CalciphylaxieCalciphylaxie

Klinik für Kardiologie und Intensivmedizin

Vincent Brandenburg

University Hospital RWTH Aachen, GermanyNephrologist

Dpt of Cardiology

Weimar, Dezember 2014

Calciphylaxis (CUA)- rare (Orpha.net # ORPHA280062),

- life-threatening syndrome,

- media calcifications of cutaneous vessels (~100µm),

- progressive, very painful lesions / ulcerations,

- reduced quality of life, high mortality,

Definition Calciphylaxie –Calcific Uremic Arteriolopathy, CUA

Medial calcification and intimal thickeningMedial calcification and intimal thickening

www.calciphylaxie.de

Calciphylaxis registry – acknowledgment

The German Calciphylaxis Registrywww.calciphylaxie.de

Baseline questions via online questionnaire:

- patient data (age, sex, cv disease, kidney disease, PTex…) 15

- lab data (creatinine, phos., calc., PTH, CRP, Hb, albumin…) 12

- dialysis modality 9

- medications (renal, cv) 24

- clinical data about CUA 6+ free text

66 items

Underlying renal disease; n = 211

Type of Kidney Disease

75%

4% 2%1%

11%

7% HDPDCKD without DialysisTransplantNo CKDn. a.

ASN Renal Week Atlanta 2014

Male / female ratio

ASN Renal Week Atlanta 2014

Total serum calcium [mmol/L] at time of registration

ASN Renal Week Atlanta 2014

> 2,4 mmol/L< 2,1 mmol/L

2,1 – 2,4mmol/L

Calciphylaxis Registry: PTH levels [pg/mL]

0

10

20

30

40

50

60

1 2 3 40

5

10

15

20

25

30

35

1 2 3 4

Calciphylaxis registryMarch 2012

NDT educational online surveyFebruary 2012

0 – 150150 - 300

300 - 600> 600

0 – 150150 - 300

300 - 600> 600

àRelevant differences between perception (right) andregistry „reality“ (left) regarding PTH levels

PTH

ASN Renal WeekAtlanta 2014

Role of vitamin K antagonist usage and CUA:Potential causalityHayashi M et al; NDT 2012

à Clear association between VKA usage and calciphylaxis: Causality?

A case-control study ofcalciphylaxis in JapaneseESRD patients

Results of using the multivariate logisticregression model to identify predictors ofCUA at the time of diagnosis

Brandenburg V; on file

Prevalence of coumadin usageIn German CUA patients

Wafarin therapy

yes53%

no47%

n. a.1%

Proportion of patients with and withoutwarfarin therapy in patients included inthe German CUA registry, n=211

Seite 13

Calciphylaxie - EVOLVEJürgen Floege et al.

ASN 2014

iPTH

(pg/

mL)

0

400600800

1200140016001800

Time (months)0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

200

800

Median iPTH CinacalcetPlacebo

Seite 14

Calciphylaxie - EVOLVEJürgen Floege et al.

ASN 2014

Cumulative Incidence Plot of Time to Calciphylaxis Adverse Event

Seite 15

Calciphylaxie - EVOLVEJürgen Floege et al.

ASN 2014

Therapeutical OptionsPathophysiology

PTH/Calcium/phosphate/Vitamin DPossible treatments

High PTHHigh bone remodeling

• Calcimimetics• Non calcium-based Phosphate

binders• Active vitamin D analogs• Bisphosphonates• Surgical parathyroidectomy

High Ca, P and Ca x PNormal/low PTHNormal/low bone remodeling

• Strict control of serum phosphate• No calcium-based phosphate binders• Low calcium dialysate (< 1.25 mM)

Acting on extracellular matrixmineralization

• STS• Bisphosphonates

Acting on extracellular matrixremodeling (growth and adhesion)

• Blocking endothelin receptor ?• Statins ?

Therapeutical OptionsPathophysiology

Hypercoagulation statesPossible treatments

Decreased activity of vitamin Kdependent inhibitors by Warfarin(MGP, OPN, ON, Gas-6)

• Stop Warfarin• Use of alternative anticoagulants

Treatment induced procoagulantstate

• Decrease or stop (CNI)

Protein C and/or S deficiency • Anticoagulation (without warfarin)• Vitamin K supplementation

Anti-phospholipid syndrome • Treatment of the associated pathologies

Endothelial dysfunction • Sodium thiosulfate (NO andantithrombotic properties

• Hyperbaric O2-therapy

Therapeutical OptionsPathophysiology Possible treatment

Redox mechanism STS and its antioxidant effects (glutathion)Proinflammatory mechanisms• Cytokines• Macrophage activation

Bisphosphonates (anti-inflammatory)•Avoid skin biopsy (unless necessary)

Tissue ischemia • STS (vasodilatating effects)• Hyperbaric oxygen• Correcting anemia• Decreasing hypotensive drugs• Restoring vessel permeability

(angioplasty)Secondary mechanisms• Trauma, infection, malnutrition

• Minimizing some acts (surgery,transports)

• Avoid subcutaneous injections• Local treatment• Avoid skin biopsy• Antibiotics• Optimizing nutritional status (parenteral)

Paraneoplasic mechanisms • Pain treatment

Although critical – treat!

After 4 months