Calcific uremic arteriolopathy (CUA), also know as calciphylaxis, is a rare but highly fatal and morbid enigmatic condition . Septicemia from the infected wounds is reported as the leading cause of death in CUA patients with 1-year mortality ranging between 45 and 80% [2–4]. In a recent report that identified 649 CUA cases among chronic hemodialysis patients in the United States Renal Data System database, 1-year death rate in CUA patients was more than three times higher compared with average death rates in chronic hemodialysis patients without CUA [5▪]. The morbidity in CUA is largely related to intractable pain, complicated skin lesions (Fig. 1), and repeated hospitalizations. CUA is predominantly seen in patients with end stage renal disease (ESRD) making ESRD the most dominant risk factor [6–11]; however, CUA is not exclusive to ESRD patients and has been described in patients with normal kidney function and in those with less advanced chronic kidney disease [12–15].
CUA is not a new disease and reports of CUA in the medical literature have been published since the 1960s [6,7,9,16–18]. However, despite more than 5 decades of recognition of the heavy morbidity and mortality burden associated with CUA, our understanding of its pathogenesis, risk factors, and natural history is extremely limited, and at present there are no effective and well-studied prevention or treatment strategies. CUA's rare incidence, lack of a systematic method to identify and track CUA cases in large databases, and absence of collaborative research efforts have largely attributed to these knowledge gaps. Recent work by our group and others is attempting to address these knowledge gaps by adopting novel methodological approaches [5▪,12]. Our center has recently established a multidisciplinary CUA team (Table 1) that draws upon the expertise from various clinical specialists to deliver multimodal treatments that have been reported to be associated with successful CUA resolutions [1,19].
In this article, recent literature in the field of CUA is appraised and a multidisciplinary approach to CUA management is reviewed.
INCIDENCE AND PREVALENCE
A single center cross-sectional study conducted in 1997 reported that the prevalence of CUA was 4.1% among chronic hemodialysis patients receiving dialysis treatment in Honolulu, Hawaii . Another single center study conducted in Winnipeg, Canada, in 2002 reported an incidence of 4.5/100 patient-years among chronic dialysis patients, whereas a population-based study conducted in Olmsted County, Minnesota, from 1997 to 2005 reported an incidence rate of 4.5 per 1 million people per year . The following reports need to be reviewed to understand the recent trends in the incidence of CUA: a Japanese study reported a prevalence rate of less than three cases per 10 000 chronic hemodialysis patients per year, a prevalence rate much lower than what is reported in the earlier studies from western countries ; a United States Renal Data System study that applied a novel algorithm incorporating administrative billing codes identified the CUA incidence between 3.7 and 5.7 per 10 000 chronic hemodialysis patients per year [5▪]. This study likely underestimated the incidence as it excluded patients who did not undergo skin biopsy procedures; however, importantly this study provided the first national level assessment of frequency trends of CUA and indicated that the CUA frequency is rising. Whether this rise in frequency is simply a reflection of more awareness or whether it is related to any biological changes remains unclear; in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, 0.62% of chronic hemodialysis patients with moderate-to-severe secondary hyperparathyroidism followed over a 4-year study period developed CUA [22▪▪,23]; and a multicenter study conducted at the Partners affiliated hospitals in Boston, Massachusetts, reported an average annual incidence rate of 0.78 per 100 hospitalized chronic hemodialysis patients and suggested that the incidence was on the rise . Collectively, these reports indicate that the annual incidence of CUA is less than 1% in chronic hemodialysis patients and the frequency of CUA may be on the rise. There are no systematic recent analyses that address the incidence of CUA in peritoneal dialysis patients, renal transplant patients, in patients with earlier stages of chronic kidney disease, or in patients with normal kidney function.
Clinical presentation of CUA includes severe painful skin lesions such as reticulate purpura, plaques, or nodules that are frequently complicated by ulcerations and infections [12,25,26]. Although skin manifestations dominate the clinical presentation, CUA is likely a systemic vascular calcification disorder and there are reports of widespread vascular calcifications involving skeletal muscle, intestines, mesentery, eyes, brain, and lungs in CUA patients [27–34]. There is now increasing recognition that vascular calcification in patients with kidney disease is an active process that resembles ossification. Early insights indicate that the vascular calcification in kidney disease is characterized by increased expression of calcification-promoting proteins such as osteocalcin, osteonectin, alkaline phosphatase, and collagen-I and loss of calcification inhibitors such as Matrix Gla Protein, fetuin, pyrophosphate, and osteoprotegerin [35,36]. In systematic analyses of skin specimens obtained from seven CUA patients, significant upregulation of osteogenesis-associated markers and extensive matrix remodeling of the subcutaneous tissue were observed . The cross-sectional nature of this study limits any inference on causality, and considering small sample size, these findings need to be confirmed in future studies.
