1. Clinical management of calciphylaxis Markus Ketteler, MD Division Chief of Nephrology at Klinikum Coburg, Academic Teaching Hospital of the University of Würzburg, and Director of the KfH Dialysis Center Coburg, Coburg, Germany © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

2. Objectives/background Calciphylaxis Clinical manifestations: Calciphylaxis is associated with high mortality: Up to 80%Calciphylaxis is associated with high mortality: Up to 80% Superinfection of necrotic skin lesions with subsequent sepsis, and/orSuperinfection of necrotic skin lesions with subsequent sepsis, and/or Parallel cardiovascular events, significantly contributing to this dramatic outcomeParallel cardiovascular events, significantly contributing to this dramatic outcome © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

3. Diagnosis Male, Caucasian, 1962 Kidney transplantation: 1995Kidney transplantation: 1995 Renal disease: Reflux nephropathyRenal disease: Reflux nephropathy Chronic transplant nephropathyChronic transplant nephropathy Cushing‘s syndromeCushing‘s syndrome Post-transplantation hyperparathyroidismPost-transplantation hyperparathyroidism History of multiple infections including pleural empyema, spondylodiscitis, and phlegmonous infections of the right foot, consecutively developing allergies to multiple antibioticsHistory of multiple infections including pleural empyema, spondylodiscitis, and phlegmonous infections of the right foot, consecutively developing allergies to multiple antibiotics Immunosuppression: Cyclosporine A, methylprednisoloneImmunosuppression: Cyclosporine A, methylprednisolone © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

4. Current history: July 2009 Male, Caucasian, 1962 Small trauma of the lateral right lower leg: Consecutive surgical adaptation Insufficient healing, local superinfection treated with antibiotics (levofloxacin, clindamycin were tolerated) Development of a very painful necrotic ulceration Conventional X-ray: Reticular distribution of small calcified cutaneous vessels Reprinted with permission from Prof. Ketteler © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

5. Laboratory findings Male, Caucasian, 1962 Key laboratory results:Initial treatment: Calcium 2.65 mmol/LAntibioticsCalcium 2.65 mmol/LAntibiotics Phosphate1.16 mmol/LAntihypertensivesPhosphate1.16 mmol/LAntihypertensives Alkaline phosphatase83 U/LCalcitriol stoppedAlkaline phosphatase83 U/LCalcitriol stopped Creatinine 3.4 mg/dL 10 mg vitamin K1 per dayCreatinine 3.4 mg/dL 10 mg vitamin K1 per day iPTH 12.8 pmol/LiPTH 12.8 pmol/L 25-OH-Vit. D 30 ng/mL25-OH-Vit. D 30 ng/mL CRP 10.2 mg/LCRP 10.2 mg/L © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

6. Rationale for treatment approach Aorta + calcitriol Calcitriol (high doses) induce vascular calcification Figure reprinted with permission from Springer Ltd, 2010 Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats Figure reprinted from the American Society of Hematology Price, et al. Calcif Tissue Int 2002;71:356-3, Schurgers, et al. Blood 2007;109:2823-1 © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

7. Multiple choice question 1 Only one of the following statements regarding the use of Vitamin K in the treatment of calciphylaxis is true. Choose the correct response: 1.Vitamin K is contraindicated because it promotes vascular calcification 2.Vitamin K inhibits the action of multiple wide-spectrum antibiotics 3.Vitamin K supplementation inhibits calcification 4.Vitamin K has not been studied in the context of vascular calcification © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

8. Common risk factors Risk factors for extraosseous calcification processes: Ageing Ageing Uremia, dialysis treatment Uremia, dialysis treatment Diabetes mellitus Diabetes mellitus Hyperphosphatemia, elevated Ca x P product Hyperphosphatemia, elevated Ca x P product Severe hyperparathyroidism (possibly relative hypoparathyroidism/adynamic bone disease) Severe hyperparathyroidism (possibly relative hypoparathyroidism/adynamic bone disease) High dose Ca intake, high dose active vitamin D intake High dose Ca intake, high dose active vitamin D intake Inflammation / calcification inhibitor deficiencies Inflammation / calcification inhibitor deficiencies Vitamin K deficiency, vitamin K antagonist treatment Vitamin K deficiency, vitamin K antagonist treatment Giachelli. Kidney Int. 2009;75:890-897; Schlieper, et al. Nat Rev Nephrol. 2009;5:539-43 Ca: Calcium; P: Phosphorus © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

