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Bone Disease in Renal Failure


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Bone Disease in Renal Failure

  1. 1. Bone Disease in Renal Failure <ul><li>Dr Anne Kleinitz and </li></ul><ul><li>Dr Cherelle Fitzclarence </li></ul><ul><li>[email_address] </li></ul>
  2. 2. Overview <ul><li>Pathogenesis </li></ul><ul><li>Normal Bone Remodeling </li></ul><ul><li>Hyperparathyroidism </li></ul><ul><li>Classifications of bone disease </li></ul><ul><li>Diagnosis of bone disease </li></ul><ul><li>Treatment of bone disease in CKD </li></ul><ul><li>Case Studies </li></ul>
  3. 3. Pathogenesis <ul><li>Kidney failure disrupts systemic calcium and phosphate homeostasis and affects the bone, GIT and parathyroid glands. </li></ul><ul><li>In kidney failure there is decreased renal excretion of phosphate and diminished production of calcitriol (1,25-dihydroxyvitamin D) </li></ul><ul><ul><li>Calitriol increases serum calcium levels </li></ul></ul><ul><li>The increased phosphate and reduced calcium, feedback and lead to secondary hyperparathyroidism, metabolic bone disease, soft tissue calcifications and other metabolic abnormalities </li></ul>
  4. 4. ↓ GFR ↑ PO4 ↓ 1,25 DHCC ↓ Ca ↑ PTH Calcitriol
  5. 5. <ul><li>Although bone disease and abnormal PTH are a major feature, CVD and excess calcification (extra-skeletal) are important causes of morbidity and mortality </li></ul>
  6. 6. <ul><li>Pathogenesis </li></ul><ul><li>Normal Bone Remodeling </li></ul>
  7. 7. Resorption osteoclasts Formation osteoblasts -> matrix Mineralisation Quiescence Normal Bone Remodelling Cycle
  8. 8. <ul><li>Pathogenesis </li></ul><ul><li>Normal Bone Remodeling </li></ul><ul><li>Hyperparathyroidism </li></ul>
  9. 9. Hyperparathyroidism <ul><li>Increase PTH is hallmark of secondary hyperparathyroidism </li></ul><ul><li>The major factors leading to it’s increase are; </li></ul><ul><ul><li>Decreased production of Vit D3 (calcitriol) </li></ul></ul><ul><ul><li>Decreased serum calcium </li></ul></ul><ul><ul><li>Increased serum phosphorous </li></ul></ul>
  10. 10. ↓ GFR ↑ PO4 ↓ 1,25 DHCC ↓ Ca ↑ PTH Calcitriol
  11. 11. <ul><li>4 or more small glands on the posterior surface of the thyroid gland. </li></ul><ul><li>Can function without neural control so can transplant to another part of the body </li></ul><ul><li>2 types of cells </li></ul><ul><li>Chief cells – produce parathyroid hormone </li></ul><ul><li>Oxyntic cells – function unknown </li></ul>
  12. 12. Role of PTH <ul><li>Responsible for maintaining serum calcium in a narrow range (2.15-2.6) </li></ul><ul><li>Does this by; </li></ul><ul><ul><li>acting directly on the distal tubule of the kidney to increase calcium reabsorption </li></ul></ul><ul><ul><ul><li>Increases calcitriol production (D3) </li></ul></ul></ul><ul><ul><ul><li>D3 increases GIT absorption of Ca and Phos and promotes osteoclast formation. </li></ul></ul></ul><ul><ul><li>Acting on bone to increase calcium and phosphate efflux </li></ul></ul>
