Multi-intervention management of calcific uremic arteriolopathy in 24 patients

Multi-intervention management of calcific uremic arteriolopathy in 24 patients Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Clinical Kidney Journal, 2018, vol. 11, no. 5, 704–709 doi: 10.1093/ckj/sfy007 Advance Access Publication Date: 9 March 2018 Original Article ORIGI N AL A R TICLE Multi-intervention management of calcific uremic arteriolopathy in 24 patients 1 1 2 1 Claire Harris , Mercedeh Kiaii , Wynnie Lau and Myriam Farah Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, BC, Canada and St Paul’s Hospital, Vancouver, BC, Canada Correspondence and offprint requests to: Myriam Farah; E-mail: mfarah@providencehealth.bc.ca ABSTRACT Background. Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition predominately occurring in patients with end-stage renal disease on dialysis. In the absence of randomized clinical trials to guide management, clinicians must rely on observational data. We have previously reported the outcomes of our multi- intervention management in seven patients and now present a larger series of patients with extended follow-up. Methods. We performed a retrospective analysis of all patients diagnosed with CUA at a single academic center between 2008 and 2017. We identified 24 patients including 13 hemodialysis, 8 peritoneal dialysis and 3 predialysis Stage 5 chronic kidney disease patients. Results. Mean age at diagnosis was 60.5 years (range 35–83) and mean follow-up 30.5 months (range<1–99). Patients were predominately female (71%) and Caucasian (83%) with diabetes mellitus diagnosed in 16 of 24 patients. Fifteen of 24 patients had ulcerating lesions suggestive of advanced disease and 20 of 24 had extensive involvement (bilateral disease or lesion size>5 cm). Treatment consisted of intensive hemodialysis (>20 h per week), sodium thiosulfate, wound care, analgesics and discontinuation of trigger medications including warfarin. Hyperbaric oxygen, cinacalcet, bisphosphonates and vitamin K were used in some cases. Overall 1 year mortality was 41% (9/22) and overall mortality at the end of follow- up was 64% (14/24). Cause of death was felt to be attributable to CUA in only four cases (16.7%). Complete or partial resolution of lesions occurred in 17 of 24 patients. One patient had recurrence of CUA 20 months after initial diagnosis. Conclusions. Although mortality remains high in this group, direct CUA-attributable mortality is lower than historic reports. We conclude that a multi-intervention approach can be successful in treating a group of patients with severe CUA lesions. Keywords: calcific uremic arteriolopathy, calciphylaxis, ESRD, sodium thiosulfate, vitamin K INTRODUCTION clinical findings include the presence of livedo reticularis and pain- Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is ful subcutaneous nodules or plaques. Without adequate treatment a rare but life-threatening condition that is characterized by progres- these lesions progress to necrosis and ulceration, with the ischemic sive cutaneous necrosis associated with small- and medium-sized skin becoming secondarily infected in many cases [1]. CUA- attribut- vessel calcification, predominately occurring in patients with end- able mortality rates in the literature range from 45 to 80% at 1 year, stage renal disease (ESRD) on renal replacement therapy [1]. Early with cause of death most frequently due to sepsis [2, 3]. Received: 8.11.2017. Editorial decision: 12.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 704 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Calcific uremic arteriolopathy | 705 The true incidence of CUA is unclear and has been difficult to between 2008 and 2017. We identified a total of 24 cases diag- ascertain using administrative data due to the lack of a unique nosed with CUA including extended follow-up on the seven International Classification of Diseases 9th or 10th Revision patients previously reported by our center [11]. Hospital charts, code. The prevalence of this rare condition was previously electronic records and medication records from the 24 patients reported as 4.1% in a study of 242 hemodialysis (HD) patients [4]. were reviewed for extraction of relevant data including pathol- Data from a large nationwide registry in Germany estimated an ogy reports, laboratory and outcome data. annual incidence rate of 0.04% in German dialysis patients [5]. Statistical analyses for categorical variables were analyzed The pathogenesis of CUA has been elucidated by the current by the Chi-squared and Fisher’s exact tests. Ethics approval for model of vascular calcification; however, it is thought that vas- this study was obtained from the institutional Clinical Research cular calcification alone does not lead to CUA without the addi- Ethics Board. tion of other mediating factors such as local hypercoagulability and inflammatory cytokine excess [6, 7]. Nevertheless, the vas- RESULTS cular calcification model explains that lesions begin with the transformation of vascular smooth muscle cells into osteoblast- Patient demographics are listed in Table 1. The mean age of like cells, which in a uremic milieu, increases reactive oxygen patients at diagnosis was 60.5 years and patients were predomi- species, and decreases inhibitors of vascular calcification nately female (70.8%) and Caucasian (83.3%). Contrary to our including Matrix Gla protein (MGP) and fetuin-A leading to previous report, the most common dialysis modality at diagno- calcification [6, 7]. A recent publication by Nigwekar et al. exam- sis was HD with 13 patients on HD (12 conventional HD, 1 home ined the role of MGP in the context of vitamin K deficiency [8]. HD, 4 h, 3 times per week), 8 patients on PD and 3 patients who Vitamin K is a cofactor for MGP carboxylation and the authors had predialysis Stage 5 CKD. One patient had no prior history of found that a reduction in the ratio of carboxylated MGP to CKD but had initiated dialysis 3 months prior to diagnosis for uncarboxylated MGP was associated with an increased risk of acute kidney injury (AKI) presumed secondary to acute tubular CUA in both warfarin users and non-users compared with con- necrosis (ATN). All patients had multiple comorbidities with trols. Vitamin K deficiency is not restricted to warfarin use but diabetes mellitus diagnosed in 16/24 of patients (66.7%). is associated with malabsorption syndromes such as Crohn’s Concurrent with the literature, obesity was a pervasive risk fac- disease or prior gastric bypass, both emerging risk factors for tor in our population with 87.5% of our patients meeting body CUA. mass index (BMI) criteria for overweight (5/24) or obese (16/24) Risk factors for CUA have been established from case report with a mean BMI of 33.4 kg/m by the Du Bois equation. Fifty per and observational data and include chronic kidney disease cent of patients (12/24) were on vitamin K antagonist therapy (CKD)-related bone mineral disease, age over the fifth decade, prior to diagnosis with high use of other trigger medications female sex, Caucasian race, diabetes, obesity, autoimmune or including activated vitamin D (11/24), calcium (22/24) and iron hypercoagulable disorders, long dialysis vintage, hypoalbumi- (15/24). Mean calcium, phosphate and intact PTH (iPTH) values nemia and medications including calcium-based phosphate at diagnosis were 2.26 mmol/L, 1.83 mmol/L and 56.88 pmol/L, binders, activated vitamin D, iron, vitamin K antagonists (war- respectively. Mean serum albumin at diagnosis was 32.7 g/L. farin), corticosteroids and subcutaneous injections for insulin or Time averaged values of calcium, phosphate and iPTH were heparin [5, 9]. The interaction between calcium, phosphate and obtained from patients in the 6 months prior to diagnosis and parathyroid hormone (PTH) levels and CUA is complex, with both yielded similar values with a mean calcium, phosphate and high and low levels of calcium and PTH associated with CUA in iPTH of 2.17 mmol/L, 1.90 mmol/L and 59.47 pmol/L, respec- observational studies [5, 9]. In one recent study, warfarin users tively. The mean dialysis vintage was 27 months with range of had a CUA incidence rate of 6.24 per 1000 patient years compared <1–169 months. The main cause of ESRD was diabetes but inter- with 3.41 per 1000 patient years in non-users [9]. Peritoneal dialy- estingly, 3/24 patients had oxalate nephropathy, higher than sis (PD) was identified as a risk factor for CUA in one prior study would be expected in the general ESRD