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CKD BMD
Dr. Ahmed Mohamed Albeyaly is a nephrology specialist and moderator in Dakahlia Health directorate. The document discusses chronic kidney disease-mineral and bone disorder (CKD-MBD), which is a systemic disorder affecting bone disease, soft tissue calcification, and abnormalities in mineral metabolism that result from kidney disease and kidney failure. The document covers pathogenesis of CKD-MBD, classifications of bone disease seen in CKD patients, diagnosis through laboratory tests and imaging, and treatment approaches including controlling calcium, phosphorus, PTH, and vitamin D levels.
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CKD BMD
- 1. DR.AHMED MOHAMED ALBEYALY NephrologySpecialist Nephrology Moderator In Dakahlia Health directorate
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- 5. Introduction Pathogenesis Normal Bone Remodeling Hyperparathyroidism Classifications of bone disease Diagnosis of bone disease Treatment of bone disease in CKD
- 6. Stage Description GFR (ml/min/1.73m2) 1 Kidney damage with normal or GFR 90 2 Kidney damage with mild GFR 60-89 3 Moderate GFR 30-59 4 Severe GFR 15-29 5 Kidney failure < 15 (or dialysis) KDOQI: CKD Staging
- 8. KI (2007) 71,31-38. Levin et. al. Prevalence of Abnormal Mineral Metabolism in CKD >4.6
- 9. CKD Stage 3 CKD Stage 4 CKD Stage5 (on dialysis) P (mg/dL) 2.7 - 4.6 2.7 - 4.6 3.5 - 5.5* Ca (mg/dL) “Normal” “Normal” 8.4 - 9.5; Hypercalcemia = >10.2 Intact PTH (pg/mL) 35 - 70 70 - 110 150 - 300* *Evidence
- 10. EU1 KDIGO Japan2 PTH pg/mL(pmol/L) 85–170 (9–18) 150–300 (16.5–33) 60–180 Ca mg/dL (mmol/L) 8.8–11 (2.2–2.7) <10.2 pref: 8.4–9.51 (<2.54 pref: 2.10–2.37) 8.4–10 (2.1–2.5) Pi mg/dL (mmol/L) 2.5–5.5 (0.8–1.8) 3.5–5.5 (1.1–1.8) 3.5–6.0 (1.1–2) Ca x P mg2/dL2 <55 mg2/dL2 <55 mg2/dL2 (not specified)
- 12. 0.01 100 10 1 0.1 Annualmortality(%) 25–34 45–54 65–748535–44 55–64 75–84 Age (years) Cardiovascular Mortality in the General Population and in Dialysis Patients General population Male Female Black White Dialysis population Male Female Black White
- 13. The termrenal osteodystrophy (ROD) should be used exclusively to define the bone pathology associated with CKD. The clinical, biochemical, and imaging abnormalities should be defined more broadly as a clinical entity or syndrome called Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).
- 14. A systemic disorderof 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
- 15. A Framework forClassification of CKD-MBD Type * Laboratory Abnormalities Bone Disease Calcification of Vascular or Other Soft Tissue L + - - LB + + - LC + - + LBC + + + * L = laboratory abnormalities (of calcium, phosphorus, PTH, alkaline phosphatase or vitamin D metabolism); B = bone disease (abnormalities in bone turnover, mineralization, volume, linear growth, or strength); C = calcification of vascular or other soft tissue.
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- 17. 17 Elevated: • FGF-23 • PTH •Phosphorus Decreased: • Calcitriol • Calcium • Coronary calcification • Aortic calcification • Calciphylaxis • Abnormal bone – Mineralization – Turnover – Volume KDIGO = Kidney Disease: Improving Global Outcomes. KDIGO® is a registered trademark of Kidney Disease: Improving Global Outcomes, Inc. Moe S, et al. Kidney Int. 2006;69:1945-1953. KDIGO® Overview slide presentation at: http://www.kdigo.org/pdf/KDIGO%20Overview%20Slide%20Set.ppt
- 18. Traditionally classifiedaccording to degree of abnormal bone turnover High Turnover (osteitis fibrosa) ◦ Hyperparathyroidism Low turnover ◦ Adynamic - Osteomalacia Beta 2 MG amyloidosis Osteoporosis ◦ Post-menopausal - Post-transplant
- 19. Kidney failuredisrupts systemic calcium and phosphate homeostasis and affects the bone, GIT and parathyroid glands. In kidney failure there is decreased renal excretion of phosphate and diminished production of calcitriol (1,25-dihydroxyvitamin D) ◦ Calitriol increases serum calcium levels The increased phosphate and reduced calcium, feedback and lead to secondary hyperparathyroidism, metabolic bone disease, soft tissue calcifications and other metabolic abnormalities
- 23. • 4 ormore small glands on the posterior surface of the thyroid gland. • Can function without neural control so can transplant to another part of the body • 2 types of cells – Chief cells – produce parathyroid hormone – Oxyntic cells – function unknown
- 24. Responsible formaintaining serum calcium in a normal range preventing hypocalcemia. Does this by; 1. acting directly on the distal tubule of the kidney to increase calcium reabsorption – Increases calcitriol production (D3) – D3 increases GIT absorption of Ca and Phos and promotes osteoclast formation. 2. Acting on bone to increase calcium and phosphate efflux
- 25. Can occuronce eGFR < 60 PTH levels increase progressively as renal function declines and by CKD stage 5(<15) most pt’s expected to have this. Usually the 1st sign and occurs before lab tests pick up phosphatemia, ↓ Vit D3 and ↓ calcium Unless treated, progresses and frequency of parathyroidectomy proportional to yrs on dialysis
- 26. Primary Adenoma 80% Multipleadenomas 4% (10% in elderly women) Hyperplasia 15% Carcinoma <1% Secondary MEDICAL TTT CRF, Malabsorption Tertiary Surgical TTT In long standing cases
- 28. In renalfailure driven by ◦Hypocalcaemia ◦Decreased vitamin D ◦hyperphosphataemia
- 32. Due toexcess PTH Increased bone turnover activity (greater number of osteoclasts and osteoblasts) and defective mineralization. Associated with bone pain and increased risk of fractures.