  13. 13. <ul><li>The net effect of PTH is to create positive calcium balance necessary to maintain homeostasis. </li></ul><ul><li>To balance out the increased phos from skeletal effects, and GIT effects of calcitriol, PTH acts secondarily to increase renal phos excretion </li></ul><ul><ul><li>By decreasing activity of sodium phosphate co-transporter in prox renal tubule. </li></ul></ul>
  14. 14. Uraemic Secondary Hyperparathyroidism <ul><li>Cause PO 4 retention </li></ul><ul><li>Low 1,25 Vit D synthesis </li></ul><ul><li>Effects Proximal weakness, Bone pain (late) </li></ul><ul><li>↑ Alk Phos, bone erosions </li></ul><ul><li>Rx Diet, PO 4 binders </li></ul><ul><li>Calcitriol, PTHx (usually for 3 o ) </li></ul>
  15. 15. Secondary hyperparathyroidism <ul><li>In renal failure driven by </li></ul><ul><ul><li>Hypocalcaemia </li></ul></ul><ul><ul><li>Decreased vitamin D </li></ul></ul><ul><ul><li>hyperphosphataemia </li></ul></ul>
  16. 16. ↓ GFR ↑ PO4 ↓ 1,25 DHCC ↓ Ca ↑ PTH Calcitriol
  17. 18. hyperPTH in CKD <ul><li>In CKD is a progressive disorder. </li></ul><ul><li>Involves both increased secretion PTH & hyperplasia </li></ul><ul><li>Can occur once eGFR < 60 </li></ul><ul><li>PTH levels increase progressively as renal function declines and by CKD stage 5(<15) most pt’s expected to have this. </li></ul><ul><li>Usually the 1 st sign and occurs before lab tests pick up  phosphatemia, ↓ Vit D3 and ↓ calcium </li></ul><ul><ul><li>Presumably as PTH is maintaining homeostasis. </li></ul></ul><ul><li>Unless treated, progresses and frequency of parathyroidectomy proportional to yrs on dialysis </li></ul>
  18. 19. Overview <ul><li>Pathogenesis </li></ul><ul><li>Normal Bone Remodeling </li></ul><ul><li>Hyperparathyroidism </li></ul><ul><li>Classifications of bone disease in CKD </li></ul>
  19. 20. Classification of Bone Disease in CKD <ul><li>The circulating level of PTH is primary determinant of bone turnover in CKD </li></ul><ul><li>Type of bone disease depends upon </li></ul><ul><ul><li>Age of pt </li></ul></ul><ul><ul><li>Duration of kidney failure </li></ul></ul><ul><ul><li>Severity of hyperPTH </li></ul></ul><ul><ul><li>Type of dialysis </li></ul></ul><ul><li>PTH & Vit D receptors, as well as calcium sensors are present on osteoblasts </li></ul>
  20. 22. Types of Renal Bone Disease <ul><li>Traditionally classified according to degree of abnormal bone turnover </li></ul><ul><li>High Turnover (osteitis fibrosa) </li></ul><ul><ul><li>Hyperparathyroidism </li></ul></ul><ul><li>Low turnover </li></ul><ul><ul><li>Adynamic - Osteomalacia </li></ul></ul><ul><li>Beta 2 MG amyloidosis </li></ul><ul><li>Osteoporosis </li></ul><ul><ul><li>Post-menopausal - Post-transplant </li></ul></ul>
  21. 23. Resorption osteoclasts Formation osteoblasts -> matrix Accelerates : High PO 4 or Low Ca 2+ , Vit D3, Retards : Vit D3, Age, Diabetes, Al 3+ , PTHx Mineralisation Quiescence Uraemic Bone Remodelling Cycle
  22. 24. Resorption osteoclasts Formation osteoblasts -> matrix Accelerates : High PO 4 or Low Ca 2+ , calcitriol, HCO 3 , oestrogen Retards : Calcitriol*, Age, Diabetes, Al 3+ , PTHx Mineralisation *Acts via osteoblasts Quiescence Uraemic Bone Remodelling Cycle Via PTH*, IL-1,6 & TNF