population and an evolv- but this result may be confounded by higher calcium-based ing risk factor for CUA. binder use in PD patients at the time of the initial study [3, 10]. The clinical diagnosis of CUA was confirmed by skin biopsy There are no consensus guidelines on the treatment of CUA. in 19 of 23 cases. In one case, skin biopsy was not performed as Evidence for treatment comes from case reports and case series, the diagnosis was felt to be clinically consistent with CUA along with no randomized controlled trials published in the literature. with concern about wound healing. In the four cases whose Treatment is generally multi-interventional and multidiscipli- pathology was not typical for CUA, the experienced dermatolo- nary. Reported treatments include wound care and pain man- gists and nephrologists involved felt the diagnosis remained agement, sodium thiosulfate (STS), management of CKD-bone CUA with no alternate diagnosis. Interestingly, two of four of mineral disease (non-calcium phosphate binders, cinacalcet these cases involved lesions on the abdomen. The majority of and bisphosphonates), optimization of dialysis, hyperbaric oxy- cases had involvement of the legs (23 of 24). Fifteen of 24 gen therapy (HBOT) and discontinuation of offending medica- patients had ulcerating lesions suggestive of advanced disease tions. A clinical trial of vitamin K administration for patients and 20 of 24 had extensive involvement defined as bilateral dis- with CUA is currently underway by Nigwekar et al. and expected ease or lesion size>5 cm. to be completed by December 2017 (ClinicalTrials.gov identifier: Details of treatment regimens are summarized in Table 2. NCT02278692). The use of vitamin K has already been reported All patients received intensified HD (at minimum 20 h per as part of multi-interventional treatment in 18% of a German week), which involved a permanent modality change to HD for registry of CUA patients [5]. the eight patients on PD at diagnosis. The details of the HD pre- scriptions are provided in the Supplementary data (Item S1) with our current protocol consisting of daily dialysis for 2 weeks MATERIALS AND METHODS followed by five times per week (4 h) for 6 weeks with tapering We performed a retrospective analysis of all patients diagnosed down of frequency depending on clinical response thereafter. with CUA at a single tertiary care hospital in Vancouver, Canada Mean duration of intensified HD was 40.3 weeks (range 1–240) Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 706 | C. Harris et al. Table 1. Patient demographics and laboratory values 2þ 2 Patient Age (years)/ Dialysis modality/ iPTH PO /Ca BMI (kg/m ) No. sex ESRD cause vintage (months) (pmol/L) (mmol/L) (Du Bois) Trigger agents 1 62/M DM PD/10 6.9 1.49/2.44 28.6 VKA, alfacalcidol, calcium, iron 2 63/F GN HD/53 145 1.38/2.4 37.3 VKA, alfacalcidol, calcium, iron 3 72/F Renovascular disease Predialysis/0 20.2 2.23/2.16 29.1 VKA, calcium, iron 4 48/F DM HD/18 6.4 1.78/2.38 46.8 Calcium, iron 5 39/F GN, previous transplant HD/9 69.4 2.22/2.1 37.0 VKA, alfacalcidol, calcium, iron 6 40/M DM/HTN HD/0 35.8 1.9/2.06 39.2 Alfacalcidol, calcium, iron 7 35/F Secondary FSGS PD/64 10 2.24/2.47 18.8 Calcium 8 75/F DM and IgM nephropathy HD/17 19.4 1.25/2.15 37.7 VKA, calcium, vitamin D 9 75/M DM HD/1 25.6 1.57/2.5 32.2 VKA 10 67/F DM PD/48 96 1.98/2.52 35.7 Alfacalcidol, calcium 11 62/F DM PD/30 84.2 2.1/2.51 37.9 Alfacalcidol, iron 12 64/F Oxalate nephropathy PD/40 16.8 1.16/1.5 20.4 VKA, calcium 13 67/F Reflux nephropathy PD/35 80.9 2.2/2.43 27.4 Calcium, iron 14 83/F Unknown HD/56 18.8 2.05/2.28 17.7 VKA, calcium, iron 15 42/M DM PD/31 35.1 2.01/2.38 29.2 Calcium, iron 16 81/M HTN Predialysis/0 28.2 1.44/2.26 33.6 VKA, alfacalcidol, calcium 17 68/F HTN þ/ oxalate nephropathy HD/0 8.2 0.89/2.28 31.3 VKA, calcitriol, calcium 18 56/F DM PD/41 15.3 1.98/2.21 37.4 Calcium, iron 19 64/F DM HD/15 11.8 1.86/2.47 36.9 Calcium, iron, prednisone 20 62/F DM/HTN HD/7 13.2 1.67/2.19 26.0 Calcium, iron 21 77/F Oxalate nephropathy Predialysis/0 30.9 2.73/1.63 23.0 Alfacalcidol, calcium 22 39/F AKI secondary to ATN HD/3 12.7 2.39/2.34 66.1 VKA, calcium 23 46/M DM HD/169 393.1 1.14/2.4 30.7 VKA, calcitriol, calcium, iron 24 64/M DM/HTN HD/5 181.3 2.34/2.2 40.6 Alfacalcidol, calcium, iron 2þ Ca , calcium; DM, diabetes mellitus; F, female; GN, glomerulonephritis; HTN, hypertension; IgM, mmunoglobulin M; M, male; No., number; PO , phosphate; VKA, vitamin K antagonist. Table 2. Patient treatment regimens and outcomes Intensive Mortality Time to death Patient STS HD HBOT Cinacalcet (*attributable from diagnosis No. (week) (weeks) (No. treatments) (*on pre-dx) Outcome to CUA) Cause of death (months) 1 9 8 N N PR Deceased CVA 2 2 18 14 Y (40) Y CR Deceased Cardiac 37 3 8 9 Y (14) Y* PR Deceased Traumatic SAH 3 4 11 94 N N CR Living 5 67 240 Y (41) Y CR Deceased Cause unknown 59 6 17 160 Y (40) Y CR Living 7 5 5 N N CR Living 8 2 2 N N NR Deceased SBO/aspiration pneumonia <1 9 4 4 N N NR Deceased* Withdrawal of dialysis secondary to CUA 1 10 14 19 N Y CR Living 11 6 7 N Y CR Living 12 10 6 N N CR Deceased Loss of vascular access 47 13 6 17 Y (11) Y NR Deceased* Sepsis secondary to CUA 7 14 9 3 N N CR Deceased Unable to tolerate hemodialysis due to BP 13 15 11 10 Y (20) N CR Deceased Cardiac arrest 38 16 4 1 N N NR Deceased Gastrointestinal bleed 1 17 4 5 N N CR Living 18 13 91 Y (44) N PR ! Living recurrence 19 1 1 N N NR Deceased Biliary sepsis <1 20 7 55 N N CR Living 21 3 5 N N CR Living 22 4 55 N N NR Deceased* Withdrawal of dialysis secondary to CUA <1 23 7 7 N N NR Deceased* Sepsis secondary to CUA 1 24 16 20 N N PR Living BP, blood pressure; CR, complete response; CVA, cerebrovascular accident; dx, diagnosis; No., number; N, No; NR, no response; PR, partial response; SAH, subarachnoid hemorrhage; SBO, small bowel obstruction; Y, yes. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Calcific uremic arteriolopathy | 707 given that we encouraged ongoing intensified dialysis regimens complete resolution of their lesions went on to undergo renal even after resolution of lesions such as long-term nocturnal transplantation. dialysis. All medications associated with an increased risk of There was no statistically significant difference in clinical response of lesions when patients were divided into those with CUA were discontinued including vitamin K antagonists, acti- extensive lesions (defined as bilateral disease or>5 cm in size) vated vitamin D, calcium and iron. Low-molecular weight hepa- versus those with limited disease (P¼ 0.8). There was no signifi- rin was used if anticoagulation was felt to be essential and non- cant difference in outcomes (clinical response or death at 1 year) calcium-based binders were substituted. Seven patients between those patients with ulcerating versus non-ulcerating received cinacalcet for treatment of hyperparathyroidism, one disease (P¼ 0.9). The 1 year mortality in our patients with ulcer- of which was on cinacalcet at the time of CUA diagnosis. ating lesions was 46% (7 of 15). Those patients with non- Patients were treated with cinacalcet if their iPTH was ulcerating lesions all survived to 1 year (zero of six); however, >60 pmol/L as per our treatment protocol (Supplementary data, the difference between two groups did not meet statistically sig- Item S1). Two additional patients met this criterion, but were nificance (P¼ 0.06). There were no differences in outcomes not treated with cinacalcet due to chronic medication nonad- between those who received or did not receive HBOT (P¼ 0.3). herence. Bisphosphonates were used in two patients with hypercalcemia (Intravenous (IV) palmidronate). STS was used in all patients three times per week (mean DISCUSSION duration 11 weeks) and was generally well tolerated. The major- We present the outcomes of 24 patients with CUA treated with ity of patients received 25 g IV thrice weekly after dialysis. Two a multi-interventional approach. Our 1 year mortality rate was of the 24 patients required dose lowering to 12.5 g and 6 patients 40.9% (9 of 22) with only four deaths found directly attributable were treated with 12.5 g thrice weekly throughout the treatment to CUA (16.7%). This result heralds more significance given that course as was the standard dose in the literature at the time of the majority of the patients had ulcerated lesions, which has their treatment. The main dose-limiting side effects were gas- been associated with mortality rates of 80% in one prior case trointestinal, in particular