- 33. Formally linkedto aluminium toxicity ◦ From aluminium based phosphate binders ◦ From contamination of water in dialysate solutions unmineralised osteoid
- 34. Characterized bylow osteoblastic activity and bone formation rates Seen in up to 30% HD May be due to excess suppression of the parathyroid gland with therapies, particularly calcium-containing phosphate binders and vitamin D analogues. Typically maintain a low serum intact PTH concentration, which is frequently accompanied by an elevated serum calcium level. Felt to represent a state of relative hypoparathyroidism NORMAL diseased
- 35. Adapted from GoodmanWG. In: Bilezikian JP, et al, eds. Principles of Bone Biology. 3rd Ed. San Diego, CA: Academic Press; 2008:1478-1510; Adapted from Moe SM, et al. In: Brenner BM, ed. The Kidney. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1784-1813. Mixed Lesion Osteitis FibrosaNormal Bone Formation High Low turnov er High turnover Adynamic Osteomalacia Low PTH
- 36. Most withCKD and mildly elevated PTH are asymptomatic When present classified as either 1. Musculoskeletal 2. Extra-skeletal
- 37. Fractures, tendonrupture and bone pain from metabolic bone disease, muscular pain and weakness. Most clinically significant is hip fracture and fracture neck of femur , 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.
- 38. Important torecognise 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)
- 39. • A, Confluentcalf 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)
- 43. A. Zerbi S,et al. J Clin Endocrinol Metab. 2008;93:1121-1122; B. London GM, et al. Nephrol Dial Transplant. 2003;18:1731-1740. B A
- 44. Slide courtesy ofD. Sherrard.
- 45. Calcification of theLung Sanders C, et al. Am J Roentgenol. 1987;149:881-887. Kuzela DC, et al. Am J Pathol. 1977;86:403-424. Slide courtesy of E. Slatopolsky. CalcifiedNoncalcified
- 49. 1. Ribeiro S,et al. Nephrol Dial Transplant. 1998;13:2037-2040. Presence of Valvular Calcification1 0% 10% 20% 30% 40% 50% 60% PercentageofPatients Dialysis Normal Mitral Annulus Aortic Annulus 45% 10% 52% 4%
- 50. Vascular calcificationwas present in 63– 69% of incident dialysis patients 1Block GA, et al. Kidney Int. 2005;68:1815-1824. 2Raggi P, et al. J Am Coll Cardiol. 2002 39:695-701.
- 51. Adapted from KalpakianMA, Mehrotra R. Semin Dial. 2007;20:139-143. 92% 83% 70% 53% 82% 92% 72% 0 10 20 30 40 50 60 70 80 90 100 Oh, 2002 Raggi, 2002 Moe, 2003 Stompor, 2003 Matsuoka, 2004 Nitta, 2004 Barreto, 2005 Prevalence(%) N 37 205 71 43 104 53 101 % Diabetes Mellitus 0% 30% 34% 9% 38% 40% 9%
- 53. Pts ondialysis for 7- 10 years can develop osteoarticular amyloid deposits. May present with carpel tunnel syndrome and arthritis
- 54. Introduction Pathogenesis Normal Bone Remodeling Hyperparathyroidism Classifications of bone disease Diagnosis of bone disease
- 55. 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
- 56. CKD Stage KDIGO 3Every 6–12 months 4 Every 3–6 months 5 or D Every 1–3 months Phosphate and Calcium
- 57. CKD Stage KDIGO 3Every 6–12 months 4 Every 6–12 months 5 or D Every 3–6 months PTH
- 58. Pathogenesis NormalBone Remodeling Hyperparathyroidism Classifications of bone disease Diagnosis of bone disease Treatment of bone disease in CKD
- 59. Controlling Ca, Pi,PTH, Vitamin D To Prevent MBD CVD lower mortality!!!!