  23. 25. High turn over bone disease <ul><li>Due to excess PTH </li></ul><ul><li>Increased bone turnover activity (greater number of osteoclasts and osteoblasts) and defective mineralization. </li></ul><ul><li>Associated with bone pain and increased risk of fractures. </li></ul><ul><li>Severe symptomatic disease is currently uncommon with modern therapy. </li></ul>
  24. 26. Mixed uraemic bone disease <ul><li>Mixture of high turn over bone disease and osteomalacia </li></ul>
  25. 27. Osteomalacia <ul><li>Formally linked to aluminium toxicity </li></ul><ul><ul><li>From aluminium based phosphate binders </li></ul></ul><ul><ul><li>From contamination of water in diasylate solutions </li></ul></ul>
  26. 28. Adynamic bone disease <ul><li>Characterized by low osteoblastic activity and bone formation rates </li></ul><ul><li>Seen in up to 40% HD and 50% PD </li></ul><ul><li>May be due to excess suppression of the parathyroid gland with therapies, particularly calcium-containing phosphate binders and vitamin D analogues. </li></ul><ul><li>Typically maintain a low serum intact PTH concentration, which is frequently accompanied by an elevated serum calcium level. </li></ul><ul><li>Felt to represent a state of relative hypoparathyroidism </li></ul>
  27. 29. Clinical manifestations of bone disease <ul><li>Most with CKD and mildly elevated PTH are asymptomatic </li></ul><ul><li>When present classified as either </li></ul><ul><ul><li>Musculoskeletal </li></ul></ul><ul><ul><li>Extra-skeletal </li></ul></ul>
  28. 30. Musculoskeletal <ul><li>Fractures, tendon rupture and bone pain from metabolic bone disease, muscular pain and weakness. </li></ul><ul><li>Most clinically significant is hip fracture, seen in CKD 5 (and is associated with increase risk of death) </li></ul><ul><ul><li>NB. In dialysis pts there is already a 4.4 x increase risk of hip fracture. </li></ul></ul>
  29. 31. Extra-skeletal <ul><li>Important to recognise disordered bone and mineral metabolism is a systemic disorder affecting soft tissues, particularly vessels, heart valves and skin. </li></ul><ul><li>CVD accounts for around half of all deaths of dialysis patients. </li></ul><ul><li>Coronary artery and vascular calcifications occur frequently in CKD 5 (and increase each year on dialysis) </li></ul>
  30. 32. Types of calcification <ul><li>Focal calcification associated with lipid laden atherosclerotic plaques </li></ul><ul><ul><li>Increases fragility and risk of plaque rupture </li></ul></ul><ul><li>Diffuse calcification </li></ul><ul><ul><li>not in atherosclerotic plaques and occurs in media of vessels </li></ul></ul><ul><ul><li>Called “Monckeberg’s sclerosis” </li></ul></ul><ul><ul><li>Increases blood vessel stiffness and reduces vascular compliance </li></ul></ul><ul><ul><ul><li>Results in widened pulse pressure </li></ul></ul></ul><ul><ul><ul><li>Increased afterload </li></ul></ul></ul><ul><ul><ul><li>LVH </li></ul></ul></ul><ul><ul><ul><ul><li>Contributing to CVD morbidity </li></ul></ul></ul></ul>
  31. 34. <ul><li>As per Cherelle “If we X-Ray most of our patients, they’ve got “tram tracks” – we hardly need an angiogram!” </li></ul>
