Calcific Uremic Arteriolopathy: A Call for Action Vincent M. Brandenburg, MD,* Mario Cozzolino, MD, PhD,† and Sandro Mazzaferro, MD‡ Summary: Calciphylaxis (calcific uremic arteriolopathy [CUA]) is a threatening disease that increasingly is acknowledged as a challenging condition at the interface of nephrology, dermatology, and cardiology. The primary CUA diagnosis is determined most often in nephrology care units because the vast majority of affected cases are detected in patients with advanced or end-stage renal disease. The typical clinical cascade starts with severe pain in initially often inconspicuous skin areas, which might progress to deep tissue ulcerations. Ulcer development is a severe complication with particularly high morbidity and mortality. Unfortunately, there has been a certain stagnancy regarding the slow progress in our understanding of how and why CUA develops. In addition, several important open issues regarding therapy have not been addressed successfully yet. Therefore, the European Renal Association – European Dialysis and Transplant Association (ERA–EDTA) scientific working group Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) has accepted the challenge and has initiated a call for action by defining calciphylaxis as one of the outstanding research targets for the upcoming years. Semin Nephrol 34:641-647 C 2014 Elsevier Inc. All rights reserved. Keywords: Calciphylaxis, calcific uremic arteriolopathy, chronic kidney disease, calcification, vascular disease
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nly rough estimates can be made regarding the true incidence and prevalence of calcific uremic arteriolopathy (CUA) in nephrology patient cohorts and no reliable statement can be made if these figures are changing over time. Recent data from the United States points toward an increase in incidence.1 Based on our experience, the incidence of CUA in dialysis patients is still less than 1% per year and, accordingly, lower than previously reported.2 Moreover, assessment of calciphylaxis incidence or prevalence always needs to take into account if these figures are truly changing or if awareness of the disease may be increasing and if therefore increasing incidence might be based simply on better diagnosis and reporting. Overall, CUA qualifies as a true rare (orphan) disease (refer to http://www.orpha.net/consor/cgi-bin/ index.php). The status of a rare disease also implies that CUA is more than just an exotic example among the long continuum of cardiovascular calcification problems in uremic patients. Such cardiovascular
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Department of Cardiology and Center for Rare Diseases (Zentrum für seltene Erkrankungen Aachen, ZSEA), RWTH University Hospital, Aachen, Germany. † Department of Health Sciences, Renal Division, San Paolo Hospital, University of Milan, Milan, Italy. ‡ Department of Cardiovascular, Respiratory, Nephrologic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy. Financial support: the German calciphylaxis registry is supported by grants from Amgen and Sanofi. Conflict of interest statement: none. Address reprint requests to Vincent M. Brandenburg, MD, Department of Cardiology and Center for Rare Diseases, University Hospital RWTH Aachen, Pauwelsstraße 30, D-52057 Aachen, Germany. E-mail: [email protected] 0270-9295/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2014.09.007
Seminars in Nephrology, Vol 34, No 6, November 2014, pp 641–647
calcifications might present as arterial calcification (both arteriosclerotic and atherosclerotic) or calcific valvular disease, and affect the majority of long-term dialysis patients. Based on the early work of Selye and Berczi3 in the 1960s, the term calciphylaxis first appeared in human medicine. The basal concept about calciphylaxis development by Selye and Berczi is not without obvious discrepancies to what we consider important in CUA pathophysiology nowadays, but nevertheless is very useful to concisely summarize our growing understanding about CUA. Presumably, CUA development requires chronically disturbed background conditions (ie, the breeding ground in the sense of Selye and Berczi's sensitization factors). These sensitization factors must be present for a certain latency or critical period and require a second-hit or final trigger—a challenging factor—to provoke the outbreak of the full-blown disease. Although chronic kidney disease (CKD) is present in most cases of calciphylaxis and therefore CKD is a predominant sensitization factor, the identification of the challenging factors is still incomplete and challenging. Despite the growing interest in CUA, many improvements in the community’s awareness and much better general knowledge in the field in the past 10 years in clinical research has failed to provide an adequate response to the threat associated with CUA. Severely impaired prognosis in terms of survival,4 plus a dramatically reduced quality of life,5 together with a high expenditure for the health system (eg, owing to long-term hospitalizations) clearly deserve our attentiveness as caregivers and scientists in charge. Moreover, we speculate that disclosing some of the secrets of CUA might finally help us in our understanding (and with prevention and treatment) of more common vascular calcification conditions such as diabetic, uremic, or senescent calcifying arterioslerosis.6 641
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We speculate that the rapidly evolving medial and softtissue calcifications as seen in the skin of calciphylaxis patients can serve as a high-speed template for arteriosclerotic vascular disease such as Mönckeberg's sclerosis or calcific aortic stenosis.