9. Disease course – August 2009 Male, Caucasian, 1962 Local treatment with silver gauze and Suprasorb gel every other day by the patient at home, in addition to medical treatment Reprinted with permission from Prof. Ketteler © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

10. Disease course – September 2009 Male, Caucasian, 1962 Hospital admission: Paralytic ileus, acute pancreatitis CT angiography: High-grade stenosis of the celiac trunk with subsequent ischaemia Partial surgical resection of small intestine Calcium 2.52 mmol/L, phosphate 2.5 mmol/L, creatinine 7 mg/dL, lipase 11334 U/L, CRP 122 mg/dL, leukocytes 18,200 μL, iPTH 48.0 pmol/L Haemodialysis initiated (atrial catheter), cyclosporine A stopped CT: computed tomography © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

11. Disease course – until December 2009 Intermittent exacerbation of calciphylaxis (inflammation- induced, e.g. fetuin-A deficiency), surgical necrosectomy Intolerance to thiosulfate (tachycardia) Cinacalcet 60 mg/day and lanthanum carbonate 3 x 1000 mg/day added © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

12. Laboratory values Lab values improved following cinacalcet/lanthanum treatment initiation: Calcium 2.48 mmol/L, Phosphate 2.72 mmol/L, iPTH 76.3 pmol/L  Calcium 2.08 mmol/L, Phosphate 1.59 mmol/L, iPTH 32.2 pmol/L Reprinted with permission from Prof. Ketteler © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

13. Key learning points Calciphylaxis There is no standard treatment approach to calciphylaxis. The following measures may be considered: Phosphate lowering, avoidance of calcium loads Phosphate lowering, avoidance of calcium loads Vitamin D status, withdrawal/substitution of warfarin, consider vitamin K supplementation (vitamin K deficiency may promote calcification by inhibiting matrix Gla protein)Vitamin D status, withdrawal/substitution of warfarin, consider vitamin K supplementation (vitamin K deficiency may promote calcification by inhibiting matrix Gla protein) Broad-spectrum antibiotics, interdisciplinary wound management Broad-spectrum antibiotics, interdisciplinary wound management Treatment of hyperparathyroidism (if present) Treatment of hyperparathyroidism (if present) Sodium thiosulfate Sodium thiosulfate Bisphosphonates (if adynamic bone disease can be excluded) Bisphosphonates (if adynamic bone disease can be excluded) (hyperbaric oxygen treatment) (hyperbaric oxygen treatment) Cinacalcet and calcium-free phosphate binders (lanthanum, sevelamer) Cinacalcet and calcium-free phosphate binders (lanthanum, sevelamer) © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

14. Multiple choice question 2 Which of the following therapeutic options is contraindicated in calciphylaxis patients? 1. Cinacalcet 2. Sodium thiosulfate 3. Pamidronate 4. Warfarin 5. Hyperbaric oxygen therapy 6. Surgical debridement 7. Vitamin K © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

15. Conclusion Calciphylaxis at presentation Typical features 1 : Patient after kidney transplantation Precipitating local trauma Exacerbation by (super-)infection Association with hyperparathyroidism Active vitamin D treatment Atypical features 1 : Initially no hyperphosphatemia No signs of significantly disturbed bone turnover Thiosulfate intolerance 1 typical/atypical based on case reports/case series – no prospective data available © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

16. Multiple choice question 3 Which of the following features of the patient cases described here is not typical of calciphylaxis? 1.Initial absence of hyperphosphatemia 2.Infection/superinfection 3.Hyperparathyroidism 4.Precipitating local trauma 5.History of renal transplantation © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

17. Perspectives Prevention of extraskeletal calcification with calcimimetics Reduction in aortic mineralisation following treatment with a calcimimetic in rats Figures reprinted by permission from Macmillan Publishers Ltd: Kidney Int, 2008 Lopez, et al. Kidney Int. 2008;73:300–7 Calcitriol Calcimimetic Calcitriol + calcimimetic Paricalcitol Paricalcitol + calcimimetic © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media

18. Treatment of advanced cardiovascular calcification with cinacalcet ADVANCE study design (results submitted for publication): Figures reprinted with permission from Prof. Ketteler © Springer Healthcare, a part of Springer Science+Business Media; 2010.Springer HealthcareSpringer Science+Business Media