  32. 35. Types of calcification <ul><li>Calciphylaxis or calcemic uremic arteriopathy </li></ul><ul><ul><li>Seen primarily in CKD 5 </li></ul></ul><ul><ul><li>Occurs in 1-4% of dialysis patients </li></ul></ul><ul><ul><li>Presents with extensive calcification of the skin, muscles and SC tissues. </li></ul></ul><ul><ul><ul><li>Extensive medial calcification of small arteries, arterioles, capillaries and venules. </li></ul></ul></ul><ul><ul><ul><li>Clinically they may have skin nodules, skin firmness, eschars, livedo reticularis and painful hyperaesthesia of the skin. </li></ul></ul></ul><ul><ul><ul><li>May lead to non healing ulcers and gangrene </li></ul></ul></ul>
  33. 36. calciphylaxis <ul><li>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) </li></ul>
  34. 37. Angulated black eschar with surrounding livedo. Note the bullous change at the inferior edge of the eschar. (courtesy Up To Date)
  35. 38. Amyloidosis <ul><li>Pts on dialysis for 7- 10 years can develop osteoarticular amyloid deposits. </li></ul><ul><li>May present with carpel tunnel syndrome and arthritis </li></ul>
  36. 39. Overview <ul><li>Pathogenesis </li></ul><ul><li>Normal Bone Remodeling </li></ul><ul><li>Hyperparathyroidism </li></ul><ul><li>Classifications of bone disease </li></ul><ul><li>Diagnosis of bone disease </li></ul>
  37. 40. Diagnosis of CKD bone disease <ul><li>Blood </li></ul><ul><ul><li>PTH </li></ul></ul><ul><ul><ul><li>Random circulating PTH (1/2 life 2-4 mins) </li></ul></ul></ul><ul><ul><ul><li>Excreted renally so present for longer in RF </li></ul></ul></ul><ul><ul><li>Calcium </li></ul></ul><ul><ul><li>Phosphate </li></ul></ul><ul><li>Bone biopsy </li></ul><ul><ul><li>no longer frequently performed </li></ul></ul><ul><li>Imaging </li></ul><ul><ul><li>In general not indicated </li></ul></ul>
  38. 41. PTH levels <ul><li>Normal ( Pathwest ) 0.7 – 7.0 pmol/L </li></ul><ul><li>In CKD there is end-organ resistance </li></ul><ul><li>Hence, recommended levels are 2 – 3 x normal. </li></ul>
  39. 42. Overview <ul><li>Pathogenesis </li></ul><ul><li>Normal Bone Remodeling </li></ul><ul><li>Hyperparathyroidism </li></ul><ul><li>Classifications of bone disease </li></ul><ul><li>Diagnosis of bone disease </li></ul><ul><li>Treatment of bone disease in CKD </li></ul>
  40. 43. Treatment of CKD bone disease <ul><li>Directed towards normalising serum calcium, phosphate and PTH, while minimizing the risks associated with Rx </li></ul>
  41. 44. Treatment of CKD bone disease <ul><li>Various Rx for secondary hyperPTH and hyperphosphataemia include; </li></ul><ul><li>Dietary phosphorous restriction </li></ul><ul><li>Calcium and non-Ca phosphate binders </li></ul><ul><li>Calcitriol or other Vit D analogues </li></ul><ul><li>Calcimimetics </li></ul><ul><li>Parathyroidectomy </li></ul>
  42. 45. ↓ GFR ↑ PO4 ↓ 1,25 DHCC ↓ Ca ↑ PTH ↓ Coke & dairy food CaCO3 with meals Calcitriol
