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Correspondence: Arturo R. Dominguez, MD, Department of Dermatology/Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390.
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TXDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
Calcific uremic arteriolopathy, otherwise known as calciphylaxis, is a rare disease characterized by skin ulceration and tissue necrosis, likely the result of vascular calcification with accompanying intimal hypertrophy and small vessel thrombosis. Although most often associated with end-stage renal disease, it has also been seen in a number of other disorders (collectively referred to as nonuremic calciphylaxis). The purpose of this review is to summarize and analyze the currently available literature regarding the pathophysiology, risk factors, clinical presentation, diagnostic features and treatment modalities for this exceptionally uncommon illness. A series of recommended treatments is proposed for optimal treatment of calciphylaxis lesions.
Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare, oftentimes fatal complication usually associated with end-stage renal disease (ESRD).
It is characterized by skin ulceration and necrosis leading to significant pain. Histopathologic examination in these patients is often significant for medial calcification and intimal proliferation of small arterioles and subcutaneous capillaries, leading to thrombosis and ischemic necrosis, although recent work has suggested far greater variability in histopathologic presentation.
Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy.
Cutaneous findings include tender, indurated subcutaneous plaques with overlying livedo racemosa that progress to nonhealing stellate-shaped ulcers covered by black eschar.
The most comprehensive analysis, conducted by the Partners Research Patient Data Registry, noted 567 cases of calciphylaxis per 10,000 patients on chronic hemodialysis (HD) from 2002-2011.
More importantly, this group described increasing incidence rates (3.7 per 10,000 dialysis patients before 2007, 5.7 per 10,000 patients after 2007). Whether this rise in incidence is due to improved recognition of the disease or increased use of calcium-based phosphate binders is unclear. Although primarily associated with chronic kidney disease, calciphylaxis has also been diagnosed in patients with normal renal function, calcium, and phosphate pathways.
The purpose of this review is to analyze the literature regarding the pathophysiology, risk factors, clinical presentation, diagnostic features and treatment modalities for this exceptionally uncommon illness. Recommended treatments are subsequently proposed for optimal treatment.
first described calciphylaxis in rodents as a hypersensitivity-like condition, wherein after sensitization by a calcifying factor, second exposure resulted in local calcification, inflammation and sclerosis. Subsequently, similar lesions were reported in uremic humans; these ischemic, ulcerated wounds were sufficiently similar in their characteristics to Selyeʼs rats that they were termed lesions of calciphylaxis. Although similar to renal osteodystrophy in that there is abnormal calcium deposition, calciphylaxis involves calcification of the tunica media of arterioles and subcutaneous capillaries (<0.6 mm in diameter), as opposed to the deposition in medium-sized vessels common to osteodystrophy.
The formation of calciphylaxis lesions likely requires 2 key steps: (1) medial calcification and intimal fibrosis of the arterioles and (2) thrombotic occlusion due to progressive calcification and endothelial dysfunction. Dysfunction of the regulatory mechanisms that manage calcium, phosphate and parathyroid hormone (PTH) levels results in vascular calcification. Dystrophic vascular calcification is divided into 2 main categories, according to lesion location and its association with atherosclerosis.
The more common is calcification of the intima, in conjunction with or secondary to the formation of atherosclerotic plaques. Conversely, calciphylaxis is characterized by calcification of arteriole media. However, both forms involve calcium hydroxyapatite and matrix vesicles within the calcified vessel walls.
Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.
Owing to the association between calcium and phosphate regulation and calciphylaxis, it is unsurprising that the majority of cases of calciphylaxis occur in patients suffering from kidney disease.
Phosphorus can rise to pathologic levels in kidney disease because of impaired excretion, and has historically been noted to cause the expression of procalcific genes.
Recent research has elaborated the process by which calcium is deposited in vessel walls further. Under the currently accepted model for vascular calcification, lesion pathogenesis begins with the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like phenotypes.
This occurs through interaction amongst the constituents of uremia—hyperphosphatemia, uremic toxins, and reactive oxygen species and the decrease of matrix gla protein (MGP), a potent calcification inhibitor. To some extent, the calciphylaxis is still influenced by the renal system, as hyperphosphatemia is thought to trigger VSMCs transformation to an osteoblastic cell type.