nausea and vomiting. Increase in series of 36 patients compared with 46% in our group with ulcer- dialysate bicarbonate was required in some cases to combat ated lesions [3]. These authors postulated that the high-mortal- metabolic acidosis from STS. Three patients were treated with ity rate in this group was a demonstration of ulceration deferoxamine (DFO), an iron chelator. One of these patients had representing a late clinical finding in the course of CUA. evidence of iron overload with a ferritin of 1868 ng/mL, while In contrast, Russo et al. recently published a case series of the other two were treated with DFO after completing a course five patients with ulcerating CUA lesions and complete of STS due to persistence of CUA lesions. All of these patients response in four of five patients with multimodal treatment had complete resolution of CUA lesions at the end of follow-up. [12]. However, in this series, a histologic diagnosis was made in Seven patients received HBOT and six received vitamin K only two of five cases and all patients had uncontrolled hyper- (10 mg thrice weekly after HD). Patients received antibiotics at parathyroidism treated with cinacalcet, distinct to our case the nephrologist’s discretion and all patients received special- series population. Thus, while we agree that ulcerating lesions ized wound care. Pain control was provided with both opioid represent a late clinical manifestation, we are encouraged that and non-opioid analgesics with consultation of palliative care the survival with multimodal treatment in our cases series and physicians in complex cases. Seventeen of 24 patients were Russo et al.’s has improved from historical reports [3, 12]. inpatients for a portion of their treatment course. Our experience is that intensive dialysis is helpful for wound Mean patient follow-up after diagnosis was 30.5 months healing in patients with CUA and our practice is to reintensify (range<1–99). Fourteen patients died during follow-up, nine dialysis if lesions worsen at any time after initial improvement. within the first year, yielding an overall 1 year mortality The literature on intensive dialysis for the treatment of CUA is of 40.9% (9 of 22). In only 4 of the 24 patients (16.7%), cause of limited but of theoretical benefit. The aim of intensive HD in death was felt to be directly attributable to CUA. In these cases, conjunction with low dialysate calcium is to reduce the calcium with cause of death secondary to sepsis from wounds or with- phosphate product and improve the uremic milieu that contrib- drawal of dialysis due to pain and worsening wounds. Mean utes to vascular calcification. Conversion from PD to HD is con- time to death was 15 months in all patients and 2.3 months in troversial in the literature but is supported by one case series CUA-attributable cases. Other causes of death are listed in that included 54 PD patients, 13 of which were switched to HD, Table 2. with improvement in 11 of 13 of cases [10]. In the absence of All surviving patients had complete or partial resolution of clinical evidence to the contrary and given the high mortality of their wounds at time of follow-up. Complete resolution this condition, our group’s opinion is that intensive HD should of CUA lesions occurred in 13 of 24 patients, with partial resolu- be performed. tion in 4/24. The remaining seven patients died shortly after STS is one of the backbones for CUA therapy and has been diagnosis with no improvement in wounds documented prior used for >10 years for this indication, although its use remains to death even in the cases where death was not felt to be attrib- off-label. There are no prospective trials to report its efficacy utable to CUA. Complete resolution was defined as the absence but many retrospective reviews of its use and case reports of any identifiable lesions on physical examination. If CUA have been published with encouraging results. Nigwekar et al. lesions were significantly improving on physical examination performed a retrospective review published in 2013 of 53 but some lesions were still evident, this was defined as a partial patients with a treatment response of >70% seen (resolution or resolution. One patient required an above-knee amputation for improvement) [13]. However, as data were collected via survey severe infection secondary to CUA lesions in addition to periph- questionnaires sent to treating physicians regarding 172 eral vascular disease and later died due to ongoing infection patients with CUA, there may have been selection bias in this and withdrawal of dialysis. Another patient has had a recur- group. Peng et al. have recently performed a systematic review rence of lesions 20 months after initial diagnosis with partial of the literature and found similar results with clinical response response and is undergoing treatment. Three patients with in 70.1% of patients and death 37.6% of patients treated with Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 708 | C. Harris et al. STS [14]. Of course, it is difficult to draw definitive conclusions keeping with a high use of calcium-containing binders and vita- regarding the effectiveness of STS given that it is almost always min D analogs in our cohort. part of a multimodal therapy. Intralesional use of STS has also Controversy still exists regarding the use of HBOT. Although been reported [15, 16]. there was no association between HBOT therapy and clinical DFO was used by some clinicians in our case series in refrac- response in our group, only a small group of patients received this tory cases. Our group has previously reported on the potential therapy both due to contraindicationsand changesinthe clinical role of iron in the pathogenesis of CUA evidenced by the pres- practice of our hyperbaric oxygen unit. Evidence for HBOT is sup- ence of iron deposition in areas of microvascular calcification ported by several observational studies and case report data, the on skin biopsy [17]. Thus DFO could be considered in cases with largest of which included 46 patients, with improvement in concomitant iron overload or those refractory to usual first-line lesions in 58% of patients [24]. Those patients who are not candi- therapies, but more evidence is required in this area. dates for hyperbaric therapy can be treated with standard oxygen Three of the 24 patients had a history of oxalate therapy but there is no evidence for this apart from the encourag- nephropathy following remote intestinal bypass procedures. ing results from our previous report [11]. Deficiencies in fat soluble vitamins A, D, E and K are known Although wound care is emphasized in the literature as a complications of intestinal bypass surgery due to fat malabsorp- crucial aspect of CUA treatment, controversy still remains tion. Given the emerging role of vitamin K in the pathophysiol- regarding how wounds are best cared for and whether surgical ogy of CUA, this may have been a contributing risk factor debridement should be part of routine CUA care [25]. This con- for CUA in these patients. Deficiencies in vitamin D following troversy stems from the concern that aggressive debridement gastric bypass and associated hypocalcemia may also result in could cause local injury that could worsen CUA lesions. the ingestion of large doses of vitamin D and calcium to main- Negative-pressure therapy (NPT) including vacuum assisted clo- V R tain normal electrolyte balance, potentially contributing to sure (VAC ) has a potential application in CUA as it is non- vascular calcification as well. A case of fatal non-uremic CUA traumatic and allows for less frequent dressing changes [25]. was reported by Allegretti et al. in a patient following gastric Other theoretical benefits of NPT include the acceleration of bypass [18]. granulation, improvement in blood flow, reduction in wound Whether vitamin K supplementation is effective in amelio- edema and potential anti-inflammatory effects [26, 27]. NPT has rating established CUA is still under investigation with a been used in CUA with successful wound healing in case randomized controlled trial by Nigwekar et al. Given the possible reports; however, the decision to use NPT must be made on an benefit of supplementation, we have elected to use vitamin K individual basis by experienced wound clinicians [25, 28]. With supplementation (both oral and IV routes) in six of our recent respect to surgical approaches, surgical debridement improved cases. The risk of vitamin K supplementation is primarily driven the 1 year survival