The histopathology of CUA is characterized by calcification, and microthrombosis of dermal arterioles leading to ischemia [38–40]. Most of the attention in terms of etiopathogenesis of CUA is focused on calcification, considered to be an early and essential process in CUA development by some [41–43]; however, uncertainty exists regarding the origin of thrombosis in this disease – is thrombosis secondary to endothelial damage from calcification vs. is CUA a presentation of an underlying hypercoagulable disorder? Reports in the literature of CUA in patients with protein C and protein S deficiency, antithrombin III deficiency, and antiphospholipid antibody syndrome certainly raise the possibility that CUA is a manifestation of a hypercoagulable disorder [44–47].
Table 2 lists the published risk factors for CUA . It is important to recognize that none of these risk factor associations has been rigorously studied to confirm causality. Studies reporting these associations frequently suffer from limitations attributed to small sample size, cross-sectional approach, and single-center experience .
The largest study to date that examined risk factors for CUA included 62 skin biopsy-confirmed hospitalized CUA patients receiving chronic hemodialysis and 124 chronic hemodialysis hospitalized patients without CUA. Hypercalcemia [odds ratio (OR): 2.25, 95% confidence intervals (CIs): 1.14–4.43], calcitriol use (OR: 5.69, 95% CI: 1.02–31.77), vitamin K antagonist/warfarin use (OR: 4.30, 95% CI: 1.57–11.74), and hypoalbuminemia (OR: 5.73, 95% CI: 2.79–11.77) were associated with increased risk of CUA in multivariable adjusted analyses, whereas statin use was associated with reduced risk of CUA (OR: 0.20, 95% CI 0.05–0.88) . Notable limitations of this study include small sample size, lack of longitudinal data, and residual confounding. In a multicenter case–control study conducted in Japan that included 28 CUA cases and 56 controls, warfarin therapy, hypoalbuminemia, elevated glucose, and hypercalcemia were associated with CUA development. Not all CUA cases from this study had a skin biopsy confirmation . In none of these studies were parathyroid hormone levels associated with increased CUA risk. In fact, in a German Calciphylaxis Registry report, more than 3/4th of the CUA patients had parathyroid hormone levels of less than 300 pg/ml at the time of CUA diagnosis [48▪]. Although it is possible that elevated parathyroid hormone levels months or years before CUA development may attribute to increased CUA risk, overall the current evidence suggests that elevated parathyroid hormone level may not be the most dominant risk factor. This may also be the reason why the incidence of CUA in the EVOLVE trial that enrolled chronic hemodialysis patients with moderate-to-severe secondary hyperparathyroidism was lower than the epidemiological estimates [22▪▪,23,48▪]. The EVOLVE trial notably demonstrated relative CUA risk reduction of 69–75% in the cinacalcet arm compared with the placebo arm. Low event rates of CUA and imbalance of risk factors, such as higher prevalence of warfarin use in placebo arm patients who developed CUA compared with cinacalcet arm patients who developed CUA, introduce a possibility that findings may have been because of chance; however, the EVOLVE trial has provided instructive risk factor data on CUA as the trial noted that female sex, higher BMI, dyslipidemia, warfarin, and parathyroidectomy were associated with increased risk of CUA. Association with warfarin use has also been described in a recent retrospective cohort study , and this association is intriguing as it provides a unique opportunity to understand the biological role of vitamin K in CUA. Our group is involved in conducting a clinical trial to investigate whether vitamin K supplementation can improve carboxylation of Matrix Gla Protein, an important vascular calcification inhibitor, in patients with CUA (NCT02278692) https://clinicaltrials.gov/ct2/show/NCT02278692.
DIAGNOSIS AND EVALUATION
A high index of clinical suspicion is required for early and accurate diagnosis of CUA [25,26]. Clinicians who are most likely to have the first encounter with these patients include nephrologists, dermatologists, wound surgeons, and vascular surgeons, and these specialists should be aware of varied presentations of CUA. At present, skin biopsy is the gold standard for diagnosis. Detection of dermal arteriolar calcification generally requires von Kossa or Alizarin red staining. Performing both von Kossa and Alizarin red stains has been shown to improve the diagnostic yield . There are also ongoing efforts to develop noninvasive modalities to improve the clinical detection of CUA, such as nuclear bone scan  and Raman spectroscopy . A systematic evaluation for risk factors described in Table 2 should be considered for a patient with suspected and confirmed CUA.
