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6 What the Evolve Study Adds to the Topic

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22 Calciphylaxis and Vitamin D



22.7



385



Vitamin K: A Key Factor in CUA?



Two of the case-control studies listed in Table 22.1 reported previous vitamin K

antagonist (VKA, coumadin) usage as potential risk factor for CUA development

[9, 12]. These findings are in line with data from the German calciphylaxis registry.

Within our patient cohort, the prevalence of previous vitamin K antagonist usage

was about 50 %. This potentially causative association deserves our particular

attention: CUA development might have iatrogenic aspects or in other words

might be a severe adverse event from VKA prescription. Moreover, the potential

association between vitamin K antagonists and CUA in chronic HD patients support Selye’s two-hit theory by providing a convincing candidate for a “challenging

factor”. In other words, VKA application might be the straw that breaks the camel’s back. The aggravation of calcification by VKA is pathophysiologically plausible. VKA interfere with the posttranslational activation of Matrix-Gla protein

(MGP). MGP is of outstanding importance in inhibiting vascular calcification.

Absence of MGP causes premature death in rodents due to fracture-like lesions in

the aorta [20]. Moreover, VKA interfere with beta-catenin signalling via transglutaminase A, which may also contribute to vascular calcification [21]. There is

substantiated evidence pointing to an accelerating effect of vitamin K antagonist

application upon vascular calcification processes in humans [22–24]. Based on

these findings a prospective randomized trial will test vitamin K replenishment as

a therapeutic approach against uremic vascular calcification in dialysis patients

(the VitaVasK trial, NCT01742273). It is unknown whether stopping therapy with

VKA, application of an alternative anticoagulant, and /or vitamin K substitution is

really a successful therapeutic intervention in CUA patients. However, such an

approach is widely applied by treating physicians based on interim analyses from

the German registry. Such a coumadin-avoiding approach is also reported from

other countries [6]. We acknowledge that stopping VKA is not without risk and

might create complex situations in those patients in whom anticoagulation alternatives are absent and the need for oral anticoagulation therapy is obvious (e.g.

patients with prosthetic heart valves) [25]. The most common indication for VKA

treatment in ESRD patients is for stroke prevention in patients with atrial fibrillation. The evidence for the efficacy of VKA treatment for stroke prevention in endstage renal disease patients is, however, weak and coupled with potential side

effects such as bleeding and vascular calcification. Therefore, we generally recommend reservation and individualized approaches in terms of VKA treatment in

ESRD [25].

A pilot clinical trial to investigate the role of vitamin K supplementation in

calciphylaxis is currently underway (NCT02278692), which investigates the

modification of MGP levels and the reduction in pain sensation in CUA patients

treated with vitamin K. Patients will be randomized to Vitamin K (phylloquinone) 10 mg orally three times a week after dialysis for 12 weeks or to

placebo.



386



22.8



V.M. Brandenburg and P.A. Ureña Torres



CUA Treatment: What Can We Do?



Does absence of evidence for therapeutic success justify therapeutic nihilism? No.

Unassertive passivity is not an option. Many aspects of CUA treatment deal with

“making dialysis patient care better” (Table 22.2). Whatever obscure nephrological

expectations regarding “optimal” dialysis patient care may be these interventions can

be shortly summarized as more intense and longer dialysis aiming at better CKDMBD control. Reducing calcium supply via lowering oral calcium intake, lowering

dialysis bath calcium and reducing active vitamin D treatment is another mainstay of

therapy. Additionally important aspects of therapy are personalized pain relief

according to WHO standards, individualized wound management and infection

control.

More specifically, more purposive are three additional therapeutic interventions

(Table 22.3).



Table 22.2 Current general treatment strategies in CUA based upon recordings in the German

calciphylaxis registry

Intensification of dialysis therapy by

Increasing dialysis length, frequency (weekly dialysis dosage)

Switch from hemodialysis to hemodiafiltration

Switch from peritoneal dialysis to hemodialysis / hemodiafiltration

Reduction of calcium supply and calcium intake

Switch to calcium-free or calcium-reduced phosphate binders (such as sevelamer or

lanthanum, magnesium- or iron-based binders)

Reduction of active vitamin D dosage

Stop vitamin K antagonist treatment and start vitamin K supplementation instead

Use alternative long-term anticoagulation therapy such as intravenous heparin or lowmolecular weight heparin in reduced dosage

Therapy of hyperparathyroidism, but avoid “over-treatment” and development of adynamic bone

disease

Application of cinacalcet

Parathyroidectomy

Optimal CKD-MBD therapy including native vitamin D supplementation (ergocalciferol,

cholecalciferol)

Reduction of calcification pressure (please refer to Table 22.3)

Improve oxygen supply e.g. via hyperbaric O2-therapy

Supportive therapy

Wound management

Treat local and systemic infection, regular wound swabs

Pain management according to WHO standards

Limb amputation in uncontrolled clinical settings

Psychological care for patients and family



387



22 Calciphylaxis and Vitamin D

Table 22.3 Specific interventions in

CUA patients aiming at a new balance

between pro-calcifying and anticalcifying factors:



22.9



Sodium-thiosulfate (STS),

Bisphosphonates, and

Parathyroidectomy/cinacalcet



Myth or Reality: Sodium Thiosulfate for Patients

with Calciphylaxis?



