Clinical management of calciphylaxis Markus Ketteler, MD Division Chief of Nephrology at Klinikum Coburg, Academic Teaching Hospital of the University

Clinical management of calciphylaxis

Markus Ketteler, MDDivision 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.

Objectives/background

CalciphylaxisCalciphylaxis

Clinical manifestations: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, Superinfection of necrotic skin lesions with subsequent sepsis, and/orand/or

• Parallel cardiovascular events, significantly contributing to this Parallel cardiovascular events, significantly contributing to this dramatic outcomedramatic outcome


Diagnosis

Male, Caucasian, 1962Male, 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, History of multiple infections including pleural empyema, spondylodiscitis, and phlegmonous infections of the right foot, spondylodiscitis, and phlegmonous infections of the right foot, consecutively developing allergies to multiple antibioticsconsecutively developing allergies to multiple antibiotics

• Immunosuppression: Cyclosporine A, methylprednisoloneImmunosuppression: Cyclosporine A, methylprednisolone


Current history: July 2009


• 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


Laboratory findings


Key laboratory results:Key laboratory results: Initial treatment:Initial treatment:

• Calcium Calcium 2.65 mmol/L2.65 mmol/L AntibioticsAntibiotics

• PhosphatePhosphate 1.16 mmol/L1.16 mmol/L AntihypertensivesAntihypertensives

• Alkaline phosphataseAlkaline phosphatase 83 U/L83 U/L Calcitriol stoppedCalcitriol stopped

• Creatinine Creatinine 3.4 mg/dL3.4 mg/dL 10 mg vitamin K1 per 10 mg vitamin K1 per dayday

• iPTH iPTH 12.8 pmol/L12.8 pmol/L

• 25-OH-Vit. D 25-OH-Vit. D 30 ng/mL30 ng/mL

• CRP CRP 10.2 mg/L10.2 mg/L© Springer Healthcare, a part of Springer Science+Business Media; 2010.

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 ratsFigure 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


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:

1.1. Vitamin K is contraindicated because it promotes vascular Vitamin K is contraindicated because it promotes vascular calcification calcification

2.2. Vitamin K inhibits the action of multiple wide-spectrum Vitamin K inhibits the action of multiple wide-spectrum antibioticsantibiotics

3.3. Vitamin K supplementation inhibits calcificationVitamin K supplementation inhibits calcification

4.4. Vitamin K has not been studied in the context of vascular Vitamin K has not been studied in the context of vascular calcificationcalcification


Common risk factors

Risk factors for extraosseous calcification processes:Risk factors for extraosseous calcification processes:• AgeingAgeing

• Uremia, dialysis treatmentUremia, dialysis treatment

• Diabetes mellitusDiabetes mellitus

• Hyperphosphatemia, elevated Ca x P productHyperphosphatemia, elevated Ca x P product

• Severe hyperparathyroidism (possibly relative Severe hyperparathyroidism (possibly relative hypoparathyroidism/adynamic bone disease)hypoparathyroidism/adynamic bone disease)

• High dose Ca intake, high dose active vitamin D intakeHigh dose Ca intake, high dose active vitamin D intake

• Inflammation / calcification inhibitor deficienciesInflammation / calcification inhibitor deficiencies

• Vitamin K deficiency, vitamin K antagonist treatmentVitamin K deficiency, vitamin K antagonist treatment

Giachelli. Kidney Int. 2009;75:890-897; Schlieper, et al. Nat Rev Nephrol. 2009;5:539-43Ca: Calcium; P: Phosphorus


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.

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.

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


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


Key learning points

CalciphylaxisThere is no standard treatment approach to calciphylaxis. The There is no standard treatment approach to calciphylaxis. The

following measures may be considered:following measures may be considered:

• Phosphate lowering, avoidance of calcium loadsPhosphate lowering, avoidance of calcium loads

• Vitamin D status, withdrawal/substitution of warfarin, consider vitamin K Vitamin D status, withdrawal/substitution of warfarin, consider vitamin K supplementation (vitamin K deficiency may promote calcification by supplementation (vitamin K deficiency may promote calcification by inhibiting matrix Gla protein)inhibiting matrix Gla protein)

• Broad-spectrum antibiotics, interdisciplinary wound managementBroad-spectrum antibiotics, interdisciplinary wound management

• Treatment of hyperparathyroidism (if present)Treatment of hyperparathyroidism (if present)

• Sodium thiosulfateSodium 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, Cinacalcet and calcium-free phosphate binders (lanthanum, sevelamer)sevelamer)



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


Conclusion

Calciphylaxis at presentationTypical features1:

• Patient after kidney transplantation

• Precipitating local trauma

• Exacerbation by (super-)infection

• Association with hyperparathyroidism

• Active vitamin D treatment

Atypical features1:

• 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



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


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, 2008Lopez, et al. Kidney Int. 2008;73:300–7

CalcitriolCalcimimeticCalcitriol +

calcimimeticParicalcitol

Paricalcitol + calcimimetic


Treatment of advanced cardiovascular calcification with cinacalcet

ADVANCE study design (results submitted for publication):ADVANCE study design (results submitted for publication):

randomized (1:1) Follow-up = 1 year

Standard therapy* (n = 165)Standard therapy* (n = 165)• HD patients

• iPTH >300 pg/mLbiPTH 160 pg/mL

• or 150-300 or 80-160 w/ Vit.D

• Ca 8.4 mg/dL(2.1 mmol/l)

• CAC score >30

PopulationPopulation

Cinacalcet + Standard th.** (n =165)Cinacalcet + Standard th.** (n =165)

• *Ca-containing phosphate binders + flexible Vit.D in standard therapy**Ca-containing phosphate binders + low dose Vit. D w/ cinacalcet

week 0 week 28 week 52week 0 week 28 week 52

• Endpoints: primary endpoint = progression of coronary calcificationssecondary enpoint = progression of aortic (valve) calcifications

Figures reprinted with permission from Prof. Ketteler


Documents

Clinical management of calciphylaxis Markus Ketteler, MD Division Chief of Nephrology at Klinikum Coburg, Academic Teaching Hospital of the University