Input from specialists relevant to the management of a CUA patient (Table 1) should be obtained as soon as the diagnosis of CUA is suspected to formulate a comprehensive and consistent plan. The overall quality of evidence for interventions tried in the management of CUA is poor and is derived from retrospective cohort studies, case series, and case reports . We have found having an experienced team with specialists who are familiar with the literature for this rare disease to be quite effective. The principles of a multidisciplinary approach to CUA management are described below:
Kidney Disease Improving Global Outcome clinical practice guidelines should be followed for goal serum calcium and phosphorous . Serum parathyroid hormone level should be maintained between 150 and 300 ng/ml with attention to avoid oversuppression [1,54]. Calcium supplements, calcium-based phosphate binders, and high dialysate calcium bath should be avoided [55–59]. Considering the potential risk of hypercalcemia associated with vitamin D analogues, cinacalcet is the preferred agent to treat secondary hyperparathyroidism [60–62]. Data on surgical parathyroidectomy in CUA patients are inconclusive [63–65].
Increasing duration or frequency, or both, of dialysis has been described in the management of CUA . This is applicable to patients who do not meet the Kidney Disease Outcomes Quality Initiative recommended goals of dialysis adequacy ; however, for those who do meet these goals, the decision needs to be individualized taking into account aggravation of pain with transfers, patient tolerability, and logistics. We do not routinely transition patients from peritoneal dialysis to hemodialysis for CUA management as it is uncertain whether peritoneal dialysis is a risk factor for CUA [1,2,67].
Sodium thiosulfate, a reducing agent with potential calcium chelating properties, is now a commonly used agent to treat CUA (off-label indication) since the first report of its use in CUA over 10 years ago [68–73]. The best available data on its CUA application are from a retrospective cohort study (n = 172) with clinician survey (n = 53) conducted at the dialysis units affiliated with the Fresenius Medical Care North America . Possible side-effects of sodium thiosulfate include nausea, vomiting, metabolic acidosis, hypotension, prolonged QT interval, and volume overload [69,74–76]. However, in this study, intravenous sodium thiosulfate was well tolerated and among surveyed patients, CUA reportedly improved in more than 70% of patients (resolution or improvement). Survey bias and other limitations of any retrospective study significantly limit conclusions of this study, and at present the efficacy of sodium thiosulfate is unclear . The most commonly used dose is 25 g mixed in 100 ml of isotonic saline administered over the last 30–40 min of dialysis (for a hemodialysis patient) and three times a week as an infusion (for a peritoneal dialysis patient). Dose adjustments are needed depending on dialysis prescription and body weight [1,78]. It is unclear what the optimal duration of sodium thiosulfate treatment is.
The goals of wound care include controlling exudate, preventing infection, and removing necrosed devitalized tissue [19,79]. Surgical debridement should be considered on a case-by-case basis in consultation with wound care and dermatology teams. Pain medicine and palliative care teams play a critical role in CUA management. Opioid analgesics are frequently required to control pain, and limited data support the efficacy of multimodal analgesia that combines opioids with neuropathic agents .
Prophylactic antibiotics are not indicated in CUA; however, a low threshold for systemic antibiotic initiation should be maintained for wounds that look infected. Patients with CUA are frequently malnourished and need input from a renal dietician. At present, there are limited data to support whether discontinuation of warfarin leads to improvement in CUA . However, considering the morbidity and mortality associated with CUA, a careful risk-benefit analysis for continuing warfarin should be conducted. Nonwarfarin anticoagulation options in the ESRD patients are limited; however, recently, dialysis dosing has become available for apixaban http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202155s002lbl.pdf.2015.
Considering limitations introduced by claustrophobia and availability, we reserve hyperbaric oxygen as a second-line therapy for recalcitrant CUA wounds [81–84]. Bisphosphonate use in CUA treatment has been described to be associated with significant improvement in a small case series and case reports [85–87]; however, more data are needed prior to their routine use for this indication.
Overall, the scientific literature on CUA is limited and suffers from methodological and sample size limitations. A multidisciplinary CUA team composed of experts from different disciplines can be helpful in addressing different aspects of this complex condition, applying the available data to an individual patient, and developing collaborative research approaches. This is particularly relevant as recent reports suggest that the incidence of CUA may be increasing and outcomes in CUA remain poor [5▪].
The author would like to thank Dr Daniela Kroshinsky, Dr Rosalynn Nazarian, Dr Carlos Rabito, Dr Rajeev Malhotra,Dr Mihir Kamdar, and Dr Jeremy Goverman for their contributions to the care of CUA patients at the Massachusetts General Hospital as a multidisciplinary team and Dr Ravi Thadhani for his mentorship.
Financial support and sponsorship
S.U.N. is supported by the National Kidney Foundation's Young Investigator Award, the Fund for Medical Discovery Award from the Massachusetts General Hospital's Executive Committee on Research (R00000000007190), the American Heart Association's NCRP Summer 2014 Mentored Clinical and Population Research Award (15CRP22900008), and by the American Heart Association's NCRP Winter 2015 Fellow-to-Faculty Transition Award (15FTF25980003).
Conflicts of interest
S.U.N. reports receiving lecture honoraria from Sanofi-Aventis and is a prior recipient of a Nephrology Fellowship Award from Sanofi-Aventis.
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