  43. 46. Phosphorus (oxidized form is phosphate) <ul><li>80% in the bone </li></ul><ul><li>Food products include; nuts, beer, chocolate, coca-cola </li></ul><ul><li>Normal level 0.8 – 1.5mmol/L ( Pathwest ) </li></ul><ul><li>Passes into glomerular filtrate and 90% reabsorbed </li></ul><ul><li>Reabsorption decreased by PTH and by calcitonin and increased if PTH is absent </li></ul><ul><li>Low levels if hyperparathyroidism with excessive losses in urine </li></ul><ul><li>High levels in hypoparathyroidism or renal failure </li></ul>
  44. 47. Phosphate binders <ul><li>Calcium-based phosphate binders </li></ul><ul><ul><li>Calcium carbonate (Cal-Sup/Caltrate) </li></ul></ul><ul><ul><li>Only Cal-Sup i PBS/S100 </li></ul></ul><ul><ul><li>Varies, eg. 1 BD, 1-4 TDS </li></ul></ul><ul><ul><li>Must be chewed with food to maximize binding of ingested phosphorous. </li></ul></ul>
  45. 48. Phosphate binders <ul><li>Non-calcium phos binder </li></ul><ul><li>Sevelamer (available for 12 months) </li></ul><ul><ul><li>Often used in conjunction with Cal-sup </li></ul></ul><ul><ul><li>Used when phos still high despite max Cal-Sup (2 TDS) </li></ul></ul><ul><ul><li>More costly </li></ul></ul>
  46. 49. Phosphate binders <ul><li>Aluminium-containing phos binders </li></ul><ul><ul><li>Alu-tabs/aluminium hydroxide </li></ul></ul><ul><ul><li>Most effective, but ceaesd use around 12 months ago when sevelamer and cinacalcet available. </li></ul></ul><ul><ul><li>Systemic absorption with subsequent neurological, haematological and bone toxicity. </li></ul></ul>
  47. 50. Calcitriol <ul><li>1,25-(OH)2 Vitamin D3 or other analogues bind to receptor on PT tissue and suppress PTH production </li></ul>
  48. 51. ↓ GFR ↑ PO4 ↓ 1,25 DHCC ↓ Ca ↑ PTH Calcitriol
  49. 52. Calcitonin <ul><li>Produced by parafollicular or C cells of the thyroid gland </li></ul><ul><li>Secreted when plasma calcium level rises </li></ul><ul><li>Main action is the lowering of plasma calcium by limiting bone resorption and it increases phosphate excretion in the urine </li></ul>
  50. 53. Calcimimetics <ul><li>Calcium receptor-sensing agonists </li></ul><ul><li>Act on PT gland and increase sensitivity of receptor to calcium </li></ul><ul><li>Cinacalcet (Sensipar) </li></ul><ul><ul><li>Significant decrease PTH, w/o  Ca or phos </li></ul></ul><ul><ul><li>Avoids calcification </li></ul></ul>
  51. 54. ↓ GFR ↑ PO4 ↓ 1,25 DHCC ↓ Ca ↑ PTH Calcitriol
  52. 55. Parathyroidectomy <ul><li>Last option </li></ul><ul><li>Considered when other methods fail to ↓ PTH </li></ul><ul><li>Either total or sub-total </li></ul><ul><ul><li>Used to re-implant in forearm. </li></ul></ul>
  53. 56. Summary of Rx <ul><li>Dietary phosphate restriction </li></ul><ul><li>Phosphate binders </li></ul><ul><li>Calcitriol or other Vit D analogues </li></ul><ul><li>Calcium supplementation/calcimimetics </li></ul><ul><li>Parathyroidectomy </li></ul>
  54. 57. Prevention of osteodystrophy ↓ GFR ↑ PO4 ↓ 1,25 DHCC ↓ Ca ↑ PTH ↓ Coke & dairy food CaCO3 with meals Calcitriol
  55. 58. Transplant <ul><li>Bony changes improve post Tx, but if severe increased PTH, levels can persist for up top 10 years. </li></ul><ul><li>Although Tx corrects many conditions leading to disordered mineral metabolism, </li></ul><ul><li>Steroids may lead to bone fragility, osteoporosis and increased fractures. </li></ul>
  56. 59. Case Studies