rate in a retrospective analysis of 63 patients by the risk of hypersensitivity reaction with the IV route (ana- with CUA compared with unmatched controls who did not phylactoid type) [19]. There is also concern regarding reversal of receive surgical debridement (61.6% survival versus 27.4%), but anticoagulation and subsequent risk of thrombosis in those this result has not been consistent across the literature and patients on vitamin K antagonist therapy. We did not observe likely relies on the surgeon’s expertise with this complex wound any adverse reactions to vitamin K. Patients on warfarin ther- type [22]. A case series of seven CUA patients treated with deep apy who were felt to have high risk of thrombosis were placed ulcer shaving and split thickness skin graft showed complete on therapeutic doses of low-molecular weight heparin therapy healing in six of seven patients and death in only one patient, with monitoring of anti-Xa levels. unrelated to CUA [29]. As the majority of patients in our case series were normocal- In summary, the treatment of CUA remains challenging with cemic at presentation, bisphosphonate therapy was only used a persistence of high mortality rates. These high mortality rates in two patients. However, bisphosphonates have been promis- should be viewed in the context of the already high mortality ing in the treatment of CUA lesions in both hypercalcemic and rates of patients with ESRD on dialysis with multiple comorbid- normocalcemic patients and can be considered as an adjunct ities. Ongoing clinical trials are needed to validate which compo- therapy, albeit more evidence is required [20, 21]. None of our nents of the multi-intervention treatment strategy are effective patients had surgical parathyroidectomy during the active in improving clinical response. Further information on the patho- treatment period and seven received cinacalcet. Cinacalcet physiology of CUA will be helpful to guide future clinical trials. remains our choice of therapy for secondary hyperparathyroid- ism in CUA patients in the absence of a survival benefit for sur- AUTHORS’ CONTRIBUTIONS gical parathyroidectomy demonstrated in the literature [22]. The literature supports a possible protective role of cinacal- M.F., M.K., W.L. and C.H. were responsible for the research idea cet against the development of CUA. Adverse event reports and study design. W.L. and C.H. performed the literature review from the ‘Evaluation of Cinacalcet Hydrochloride Therapy to and data acquisition. C.H. carried out statistical analysis. Each Lower Cardiovascular Events’ (EVOLVE) trial revealed a lower author contributed important intellectual content during manu- incidence of CUA in the group of patients that received cinacal- script drafting or revision and accepts accountability for the cet compared with placebo [23]. However, the ability to draw overall work. conclusions from this study is limited by the low event rate. Interestingly, the reduced incidence of CUA in the cinacalcet CONFLICT OF INTEREST STATEMENT group appeared to be independent of iPTH level. As both ady- namic bone disease and uncontrolled hyperparathyroidism are None declared. risk factors for CUA, further exploration of an optimal iPTH to mitigate CUA risk is needed. Although our mean iPTH was SUPPLEMENTARY DATA 56.88 pmol/L, our median iPTH was 22.9, indicating possible rel- ative oversuppression of PTH in some patients. This is in Supplementary data are available at ckj online. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Calcific uremic arteriolopathy | 709 16. Isoherranen K, Bouchard L, Kluger N. Benefits of intrale- REFERENCES sional injections of sodium thiosulfate in the treatment of 1. Wolff K, Johnson R. Fitzpatrick’s Color Atlas and Synopsis of calciphylaxis (21 March 2017). Int Wound J 2017; 14: 955–959 Clinical Dermatology, 6th edn. New York, NY: McGraw-Hill 17. Farah M, Crawford RI, Levin A et al. Calciphylaxis in the cur- Professional, 2009 rent era: emerging ‘ironic’ features? Nephrol Dial Transplant 2. Nigwekar SU, Kroshinsky D, Nazarian RM et al. 2011; 26: 191–195 Calciphylaxis: risk factors, diagnosis, and treatment. Am J 18. Allegretti AS, Nazarian RM, Goverman J et al. Calciphylaxis: a Kidney Dis 2015; 66: 133–146 rare but fatal delayed complication of Roux-en-Y gastric 3. Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: bypass surgery. Am J Kidney Dis 2014; 64: 274–277 risk factors, outcome and therapy. Kidney Int 2002; 61: 19. Fiore LD, Scola MA, Cantillon CE et al. Anaphylactoid reac- 2210–2217 tions to vitamin K. J Thromb Thrombolysis 2001; 11: 175–183 4. Angelis M, Wong LL, Myers SA et al. Calciphylaxis in 20. Torregrosa JV, Dura ´ n CE, Barros X et al. Successful treatment patients on hemodialysis: a prevalence study. Surgery 1997; of calcific uraemic arteriolopathy with bisphosphonates. 122: 1083 Nefrologia 2012; 32: 329–334 5. Brandenburg VM, Kramann R, Rothe H. Calcific uraemic arte- 21. Monney P, Nguyen QV, Perroud H et al. Rapid improvement riolopathy (calciphylaxis): data from a large nationwide of calciphylaxis after intravenous pamidronate therapy in a registry. Nephrol Dial Transplant 2017; 32: 126–132 patient with chronic renal failure. Nephrol Dial Transplant 6. Jeong HS, Dominguez AR. Calciphylaxis: controversies in 2004; 19: 2130–2132 pathogenesis, diagnosis and treatment. Am J Med Sci 2016; 22. Weenig RH, Sewell LD, Davis MD et al. Calciphylaxis: natural 351: 217–227 history, risk factor analysis and outcome. J Am Acad Dermatol 7. Sowers KM, Hayden MR. Calcific uremic arteriolopathy: 2007; 56 569–579 pathophysiology, reactive oxygen species and therapeutic 23. Floege J, Kubo Y, Floege A et al. The effect of cinacalcet on approaches. Oxid Med Cell Longev 2010; 3: 109–121 calcific uremic arteriolopathy events in patients receiving 8. Nigwekar SU, Bloch DB, Nazarian RM et al. Vitamin hemodialysis: the EVOLVE trial. Clin J Am Soc Nephrol 2015; K-dependent carboxylation of matrix Gla protein influences 10: 800–807 the risk of calciphylaxis. J Am Soc Nephrol 2017; 28: 1717–1722 24. An J, Devaney B, Ooi KY et al. Hyperbaric oxygen in the treat- 9. Nigwekar SU, Zhao S, WengerJ et al. A nationally representa- ment of calciphylaxis: a case series and literature review. tive study of calcific uremic arteriolopathy risk factors. JAm Nephrology 2015; 20: 444–450 Soc Nephrol 2016; 27: 3421–3429 25. Lorriaux A, Chaby G, Dhaille F et al. Nonuremic calciphylaxis: 10. Fine A, Fontaine B. Calciphylaxis: the beginning of the end? response to treatment with palmidronate and negative pres- Perit Dial Int 2008; 28: 268. sure therapy. Clin Exp Dermatol 2015; 40: 52–55 11. Baldwin C, Farah M, Leung M et al. Multi-intervention man- 26. Hasan MY, Teo R, Nather A. Negative-pressure wound ther- agement of calciphylaxis: a report of 7 cases. Am J Kidney Dis apy for management of diabetic foot wounds: a review of 2011; 58: 988–991 the mechanism of action, clinical applications, and recent 12. Russo D, Capuano A, Cozzolino M et al. Multimodal treat- developments. Diabet Foot Ankle 2015; 6: 27618–27628 ment of calcific uraemic arteriolopathy (calciphylaxis): a 27. Wang T, He R, Zhao J et al. Negative pressure wound therapy case series. Clin Kidney J 2016; 9: 108–112 inhibits inflammation and upregulates activating transcrip- 13. Nigwekar SU, Brunelli SM, Meade D et al. Sodium thiosulfate tion factor-3 and downregulates nuclear factor-jB in dia- therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol 2013; 8: 1162–1170 betic patients with foot ulcerations. Diabetes Metab Res Rev 2017; 33: e2871 14. Peng T, Zhuo L, Wang Y et al. A systematic review of sodium thi- osulfate in treating calciphylaxis in chronic kidney disease 28. Emohare O, Kowal-Vern A, Wiley D et al. Vacuum-assisted closure use in calciphylaxis. J Burn Care Rehabil 2004; 25: patients. Nephrology doi: 10.1111/nep.13081 (Epub ahead of print, 11 June 2017) 161–164 15. Strazzula L, Nigwekar SU, Steele D et al. Intralesional sodium 29. Wollina U, Helm C, Hansel G et al. Deep ulcer shaving com- thiosulfate for the treatment of calciphylaxis. JAMA Dermatol bined with split-skin transplantation in distal calciphylaxis. 2013; 149: 946–949 Int J Low Extrem Wounds 2008; 7: 102–107 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Multi-intervention management of calcific uremic arteriolopathy in 24 patients

Free
6 pages

Loading next page...
 
/lp/ou_press/multi-intervention-management-of-calcific-uremic-arteriolopathy-in-24-5xK5ZNnQTM
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.