Bone morphogenetic protein-4 and osteopontin, normal constituents in bone repair and development, are also expressed in lesional biopsies of patients with calciphylaxis and are thought to serve as makers of osteoblastic transformation.
The activity of bone morphogenetic protein-4 in catalyzing extraskeletal calcification is dependent on reactive oxygen species, which act through nuclear factor kappa B (NFkB) to spur the calcification process.
Alternatively, NFkB can be upregulated through loss of constituent inhibitors, such as osteoprotegerin.
However, medial calcification and sub-intimal fibrosis of arterioles alone is likely not sufficient to cause calciphylaxis. The role of hypercoagulability in the development of calciphylaxis is gaining increasing attention. In 1 cohort of patients with CUA, up to 38% and 43% of reported cases had decreased levels of proteins C and S, respectively, on laboratory evaluation.
The same study has reported cases of calciphylaxis in patients with multiple hypercoagulable states. Evidence for the role of hypercoagulability in calciphylaxis is further supported by histopathologic findings demonstrating thrombosis in 38 of 44 patients (86%) in 1 cohort, with no inflammatory infiltrates suggestive of a vasculitic process.
The induction of local hypercoagulability may also lead to discrete prothrombotic regions. Inflammatory cytokines, including TNF-alpha, IL-1 and IL-6, may reduce anti-thrombotic responses such as protein C and S receptor expression, thrombomodulin expression, and vascular heparin-like molecules, promoting thrombosis.
Similarly, other factors linked to calciphylaxis (later) are thought to enhance thrombosis by reducing anti-thrombotic processes or enhancing prothrombotic mechanisms, as opposed to inducing calcification.
This is further supported by the rise of calciphylaxis in patients with normal kidney function, a phenomenon called nonuremic calciphylaxis. A systemic review of nonuremic calciphylaxis
identified associations between calciphylaxis and the following medical diseases: primary hyperparathyroidism (27.8% of available cases), cholangiocarcinoma, chronic myeloid leukemia, melanoma and other malignancies (22.2%), alcoholic liver disease (16.7%) and connective tissue diseases (11.1%). Disease characteristics are virtually identical to CUA. The presence of calciphylaxis in patients with normal renal function and mineral bone axes imply that hyperphosphatemia may not be an absolute requirement for lesion induction.
Clinical Presentation
History
Patients with calciphylaxis typically present with significant pain and chronic nonhealing wounds. The wounds themselves show signs of poor healing, including black eschar. Furthermore, the open, chronic wounds are often secondarily super-infected, leading to erythema, edema and purulent discharge. Left untreated, these wounds can progress to systemic infections, with all of the associated complications.
Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy.
Although the cutaneous complications are often the patientʼs primary concern, vascular calcification has also been noted in skeletal muscle, brain, lungs, intestines and other organ systems,
suggesting a more systemic process. Interestingly, many cases of systemic calciphylaxis lack vascular thrombosis of the involved organs on histopathology, bringing into question whether these cases represent metastatic calcification rather than calciphylaxis.
There has been a significant effort toward understanding the characteristics that predispose patients to calciphylaxis. Individual studies are often limited owing to the sheer rarity of the disease, and thus prone to limitations in sample size, demographic heterogeneity and selection bias. However, the summation of these works reveals several recurring connections between certain factors and the development of calciphylaxis.
The most commonly associated risk factors involve mineral components of the renal system. Hyperphosphatemia, an elevated calcium-phosphorus product, hyperparathyroidism and vitamin D deficiency are significantly associated with calciphylaxis.
Initial investigation into calciphylaxis likely started with these factors due to the increased rates in patients with chronic kidney disease. A variety of medications are associated with increased risk for developing calciphylaxis. Calcium supplements, calcium-based phosphate binders and active vitamin D increase the available calcium for deposition, thus explaining their association.
A case-control study in Japanese ESRD patients found that warfarin therapy was significantly associated with calciphylaxis (odds ratio = 11.4, P = 0.0009). A similar study from a German registry notes that approximately 50% of incident patients with calciphylaxis had been treated with vitamin K antagonists.