The most intensively discussed therapeutic options for CUA is currently sodiumthiosulfate (STS), which holds some promise due to reports about potential effectiveness and acceptable tolerability in CUA patients. The exact mechanism of action

of STS is unknown – interference with calcium phosphate crystal formation and

anti-inflammatory actions are among the options [26, 27]. Nausea, vomiting, thrombophlebitis, headache, and hypocalcemia may occur with fast STS infusion. A central venous catheter might be necessary. Physicians should take the additional

sodium load induced by STS into account, which might aggravate thirst and weight

gain. The biological impact of STS-induced metabolic acidosis is unclear and

appears to be a limited problem in dialysis patients with regular monitoring of blood

pH [28]. Overall, the evidence to treat CUA patients with STS is low. We cannot

exclude publication bias regarding STS failure.

Two recent uncontrolled retrospective case series (n = 27 [6] and n = 172 [29])

nicely summarize local experiences with STS. In both studies STS was not a singular study drug but part of an interdisciplinary, multimodal approach. STS application scheme was similar in both studies: Infusion of 25 g STS solution during the

last hour of hemodialysis or shortly after each dialysis session. The overall length of

treatment was weeks to several months, which is also our recommended application

regimen. STS may also be given via alternative routes such as orally, intraperitoneally or via topical application directly to the wound surface.

Outcome data with STS regarding the local clinical findings are impressive at

first sight: Zitt et al. reported complete remission in 52 % and partial remission in

19 % of their patients [6]. Nigwekar et al. reported complete remission in 26 %,

marked improvement in 19 %, and some improvement in 28 % [29]. However, looking at survival data CUA conditions were apparently much more severe in the

smaller Austrian cohort: 52 % patients died during a median follow up of 101 days

in [6], whilst 1-year mortality was reported as only 35 % in the US cohort [29].

Moreover Nigwekar et al. cautiously speculated about survival improvement with

STS application. The authors compared their 1-year survival data in STS treated

patients (=35 %) [29] with a historical cohort described by Mazhar et al. characterized by a mortality rate of 55 % without STS [11] However, this comparison is

dubious based on the remarkable imbalance in disease severity: All patients were

stable outpatients in the Nigwekar et al. cohort [29] whereas the Mazhar study

recruited mainly hospitalized patients [11]. Consequently, comparing CUA



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V.M. Brandenburg and P.A. Ureña Torres



outpatients with hospitalized patients represents a clinically meaningful selection

bias. In both studies no systematic outcome assessment regarding wound size was

performed but efficacy solely relied on subjective assessment by the treating physician. So we are still far away from any clear message regarding survival improvement with STS application in CUA patients.

The optimal duration of STS application is unknown. If within the first weeks

some improvement is detectable e.g. as evidenced by wound healing and pain relief

ongoing STS application is indicated. However, preliminary data indicate that in

some patients bone demineralization occurs with (long-term) STS treatment.

Animal data from Pasch et al. obtained in adenine-induced chronic renal failure rats

as well as in rats without renal failure [30] show that STS application lowered the

mechanical load which was necessary to fracture the femur. A human study with

dialysis patients who received STS in a trial investigating STS effects upon coronary artery calcification [31], also investigated bone mineral density development.

Twenty-five percent STS (12.5 g), was given intravenously over 15–20 min after

HD treatment was completed twice a week for a period of at least 4 months. This

regimen led to a significant drop in total hip bone mineral density in the treatment

group compared to controls. Facing the life-threatening prognosis of CUA patients

we consider STS as a part of a multimodal treatment approach, in which, however,

the specific contribution of each particular intervention is difficult to establish.

Costs regarding STS application play an important role in the decision if and how

long CUA patients should receive it. Large discrepancies exist between countries

regarding costs and in contrast to North America the low price of STS in Germany

and Europe helps treating physicians with a liberal application scheme.



22.10



International Registry Initiatives



Several groups world-wide address CUA and the yet unsolved issues around the

disease with systematic registry approaches. Collecting patient related data through

these registries will significantly increase our understanding of the disease. The

European EuCalNet initiative will record detailed data upon therapy prior to disease

outbreak hence providing novel insights into the potential role of (active) vitamin D

treatment as potential CUA challenging factor (Table 22.4).

Table 22.4 Currently recruiting CUA registries

UK Calciphylaxis Study

EuCalNet (including the

German registry)

Kansas University registry

Australian Calciphylaxis

Registry



http://www.gmann.co.uk/website/trials/iccn/home.cfm

http://www.calciphylaxis.net/

https://www2.kumc.edu/calciphylaxisregistry/

http://www.calciphylaxis.org.au/



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