ISSN
2048-8505
eISSN
2048-8513
D.O.I.
10.1093/ckj/sfy007
Publisher site
See Article on Publisher Site

Abstract

Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Clinical Kidney Journal, 2018, vol. 11, no. 5, 704–709 doi: 10.1093/ckj/sfy007 Advance Access Publication Date: 9 March 2018 Original Article ORIGI N AL A R TICLE Multi-intervention management of calcific uremic arteriolopathy in 24 patients 1 1 2 1 Claire Harris , Mercedeh Kiaii , Wynnie Lau and Myriam Farah Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, BC, Canada and St Paul’s Hospital, Vancouver, BC, Canada Correspondence and offprint requests to: Myriam Farah; E-mail: mfarah@providencehealth.bc.ca ABSTRACT Background. Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition predominately occurring in patients with end-stage renal disease on dialysis. In the absence of randomized clinical trials to guide management, clinicians must rely on observational data. We have previously reported the outcomes of our multi- intervention management in seven patients and now present a larger series of patients with extended follow-up. Methods. We performed a retrospective analysis of all patients diagnosed with CUA at a single academic center between 2008 and 2017. We identified 24 patients including 13 hemodialysis, 8 peritoneal dialysis and 3 predialysis Stage 5 chronic kidney disease patients. Results. Mean age at diagnosis was 60.5 years (range 35–83) and mean follow-up 30.5 months (range<1–99). Patients were predominately female (71%) and Caucasian (83%) with diabetes mellitus diagnosed in 16 of 24 patients. Fifteen of 24 patients had ulcerating lesions suggestive of advanced disease and 20 of 24 had extensive involvement (bilateral disease or lesion size>5 cm). Treatment consisted of intensive hemodialysis (>20 h per week), sodium thiosulfate, wound care, analgesics and discontinuation of trigger medications including warfarin. Hyperbaric oxygen, cinacalcet, bisphosphonates and vitamin K were used in some cases. Overall 1 year mortality was 41% (9/22) and overall mortality at the end of follow- up was 64% (14/24). Cause of death was felt to be attributable to CUA in only four cases (16.7%). Complete or partial resolution of lesions occurred in 17 of 24 patients. One patient had recurrence of CUA 20 months after initial diagnosis. Conclusions. Although mortality remains high in this group, direct CUA-attributable mortality is lower than historic reports. We conclude that a multi-intervention approach can be successful in treating a group of patients with severe CUA lesions. Keywords: calcific uremic arteriolopathy, calciphylaxis, ESRD, sodium thiosulfate, vitamin K INTRODUCTION clinical findings include the presence of livedo reticularis and pain- Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is ful subcutaneous nodules or plaques. Without adequate treatment a rare but life-threatening condition that is characterized by progres- these lesions progress to necrosis and ulceration, with the ischemic sive cutaneous necrosis associated with small- and medium-sized skin becoming secondarily infected in many cases [1]. CUA- attribut- vessel calcification, predominately occurring in patients with end- able mortality rates in the literature range from 45 to 80% at 1 year, stage renal disease (ESRD) on renal replacement therapy [1]. Early with cause of death most frequently due to sepsis [2, 3]. Received: 8.11.2017. Editorial decision: 12.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 704 Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Calcific uremic arteriolopathy | 705 The true incidence of CUA is unclear and has been difficult to between 2008 and 2017. We identified a total of 24 cases diag- ascertain using administrative data due to the lack of a unique nosed with CUA including extended follow-up on the seven International Classification of Diseases 9th or 10th Revision patients previously reported by our center [11]. Hospital charts, code. The prevalence of this rare condition was previously electronic records and medication records from the 24 patients reported as 4.1% in a study of 242 hemodialysis (HD) patients [4]. were reviewed for extraction of relevant data including pathol- Data from a large nationwide registry in Germany estimated an ogy reports, laboratory and outcome data. annual incidence rate of 0.04% in German dialysis patients [5]. Statistical analyses for categorical variables were analyzed The pathogenesis of CUA has been elucidated by the current by the Chi-squared and Fisher’s exact tests. Ethics approval for model of vascular calcification; however, it is thought that vas- this study was obtained from the institutional Clinical Research cular calcification alone does not lead to CUA without the addi- Ethics Board. tion of other mediating factors such as local hypercoagulability and inflammatory cytokine excess [6, 7]. Nevertheless, the vas- RESULTS cular calcification model explains that lesions begin with the transformation of vascular smooth muscle cells into osteoblast- Patient demographics are listed in Table 1. The mean age of like cells, which in a uremic milieu, increases reactive oxygen patients at diagnosis was 60.5 years and patients were predomi- species, and decreases inhibitors of vascular calcification nately female (70.8%) and Caucasian (83.3%). Contrary to our including Matrix Gla protein (MGP) and fetuin-A leading to previous report, the most common dialysis modality at diagno- calcification [6, 7]. A recent publication by Nigwekar et al. exam- sis was HD with 13 patients on HD (12 conventional HD, 1 home ined the role of MGP in the context of vitamin K deficiency [8]. HD, 4 h, 3 times per week), 8 patients on PD and 3 patients who Vitamin K is a cofactor for MGP carboxylation and the authors had predialysis Stage 5 CKD. One patient had no prior history of found that a reduction in the ratio of carboxylated MGP to CKD but had initiated dialysis 3 months prior to diagnosis for uncarboxylated MGP was associated with an increased risk of acute kidney injury (AKI) presumed secondary to acute tubular CUA in both warfarin users and non-users compared with con- necrosis (ATN). All patients had multiple comorbidities with trols. Vitamin K deficiency is not restricted to warfarin use but diabetes mellitus diagnosed in 16/24 of patients (66.7%). is associated with malabsorption syndromes such as Crohn’s Concurrent with the literature, obesity was a pervasive risk fac- disease or prior gastric bypass, both emerging risk factors for tor in our population with 87.5% of our patients meeting body CUA. mass index (BMI) criteria for overweight (5/24) or obese (16/24) Risk factors for CUA have been established from case report with a mean BMI of 33.4 kg/m by the Du Bois equation. Fifty per and observational data and include chronic kidney disease cent of patients (12/24) were on vitamin K antagonist therapy (CKD)-related bone mineral disease, age over the fifth decade, prior to diagnosis with high use of other trigger medications female sex, Caucasian race, diabetes, obesity, autoimmune or including activated vitamin D (11/24), calcium (22/24) and iron hypercoagulable disorders, long dialysis vintage, hypoalbumi- (15/24). Mean calcium, phosphate and intact PTH (iPTH) values nemia and medications including calcium-based phosphate at diagnosis were 2.26 mmol/L, 1.83 mmol/L and 56.88 pmol/L, binders, activated vitamin D, iron, vitamin K antagonists (war- respectively. Mean serum albumin at diagnosis was 32.7 g/L. farin), corticosteroids and subcutaneous injections for insulin or Time averaged values of calcium, phosphate and iPTH were heparin [5, 9]. The interaction between calcium, phosphate and obtained from patients in the 6 months prior to diagnosis and parathyroid hormone (PTH) levels and CUA is complex, with both yielded similar values with a mean calcium, phosphate and high and low levels of calcium and PTH associated with CUA in iPTH of 2.17 mmol/L, 1.90 mmol/L and 59.47 pmol/L, respec- observational studies [5, 9]. In one recent study, warfarin users tively. The mean dialysis vintage was 27 months with range of had a CUA incidence rate of 6.24 per 1000 patient years compared <1–169 months. The main cause of ESRD was diabetes but inter- with 3.41 per 1000 patient years in non-users [9]. Peritoneal dialy- estingly, 3/24 patients had oxalate nephropathy, higher than sis (PD) was identified as a risk factor for CUA in one prior study would be expected in the general ESRD population