibrosis 1. Block GA, et al. Am J Kidney Dis. 2000;35:1226-1237. 70% of Patients Have Elevated Phosphorus 25% Percentage of Patients Patients Above Normal CMAS (1990) mean = 2.00 DMMS (1993) mean = 2.00 20% 15% 10% 5% 0% 0.320.94 0.971.26 1.291.58 1.611.91 1.942.23 2.262.55 2.582.87 2.913.20 3.235.49 Serum Phosphorus (mmol/L) Block GA, et al. Am J Kidney Dis. 1998;31:607-617. Percentage of patients 100 10 20 30 40 50 60 70 80 90 0 Dorset 69% Lower 95% CI Upper 95% CI % with phos < 1.8 N = 8,327 Percentage patients in each centre with serum phosphate <1.8 mmol/L : haemodialysis Centre 7 Kings 1 H&CX 2 Redng 8 York 15 Carsh 14 Plym 1 Leeds 1 Wolve 11 Stevng 0 Bangr 31 ManWst 14 Livrpl 12 Derby 5 Oxfrd 5 Sthend 7 Carls 0 Bradf 14 Wrexm 3 Middlbr 2 Prstn 7 Heart 3 Newc 4 Sund 3 Nottm 28 Swnse 0 Ipswi 4 Guys 5 Crdff 1 Words 1 Bristl 2 Truro 6 Clwyd 2 Leic 6 Ports 0 Sheff 2 Glouc 29 Camb 3 Extr 4 Hull 1 Covnt 7 Eng 12 Wls 8 E&W Percentage of patients 100 10 Upper 95% CI Lower 95% CI N = 3084 20 30 40 50 60 70 80 90 0 % with phos < 1.8 Dorset 71% Percentage patients in each centre with serum phosphate <1.8mmol/L : peritoneal dialysis Centre 0 Redng 0 Sund 0 Camb 1 Carsh 0 Sthend 1 H&CX 0 Nottm 2 Ipswi 0 Oxfrd 2 Leeds 0 Bangr 3 Crdff 1 Prstn 1 Leic 2 Stevng 2 Plym 8 Wrexm 7 Covnt 2 Bradf 0 Extr 0 Wolve 0 Guys 4 Livrpl 12 Kings 7 Derby 0 Glouc 0 York 0 Sheff 0 Heart 2 Words 2 Hull 6 Truro 2 Newc 0 Bristl 2 ManWst 6 Carls 0 Clwyd 2 Swnse 0 Middlbr 19 Ports 3 Eng 3 Wls 3 E&W Percentage of patients 100 90 80 70 60 50 40 30 20 10 0 20 Wrexm 7 York 0 Sheff 10 Wolve 2 Redng 6 Ports 1 H&CX 1 Leeds 2 Truro 3 Middlbr 0 Bangr 7 Heart 12 Derby 0 Bradf 2 Leic 3 Nottm 7 Carls 0 Ipswi 17 Livrpl 4 Guys 3 Extr 1 Bristl 31 ManWst 5 Hull 6 Clwyd 9 Eng 11 Wls 9 E&W N = 5451 Centre Upper 95% CI % with corr calc 2.2 - 2.6 Lower 95% CI Dorset 87.5% Percentage of patients with corrected calcium within 2.2 -2.6 mmol/L : haemodialysis Percentage of patients 100 10 Lower 95% CI Upper 95% CI % with corr calc 2.2 - 2.6 20 30 40 50 60 70 80 90 0 0 York 0 Wolve 0 Middlbr 1 H&CX 0 Sheff 0 Redng 2 Leeds 18 Ports 4 Bangr 4 Livrpl 6 Derby 26 Wrexm 0 Guys 0 Bradf 0 Clwyd 2 ManWst 0 Nottm 0 Bristl 0 Extr 0 Ipswi 6 Carls 1 Leic 0 Heart 6 Truro 2 Hull 7 Eng 16 Wls 8 E&W Centre Dorset 74% Percentage of patients with corrected calcium within 2.2 -2.6 mmol/L : peritoneal dialysis Dorset 63% Percentage of patients 100 10 Upper 95% CI % with iPTH < 32 Lower 95% CI 20 30 40 50 60 70 80 90 0 Dorset 71% Percentage of Patients with iPTH < 32 pmol/L : peritoneal dialysis Centre 3 Leeds 19 York 9 Oxfrd 9 Hull 14 Wrexm 11 H&CX 21 Plym 0 Extr 23 Covnt 8 Bangr 4 Nottm 7 Kings 23 Carsh 9 Truro 6 Carls 20 Sheff 1 Bristl 3 Wolve 4 Redng 5 Camb 5 Ipswi 25 Heart 7 ManWst 14 Middlbr 1 Prstn 13 Stevng 9 Swnse 32 Sthend 28 Newc 9 Leic 6 Crdff 6 Glouc 2 Guys 22 Livrpl 14 Bradf 0 Sund 17 Eng 11 Wls 16 E&W Morbid effects of Metastatic Calcification Type of Calcification Myocardial and Valvular Morbid Effects Atrioventricular block, cardiac failure, Pulmonary hypertension,arrhythmia, left and right ventricular hypertrophy Bone and soft tissue necrosis Cough, dyspnea, restrictive defects, decreased diffusion, hypoxia Small peripheral arteries Pulmonary Tumoral calcinosis Septicemia (especially after surgery) Elevated Serum Phosphorus Increases Mortality Risk1 Relative Mortality Risk (RR) 1.50 1.39** 1.25 1.18* 1.00 1.00 1.00 1.02 