These reports hypothesized that inhibition of vitamin K leads to under-carboxylation of MGP, a structure produced by VSMCs to inhibit vascular calcification in large arteries,
although it may also contribute to thrombosis through inhibition of proteins C and S. Lack of MGP is thought to contribute to medial calcification, and is thought to be one pathway by which warfarin promotes calciphylaxis. In animal models, deficiency or antagonism of vitamin K2 (such as with warfarin) has been associated with calcification of the arterial vasculature,
CUA has also been linked to a number of comorbid conditions and demographic factors whose effect on arteriolar calcification is less well defined. Female gender, the co-presence of diabetes mellitus or obesity
as well as end-stage liver disease and hypoalbuminemia. Although the exact mechanism is incompletely known, upregulation of the NFkB pathway is likely a key component.
As noted above, calciphylaxis lesions present as tender, indurated subcutaneous plaques with overlying livedo racemosa that progress to nonhealing, stellate-shaped ulcers covered by black eschar (FIGURE 1, FIGURE 2). These wounds primarily involve the adipose-rich areas of the trunk, including the breasts, abdominal pannus, flanks, and lower back and buttocks, as well as the proximal lower extremities, in particular the medial and lateral aspects of the thighs and calves. However, multiple case reports have described an atypical presentation in the form of acral ischemia with both genital and digital involvement.
FIGURE 1(A) Top left: Early calciphylaxis—right anterior-medial thigh. Erythematous and violaceous broken circles of livedo racemosa signifying active ischemia. (B) Top right: Early calciphylaxis—left anterior thigh. Livedo racemosa with bullae formation and crusting from ischemia and subsequent skin necrosis. (C) Bottom left: Calciphylaxis as panninculitis—right lateral thigh. Painful indurated subcutaneous plaque with surrounding livedo racemosa. Note the “forked lightening’ erythema to the right of the indurated and dimpled plaque. (D) Bottom right: Progressive calciphylaxis—bilateral anterior thighs. Slightly more advanced stage than previous pictures. Livedo racemosa is present but has progressed to retiform purpura on right anterior thigh. There is eschar formation from skin that has already necrosed due to ischemic injury.
FIGURE 2(A) Top left: Active calciphylaxis ulcer—right medial thigh. Stellate-shaped ulcer with surrounding livedo racemosa and retiform purpura signifying ongoing ischemia. (B) Top right: Nonhealing calciphylaxis ulcer—right calf. Stellate-shaped ulcer with overlying black eschar with smaller additional areas of retiform purpura. (C) Bottom left: Acral calciphylaxis—right hand. Fourth digit with dry gangrene. Third volar digit with visible livedo from active ischemia. (D) Bottom right: Penile calciphylaxis. Dorsal shaft and glans penis. Ulcer with fibrinous base. Note the retiform purpura on superior dorsal shaft.
The morphology of lesions is due to the anatomy of the cutaneous vasculature, which consists of central arterioles arising perpendicularly from vessels in the fascia. Each arteriole supports a 1- to 4-cm-diameter zone of the skin. Cyanosis from the accumulation of deoxygenated blood at the junction between these vessels leads to the classic net-like pattern of lesions. Lesions often progress from the mottled, net-like vascular pattern of livedo reticularis to irregular, broken circles reminiscent of forked lightning, called livedo racemosa to finally, the branching purpuric lesions of retiform purpura, as determined by the severity and duration of blood obstruction. As a result, the morphology observed will reflect the stage of the disease.
Differential Diagnosis
The differential diagnosis for CUA encompasses diseases of both iatrogenic and organic etiology whose common presenting finding is livedo racemosa. Warfarin-induced skin necrosis (WISN) in particular is difficult to differentiate clinically from calciphylaxis because the 2 diseases are for the most part indistinguishable. Early findings in WISN can include petechiae, ecchymoses and hemorrhagic bullae. The clinical presentation of both diseases converges upon the shared finding of painful full-thickness skin necrosis and stellate deep ulcers. Furthermore, WISN also tends to favor adipose-rich areas, preventing clinicians from differentiating between the 2 diseases based on the distribution of lesions.
Differentiation based on histopathology is also often not possible because the findings of inflammatory microthrombi in the dermis and subcutaneous tissue are components of both diseases. Calcification of subcutaneous capillaries may be more supportive of calciphylaxis.