and an evolv- but this result may be confounded by higher calcium-based ing risk factor for CUA. binder use in PD patients at the time of the initial study [3, 10]. The clinical diagnosis of CUA was confirmed by skin biopsy There are no consensus guidelines on the treatment of CUA. in 19 of 23 cases. In one case, skin biopsy was not performed as Evidence for treatment comes from case reports and case series, the diagnosis was felt to be clinically consistent with CUA along with no randomized controlled trials published in the literature. with concern about wound healing. In the four cases whose Treatment is generally multi-interventional and multidiscipli- pathology was not typical for CUA, the experienced dermatolo- nary. Reported treatments include wound care and pain man- gists and nephrologists involved felt the diagnosis remained agement, sodium thiosulfate (STS), management of CKD-bone CUA with no alternate diagnosis. Interestingly, two of four of mineral disease (non-calcium phosphate binders, cinacalcet these cases involved lesions on the abdomen. The majority of and bisphosphonates), optimization of dialysis, hyperbaric oxy- cases had involvement of the legs (23 of 24). Fifteen of 24 gen therapy (HBOT) and discontinuation of offending medica- patients had ulcerating lesions suggestive of advanced disease tions. A clinical trial of vitamin K administration for patients and 20 of 24 had extensive involvement defined as bilateral dis- with CUA is currently underway by Nigwekar et al. and expected ease or lesion size>5 cm. to be completed by December 2017 (ClinicalTrials.gov identifier: Details of treatment regimens are summarized in Table 2. NCT02278692). The use of vitamin K has already been reported All patients received intensified HD (at minimum 20 h per as part of multi-interventional treatment in 18% of a German week), which involved a permanent modality change to HD for registry of CUA patients [5]. the eight patients on PD at diagnosis. The details of the HD pre- scriptions are provided in the Supplementary data (Item S1) with our current protocol consisting of daily dialysis for 2 weeks MATERIALS AND METHODS followed by five times per week (4 h) for 6 weeks with tapering We performed a retrospective analysis of all patients diagnosed down of frequency depending on clinical response thereafter. with CUA at a single tertiary care hospital in Vancouver, Canada Mean duration of intensified HD was 40.3 weeks (range 1–240) Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 706 | C. Harris et al. Table 1. Patient demographics and laboratory values 2þ 2 Patient Age (years)/ Dialysis modality/ iPTH PO /Ca BMI (kg/m ) No. sex ESRD cause vintage (months) (pmol/L) (mmol/L) (Du Bois) Trigger agents 1 62/M DM PD/10 6.9 1.49/2.44 28.6 VKA, alfacalcidol, calcium, iron 2 63/F GN HD/53 145 1.38/2.4 37.3 VKA, alfacalcidol, calcium, iron 3 72/F Renovascular disease Predialysis/0 20.2 2.23/2.16 29.1 VKA, calcium, iron 4 48/F DM HD/18 6.4 1.78/2.38 46.8 Calcium, iron 5 39/F GN, previous transplant HD/9 69.4 2.22/2.1 37.0 VKA, alfacalcidol, calcium, iron 6 40/M DM/HTN HD/0 35.8 1.9/2.06 39.2 Alfacalcidol, calcium, iron 7 35/F Secondary FSGS PD/64 10 2.24/2.47 18.8 Calcium 8 75/F DM and IgM nephropathy HD/17 19.4 1.25/2.15 37.7 VKA, calcium, vitamin D 9 75/M DM HD/1 25.6 1.57/2.5 32.2 VKA 10 67/F DM PD/48 96 1.98/2.52 35.7 Alfacalcidol, calcium 11 62/F DM PD/30 84.2 2.1/2.51 37.9 Alfacalcidol, iron 12 64/F Oxalate nephropathy PD/40 16.8 1.16/1.5 20.4 VKA, calcium 13 67/F Reflux nephropathy PD/35 80.9 2.2/2.43 27.4 Calcium, iron 14 83/F Unknown HD/56 18.8 2.05/2.28 17.7 VKA, calcium, iron 15 42/M DM PD/31 35.1 2.01/2.38 29.2 Calcium, iron 16 81/M HTN Predialysis/0 28.2 1.44/2.26 33.6 VKA, alfacalcidol, calcium 17 68/F HTN þ/ oxalate nephropathy HD/0 8.2 0.89/2.28 31.3 VKA, calcitriol, calcium 18 56/F DM PD/41 15.3 1.98/2.21 37.4 Calcium, iron 19 64/F DM HD/15 11.8 1.86/2.47 36.9 Calcium, iron, prednisone 20 62/F DM/HTN HD/7 13.2 1.67/2.19 26.0 Calcium, iron 21 77/F Oxalate nephropathy Predialysis/0 30.9 2.73/1.63 23.0 Alfacalcidol, calcium 22 39/F AKI secondary to ATN HD/3 12.7 2.39/2.34 66.1 VKA, calcium 23 46/M DM HD/169 393.1 1.14/2.4 30.7 VKA, calcitriol, calcium, iron 24 64/M DM/HTN HD/5 181.3 2.34/2.2 40.6 Alfacalcidol, calcium, iron 2þ Ca , calcium; DM, diabetes mellitus; F, female; GN, glomerulonephritis; HTN, hypertension; IgM, mmunoglobulin M; M, male; No., number; PO , phosphate; VKA, vitamin K antagonist. Table 2. Patient treatment regimens and outcomes Intensive Mortality Time to death Patient STS HD HBOT Cinacalcet (*attributable from diagnosis No. (week) (weeks) (No. treatments) (*on pre-dx) Outcome to CUA) Cause of death (months) 1 9 8 N N PR Deceased CVA 2 2 18 14 Y (40) Y CR Deceased Cardiac 37 3 8 9 Y (14) Y* PR Deceased Traumatic SAH 3 4 11 94 N N CR Living 5 67 240 Y (41) Y CR Deceased Cause unknown 59 6 17 160 Y (40) Y CR Living 7 5 5 N N CR Living 8 2 2 N N NR Deceased SBO/aspiration pneumonia <1 9 4 4 N N NR Deceased* Withdrawal of dialysis secondary to CUA 1 10 14 19 N Y CR Living 11 6 7 N Y CR Living 12 10 6 N N CR Deceased Loss of vascular access 47 13 6 17 Y (11) Y NR Deceased* Sepsis secondary to CUA 7 14 9 3 N N CR Deceased Unable to tolerate hemodialysis due to BP 13 15 11 10 Y (20) N CR Deceased Cardiac arrest 38 16 4 1 N N NR Deceased Gastrointestinal bleed 1 17 4 5 N N CR Living 18 13 91 Y (44) N PR ! Living recurrence 19 1 1 N N NR Deceased Biliary sepsis <1 20 7 55 N N CR Living 21 3 5 N N CR Living 22 4 55 N N NR Deceased* Withdrawal of dialysis secondary to CUA <1 23 7 7 N N NR Deceased* Sepsis secondary to CUA 1 24 16 20 N N PR Living BP, blood pressure; CR, complete response; CVA, cerebrovascular accident; dx, diagnosis; No., number; N, No; NR, no response; PR, partial response; SAH, subarachnoid hemorrhage; SBO, small bowel obstruction; Y, yes. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Calcific uremic arteriolopathy | 707 given that we encouraged ongoing intensified dialysis regimens complete resolution of their lesions went on to undergo renal even after resolution of lesions such as long-term nocturnal transplantation. dialysis. All medications associated with an increased risk of There was no statistically significant difference in clinical response of lesions when patients were divided into those with CUA were discontinued including vitamin K antagonists, acti- extensive lesions (defined as bilateral disease or>5 cm in size) vated vitamin D, calcium and iron. Low-molecular weight hepa- versus those with limited disease (P¼ 0.8). There was no signifi- rin was used if anticoagulation was felt to be essential and non- cant difference in outcomes (clinical response or death at 1 year) calcium-based binders were substituted. Seven patients between those patients with ulcerating versus non-ulcerating received cinacalcet for treatment of hyperparathyroidism, one disease (P¼ 0.9). The 1 year mortality in our patients with ulcer- of which was on cinacalcet at the time of CUA diagnosis. ating lesions was 46% (7 of 15). Those patients with non- Patients were treated with cinacalcet if their iPTH was ulcerating lesions all survived to 1 year (zero of six); however, >60 pmol/L as per our treatment protocol (Supplementary data, the difference between two groups did not meet statistically sig- Item S1). Two additional patients met this criterion, but were nificance (P¼ 0.06). There were no differences in outcomes not treated with cinacalcet due to chronic medication nonad- between those who received or did not receive HBOT (P¼ 0.3). herence. Bisphosphonates were used in two patients with hypercalcemia (Intravenous (IV) palmidronate). STS was used in all patients three times per week (mean DISCUSSION duration 11 weeks) and was generally well tolerated. The major- We present the outcomes of 24 patients with CUA treated with ity of patients received 25 g IV thrice weekly after dialysis. Two a multi-interventional approach. Our 1 year mortality rate was of the 24 patients required dose lowering to 12.5 g and 6 patients 40.9% (9 of 22) with only four deaths found directly attributable were treated with 12.5 g thrice weekly throughout the treatment to CUA (16.7%). This result heralds more significance given that course as was the standard dose in the literature at the time of the majority of the patients had ulcerated lesions, which has their treatment. The main dose-limiting side effects were gas- been associated with mortality rates of 80% in one prior