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CKD

CKD. Affects 5 – 10 % of population Increasingly common Ageing, diabetes, undetected hypertension Associated with: Cardiovascular disease Premature death Disorders of bone and mineral metabolism. Revised classification CKD. KDIGO 2013. CKD-MBD CKD mineral bone disorder.

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CKD

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  1. CKD • Affects 5 – 10 % of population • Increasingly common • Ageing, diabetes, undetected hypertension • Associated with: • Cardiovascular disease • Premature death • Disorders of bone and mineral metabolism

  2. Revised classification CKD KDIGO 2013

  3. CKD-MBDCKD mineral bone disorder Systemic disorder of mineral and bone metabolism including one or more of: • Abnormalities of Ca2+, PO4, PTH, or Vit D • Abnormalities of bone turnover, mineralization, volume, strength • Vascular or other soft tissue calcification KDIGO Kidney International 2009; 76 (Suppl 113): S1–S130

  4. Renal osteodystrophy • Skeletal pathology component of the CKD-MBD syndrome • Histomorphometry KDIGO 2009

  5. CKD-MBD Normal serum levels of Ca2+ and PO4 maintained by 3 hormones • PTH • 1,25(OH)2D • calcitriol • Phosphatonins • FGF23 Act on kidney, bone and intestine

  6. CKD-MBD Kidneys responsible for: • PTH mediated PO4 excretion and Ca2+ reabsorption • Increased PO4 excretion mediated by FGF23 • Conversion of 25(OH)D to 1,25(OH)2D

  7. CKD-MBD Disturbances in mineral metabolism are common occurring early in CKD Begins in CKD 3: • Unable to fully excrete PO4 causing in FGF23 • Compensatory 2o hyperparathyroidism • production of 1,25(OH)2D Changes in FGF23 and PTH occur first Isakova T 2011 Kidney Int 79

  8. As CKD progresses … • PO4 will tend to • Ca2+ will at first tend to • In more advanced disease especially for patients on dialysis, hypercalcaemia may occur • Hyperplasia of PTh glands • Iatrogenic • Calcitriol, calcium containing PO4 binders

  9. Renal osteodystrophy (ROD) • Seen universally in those on dialysis • Majority of patients with CKD 3b – 5 • High bone turnover - predominant hyperPTH • Low bone turnover – adynamic (aluminium induced) and/or osteomalacia • Mixed - hyperPTH and mineralisation defect • Histology may transform from one category to another

  10. CKD-MBD • Osteoporosis may coexist with ROD • hyperPTH • Vitamin D deficiency • Acidosis • sclerostin • Fracture rates are about 4 fold higher and to a certain extent independent of BMD • Cortical bone loss may outstrip trabecular Jamal S OsteoporInt 2012; 23

  11. CKD-MBDClinical manifestations • Fracture risk higher • Vascular calcification • Systolic hypertension, cardiovascular disease • Heterotopic mineralisation • Skin: calciphylaxis – skin necrosis • Lung: restrictive lung disease • Heart – arrhythmias, CCF • Tumoralcalcinosis: periarticular • Bone pain

  12. Medical management of CKD-MBD • “Conspicuous lack of robust evidence esp in context of clinically relevant outcomes” • Cunningham J The spectrum of bone and mineral disorders in CKD. OUP, 2010

  13. Diagnosis of CKD-MBD To define and monitor CKD-MBD: • Measure PTH, 25(OH)D, calcium and phosphate • Base decisions on serial measurements and consider results together • Serum FGF23 not routinely measured • Bone markers + bone biopsies not commonly used Renal Association Guidelines 2015

  14. Diagnosis of CKD-MBD • No test other than bone biopsy identifies subtypes of bone disease in CKD BUT Not clear that bone biopsy result: • is clinically important or • can be used to direct treatment Alshayeb and Quarles. Primer on the Metabolic Bone Diseases and disorders of Mineral Metabolism Ch 78 p640 - 650

  15. Treatment of CKD-MBD Clinical practice guidelines by National Kidney Foundation: • Kidney disease: Outcomes Quality Initiative • KDOQI 2003 • Kidney Disease: Improving Global outcomes • KDIGO 2009 • Clinical Practice Guideline Update • KDIGO 2017 Renal Association (UK) Guidelines 2015

  16. Treatment of CKD-MBD KDIGO 2017 - More emphasis on lack of evidence! Treatment Goals • Aim to avoid hypercalcaemia • Mild hypocalcaemia may be acceptable • calcimimetics • Lower elevated PO4 into normal range

  17. Treatment of CKD-MBD Treatment Goals • PTH optimum level “unknown” except CKD 5D where aim for 2 to 9 x ULN • Aim for normal PTH in CKD 3 • As CKD advances aim for PTH no lower than 2.5 to 3 x ULN • Modest increases in PTH may be appropriate adaptive response • Look for trends eg progressively rising KDIGO 2017

  18. Treatment Goals CKD-MBDRationale for PTH • PTH too high • leads to progressive PTh bone disease, fractures, tertiary hyperparathyroidism, parathyroidectomy • Association with cardiovascular events and death • PTH too low • Increases risk of low bone turnover • ? relevance

  19. Treatment of CKD-MBD Phosphate binders • Ca2+ salts (acetate binds more PO4 than carbonate) • Risk of hypercalcaemia • Non Ca2+ • Avoid hypercalcaemia • Generally preferred KDIGO 2017