CALCIPHYLAXIS RESEARCH AND PATIENT CARE: WHERE DO WE STAND AND WHERE DO WE WANT TO GO? A recent PubMed search (www.pubmed.org) for the term “calciphylaxis” in March 2014 showed approximately 1,000 citations. By using the prespecified filter functions of PubMed we detected a relatively stable and constant yearly rate of publications ranging from 42 to 76 between 2007 and 2013. The number of case reports, case series, and review articles among the publications was remarkably high. This contrasts in a noteworthy way with the low number of articles presenting original work about CUA. This imbalance is prototypic for medical conditions, with a long way to go to close the gap between speculation and evidence. Even more striking is that PUBMED currently lists only 4 articles as clinical trials in the field of calciphylaxis. However, even 4 clinical trials is flattering considering that there are no randomized, controlled, prospective, intervention studies. Performing a randomized, prospective trial in calciphylaxis faces significant difficulties such as the overall low incidence. In addition, the severity of the disease per se together with the high comorbidity burden is challenging for a study set-up. Collecting and analyzing prospective observational noninterventional data on therapeutic approaches together with detailed outcome recordings might help overcome this unacceptable situation. Such an approach can be realized via registry initiatives. European registry activities are ongoing in the United Kingdom and Germany. Access, patient registration, as well as data recording, transfer, and storage are performed via the internet at www.calci phylaxis.net (German registry) or at www.calciphy laxis.org.uk (UK registry). Data monitoring, plausibility checks, and data cleaning are organized centrally in these registries. Registries show genuine weaknesses and limits compared with data generated in randomized trials, but they can provide valuable support for the search of risk factors, the clinical picture, and the course of CUA. We currently are overseeing approximately 220 patients in the German calciphylaxis registry who have been notified over the past 6 years. In terms of therapy, clustering and analyzing data from these 220 patients allows us to summarize a good overview on what currently is regarded as the standard of care in (German) CUA patients. The details are described in later sections. Therefore, as long as
V.M. Brandenburg, M. Cozzolino, and S. Mazzaferro
interventional, prospectively recorded data are missing, the contribution coming from prospective CUA registry data cannot be overestimated. These registries can provide valuable input to our understanding of calciphylaxis. In consequence, the European Renal Association – European Dialysis and Transplant Association (ERA–EDTA) scientific working group Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) actively is initiating an international calciphylaxis registry in 7 European countries (Belgium, Spain, Portugal, Italy, The Netherlands, Germany, and France): the European Calciphylaxis Network (EuCalNet project) (for details, please see www.calciphylaxis.net). The EuCalNet consortium is planning to initiate an internet-based multilingual registry in which treating physicians can provide patient data on demographics and comorbidities; the clinical picture, including photographic documentation and pain scale reporting; comorbidities; laboratory data of patients at the time of CUA diagnosis; and medical treatments including dialysis, surgeries, and wound management. Another CUA aspect still remains unsolved: is it really one single disease? We currently assume that it is. However, experts agree that differentiating CUA in terms of lesions size, character, and localization is quite important for outcome. Lesion size may vary from single nodular nonulcerative lesions (Fig. 1) to an
Figure 1. Localized CUA lesion at the lower leg.
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Table 1. Expected Support for Physicians and Scientists From the International EuCalNet Registry Project
Figure 2. Typical CUA affection of the abdominal wall.
effect on large skin areas (Fig. 2), and the patient may end up with deep soft-tissue ulcerations (Fig. 3). Such large, deep, soft-tissue ulcerations predispose the patient to local and systemic infections, which contribute to the high mortality rate in calciphylaxis patients. Therefore, a large-scale, international calciphylaxis registry project, such as the EuCalNet project, can help us to address important open issues (Table 1).
RISK FACTORS FOR CALCIPHYLAXIS The identification of risk factors for CUA development is critical. Case-control series may help to establish risk factors and avoid to some extent the confusion between pure associations and true causality.6 Although from time to time singular case reports have emerged regarding CUA patients without relevant underlying kidney disease,7 these were exceptional cases and does not modify the fact that by far most CUA cases have been reported in patients with
Figure 3. Deep soft tissue ulceration at the lateral abdominal wall.
More rapid identification of patients with calciphylaxis than on a national basis alone Help establish diagnostic algorithms Increases awareness of the disease More detailed identification of risk factors Identification of biomarkers for estimation of prognosis Identification of preventive tools Investigations regarding subgroups of patients (central versus peripheral calciphylaxis) Estimation of overall prognosis and prognosis in subgroups of patients Genotype/phenotype correlations Establishing a biobank for serum, plasma, and tissue (skin) samples, as well as autopsy findings Description of international state-of-the art treatment Regular exchange between experts and treating physicians about treatment strategies (networking)
Table 2. Case-Control Studies Identified the Following Parameters and Clinical Conditions as Risk Factors for Calciphylaxis Obesity, liver disease, and systemic corticosteroid use4 Low albumin levels and previous warfarin application8 High serum phosphate, high calcium-phosphate product, previous calcium, and vitamin D therapy9 Female sex, low albumin levels, high alkaline phosphatase level, and high serum phosphorus levels10 Low albumin level, previous calcitriol therapy, not using statins, high serum calcium levels, and previous warfarin use11
end-stage renal disease (dialysis patients). It is still a mystery which uremic factors exactly predispose dialysis patients to developing calciphylaxis and why the occurrence of CUA is a dichotomic event (meaning yes or no). CUA is not a gradual phenomenon, therefore CUA development is in sharp contrast to, for example, arterial calcification, which develops slowly in a creeping fashion. Presumably, a combination of uremic factors is a prerequisite for calciphylaxis development (with an imbalance between procalcifying and anticalcifying factors). Aside from almost omnipresent uremia, several case-control studies elaborated the following list of potential additional risk factors for CUA (Table 2). We currently are unable to establish causality clearly between the factors listed in Table 2 and CUA development. Low albumin levels, for example, presumably are not causative per se. Instead, 2 alternative theories link low albumin levels with calciphylaxis. First, a low albumin level reflects low protein levels in
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general and in particular low fetuin-A levels, the latter being an important systemic calcification inhibitor.12 Fetuin-A deficiency is associated with a general predisposition for extraosseous, ectopic calcification processes and therefore also might contribute to calciphylaxis development. Second, causality between low albumin (protein) levels and CUA actually might be reversed because large wound areas might induce low protein levels via transdermal loss of proteins, or chronic inflammation and infection may disturb liver protein synthesis.