case trointestinal, in particular nausea and vomiting. Increase in series of 36 patients compared with 46% in our group with ulcer- dialysate bicarbonate was required in some cases to combat ated lesions [3]. These authors postulated that the high-mortal- metabolic acidosis from STS. Three patients were treated with ity rate in this group was a demonstration of ulceration deferoxamine (DFO), an iron chelator. One of these patients had representing a late clinical finding in the course of CUA. evidence of iron overload with a ferritin of 1868 ng/mL, while In contrast, Russo et al. recently published a case series of the other two were treated with DFO after completing a course five patients with ulcerating CUA lesions and complete of STS due to persistence of CUA lesions. All of these patients response in four of five patients with multimodal treatment had complete resolution of CUA lesions at the end of follow-up. [12]. However, in this series, a histologic diagnosis was made in Seven patients received HBOT and six received vitamin K only two of five cases and all patients had uncontrolled hyper- (10 mg thrice weekly after HD). Patients received antibiotics at parathyroidism treated with cinacalcet, distinct to our case the nephrologist’s discretion and all patients received special- series population. Thus, while we agree that ulcerating lesions ized wound care. Pain control was provided with both opioid represent a late clinical manifestation, we are encouraged that and non-opioid analgesics with consultation of palliative care the survival with multimodal treatment in our cases series and physicians in complex cases. Seventeen of 24 patients were Russo et al.’s has improved from historical reports [3, 12]. inpatients for a portion of their treatment course. Our experience is that intensive dialysis is helpful for wound Mean patient follow-up after diagnosis was 30.5 months healing in patients with CUA and our practice is to reintensify (range<1–99). Fourteen patients died during follow-up, nine dialysis if lesions worsen at any time after initial improvement. within the first year, yielding an overall 1 year mortality The literature on intensive dialysis for the treatment of CUA is of 40.9% (9 of 22). In only 4 of the 24 patients (16.7%), cause of limited but of theoretical benefit. The aim of intensive HD in death was felt to be directly attributable to CUA. In these cases, conjunction with low dialysate calcium is to reduce the calcium with cause of death secondary to sepsis from wounds or with- phosphate product and improve the uremic milieu that contrib- drawal of dialysis due to pain and worsening wounds. Mean utes to vascular calcification. Conversion from PD to HD is con- time to death was 15 months in all patients and 2.3 months in troversial in the literature but is supported by one case series CUA-attributable cases. Other causes of death are listed in that included 54 PD patients, 13 of which were switched to HD, Table 2. with improvement in 11 of 13 of cases [10]. In the absence of All surviving patients had complete or partial resolution of clinical evidence to the contrary and given the high mortality of their wounds at time of follow-up. Complete resolution this condition, our group’s opinion is that intensive HD should of CUA lesions occurred in 13 of 24 patients, with partial resolu- be performed. tion in 4/24. The remaining seven patients died shortly after STS is one of the backbones for CUA therapy and has been diagnosis with no improvement in wounds documented prior used for >10 years for this indication, although its use remains to death even in the cases where death was not felt to be attrib- off-label. There are no prospective trials to report its efficacy utable to CUA. Complete resolution was defined as the absence but many retrospective reviews of its use and case reports of any identifiable lesions on physical examination. If CUA have been published with encouraging results. Nigwekar et al. lesions were significantly improving on physical examination performed a retrospective review published in 2013 of 53 but some lesions were still evident, this was defined as a partial patients with a treatment response of >70% seen (resolution or resolution. One patient required an above-knee amputation for improvement) [13]. However, as data were collected via survey severe infection secondary to CUA lesions in addition to periph- questionnaires sent to treating physicians regarding 172 eral vascular disease and later died due to ongoing infection patients with CUA, there may have been selection bias in this and withdrawal of dialysis. Another patient has had a recur- group. Peng et al. have recently performed a systematic review rence of lesions 20 months after initial diagnosis with partial of the literature and found similar results with clinical response response and is undergoing treatment. Three patients with in 70.1% of patients and death 37.6% of patients treated with Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 708 | C. Harris et al. STS [14]. Of course, it is difficult to draw definitive conclusions keeping with a high use of calcium-containing binders and vita- regarding the effectiveness of STS given that it is almost always min D analogs in our cohort. part of a multimodal therapy. Intralesional use of STS has also Controversy still exists regarding the use of HBOT. Although been reported [15, 16]. there was no association between HBOT therapy and clinical DFO was used by some clinicians in our case series in refrac- response in our group, only a small group of patients received this tory cases. Our group has previously reported on the potential therapy both due to contraindicationsand changesinthe clinical role of iron in the pathogenesis of CUA evidenced by the pres- practice of our hyperbaric oxygen unit. Evidence for HBOT is sup- ence of iron deposition in areas of microvascular calcification ported by several observational studies and case report data, the on skin biopsy [17]. Thus DFO could be considered in cases with largest of which included 46 patients, with improvement in concomitant iron overload or those refractory to usual first-line lesions in 58% of patients [24]. Those patients who are not candi- therapies, but more evidence is required in this area. dates for hyperbaric therapy can be treated with standard oxygen Three of the 24 patients had a history of oxalate therapy but there is no evidence for this apart from the encourag- nephropathy following remote intestinal bypass procedures. ing results from our previous report [11]. Deficiencies in fat soluble vitamins A, D, E and K are known Although wound care is emphasized in the literature as a complications of intestinal bypass surgery due to fat malabsorp- crucial aspect of CUA treatment, controversy still remains tion. Given the emerging role of vitamin K in the pathophysiol- regarding how wounds are best cared for and whether surgical ogy of CUA, this may have been a contributing risk factor debridement should be part of routine CUA care [25]. This con- for CUA in these patients. Deficiencies in vitamin D following troversy stems from the concern that aggressive debridement gastric bypass and associated hypocalcemia may also result in could cause local injury that could worsen CUA lesions. the ingestion of large doses of vitamin D and calcium to main- Negative-pressure therapy (NPT) including vacuum assisted clo- V R tain normal electrolyte balance, potentially contributing to sure (VAC ) has a potential application in CUA as it is non- vascular calcification as well. A case of fatal non-uremic CUA traumatic and allows for less frequent dressing changes [25]. was reported by Allegretti et al. in a patient following gastric Other theoretical benefits of NPT include the acceleration of bypass [18]. granulation, improvement in blood flow, reduction in wound Whether vitamin K supplementation is effective in amelio- edema and potential anti-inflammatory effects [26, 27]. NPT has rating established CUA is still under investigation with a been used in CUA with successful wound healing in case randomized controlled trial by Nigwekar et al. Given the possible reports; however, the decision to use NPT must be made on an benefit of supplementation, we have elected to use vitamin K individual basis by experienced wound clinicians [25, 28]. With supplementation (both oral and IV routes) in six of our recent respect to surgical approaches, surgical debridement improved cases. The risk