0.36-1.45 1.49-1.78 1.81-2.10 2.13-2.52 2.55-5.46 Serum Phosphorus Quintile (mmol/L) *P=0.03 **P<0.0001 (N=6407) 1. Adapted from Block GA, et al. Am J Kidney Dis. 1998;31:607-617. Elevated Ca  P Product 1 Increases Mortality Risk Relative Mortality Risk (RR) 1.50 1.34* 1.25 1.13 1.08 1.00 1.06 1.00 1.13-3.39 3.47-4.20 4.28-4.84 4.92-5.81 5.89-10.65 Ca x P Product Quintile (mmol2/L2) *P=0.01 (N=2669) 1. Adapted from Block GA, et al. Am J Kidney Dis. 1998;31:607-617. Consequences of Cardiac Calcification1 • • • • • Ischemic heart disease Left ventricle dysfunction Arrhythmia Cardiac failure Death “Calcium and phosphate overload are perhaps the major factors leading to soft tissue calcification….” 2 1. Llach F. Kidney Int. 1999;56(suppl 73):S31–S-37. 2. Hsu CH. Am J Kidney Dis. 1997;28:641649. Cause-Specific Death Rates in Dialysis Patients 350 Deaths per 1000 Pt. Yrs. 313 300 250 200 150 100 50 0 20-44 45-64 Age (years) 65+ All others 90 159 All cardiac Cerebrovasc Infection / Malignancy USRDS Annual Data Report. 1999. Annual CVD Mortality (%) Cardiovascular Disease Mortality General Population vs ESRD 100 Dialysis Patients 10 1 0.1 0.01 0.001 25-34 35-44 45-54 55-64 66-74 75-84 >85 GP Male GP Female GP Black GP White Dialysis Male Dialysis Female Dialysis Black Dialysis White Age (years) GP: General Population. Foley RN, et al. Am J Kidney Dis. 1998;32:S112S119. Cardiac Risk Is Dramatically Increased in Dialysis Patients1 Annual Risk of CV Death 10% 8% 6% 4% 2% 0.3% 9.2% 0% General Population Hemodialysis Patients • Risk factors include:  Hypertension  LVH  Glucose intolerance  Lipid abnormalities  Cardiovascular and valvular calcification 1. Foley RN, et al. Am J Kidney Dis. 1998;32:S112S119. Atherosclerotic Lesions in Dialysis Patients Moderately Severe Severe Slides courtesy of D. Sherrard. Increased Risk of Cardiovascular Calcification in Dialysis Patients Mean Coronary Calcium Score 2500 2000 1500 1000 500 0 28-39 40-49 50-59 60-69 (N=49) No CAD CAD Dialysis Age (years) Adapted from Braun J, et al. Am J Kid Dis. 1996;27:394-401. Presence of Valvular 1 Calcification 60% 52% Dialysis Normal Percentage of Patients 50% 40% 30% 20% 45% 10% 10% 0% Mitral Annulus 4% Aortic Annulus 1. Ribeiro S, et al. Nephrol Dial Transplant. 1998;13:2037-2040. Coronary Artery Calcification in Young Dialysis Patients 10000 Calcification Score 1000 100 10 1 0.1 0 5 10 15 20 25 30 35 Age (years) Adapted from Goodman WG, et al. N Engl J Med. 2000;342:14781483. Electron Beam Computed Tomography (EBCT) Slide courtesy of P. Raggi. EBCT Scans Reveal Coronary Artery Calcification in a Dialysis Patient Yellow indicates calcium deposition Slide courtesy of P. Raggi. Calcification: Normal vs ESRD Normal ESRD Scan courtesy of P. Raggi. Mitral Valve Calcification in a Dialysis Patient Scan courtesy of P. Raggi. Extensive Triple Vessel (Coronary Arteries) Calcification in a Dialysis Patient Scan courtesy of P. Raggi. Calcification of the Lung Noncalcified Calcified Sanders C, et al. Am J Roentgenol. 1987;149:881887. Kuzela DC, et al. Am J Pathol. 