  57. 60. Case 1 <ul><li>MC </li></ul><ul><li>Diabetic nephropathy – Haemodialysis </li></ul><ul><li>Hypothyroidism </li></ul><ul><li>Pancreatic pseudocyst </li></ul><ul><li>Epilepsy </li></ul><ul><li>Anaemia </li></ul><ul><li>Hypertension </li></ul>
  58. 61. Case 1 <ul><li>Currently PTH 104 </li></ul><ul><li>Ca corrected 2.04 </li></ul><ul><li>Po4 1.77 </li></ul><ul><li>Medications </li></ul><ul><ul><li>Calcium carbonate 2 three times with meals </li></ul></ul><ul><ul><li>Calcitriol 1mic 3 times a week </li></ul></ul>
  59. 62. Case 1 <ul><li>What do we do? </li></ul><ul><li>Thoughts? </li></ul>
  60. 63. Case 1 <ul><li>This lady is non compliant! </li></ul><ul><li>No point changing her regime if she is not taking what you have written up </li></ul><ul><li>Encourage compliance </li></ul><ul><li>Explain the essential nature of compliance with this therapy </li></ul>
  61. 64. Case 2 <ul><li>RJ </li></ul><ul><li>Diabetes </li></ul><ul><li>Anaemia </li></ul><ul><li>Dementia </li></ul><ul><li>Alcoholism </li></ul><ul><li>End stage kidney disease – CAPD </li></ul><ul><li>IHD/cardiomyopathy – recent massive AMI </li></ul><ul><li>Syphilis </li></ul>
  62. 65. Case 2 <ul><li>PO4 3.77 </li></ul><ul><li>Ca 1.82 </li></ul><ul><li>Product 6.86 </li></ul><ul><li>PTH 166 </li></ul><ul><li>Thoughts? </li></ul>
  63. 66. Case 2 <ul><li>Again non compliance </li></ul><ul><li>Recent finding of around 20 webster packs in his room </li></ul>
  64. 67. Case 3 <ul><li>DB </li></ul><ul><li>Diabetes </li></ul><ul><li>End stage kidney disease – HD </li></ul><ul><li>Hypothyroidism </li></ul><ul><li>Hypertension </li></ul><ul><li>Anaemia </li></ul><ul><li>Recurrent laryngeal palsy </li></ul><ul><li>IHD </li></ul><ul><li>Constipation </li></ul><ul><li>Depression </li></ul><ul><li>Cerebrovasvcular disease </li></ul>
  65. 68. Case 3 <ul><li>Ca 2.72 </li></ul><ul><li>PO4 1.39 </li></ul><ul><li>PTH 20.1 </li></ul><ul><li>Product 3.7 </li></ul><ul><li>Thoughts? </li></ul>
  66. 69. Case 3 <ul><li>Has had parathyroidectomy (hence the recurrent laryngeal palsy) and parameters are exactly where we want them </li></ul><ul><li>Meds </li></ul><ul><ul><li>Calsup 2 tds with food </li></ul></ul><ul><ul><li>Calcitriol 6 (1.5mics) twice a week at dialysis </li></ul></ul>
  67. 70. Case 4 <ul><li>ID </li></ul><ul><li>Usual litany of problems </li></ul><ul><li>HD </li></ul><ul><li>Po4 1.0 </li></ul><ul><li>Ca 2.6 </li></ul><ul><li>PTH 3.1 </li></ul><ul><li>Thoughts? </li></ul>
  68. 71. Case 4 <ul><li>Oversuppressed </li></ul><ul><li>Need the PTH to be 2-3 times normal or patient will likely get adynamic bone disease </li></ul><ul><li>Back off Vit D and Calcium </li></ul><ul><li>In this case pt was on Calsup 2 tds and Calcitriol 6 (1.5mics) twice a week. Decrease Calcitriol eg 1.5mics once a week and decrease Calsup to 1 tds </li></ul><ul><li>Monitor </li></ul>
  69. 72. Thank you! <ul><li>[email_address] </li></ul>
  70. 73. Calcium and Phosphorus Homeostasis
  71. 74. References <ul><li>Dr Mark Thomas, Nephrologist, Royal Perth Hospital </li></ul><ul><li>Primer on Kidney Diseases, 5 th Edition. Greenberg, National Kidney Foundation. 2009 </li></ul>