  20. Treatment of CKD-MBDControlling PTH levels CKD 4 to 5 • Calcitriol and vitamin D analogues no longer recommended for routine use • Reserve for progressive and severe hyperparathyroidism KDIGO 2017

  21. Treatment of CKD-MBDControlling PTH levels • Calcitriol or alfacalcidoland/or calcimimetics • Titrate against PTH levels • Look for trends in PTH levels • Take into account calcium and PO4 levels Calcimimetics lower Ca2+ and PO4 (CKD5) Vitamin D analogues increase Ca2+ and PO4

  22. Treatment of CKD-MBDControlling PTH levels Vitamin D3/D2 supplements • Worth correcting vitamin D deficiency/insufficiency in all • Peripheral hydroxylation in cardiovascular and immune system • Association with better clinical outcomes • Vitamin D supplements can modestly suppress PTH in CKD 3 - 4 KDIGO 2009

  23. Treatment of CKD-MBDControlling PTH levels Parathyroidectomy • Most severe forms of hyperparathyroidism • Medical management has failed • Usually ESRD • Indications • Severe hypercalcaemia or hyperphosphataemia • Symptomatic bone disease • Calciphylaxis KDIGO 2009

  24. CKD-MBD62 y/o man • Haemodialysis • Calciphylaxis • Peripheral vascular disease • Skin necrosis • R BKA • Vertebral fractures • Parathyroid bone disease • Refused surgery • PTH = 270 (ULN 5)

  25. CKD-MBD62 y/o man

  26. CKD-MBD62 y/o man • Treated with Cinacalcet • Serum calcium lower limit of normal • started on calcitriol • PO4 normal • PTH decreased to 130 • Died from multiorgan failure 6 months later

  27. Osteoporosis and renal disease Osteoporosis 24% CrCl <35 50% CrCl < 35 if >80 y/o Klawansky OI 2003

  28. Osteoporosis and renal disease • Fractures in CKD could be due to osteoporosis, CKD-MBD or both CKD 1-3 • RCTs include patients with CKD 1 to 3 so OK to diagnose and treat as usual • Preferably correct any biochemical abnormalities of CKD-MBD

  29. Osteoporosis and renal disease CKD 4-5 • DXA less reliable but is now recommended • We do measure BMD in patients with fractures • Vertebral imaging can be useful • Not sure if antiresorptives effective • Antiresorptives may be harmful if • Adynamic bone disease or osteomalacia • Low PTH and/or low bALP KDIGO 2017 My own opinion

  30. Osteoporosis and renal disease Data for antiresorptives CKD 4 • Post hoc analyses • Risedronate • Denosumab • Limited vertebral fracture data • Safety looked alright

  31. Consistent risk reduction in vertebral fracture at 36 months by baseline CrCl in FREEDOM Placebo (N=3906) DMAb (N=3902) 10 9.1 Percent Incidence at Month 36 9 8.1 8 7.2 7.0 7.0 7 6 5 4 * * 3.2 3.1 2.9 * 3 * 2.3 1.8 2 1 0 N1 3691 3702 33 31 1309 1332 1952 1924 394 413 15 – 29 mL/min 30 – 59 mL/min 60 – 89 mL/min ≥ 90 mL/min All N = number of randomized subjects. N1 = number of randomized subjects with an evaluation during the time period of interest. There were no subjects with a CrCl < 15 mL/min. *P < 0.05 • The interaction terms were NOT statistically significant, indicating no difference in effect of DMAb by level of renal function SA Jamal Oral Abstract ASBMR 2010 34

  32. Osteoporosis and renal disease Denosumab • Be very careful if GFR < 30 • Risk of hypocalcaemia • Can be profound and prolonged if CKD 5 • Do not use it if PTH very high • Suggest : do not use in CKD 5 MHRA safety update 2012 and my own opinion

  33. Osteoporosis and renal disease Practical message In patient with severe renal disease having low trauma fractures with low BMD and no clear evidence of low bone turnover • Reasonable to consider oral risedronate • IV ibandronate once per 3 to 6 months • Otherwise treat CKD-MBD and preferably have patient on calcitriol/alfacalcidol

  34. Renal transplantation Practical message Most things get better! • CKD-MBD • Bone strength Sometimes best to wait for transplant rather than try and tackle their bone disease with unproven treatments Harding KA et al ASBMR Annual Meeting 2000

  35. SummaryCKD-MBD • Monitor serum Ca2+, PO4 , PTH, 25(OH)D • Modestly raised PTH acceptable • Evidence base for treatment poor • Osteoporosis often coexists • CKD 4/5 – cautious use of antiresorptives • CKD 5 – best to avoid denosumab

  36. Further reading KDIGO guidelines for CKD-MBD • Kidney International 2009; 76 (Suppl 113): S1–S130 • Clinical Update 2017 Kidney International Supplements 7: 1–59 Primer on the Metabolic Bone Diseases and disorders of Mineral Metabolism, 8th Edition, Rosen CJ (Ed) Wiley-Blackwell , 2013. Chapters 77 and 78

  37. Further reading http://www.renal.org/guidelines/modules/ckd-mineral-and-bone-disorders-(ckd-mbd)#2f7da031-1815-6165-9443-ff000014d4d8

  38. Further reading The spectrum of Mineral and Bone Disorders in Chronic Kidney Disease, Second edition, Olgaard K, Salusky S, Silver J (Eds) OUP, 2010

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