of vitamin K supplementation is primarily driven the 1 year survival rate in a retrospective analysis of 63 patients by the risk of hypersensitivity reaction with the IV route (ana- with CUA compared with unmatched controls who did not phylactoid type) [19]. There is also concern regarding reversal of receive surgical debridement (61.6% survival versus 27.4%), but anticoagulation and subsequent risk of thrombosis in those this result has not been consistent across the literature and patients on vitamin K antagonist therapy. We did not observe likely relies on the surgeon’s expertise with this complex wound any adverse reactions to vitamin K. Patients on warfarin ther- type [22]. A case series of seven CUA patients treated with deep apy who were felt to have high risk of thrombosis were placed ulcer shaving and split thickness skin graft showed complete on therapeutic doses of low-molecular weight heparin therapy healing in six of seven patients and death in only one patient, with monitoring of anti-Xa levels. unrelated to CUA [29]. As the majority of patients in our case series were normocal- In summary, the treatment of CUA remains challenging with cemic at presentation, bisphosphonate therapy was only used a persistence of high mortality rates. These high mortality rates in two patients. However, bisphosphonates have been promis- should be viewed in the context of the already high mortality ing in the treatment of CUA lesions in both hypercalcemic and rates of patients with ESRD on dialysis with multiple comorbid- normocalcemic patients and can be considered as an adjunct ities. Ongoing clinical trials are needed to validate which compo- therapy, albeit more evidence is required [20, 21]. None of our nents of the multi-intervention treatment strategy are effective patients had surgical parathyroidectomy during the active in improving clinical response. Further information on the patho- treatment period and seven received cinacalcet. Cinacalcet physiology of CUA will be helpful to guide future clinical trials. remains our choice of therapy for secondary hyperparathyroid- ism in CUA patients in the absence of a survival benefit for sur- AUTHORS’ CONTRIBUTIONS gical parathyroidectomy demonstrated in the literature [22]. The literature supports a possible protective role of cinacal- M.F., M.K., W.L. and C.H. were responsible for the research idea cet against the development of CUA. Adverse event reports and study design. W.L. and C.H. performed the literature review from the ‘Evaluation of Cinacalcet Hydrochloride Therapy to and data acquisition. C.H. carried out statistical analysis. Each Lower Cardiovascular Events’ (EVOLVE) trial revealed a lower author contributed important intellectual content during manu- incidence of CUA in the group of patients that received cinacal- script drafting or revision and accepts accountability for the cet compared with placebo [23]. However, the ability to draw overall work. conclusions from this study is limited by the low event rate. Interestingly, the reduced incidence of CUA in the cinacalcet CONFLICT OF INTEREST STATEMENT group appeared to be independent of iPTH level. As both ady- namic bone disease and uncontrolled hyperparathyroidism are None declared. risk factors for CUA, further exploration of an optimal iPTH to mitigate CUA risk is needed. Although our mean iPTH was SUPPLEMENTARY DATA 56.88 pmol/L, our median iPTH was 22.9, indicating possible rel- ative oversuppression of PTH in some patients. This is in Supplementary data are available at ckj online. Downloaded from https://academic.oup.com/ckj/article-abstract/11/5/704/4925437 by Ed 'DeepDyve' Gillespie user on 17 October 2018 Calcific uremic arteriolopathy | 709 16. Isoherranen K, Bouchard L, Kluger N. Benefits of intrale- REFERENCES sional injections of sodium thiosulfate in the treatment of 1. Wolff K, Johnson R. Fitzpatrick’s Color Atlas and Synopsis of calciphylaxis (21 March 2017). Int Wound J 2017; 14: 955–959 Clinical Dermatology, 6th edn. New York, NY: McGraw-Hill 17. Farah M, Crawford RI, Levin A et al. Calciphylaxis in the cur- Professional, 2009 rent era: emerging ‘ironic’ features? Nephrol Dial Transplant 2. Nigwekar SU, Kroshinsky D, Nazarian RM et al. 2011; 26: 191–195 Calciphylaxis: risk factors, diagnosis, and treatment. Am J 18. Allegretti AS, Nazarian RM, Goverman J et al. Calciphylaxis: a Kidney Dis 2015; 66: 133–146 rare but fatal delayed complication of Roux-en-Y gastric 3. Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: bypass surgery. Am J Kidney Dis 2014; 64: 274–277 risk factors, outcome and therapy. Kidney Int 2002; 61: 19. Fiore LD, Scola MA, Cantillon CE et al. Anaphylactoid reac- 2210–2217 tions to vitamin K. J Thromb Thrombolysis 2001; 11: 175–183 4. Angelis M, Wong LL, Myers SA et al. Calciphylaxis in 20. Torregrosa JV, Dura ´ n CE, Barros X et al. Successful treatment patients on hemodialysis: a prevalence study. Surgery 1997; of calcific uraemic arteriolopathy with bisphosphonates. 122: 1083 Nefrologia 2012; 32: 329–334 5. Brandenburg VM, Kramann R, Rothe H. Calcific uraemic arte- 21. Monney P, Nguyen QV, Perroud H et al. Rapid improvement riolopathy (calciphylaxis): data from a large nationwide of calciphylaxis after intravenous pamidronate therapy in a registry. Nephrol Dial Transplant 2017; 32: 126–132 patient with chronic renal failure. Nephrol Dial Transplant 6. Jeong HS, Dominguez AR. Calciphylaxis: controversies in 2004; 19: 2130–2132 pathogenesis, diagnosis and treatment. Am J Med Sci 2016; 22. Weenig RH, Sewell LD, Davis MD et al. Calciphylaxis: natural 351: 217–227 history, risk factor analysis and outcome. J Am Acad Dermatol 7. Sowers KM, Hayden MR. Calcific uremic arteriolopathy: 2007; 56 569–579 pathophysiology, reactive oxygen species and therapeutic 23. Floege J, Kubo Y, Floege A et al. The effect of cinacalcet on approaches. Oxid Med Cell Longev 2010; 3: 109–121 calcific uremic arteriolopathy events in patients receiving 8. Nigwekar SU, Bloch DB, Nazarian RM et al. Vitamin hemodialysis: the EVOLVE trial. Clin J Am Soc Nephrol 2015; K-dependent carboxylation of matrix Gla protein influences 10: 800–807 the risk of calciphylaxis. J Am Soc Nephrol 2017; 28: 1717–1722 24. An J, Devaney B, Ooi KY et al. Hyperbaric oxygen in the treat- 9. Nigwekar SU, Zhao S, WengerJ et al. A nationally representa- ment of calciphylaxis: a case series and literature review. tive study of calcific uremic arteriolopathy risk factors. JAm Nephrology 2015; 20: 444–450 Soc Nephrol 2016; 27: 3421–3429 25. Lorriaux A, Chaby G, Dhaille F et al. Nonuremic calciphylaxis: 10. Fine A, Fontaine B. Calciphylaxis: the beginning of the end? response to treatment with palmidronate and negative pres- Perit Dial Int 2008; 28: 268. sure therapy. Clin Exp Dermatol 2015; 40: 52–55 11. Baldwin C, Farah M, Leung M et al. Multi-intervention man- 26. Hasan MY, Teo R, Nather A. Negative-pressure wound ther- agement of calciphylaxis: a report of 7 cases. Am J Kidney Dis apy for management of diabetic foot wounds: a review of 2011; 58: 988–991 the mechanism of action, clinical applications, and recent 12. Russo D, Capuano A, Cozzolino M et al. Multimodal treat- developments. Diabet Foot Ankle 2015; 6: 27618–27628 ment of calcific uraemic arteriolopathy (calciphylaxis): a 27. Wang T, He R, Zhao J et al. Negative pressure wound therapy case series. Clin Kidney J 2016; 9: 108–112 inhibits inflammation and upregulates activating transcrip- 13. Nigwekar SU, Brunelli SM, Meade D et al. Sodium thiosulfate tion factor-3 and downregulates nuclear factor-jB in dia- therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol 2013; 8: 1162–1170 betic patients with foot ulcerations. Diabetes Metab Res Rev 2017; 33: e2871 14. Peng T, Zhuo L, Wang Y et al. A systematic review of sodium thi- osulfate in treating calciphylaxis in chronic kidney disease 28. Emohare O, Kowal-Vern A, Wiley D et al. Vacuum-assisted closure use in calciphylaxis. J Burn Care Rehabil 2004; 25: patients. Nephrology doi: 10.1111/nep.13081 (Epub ahead of print, 11 June 2017) 161–164 15. Strazzula L, Nigwekar SU, Steele D et al. Intralesional sodium 29. Wollina U, Helm C, Hansel G et al. Deep ulcer shaving com- thiosulfate for the treatment of calciphylaxis. JAMA Dermatol bined with split-skin transplantation in distal calciphylaxis. 2013; 149: 946–949 Int J Low Extrem Wounds 2008; 7: 102–107

Journal

Clinical Kidney JournalOxford University Press

Published: Mar 9, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off