1977;86:403-424. Slide courtesy of E. Slatopolsky. Periarticular Calcification Slide courtesy of D. Sherrard. Cutaneous/Subcutaneous Calcification Slide courtesy of H. Malluche. Phosphate – Target levels in CRF • Stage 3 and 4 CKD: 0.87 – 1.49mmol/l • Stage 5 CKD: 1.13 – 1.78mmol/l (only 44% stage 5 CKD achieved this in DOPPS II Study) Management of phosphate • Dietary phosphate restriction • Dialysis • Phosphate binders: Aluminium-based Calcium-based Non Ca2+/Al Management of phosphate – limitations of diet • Compliance: 800 - 1000 mg/day • Phosphate restriction compromises protein intake and nutritional status • Highly processed foods contain more easily absorbed phosphate Management of phosphate dialysis • Adequate dialysis • Nocturnal dialysis • Low calcium dialysis fluid (1.25 mmol/l) to reduce calcium-phosphate product • Very low calcium dialysate may exacerbate hyperparathyroidism Management of phosphate – phosphate binders • Aluminium-based – risk of toxicity • Calcium-based – risk of metastatic calcification (due to inability to excrete calcium, and low turnover bone disease in some cases) • Non-Ca2+/Al-based – effective, but costly and large numbers of tablets required - Sevelemer hydrochloride (Renegel); Lanthanum (Fosrenol) Sevelemer • Lower hypercalcaemia (5% vs 16%) • Lower LDL-cholesterol (1.68 vs 2.66 mmol/l) • Lower percentage increase in coronary artery (5% vs 25%), and aorta calcification (5% vs 28%) • Decrease in CRP Vitamin D Therapy • Suppress PTH secretion in low calcium states • Avoid if Ca2+ > 2.37 or PO4- > 1.49mmol/l • Ergocalciferol, Cholecalciferol • One-alpha calcidol – requires 25 hydroxylation in liver, Calcitriol (1,25 dihydroxy-D3) • Vitamin D analogues (Paricalcitol, Doxercalciferol, 22-oxacalcitriol) Vitamin D Therapy - Monitoring • CKD Stages 3 and 4: If PTH raised, measure Vitamin D level and supplement (non-active Vitamin D preparation) if low (< 75 nmol/l). If normal, measure Vitamin D annually. • If Vitamin D level > 75 nmol/l, and PTH still high, use active Vitamin D preparation • Patients on Vitamin D should have calcium and phosphate levels measured 3 monthly, and annual Vitamin D levels. • PTH levels 3 monthly if on active Vitamin D Management of tertiary hyperparathyroidism • Risk of metastatic calcification • Subtotal/total parathyroidectomy – PTH > 88 pmol/l with raised Ca2+ and/or PO4• Calcimimetics (calcium receptor agonists) • Risk of low turnover (adynamic) bone disease in absence of PTH Calcimimetics • Increases the sensitivity of the calcium sensing receptor in the parathyroid glands • Dose 30 – 180 mg/day • Reduced PTH, Ca2+, and PO4• Less likely to have parathyroidectomy • Less likely to fracture Cunningham J et al. Kidney Int 2005; 68: 1794 Treatment goals • Phosphate – CKD 3/4 (0.87 – 1.49 mmol/l) CKD 5 (1.13 – 1.78 mmol/l) • Calcium – low normal (2.1 – 2.37 mmol/l) • PTH – CKD 3 (3.85 – 7.7 pmol/l) CKD 4 (7.7 – 12.1 pmol/l) CKD 5 (16.5 – 33 pmol/l) • Ensure calcium-phosphate product does not exceed 4.44 mmol2/l2 Achievement of Treatment Goals • • • • 26% PTH 44% PO443% Ca2+ 61% Ca2+/PO4- product • DOPPS II Study (Am J Kidney Dis 2004; 44: 34) Monitoring of Ca2+/PO4-/PTH CKD Stage 3 4 PTH 12 months 3 months Ca2+/PO412 months 3 months 5 3 months 1 month Post-transplant monitoring • Bone densitometry: Baseline, 1 and 2 years post-transplant • Calcium, Phosphate, Bicarbonate: Fortnightly for 3 months, then monthly during first year • PTH: Monthly during first 3 months, then 3monthly during first year. Thereafter according to CKD guidelines UK RCGP Guidelines • Stage 3 CKD – check PTH • If PTH raised, check Vitamin D level • If Vitamin D level low, give non-active Vitamin D + calcium supplement • Repeat PTH at 3 months – if still high refer