There are 2 clinical points to help differentiate between WISN and calciphylaxis, the timing from medication administration to onset of the characteristic skin lesions and response to warfarin cessation. WISN typically presents within the first 10 days of drug administration, whereas calciphylaxis potentially triggered by warfarin requires a prolonged period of use before lesion onset. Similarly, WISN responds quickly to warfarin cessation and heparin anticoagulation, whereas calciphylaxis lesions persist much longer despite discontinuation of causative agents. Clinicians should be counseled against using the timing of lesions as the definitive criteria for separating the 2 diseases, as there are reports of late onset WISN, typically because of inconsistent administration in non-adherent patients.
Calciphylaxis is predominantly a clinical diagnosis. In a patient with ESRD presenting with painful, erythematous, livedoid skin changes on adipose-rich areas, the diagnosis is calciphylaxis until proven otherwise. The formal diagnosis of calciphylaxis has traditionally necessitated a skin biopsy and can be considered in atypical clinical scenarios. Biopsy can demonstrate medial calcification and intimal proliferation of small arteries leading to ischemic epidermal necrosis.
Other salient features include extravascular soft tissue calcification, septal and lobular panniculitis, dermal-epidermal separation and epidermal necrosis. Sensitivity can be increased through special stains such as von Kossa or Alizarin red, which allow for better detection of microcalcification. In particular, perieccrine calcification is believed to be highly specific for calciphylaxis.
Although calcification, when present, can aid greatly in solidifying the diagnosis of calciphylaxis, patients can have biopsies that lack this feature. One retrospective review of 56 biopsies from confirmed calciphylaxis patients noted classic features of calcification in arterioles in only 18% of samples.
The possible reasons behind this low sensitivity are multiple. First, the histopathology of early calciphylaxis may demonstrate a thrombotic vasculopathy of the superficial dermal vessels, a finding typical of many hypercoagulable conditions. Furthermore, limitations of biopsies, including limited specimen depth, sampling error, technical errors during processing and the clinical stage of the process at the sampled lesion contribute partly to this inability to make a firm diagnosis. The role of noncalcific processes in calciphylaxis may also contribute to the lack of classic histopathological findings.
Nevertheless, if a biopsy is pursued because of an unclear clinical diagnosis, the authors recommend an excisional biopsy at a site where the edge of the necrotic eschar, the livedoid area, and the indurated skin can all be simultaneously captured. Alternatively, a 6-8 mm punch biopsy can suffice, so long as an adequate sample of subcutaneous tissue can be obtained. If necessary, a telescoping 4 mm punch biopsy can be performed within the base of the large 6-8 mm punch biopsy location to obtain sufficient tissue. Owing to the low yield of biopsy samples in calciphylaxis, and the subtlety of early findings, having a pathologist or dermatopathologist with experience diagnosing calciphylaxis is essential.
Studies
The laboratory evaluation of a patient suspected of having calciphylaxis should consider 2 major goals: to assess for the presence of any potential risk factors and to rule out other disorders that may mimic the physical examination findings. These are presented in Table 2. Clinical imaging, chief among these plain X-rays and 3-phase nuclear bone scans, has been supported by some isolated studies.
However, large-scale clinical trials for these diagnostic tools are lacking. Further evaluation of these tools in the diagnosis of calciphylaxis is necessary before they are recommended in the routine workup of patients with suspected calciphylaxis.
TABLE 2Laboratory evaluation of patients with calciphylaxis.
Labs to evaluate for risk factors
Labs to rule out other diseases
Kidney damage
Mineral bone disease axis
Infectious workup
Hypercoagulability
Anti-nuclear antigens, extractable nuclear antigens, and other clinical mimics
Calciphylaxis is a wide-reaching disease that involves multiple organ systems. As such, treatment also requires collaboration amongst multiple specialties, including dermatology, nephrology, wound care, nutrition and pain management. Additional comorbid conditions should lead providers to consider close including cardiology, pulmonology, hematology and other specialty physicians depending on the exact condition.
Many treatments have been proposed for the management of calciphylaxis. However, randomized, blinded studies have not been conducted on any of these treatment options. The majority of reports supporting these interventions come from retrospective case reports, case series and cohort studies. Nevertheless, several treatment modalities appear to show great promise based on preliminary studies, and are included here for consideration.
