Bone Disease in Renal Failure

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  • The bone remodelling cycle goes through four stages in order: quiescence, resorption, formation, mineralisation. It is accelerated by hyperPTHism, in turn stimulated by phosphate retention, or low levels of calcium, calcitriol, oestrogen or acidosis. Turnover is slowed by calcitriol, acting in mutiple sections of the bone cycle, especially in the elderly, diabetic, the aluminium exposed or following parathyroidectomy. Cytokine mediators particularly involved include: IL-1 and -6, and TNK, promoting high turnover, and TGF beta, slowing resorption
  • The bone remodelling cycle goes through four stages in order: quiescence, resorption, formation, mineralisation. It is accelerated by hyperPTHism, in turn stimulated by phosphate retention, or low levels of calcium, calcitriol, oestrogen or acidosis. Turnover is slowed by calcitriol, acting in mutiple sections of the bone cycle, especially in the elderly, diabetic, the aluminium exposed or following parathyroidectomy. Cytokine mediators particularly involved include: IL-1 and -6, and TNK, promoting high turnover, and TGF beta, slowing resorption
  • The bone remodelling cycle goes through four stages in order: quiescence, resorption, formation, mineralisation. It is accelerated by hyperPTHism, in turn stimulated by phosphate retention, or low levels of calcium, calcitriol, oestrogen or acidosis. Turnover is slowed by calcitriol, acting in mutiple sections of the bone cycle, especially in the elderly, diabetic, the aluminium exposed or following parathyroidectomy. Cytokine mediators particularly involved include: IL-1 and -6, and TNK, promoting high turnover, and TGF beta, slowing resorption
  • 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>

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