ONLY A SMALL STEP FROM RISK FACTOR TO INTERVENTION: DISTURBED VITAMIN K METABOLISM Two of these case-control studies (Table 2) reported previous vitamin K antagonist (VKA) use as a potential risk factor for CUA development.8,11 These findings are in line with data from the German calciphylaxis registry. Within our patient cohort, the prevalence of previous vitamin K antagonist use was approximately 50%. This potentially causative association is challenging for several reasons. First, CUA development might have iatrogenic aspects or, in other words, might be a severe adverse event resulting from VKA treatment. Second, these VKA-associated cases point to an important aspect in the pathophysiology of vascular calcification in general. Moreover, they particularly support Selye and Berczi's challenging factor hypothesis: VKA application may be the straw that breaks the camel's back. Third, CUA cases with VKA application might show unique therapeutic options (ie, stopping VKA and adding vitamin K replenishment). VKA interferes with the posttranslational activation of matrix-Gla protein (MGP). MGP is of outstanding importance in inhibiting vascular calcification. An absence of MGP causes premature death in rodents owing to fracture-like lesions in the aorta.13 Moreover, VKA interferes with β-catenin signaling via transglutaminas A, which also may contribute to vascular calcification.14 There is substantiated evidence that points to an accelerated effect of vitamin K antagonist application upon vascular calcification processes in human beings.15–17 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, ClinicalTrials.gov identifier: NCT01742273). It is unknown whether stopping therapy with vitamin K antagonists, application of an alternative anticoagulant, and/or vitamin K substitution is really a successful therapeutic intervention in CUA patients. However, such an approach is applied widely by treating physicians based on interim analyses from the German
V.M. Brandenburg, M. Cozzolino, and S. Mazzaferro
registry. This VKA-avoidance approach also has been reported from other countries.18 We acknowledge that stopping VKA is not without contradiction and may create complex situations in those patients in whom anticoagulation alternatives are absent and the need for oral anticoagulation therapy is obvious (eg, patients with prosthetic heart valves).19 The most common indication for VKA treatment in end-stage renal disease patients is for stroke prevention in patients with atrial fibrillation. The evidence for the efficacy of VKA treatment for stroke prevention in end-stage renal disease patients, however, is 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 end-stage renal disease.19
CUA TREATMENT: WHAT ELSE CAN WE DO? Does the 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 3). Whatever obscure nephrologic expectations regarding optimal dialysis patient care maybe, these interventions Table 3. Summary of treatment options in calciphylaxis Intensification of dialysis therapy Increasing dialysis length, frequency (weekly dialysis dose) 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, magnesiumbased, or iron-based binders) Reduction of active vitamin D dose Stop vitamin K antagonist treatment and start vitamin K supplementation instead Use alternative long-term anticoagulation therapy such as intravenous heparin or low-molecular-weight heparin in a reduced dose Therapy of hyperparathyroidism without induction of adynamic bone disease Application of cinacalcet Parathyroidectomy Optimal CKD-MBD therapy including native vitamin D supplementation (ergocalciferol, cholecalciferol) Reduction of calcification pressure (Table 4) Improve oxygen supply (eg via hyperbaric O2 therapy) Supportive therapy Wound management Treat local and systemic infection, regular wound swabs Pain management according to World Health Organization standards Limb amputation in uncontrolled clinical settings Psychological care for patients and family
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Table 4. Specific Interventions in CUA Patients Aimed at a New Balance Between Procalcifying and Anticalcifying Factors Sodium-thiosulfate (STS) Bisphosphonates Parathyroidectomy/cinacalcet
can be summarized briefly as more intense but longer lasting, aiming at better CKD-MBD control. Reducing the calcium supply is another mainstay of therapy. In addition, important aspects of therapy are as follows: personalized pain relief according to World Health Organization standards, individualized wound management, and infection control. Table 3 provides an overview of current general treatment strategies in CUA based on documentation in the German calciphylaxis registry. Three more specific additional therapeutic interventions are shown in Table 4.
SODIUM THIOSULFATE FOR PATIENTS WITH CALCIPHYLAXIS The most intensively discussed therapeutic option for CUA is sodium-thiosulfate (STS), which holds some promise according to reports regarding its 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.20,21 Nausea, vomiting, thrombophlebitis at the site of infusion, headache, and hypocalcemia may occur with fast STS infusion. These side effects all can be avoided and managed, respectively, with slow infusion time and careful infusion practice. A central venous catheter might be necessary. Physicians should take the additional sodium load induced by STS into account, which might be associated with 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 level.22 What is the evidence for STS in patients with calciphylaxis? The evidence is low. A publication bias (success is reported more willingly than failure) prohibits a neutral analysis regarding efficacy. Two recent uncontrolled retrospective case series (n ¼ 2718 and n ¼ 17223) tried to overcome our lack of evidence regarding STS application. In both studies, STS was not a singular study drug but part of an interdisciplinary, multimodal approach. The 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 length of treatment was weeks to several
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months. This was also our recommended application regimen. STS also may be given via alternative routes such as intraperitoneally or via topical application directly to the wound surface. Outcome data regarding the local clinical findings are impressive at first sight. Zitt et al18 reported complete remission in 52% and partial remission in 19% of their patients. Nigwekar et al23 reported complete remission in 26%, marked improvement in 19%, and some improvement in 28% in their patients. However, looking at survival data, CUA conditions were apparently much more severe in the smaller Austrian cohort: 52% of patients died during a median follow-up period of 101 days by Zitt et al,18 whereas the 1-year mortality rate was reported as only 35% in the US cohort.23 Moreover, Nigwekar et al23 cautiously speculated about survival improvement with STS application. The investigators compared their 1-year survival data in STS-treated patients (35%) with a historical cohort described by Mazhar et al10 characterized by a mortality rate of 55% without STS. However, this comparison is dubious based on the imbalance in disease severity: all patients were stable outpatients in the former cohort23 whereas the Mazhar et al10 study recruited mainly hospitalized patients. Comparing CUA outpatients with hospitalized patients represents a clinically meaningful selection bias. In both studies no systematic outcome assessment regarding wound size was performed, instead efficacy solely relied on the subjective assessment of the treating physician. We are still far 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 (eg, 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 al24 obtained in adenine-induced chronic renal failure rats as well as in rats without renal failure showed that STS application decreased the mechanical load, which was necessary to fracture the femur. A human study with dialysis patients who received STS in a trial investigating the effects of STS on coronary artery calcification,25 also investigated bone mineral density development. STS (12.5g, 25% solution) was given intravenously over 15 to 20 minutes after hemodialysis treatment was completed twice a week for a period of at least 4 months. This regimen led to a significant decrease in total hip bone mineral density in the treatment group compared with controls. Faced with the life-threatening prognosis of CUA, we consider STS part of a multimodal treatment approach, in which, however, the specific contribution of each
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particular intervention is difficult to establish. Costs regarding STS application play an important role in the decision of whether and for how long CUA patients should receive it. Large discrepancies exist between countries regarding cost, and the low price of STS in Germany helps treating physicians prescribe a liberal dosing scheme.