The prognosis for patients with calciphylaxis is grim, with 1-year survival rates failing to reach 50% (45.8%) and 2-year survival rates approaching 20%.
Patients on dialysis at diagnosis have reduced median survival (2.4 months) compared to nondialysis patients with calciphylaxis (8.4 months). Although no significant difference in survival was noted based on lesion distribution (proximal versus distal), those with both distal and proximal disease suffer from higher mortality, likely because of the increased burden of disease (44.7%, 32.2% and 12.5% 1-year survival rates). Penile calciphylaxis is also notable for a mortality rate of 69% in 6 months.
Compared to patients on dialysis without calciphylaxis, the Kaplan-Meier survival rates at 1, 2 and 5 years for those on dialysis with calciphylaxis are markedly reduced (29%, 14.5% and 9.1% versus 88.1%, 74.4% and 46.9%).
End of Life Discussions
Owing to the intense pain and morbidity suffered by those with progressive calciphylaxis, as well as the marked decrease in survival, early discussion with patients and their families regarding their prognosis and approach to future therapy is warranted. Some patients may desire to stop HD and other adjunct therapies rather than deal with excruciating pain and an unfavorable prognosis. As a result, we recommend these discussions occur immediately after patients have had an opportunity to process the effect of their diagnosis and become ready to discuss their future management.
Pain Control
As intense pain is the primary complaint in patients with calciphylaxis, appropriate palliative measures are warranted in therapeutic management. Although narcotic analgesia is recommended, morphine is thought to cause accumulation of toxic byproducts that further compromise tissue perfusion. Fentanyl patches may be preferred for baseline pain control,
but this should be supplemented with hydromorphone for breakthrough pain or wound dressing changes.
Wound Care
Because of the significant risk of infection in patients with calciphylaxis, meticulous wound care should represent a primary cornerstone of therapy in all patients. Goals of wound management should include removal of necrotic tissue, aiding wound healing and preventing infection. Gentle debridement of necrotic tissue is recommended to allow proper wound healing, but is best done when there are no signs of active ischemia.
The few studies that promoted surgical intervention were largely retrospective studies that were not standardized to the indications for intervention or the surgical technique, giving their results questionable validity.
Dressings should provide a moist environment to promote healing and remove excess exudates while being easy to apply and remove to reduce the incidence of skin trauma.
but the choice of dressing should reflect the priorities listed above; popular types include hydrocolloid and silver foam dressings changed 2-3 times per week.
Other adjunct therapies thought to promote wound healing are hyperbaric oxygen and maggot debridement. In a group of 46 individuals with calciphylaxis treated with hyperbaric oxygen,
58% demonstrated improvement in wound scores, and half of those progressed to complete healing. Maggot therapy may also provide gentle debridement of necrotic tissue, prevent systemic infection, and thereby promote wound healing. Only isolated reports on the successful use of maggot therapy in calciphylaxis exist.
Although maggot therapy may be cost-effective, it is a labor-intensive, occasionally pain-inducing therapy (despite claims to the contrary), and there is a risk of hemorrhage in fully anticoagulated patients or those with deep wounds.
An evaluation for peripheral vascular disease in those with acral necrosis is warranted to assess whether revascularization might be indicated. Insufficient evidence exists to make firm recommendations regarding revascularization in promoting wound healing in calciphylaxis. Notably, the very need for vascular procedures has been associated with poor survival in calciphylaxis patients
; it is unclear what influence the procedure itself may have played in affecting these morbidity figures.
Lastly, patients with calciphylaxis are often malnourished because of decreased oral intake and increased metabolic demands from inflammation and chronic wounds. Malnutrition contributes to poor wound-healing and may even provoke further lesions. Therefore, a dietary consult should be obtained in all patients with calciphylaxis. If nutritional demands cannot be met through oral intake, consideration should be given to enteral or parenteral nutrition if consistent with the patientʼs goals of care.
Sodium Thiosulfate
Sodium thiosulfate has been shown to contribute significantly in treating calciphylaxis, and has become one of the primary treatment modalities. The exact mechanism of action is unknown. Hypotheses include vasodilatory and antioxidant properties, an increase in calcium solubility, or combination with calcium to form a dialyzable salt.