- 60. Phosphorus isunevenly distributed in the body The major portion of phosphorus removed by HD is from cell cytoplasm. The rate of phosphorus removal is slowed by rate of transfer from within cells to plasma ◦ haemodialysis (HD) removes ~800 mg Pi/treatment ◦ peritoneal dialysis (PD) removes 150–200 mg Pi/PAK Average phosphorus absorption = 600 mg/day or 4,200 mg/week 3 x weekly HD (4-hour sessions) removes 2,400 mg phosphorus leaving 1,800 mg or 257 mg/day1
- 61. Aluminium usedhistorically but now rarely used as concerns re bone/CNS toxicity. May not be an issue if water quality good for dialysis Calcium based binders but concerns about about exacerbating hypercalcaemia and thereby promoting vascular calcification. Also concerns about promoting hypercalcaemia in adynamic low turnover) bone disease Sevelamer Hydrochloride and Lanthanum Carbonate are the current non-calcium based binders used in clinical practice. May avoid problems associated with calcium based binders but more expensive
- 62. Brand Compound /formDose (mg/day) Type Manufacturer Alu-cap® Aluminium hydroxide capsule 4–20 x 475 mg/day (2–10 g) Metal Meda Pharmaceuticals (UK) Calcichew® Calcium carbonate tablet 2–3 x 1250 mg/day Calcium Shire Pharmaceuticals Calcium 500® Calcium carbonate tablet 1–2 x 1250 mg/day Calcium Generic (Twinlab, etc) Phosex® Calcium acetate tablet 3–6 x 250 mg/day Calcium Vitaline Pharma (UK) Titralac® Calcium carbonate tablet Up to 20 x 420 mg/day Calcium 3M Health Care PhosLo® Calcium acetate (generic) 9–12 x 667 mg/day Calcium Generic (Fresenius Medical Care) Fosrenol® Lanthanum carbonate tablet 750–3750 mg/day Metal Shire Pharmaceuticals RenaGel® Sevelamer hydrochloride capsule 3–9 x 800 mg/day Non-metal Genzyme Renvela® Sevelamer carbonate film- coated tablet 3–6 x 800 mg/day Non-metal Genzyme (USA) OsvaRen® (EU) Rephoren (UK) Calcium acetate/ magnesium carbonate tablet 3–12 x 435/235 mg/day Metal Fresenius
- 63. Class of phosphatebinder Advantages Disadvantages Al-based (Al hydroxide) Effective across wide pH range, inexpensive1 Absorption of Al can lead to long-term toxicity resulting in neurological damage and possible death1 Ca-based (Ca acetate, Ca carbonate) Effective, inexpensive, well tolerated, well established, widely available Likely to increase hypercalcaemia, and risk of arterial calcification, function over a narrow gastric pH range, high tablet burden Sevelamer (hydrogel polymer/resin) Metal-free, low toxicity, lowers lipids and arterial calcification – does not affect Ca Acidosis due to HCl, expensive. Benefits in controlling Pi levels and reduced calcification not sufficiently evaluated in comparison with other treatments.2 Not effective over wide pH range La-based (La carbonate) Effective, well tolerated, low toxicity, low tablet burden Ca-free, reasonable cost Efficacy similar to Ca-based binders. Possible tissue accumulation not ruled out but refuted by some authors
- 64. Rationale: elevatedPTH may increase Ca and Pi thereby promoting vascular calcification Vitamin D analogues 1st line therapy as PTH driven by lack of activated vitamin D Calcimimetics avoid adverse effects on Ca and Pi Low PTH associated with adynamic bone disease
- 65. Vitamin D -decreases PTH secretion but increases Ca uptake from intestine - vitamin D sterols include calcitriol, alfacalcidol, doxercalciferol, paricalcitol Calcimimetics - increase sensitivity of parathyroid Ca receptor thereby reducing PTH – without increasing Ca2 - also reduce Phosphate Surgery • permanently reduces PTH secretion in patients unresponsive to medication • BUT may result in adynamic bone disease Phosphate binders are also used to manage hyperphosphataemia associated with SHPT
- 66. Calcitriol directlysuppresses PTH secretion Vitamin D receptor on PTH gland down regulated as hyperplasia of the gland is advanced
- 67. Intravenous ororal pulses are equally effective Equal efficacy of daily versus equivalent pulse doses Hypercalcaemia remains a complication Hyperphosphatemia also a complication
- 71. Therapy Advantages Disadvantages CinacalcetEffective in reducing PTH levels No hypercalcaemia Phosphate levels may improve Lack of good outcome data showing reductions in CV events and bone effects Expensive Vitamin D and analogues Effective in reducing PTH levels Studies show improved survival Can cause hypercalcaemia Can cause hyperphosphataemia Surgery Permanent/irreversible Can cause adynamic bone disease Can injure local nerve tissue
- 73. Autonomous hypersecretionwhich continues despite of correction of the underlying renal disease by transplantation
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