BISPHOSPHONATES, CINACALCET, AND PARATHYROIDECTOMY Less homogenous and also smaller than the plethora of positive STS case reports is the publication history regarding bisphosphonate application and parathyroidectomy. Based on the German CUA registry data, uncontrolled hyperparathyroidism with parathyroid hormone (PTH) levels exceeding the current Kidney Disease Improving Global Outcomes (KDIGO) range for PTH was present only in a minority of CUA patients. Both bisphosphonates and parathyroidectomy have been shown in case studies to be effective in calciphylaxis.26,27 For both interventions controlled data were missing and both interventions faced potential negative effects on bone metabolism by induction or aggravation of adynamic bone disease. To date, preselected CUA cases with underlying severe, uncontrolled hyperparathyroidism and normal to high bone turnover, have parathyroidectomy and bisphosphonate application as an option. Case reports and series have described the use of cinacalcet as an alternative to parathyroidectomy, however, with unproven benefits.18 The EVOLVE study28 stimulated discussion about the potential positive effects of cinacalcet on CUA development, with significantly fewer reported cases compared with the control arm. In EVOLVE, there were 3,883 hemodialysis patients with moderate-to-severe hyperparathyroidism assigned randomly to cinacalcet or placebo. The mean baseline PTH level was approximately 700 pg/mL and the median duration of study drug exposure was 21 months. Calciphylaxis was reported as an adverse events. There were 6 (0.3%) reported cases of CUA in cinacalcet-treated patients and 18 (0.9%) reported cases of CUA in placebo-treated patients, corresponding to exposure-adjusted rates of 0.1 and 0.5 per 100 patient-years (P ¼ .009). However, the overall very low number of cases and ambiguous diagnostic criteria prevent definite conclusions.
CALL FOR ACTION: WHAT A RANDOMIZED CUA INTERVENTION STUDY SHOULD LOOK LIKE We are actively participating in ongoing discussions about how a potential interventional study of CUA should be structured. Several significant obstacles block the straightforward way to conduct a large
V.M. Brandenburg, M. Cozzolino, and S. Mazzaferro
interventional trial. CUA patients most often are elderly, frail, dialysis patients and disease signs and symptoms impede traveling to central study sites and study visits. Regarding the study design, 3 questions are among the most intensively discussed controversial subjects. Do We Need a Control Arm or What Is Standard Therapy? Puristic advocates of evidence-based medicine argue against an active control arm in such a trial because evidence for any substance to modify outcome in CUA is absent. That means any test substance first should undergo comparison only against placebo while background therapy could be defined ad libitum. The argument against this approach is that some established interventions (presumably) influence the course of the disease. Therefore, those who support this point of view favor testing a novel substance only against standard therapy (eg, including STS). But what exactly is standard therapy? Do We Design an All-Comer Study or Define Prespecified Inclusion Criteria? If we look at limited numbers of patients and limited trial centers for recruitment, an all-comer study substantially would accelerate patient inclusion and study progress. However, this approach faces significant drawbacks in terms of inhomogeneous baseline characteristics. Is it reasonable to include both outpatients as well as inpatients, VKA-related cases and non–VKA-related cases, peripheral versus central forms, and ulcerative versus nonulcerative forms of CUA (Figs. 1–3)? Probably not. It currently is unproven that CUA is one single disease state. If a test drug shows efficacy in a prespecified subgroup of CUA patients, would that allow its use in all cases? What End Points Do We Define? Assuming a mortality reduction trial is out of reach (eg, for financial reasons), what is the next best surrogate end point in a CUA trial? Among those most seriously discussed are pain relief or more generally quality of life, wound size and composition, and need for hospitalization. However, the nephrology community very well knows that positively influencing surrogates does not necessarily translate into relevant end points. That lesson has been taught by several previously en vogue drugs that later became obsolete. Moreover, can we reliably and reproducibly measure surrogates such as wound composition and size in clinical practice?
Calciphylaxis
SUMMARY CUA is a challenge. The ERA-EDTA scientific working group CKD-MBD is honored by ERA-EDTA's invitation to establish a European networking basis to increase our understanding of CUA. The initiation of the multinational registry (EuCalNet) is an important first step. The final target, however, should be an interventional trial that provides results strong and that is reliable enough to create evidence. Such a trial is being discussed extensively among experts.
REFERENCES 1. Nigwekar SU, Solid CA, Ankers E, Malhotra R, Eggert W, Turchin A, et al. Quantifying a rare disease in administrative data: the example of calciphylaxis. J Gen Intern Med. 2014;29 (Suppl 3):724-31. 2. Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery. 1997;122:1083-9. 3. Selye H, Berczi I. The present status of calciphylaxis and calcergy. Clin Orthop Relat Res. 1970;69:28-54. 4. Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56:569-79. 5. Brandenburg VM, Cozzolino M, Ketteler M. Calciphylaxis: a still unmet challenge. J Nephrol. 2011;24:142-8. 6. Brandenburg VM, Sinha S, Specht P, Ketteler M. Calcific uraemic arteriolopathy: a rare disease with a potentially high impact on chronic kidney disease-mineral and bone disorder. Pediatr Nephrol. 2014. Epub ahead of print. 7. Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3:1139-43. 8. Hayashi M, Takamatsu I, Kanno Y, Yoshida T, Abe T, Sato Y. A case-control study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant. 2011;27:1580-4. 9. Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61:2210-7. 10. Mazhar AR, Johnson RJ, Gillen D, Stivelman JC, Ryan MJ, Davis CL, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int. 2001;60: 324-32. 11. Nigwekar SU, Bhan I, Turchin A, Skentzos SC, Hajhosseiny R, Steele D, et al. Statin use and calcific uremic arteriolopathy: a matched case-control study. Am J Nephrol. 2013;37:325-32. 12. Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, et al. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest. 2003;112:357-66.