Although intralesional (260 mg/mL) administration may be appropriate in isolated wounds, it is likely unfeasible for those with multiple lesions. Intravenous administration of sodium thiosulfate 25 g 3 times weekly with dialysis sessions has demonstrated good efficacy in the treatment of calciphylaxis,
The first 3 adverse effects often improve with subsequent infusions, and titrating the medication upwards from a low initial dose may prevent these side effects. Although reported to affect morbidity, with 1 case series demonstrating 29 of 34 patients with lesion improvement,
it is still unclear whether there are tangible improvements in mortality. Owing to the novelty of sodium thiosulfate, patients can experience great difficulty in obtaining this drug for outpatient treatment, as well as in locating a dialysis center comfortable with performing the infusions. Cost can be a barrier, as the monthly cost of IV sodium thiosulfate has been reported to approach $10,000.
Correction of Underlying Calcium and Phosphorus Derangements
Derangements of calcium and phosphorus regulation in renal failure, as measured by calcium, phosphorus, PTH and vitamin D levels, are one of the primary associations of calciphylaxis. As a result, establishing control over these abnormal processes through regulation of substrate levels can be an important adjunct treatment to minimizing the formation of lesions.
Sevelamer, a polyallylamine crosslinked to epichlorohydrin, is a phosphate-binding drug used to control phosphate levels in patients with chronic kidney disease.
Control of phosphate is critical given that high phosphate levels are currently hypothesized to be the metabolic trigger behind smooth muscle metaplasia into osteoblastic cell types. Also, because sevelamer helps reduce serum uric acid levels,
it may also play a role in reducing other mechanisms of lesion pathogenesis.
An alternative method for maintaining control of the substances mentioned above may be through intense HD in excess of those provided at typical dialysis sessions. Although all patients should be optimized to National Kidney Foundation—Kidney Disease Outcomes Quality Initiative goals of dialysis adequacy, increased length and frequency of dialysis might help keep serum levels within a narrow therapeutic window, thereby reducing the incidence of calciphylaxis, limiting lesion progression, and promoting faster healing times. Whether this benefit is actually realized in patients remains to be seen. Whether peritoneal dialysis imparts a higher calciphylaxis risk when compared to HD is unclear, and it is not currently standard practice to transition peritoneal dialysis patients to HD.
In patients with calciphylaxis where it appears vascular calcification is driven by PTH, cinacalcet represents the preferred treatment for control of PTH levels as demonstrated by the EVOLVE trial.
However, the risks associated with surgery, especially in medically complicated patients make this a second line treatment following failed medical management.
Anticoagulation as a Standalone or Adjunct Treatment
Theoretically, an argument can be made for anticoagulants in the management of patients with calciphylaxis. As detailed above, there does seem to be interplay between calcific processes and hypercoagulability in lesion development in some patients (such as protein C and S deficiency), and others have developed lesions in the setting of normal renal function. Although patients with known hypercoagulable states and calciphylaxis may benefit from anticoagulation, full anticoagulation in all patients with calciphylaxis is not currently indicated due to the lack of efficacy, safety and nonwarfarin options in patients with ESRD.
Nevertheless, pentoxifylline, a methylated xanthine derivative, can be considered an adjunctive agent due to its ability to reduce blood viscosity, decrease platelet aggregation, and thus mitigate thrombus formation.
Although its mechanism of action demonstrates some potential benefit, there are no validated studies outside of individual case reports documenting its efficacy. Further research is needed to elucidate the utility of anticoagulants as standalone or adjunct treatments in calciphylaxis patients without comorbidities necessitating anticoagulation.
Anticoagulant Selection in Patients With Warfarin-Induced Calciphylaxis and Cardiac Comorbidities
Similarly, little is known regarding anticoagulant selection in patients with comorbidities necessitating chronic anticoagulation, who subsequently develop calciphylaxis. Providing therapeutic anticoagulation in these patients is extremely difficult because the simultaneous presence of ESRD, calciphylaxis and cardiac comorbidities necessitating chronic anticoagulation represents an intersection of medical diseases without clear treatment guidelines. Warfarin is often not tenable as a treatment modality due to its association with worsening calciphylaxis and alternative anticoagulants are largely prohibited because of impaired renal function. In such cases, clinicians are often left balancing the morbidity inflicted by calciphylaxis against an elevated risk of thrombotic events should anticoagulation cease.