647 13. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78-81. 14. Beazley KE, Deasey S, Lima F, Nurminskaya MV. Transglutaminase 2-mediated activation of beta-catenin signaling has a critical role in warfarin-induced vascular calcification. Arterioscler Thromb Vasc Biol. 2012;32:123-30. 15. Krueger T, Westenfeld R, Schurgers L, Brandenburg V. Coagulation meets calcification: the vitamin K system. Int J Artif Organs. 2009;32:67-74. 16. Cozzolino M, Brandenburg V. Warfarin: to use or not to use in chronic kidney disease patients? J Nephrol. 2010;23:648-52. 17. Kruger T, Floege J. Vitamin k antagonists: beyond bleeding. Semin Dial. 2014;27:37-41. 18. Zitt E, Konig M, Vychytil A, Auinger M, Wallner M, Lingenhel G, et al. Use of sodium thiosulphate in a multiinterventional setting for the treatment of calciphylaxis in dialysis patients. Nephrol Dial Transplant. 2013;28:1232-40. 19. Kruger T, Brandenburg V, Schlieper G, Marx N, Floege J. Sailing between Scylla and Charybdis: oral long-term anticoagulation in dialysis patients. Nephrol Dial Transplant. 2013;28:534-41. 20. O'Neill WC, Hardcastle KI. The chemistry of thiosulfate and vascular calcification. Nephrol Dial Transplant. 2011;27:521-6. 21. O'Neill WC. Sodium thiosulfate: mythical treatment for a mysterious disease? Clin J Am Soc Nephrol. 2013;8:1068-9. 22. Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. J Am Acad Dermatol. 2011;67:253-60. 23. Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8:1162-70. 24. Pasch A, Schaffner T, Huynh-Do U, Frey BM, Frey FJ, Farese S. Sodium thiosulfate prevents vascular calcifications in uremic rats. Kidney Int. 2008;74:1444-53. 25. Adirekkiat S, Sumethkul V, Ingsathit A, Domrongkitchaiporn S, Phakdeekitcharoen B, Kantachuvesiri S, et al. Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients. Nephrol Dial Transplant. 2010;25:1923-9. 26. Torregrosa JV, Duran CE, Barros X, Blasco M, Arias M, Cases A, et al. Successful treatment of calcific uraemic arteriolopathy with bisphosphonates. Nefrologia. 2012;32:329-34. 27. Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130:645-50. 28. Chertow GM, Block GA, Correa-Rotter R, Drueke TB, Floege J, Goodman WG, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367:2482-94.
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nly rough estimates can be made regarding the true incidence and prevalence of calcific uremic arteriolopathy (CUA) in nephrology patient cohorts and no reliable statement can be made if these figures are changing over time. Recent data from the United States points toward an increase in incidence.1 Based on our experience, the incidence of CUA in dialysis patients is still less than 1% per year and, accordingly, lower than previously reported.2 Moreover, assessment of calciphylaxis incidence or prevalence always needs to take into account if these figures are truly changing or if awareness of the disease may be increasing and if therefore increasing incidence might be based simply on better diagnosis and reporting. Overall, CUA qualifies as a true rare (orphan) disease (refer to http://www.orpha.net/consor/cgi-bin/ index.php). The status of a rare disease also implies that CUA is more than just an exotic example among the long continuum of cardiovascular calcification problems in uremic patients. Such cardiovascular
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Department of Cardiology and Center for Rare Diseases (Zentrum für seltene Erkrankungen Aachen, ZSEA), RWTH University Hospital, Aachen, Germany. † Department of Health Sciences, Renal Division, San Paolo Hospital, University of Milan, Milan, Italy. ‡ Department of Cardiovascular, Respiratory, Nephrologic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy. Financial support: the German calciphylaxis registry is supported by grants from Amgen and Sanofi. Conflict of interest statement: none. Address reprint requests to Vincent M. Brandenburg, MD, Department of Cardiology and Center for Rare Diseases, University Hospital RWTH Aachen, Pauwelsstraße 30, D-52057 Aachen, Germany. E-mail: [email protected] 0270-9295/ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semnephrol.2014.09.007
Seminars in Nephrology, Vol 34, No 6, November 2014, pp 641–647
calcifications might present as arterial calcification (both arteriosclerotic and atherosclerotic) or calcific valvular disease, and affect the majority of long-term dialysis patients. Based on the early work of Selye and Berczi3 in the 1960s, the term calciphylaxis first appeared in human medicine. The basal concept about calciphylaxis development by Selye and Berczi is not without obvious discrepancies to what we consider important in CUA pathophysiology nowadays, but nevertheless is very useful to concisely summarize our growing understanding about CUA. Presumably, CUA development requires chronically disturbed background conditions (ie, the breeding ground in the sense of Selye and Berczi's sensitization factors). These sensitization factors must be present for a certain latency or critical period and require a second-hit or final trigger—a challenging factor—to provoke the outbreak of the full-blown disease. Although chronic kidney disease (CKD) is present in most cases of calciphylaxis and therefore CKD is a predominant sensitization factor, the identification of the challenging factors is still incomplete and challenging. Despite the growing interest in CUA, many improvements in the community’s awareness and much better general knowledge in the field in the past 10 years in clinical research has failed to provide an adequate response to the threat associated with CUA. Severely impaired prognosis in terms of survival,4 plus a dramatically reduced quality of life,5 together with a high expenditure for the health system (eg, owing to long-term hospitalizations) clearly deserve our attentiveness as caregivers and scientists in charge. Moreover, we speculate that disclosing some of the secrets of CUA might finally help us in our understanding (and with prevention and treatment) of more common vascular calcification conditions such as diabetic, uremic, or senescent calcifying arterioslerosis.6 641
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We speculate that the rapidly evolving medial and softtissue calcifications as seen in the skin of calciphylaxis patients can serve as a high-speed template for arteriosclerotic vascular disease such as Mönckeberg's sclerosis or calcific aortic stenosis.
CALCIPHYLAXIS RESEARCH AND PATIENT CARE: WHERE DO WE STAND AND WHERE DO WE WANT TO GO? A recent PubMed search (www.pubmed.org) for the term “calciphylaxis” in March 2014 showed approximately 1,000 citations. By using the prespecified filter functions of PubMed we detected a relatively stable and constant yearly rate of publications ranging from 42 to 76 between 2007 and 2013. The number of case reports, case series, and review articles among the publications was remarkably high. This contrasts in a noteworthy way with the low number of articles presenting original work about CUA. This imbalance is prototypic for medical conditions, with a long way to go to close the gap between speculation and evidence. Even more striking is that PUBMED currently lists only 4 articles as clinical trials in the field of calciphylaxis. However, even 4 clinical trials is flattering considering that there are no randomized, controlled, prospective, intervention studies. Performing a randomized, prospective trial in calciphylaxis faces significant difficulties such as the overall low incidence. In addition, the severity of the disease per se together with the high comorbidity burden is challenging for a study set-up. Collecting and analyzing prospective observational noninterventional data on therapeutic approaches together with detailed outcome recordings might help overcome this unacceptable situation. Such an approach can be realized via registry initiatives. European registry activities are ongoing in the United Kingdom and Germany. Access, patient registration, as well as data recording, transfer, and storage are performed via the internet at www.calci phylaxis.net (German registry) or at www.calciphy laxis.org.uk (UK registry). Data monitoring, plausibility checks, and data cleaning are organized centrally in these registries. Registries show genuine weaknesses and limits compared with data generated in randomized trials, but they can provide valuable support for the search of risk factors, the clinical picture, and the course of CUA. We currently are overseeing approximately 220 patients in the German calciphylaxis registry who have been notified over the past 6 years. In terms of therapy, clustering and analyzing data from these 220 patients allows us to summarize a good overview on what currently is regarded as the standard of care in (German) CUA patients. The details are described in later sections. Therefore, as long as
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interventional, prospectively recorded data are missing, the contribution coming from prospective CUA registry data cannot be overestimated. These registries can provide valuable input to our understanding of calciphylaxis. In consequence, the European Renal Association – European Dialysis and Transplant Association (ERA–EDTA) scientific working group Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) actively is initiating an international calciphylaxis registry in 7 European countries (Belgium, Spain, Portugal, Italy, The Netherlands, Germany, and France): the European Calciphylaxis Network (EuCalNet project) (for details, please see www.calciphylaxis.net). The EuCalNet consortium is planning to initiate an internet-based multilingual registry in which treating physicians can provide patient data on demographics and comorbidities; the clinical picture, including photographic documentation and pain scale reporting; comorbidities; laboratory data of patients at the time of CUA diagnosis; and medical treatments including dialysis, surgeries, and wound management. Another CUA aspect still remains unsolved: is it really one single disease? We currently assume that it is. However, experts agree that differentiating CUA in terms of lesions size, character, and localization is quite important for outcome. Lesion size may vary from single nodular nonulcerative lesions (Fig. 1) to an
Figure 1. Localized CUA lesion at the lower leg.
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Table 1. Expected Support for Physicians and Scientists From the International EuCalNet Registry Project
Figure 2. Typical CUA affection of the abdominal wall.
effect on large skin areas (Fig. 2), and the patient may end up with deep soft-tissue ulcerations (Fig. 3). Such large, deep, soft-tissue ulcerations predispose the patient to local and systemic infections, which contribute to the high mortality rate in calciphylaxis patients. Therefore, a large-scale, international calciphylaxis registry project, such as the EuCalNet project, can help us to address important open issues (Table 1).
RISK FACTORS FOR CALCIPHYLAXIS The identification of risk factors for CUA development is critical. Case-control series may help to establish risk factors and avoid to some extent the confusion between pure associations and true causality.6 Although from time to time singular case reports have emerged regarding CUA patients without relevant underlying kidney disease,7 these were exceptional cases and does not modify the fact that by far most CUA cases have been reported in patients with
Figure 3. Deep soft tissue ulceration at the lateral abdominal wall.
More rapid identification of patients with calciphylaxis than on a national basis alone Help establish diagnostic algorithms Increases awareness of the disease More detailed identification of risk factors Identification of biomarkers for estimation of prognosis Identification of preventive tools Investigations regarding subgroups of patients (central versus peripheral calciphylaxis) Estimation of overall prognosis and prognosis in subgroups of patients Genotype/phenotype correlations Establishing a biobank for serum, plasma, and tissue (skin) samples, as well as autopsy findings Description of international state-of-the art treatment Regular exchange between experts and treating physicians about treatment strategies (networking)
Table 2. Case-Control Studies Identified the Following Parameters and Clinical Conditions as Risk Factors for Calciphylaxis Obesity, liver disease, and systemic corticosteroid use4 Low albumin levels and previous warfarin application8 High serum phosphate, high calcium-phosphate product, previous calcium, and vitamin D therapy9 Female sex, low albumin levels, high alkaline phosphatase level, and high serum phosphorus levels10 Low albumin level, previous calcitriol therapy, not using statins, high serum calcium levels, and previous warfarin use11
end-stage renal disease (dialysis patients). It is still a mystery which uremic factors exactly predispose dialysis patients to developing calciphylaxis and why the occurrence of CUA is a dichotomic event (meaning yes or no). CUA is not a gradual phenomenon, therefore CUA development is in sharp contrast to, for example, arterial calcification, which develops slowly in a creeping fashion. Presumably, a combination of uremic factors is a prerequisite for calciphylaxis development (with an imbalance between procalcifying and anticalcifying factors). Aside from almost omnipresent uremia, several case-control studies elaborated the following list of potential additional risk factors for CUA (Table 2). We currently are unable to establish causality clearly between the factors listed in Table 2 and CUA development. Low albumin levels, for example, presumably are not causative per se. Instead, 2 alternative theories link low albumin levels with calciphylaxis. First, a low albumin level reflects low protein levels in
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general and in particular low fetuin-A levels, the latter being an important systemic calcification inhibitor.12 Fetuin-A deficiency is associated with a general predisposition for extraosseous, ectopic calcification processes and therefore also might contribute to calciphylaxis development. Second, causality between low albumin (protein) levels and CUA actually might be reversed because large wound areas might induce low protein levels via transdermal loss of proteins, or chronic inflammation and infection may disturb liver protein synthesis.
ONLY A SMALL STEP FROM RISK FACTOR TO INTERVENTION: DISTURBED VITAMIN K METABOLISM Two of these case-control studies (Table 2) reported previous vitamin K antagonist (VKA) use as a potential risk factor for CUA development.8,11 These findings are in line with data from the German calciphylaxis registry. Within our patient cohort, the prevalence of previous vitamin K antagonist use was approximately 50%. This potentially causative association is challenging for several reasons. First, CUA development might have iatrogenic aspects or, in other words, might be a severe adverse event resulting from VKA treatment. Second, these VKA-associated cases point to an important aspect in the pathophysiology of vascular calcification in general. Moreover, they particularly support Selye and Berczi's challenging factor hypothesis: VKA application may be the straw that breaks the camel's back. Third, CUA cases with VKA application might show unique therapeutic options (ie, stopping VKA and adding vitamin K replenishment). VKA interferes with the posttranslational activation of matrix-Gla protein (MGP). MGP is of outstanding importance in inhibiting vascular calcification. An absence of MGP causes premature death in rodents owing to fracture-like lesions in the aorta.13 Moreover, VKA interferes with β-catenin signaling via transglutaminas A, which also may contribute to vascular calcification.14 There is substantiated evidence that points to an accelerated effect of vitamin K antagonist application upon vascular calcification processes in human beings.15–17 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, ClinicalTrials.gov identifier: NCT01742273). It is unknown whether stopping therapy with vitamin K antagonists, application of an alternative anticoagulant, and/or vitamin K substitution is really a successful therapeutic intervention in CUA patients. However, such an approach is applied widely by treating physicians based on interim analyses from the German
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registry. This VKA-avoidance approach also has been reported from other countries.18 We acknowledge that stopping VKA is not without contradiction and may create complex situations in those patients in whom anticoagulation alternatives are absent and the need for oral anticoagulation therapy is obvious (eg, patients with prosthetic heart valves).19 The most common indication for VKA treatment in end-stage renal disease patients is for stroke prevention in patients with atrial fibrillation. The evidence for the efficacy of VKA treatment for stroke prevention in end-stage renal disease patients, however, is 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 end-stage renal disease.19
CUA TREATMENT: WHAT ELSE CAN WE DO? Does the 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 3). Whatever obscure nephrologic expectations regarding optimal dialysis patient care maybe, these interventions Table 3. Summary of treatment options in calciphylaxis Intensification of dialysis therapy Increasing dialysis length, frequency (weekly dialysis dose) 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, magnesiumbased, or iron-based binders) Reduction of active vitamin D dose Stop vitamin K antagonist treatment and start vitamin K supplementation instead Use alternative long-term anticoagulation therapy such as intravenous heparin or low-molecular-weight heparin in a reduced dose Therapy of hyperparathyroidism without induction of adynamic bone disease Application of cinacalcet Parathyroidectomy Optimal CKD-MBD therapy including native vitamin D supplementation (ergocalciferol, cholecalciferol) Reduction of calcification pressure (Table 4) Improve oxygen supply (eg via hyperbaric O2 therapy) Supportive therapy Wound management Treat local and systemic infection, regular wound swabs Pain management according to World Health Organization standards Limb amputation in uncontrolled clinical settings Psychological care for patients and family
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Table 4. Specific Interventions in CUA Patients Aimed at a New Balance Between Procalcifying and Anticalcifying Factors Sodium-thiosulfate (STS) Bisphosphonates Parathyroidectomy/cinacalcet
can be summarized briefly as more intense but longer lasting, aiming at better CKD-MBD control. Reducing the calcium supply is another mainstay of therapy. In addition, important aspects of therapy are as follows: personalized pain relief according to World Health Organization standards, individualized wound management, and infection control. Table 3 provides an overview of current general treatment strategies in CUA based on documentation in the German calciphylaxis registry. Three more specific additional therapeutic interventions are shown in Table 4.
SODIUM THIOSULFATE FOR PATIENTS WITH CALCIPHYLAXIS The most intensively discussed therapeutic option for CUA is sodium-thiosulfate (STS), which holds some promise according to reports regarding its 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.20,21 Nausea, vomiting, thrombophlebitis at the site of infusion, headache, and hypocalcemia may occur with fast STS infusion. These side effects all can be avoided and managed, respectively, with slow infusion time and careful infusion practice. A central venous catheter might be necessary. Physicians should take the additional sodium load induced by STS into account, which might be associated with 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 level.22 What is the evidence for STS in patients with calciphylaxis? The evidence is low. A publication bias (success is reported more willingly than failure) prohibits a neutral analysis regarding efficacy. Two recent uncontrolled retrospective case series (n ¼ 2718 and n ¼ 17223) tried to overcome our lack of evidence regarding STS application. In both studies, STS was not a singular study drug but part of an interdisciplinary, multimodal approach. The 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 length of treatment was weeks to several
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months. This was also our recommended application regimen. STS also may be given via alternative routes such as intraperitoneally or via topical application directly to the wound surface. Outcome data regarding the local clinical findings are impressive at first sight. Zitt et al18 reported complete remission in 52% and partial remission in 19% of their patients. Nigwekar et al23 reported complete remission in 26%, marked improvement in 19%, and some improvement in 28% in their patients. However, looking at survival data, CUA conditions were apparently much more severe in the smaller Austrian cohort: 52% of patients died during a median follow-up period of 101 days by Zitt et al,18 whereas the 1-year mortality rate was reported as only 35% in the US cohort.23 Moreover, Nigwekar et al23 cautiously speculated about survival improvement with STS application. The investigators compared their 1-year survival data in STS-treated patients (35%) with a historical cohort described by Mazhar et al10 characterized by a mortality rate of 55% without STS. However, this comparison is dubious based on the imbalance in disease severity: all patients were stable outpatients in the former cohort23 whereas the Mazhar et al10 study recruited mainly hospitalized patients. Comparing CUA outpatients with hospitalized patients represents a clinically meaningful selection bias. In both studies no systematic outcome assessment regarding wound size was performed, instead efficacy solely relied on the subjective assessment of the treating physician. We are still far 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 (eg, 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 al24 obtained in adenine-induced chronic renal failure rats as well as in rats without renal failure showed that STS application decreased the mechanical load, which was necessary to fracture the femur. A human study with dialysis patients who received STS in a trial investigating the effects of STS on coronary artery calcification,25 also investigated bone mineral density development. STS (12.5g, 25% solution) was given intravenously over 15 to 20 minutes after hemodialysis treatment was completed twice a week for a period of at least 4 months. This regimen led to a significant decrease in total hip bone mineral density in the treatment group compared with controls. Faced with the life-threatening prognosis of CUA, we consider STS part of a multimodal treatment approach, in which, however, the specific contribution of each
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particular intervention is difficult to establish. Costs regarding STS application play an important role in the decision of whether and for how long CUA patients should receive it. Large discrepancies exist between countries regarding cost, and the low price of STS in Germany helps treating physicians prescribe a liberal dosing scheme.
BISPHOSPHONATES, CINACALCET, AND PARATHYROIDECTOMY Less homogenous and also smaller than the plethora of positive STS case reports is the publication history regarding bisphosphonate application and parathyroidectomy. Based on the German CUA registry data, uncontrolled hyperparathyroidism with parathyroid hormone (PTH) levels exceeding the current Kidney Disease Improving Global Outcomes (KDIGO) range for PTH was present only in a minority of CUA patients. Both bisphosphonates and parathyroidectomy have been shown in case studies to be effective in calciphylaxis.26,27 For both interventions controlled data were missing and both interventions faced potential negative effects on bone metabolism by induction or aggravation of adynamic bone disease. To date, preselected CUA cases with underlying severe, uncontrolled hyperparathyroidism and normal to high bone turnover, have parathyroidectomy and bisphosphonate application as an option. Case reports and series have described the use of cinacalcet as an alternative to parathyroidectomy, however, with unproven benefits.18 The EVOLVE study28 stimulated discussion about the potential positive effects of cinacalcet on CUA development, with significantly fewer reported cases compared with the control arm. In EVOLVE, there were 3,883 hemodialysis patients with moderate-to-severe hyperparathyroidism assigned randomly to cinacalcet or placebo. The mean baseline PTH level was approximately 700 pg/mL and the median duration of study drug exposure was 21 months. Calciphylaxis was reported as an adverse events. There were 6 (0.3%) reported cases of CUA in cinacalcet-treated patients and 18 (0.9%) reported cases of CUA in placebo-treated patients, corresponding to exposure-adjusted rates of 0.1 and 0.5 per 100 patient-years (P ¼ .009). However, the overall very low number of cases and ambiguous diagnostic criteria prevent definite conclusions.
CALL FOR ACTION: WHAT A RANDOMIZED CUA INTERVENTION STUDY SHOULD LOOK LIKE We are actively participating in ongoing discussions about how a potential interventional study of CUA should be structured. Several significant obstacles block the straightforward way to conduct a large
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interventional trial. CUA patients most often are elderly, frail, dialysis patients and disease signs and symptoms impede traveling to central study sites and study visits. Regarding the study design, 3 questions are among the most intensively discussed controversial subjects. Do We Need a Control Arm or What Is Standard Therapy? Puristic advocates of evidence-based medicine argue against an active control arm in such a trial because evidence for any substance to modify outcome in CUA is absent. That means any test substance first should undergo comparison only against placebo while background therapy could be defined ad libitum. The argument against this approach is that some established interventions (presumably) influence the course of the disease. Therefore, those who support this point of view favor testing a novel substance only against standard therapy (eg, including STS). But what exactly is standard therapy? Do We Design an All-Comer Study or Define Prespecified Inclusion Criteria? If we look at limited numbers of patients and limited trial centers for recruitment, an all-comer study substantially would accelerate patient inclusion and study progress. However, this approach faces significant drawbacks in terms of inhomogeneous baseline characteristics. Is it reasonable to include both outpatients as well as inpatients, VKA-related cases and non–VKA-related cases, peripheral versus central forms, and ulcerative versus nonulcerative forms of CUA (Figs. 1–3)? Probably not. It currently is unproven that CUA is one single disease state. If a test drug shows efficacy in a prespecified subgroup of CUA patients, would that allow its use in all cases? What End Points Do We Define? Assuming a mortality reduction trial is out of reach (eg, for financial reasons), what is the next best surrogate end point in a CUA trial? Among those most seriously discussed are pain relief or more generally quality of life, wound size and composition, and need for hospitalization. However, the nephrology community very well knows that positively influencing surrogates does not necessarily translate into relevant end points. That lesson has been taught by several previously en vogue drugs that later became obsolete. Moreover, can we reliably and reproducibly measure surrogates such as wound composition and size in clinical practice?
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SUMMARY CUA is a challenge. The ERA-EDTA scientific working group CKD-MBD is honored by ERA-EDTA's invitation to establish a European networking basis to increase our understanding of CUA. The initiation of the multinational registry (EuCalNet) is an important first step. The final target, however, should be an interventional trial that provides results strong and that is reliable enough to create evidence. Such a trial is being discussed extensively among experts.
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647 13. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78-81. 14. Beazley KE, Deasey S, Lima F, Nurminskaya MV. Transglutaminase 2-mediated activation of beta-catenin signaling has a critical role in warfarin-induced vascular calcification. Arterioscler Thromb Vasc Biol. 2012;32:123-30. 15. Krueger T, Westenfeld R, Schurgers L, Brandenburg V. Coagulation meets calcification: the vitamin K system. Int J Artif Organs. 2009;32:67-74. 16. Cozzolino M, Brandenburg V. Warfarin: to use or not to use in chronic kidney disease patients? J Nephrol. 2010;23:648-52. 17. Kruger T, Floege J. Vitamin k antagonists: beyond bleeding. Semin Dial. 2014;27:37-41. 18. Zitt E, Konig M, Vychytil A, Auinger M, Wallner M, Lingenhel G, et al. Use of sodium thiosulphate in a multiinterventional setting for the treatment of calciphylaxis in dialysis patients. Nephrol Dial Transplant. 2013;28:1232-40. 19. Kruger T, Brandenburg V, Schlieper G, Marx N, Floege J. Sailing between Scylla and Charybdis: oral long-term anticoagulation in dialysis patients. Nephrol Dial Transplant. 2013;28:534-41. 20. O'Neill WC, Hardcastle KI. The chemistry of thiosulfate and vascular calcification. Nephrol Dial Transplant. 2011;27:521-6. 21. O'Neill WC. Sodium thiosulfate: mythical treatment for a mysterious disease? Clin J Am Soc Nephrol. 2013;8:1068-9. 22. Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. J Am Acad Dermatol. 2011;67:253-60. 23. Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8:1162-70. 24. Pasch A, Schaffner T, Huynh-Do U, Frey BM, Frey FJ, Farese S. Sodium thiosulfate prevents vascular calcifications in uremic rats. Kidney Int. 2008;74:1444-53. 25. Adirekkiat S, Sumethkul V, Ingsathit A, Domrongkitchaiporn S, Phakdeekitcharoen B, Kantachuvesiri S, et al. Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients. Nephrol Dial Transplant. 2010;25:1923-9. 26. Torregrosa JV, Duran CE, Barros X, Blasco M, Arias M, Cases A, et al. Successful treatment of calcific uraemic arteriolopathy with bisphosphonates. Nefrologia. 2012;32:329-34. 27. Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130:645-50. 28. Chertow GM, Block GA, Correa-Rotter R, Drueke TB, Floege J, Goodman WG, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367:2482-94.