The American College of Chest Physicians and American Heart Association or American College of Cardiology publish guidelines for anticoagulation in a variety of conditions. However, their recommendations are intended for general anticoagulant coverage in patients with many different medical conditions. There are no specific protocols for this unique subset of patients with renal, cardiac, and dermatologic disease, and the broad rules proposed by these groups are largely inappropriate for these patients.
In individuals with kidney disease, cardiac comorbidities, and calciphylaxis who require long-term anticoagulation, there are 2 alternatives to warfarin: full-intensity subcutaneous unfractionated heparin (UFH) and tinzaparin, a high molecular weight LMWH less dependent on renal clearance. Both are considered viable alternatives to warfarin for chronic anticoagulation.
However, if UFH is selected, providers should remain vigilant for signs of heparin-induced thrombocytopenia, a rare but serious complication. Ultimately, hospitalization and continuous UFH infusion may be the safest method of providing full anticoagulation while calciphylaxis lesions heal, but this must be weighed against the risk of nosocomial infection.
Finally, in all patients with calciphylaxis, a workup for underlying hypercoagulable states should take place, as these diseases place patients at greater risk for thrombotic events and possibly further progression of their calciphylaxis lesions. If an underlying condition is uncovered that mandates chronic anticoagulation, we recommend full anticoagulation with full intensity subcutaneous UFH, continuous heparin infusion, or tinzaparin, where available. The newer target specific oral anticoagulants can also be considered although most are not approved for patients with chronic kidney disease.
Other Adjuncts
Bisphosphonates are well-studied and frequently administered treatment for the mitigation of bone loss and prevention of hypercalcemia, especially in diseases where calcium levels are elevated through the action of PTH bone cells. PTH has been identified as a significant risk factor for calciphylaxis, as mentioned previously. In such cases, bisphosphonates may help maintain normal calcium levels by blunting the effects of PTH. In fact, bisphosphonates have demonstrated an ability to facilitate healing of calciphylaxis lesions regardless of PTH levels. Authors have proposed a number of hypotheses regarding the mechanism of action of these medications in promoting healing in calciphylaxis. These include modification of calcium hydroxyapatite formation, binding of bisphosphonates to VSMC that mimic osteoclasts and osteoblasts in phenotype, and many others; however, the true mechanism is currently unknown.
Vitamin K also plays a key role in the gamma-carboxylation of MGP. This lack of active vitamin K-dependent MGP has been documented in dialysis patients, and these individuals have demonstrated increased levels of the inactive form of MGP.
Iatrogenic administration of vitamin K2 (menaquinone) may help improve the calcification inhibitory activity of this protein. Supraphysiologic doses have not been shown to induce toxicity or increase clotting risk, and they have actually been shown to reverse warfarin-induced calcification in rats.
Kidney Transplantation
The utility of kidney transplantation remains unclear in the treatment of calciphylaxis. Because CUA develops largely from derangements of the mineral bone disease axis secondary to an improperly or nonfunctioning kidney, correction of these imbalances through transplantation of a working donor kidney should theoretically restore mineral levels to their prior baselines and prevent the development or progression of calciphylaxis.
In practical application, reports noting both the resolution of calciphylaxis and new onset of calciphylaxis after transplantation exist.
Whether this is due to changes in VSMCs that are not undone through transplantation, or the influence of hypercoagulability or other pathologic processes is currently unclear, and more work is necessary to resolve these uncertainties.
Skilled Nursing Facility and Long-term Acute Care Issues
The long-term management and care of patients with calciphylaxis is likely to occur at skilled nursing facilities and other long-term acute care (LTAC) centers. Although these locations are designed for patients with serious medical problems that require intense treatment for extended periods of time, they are likely not trained or equipped to deal with the unique requirements of those with calciphylaxis. Dedicated in-house wound care nurses are often not present, and contracted providers who perform this function often do not visit with the frequency necessary for the optimal treatment of calciphylaxis patients.
Finally, the physicians who treat patients who enter LTAC centers may not be intimately familiar with the management of patients with calciphylaxis. These physicians would also become responsible for coordinating care between multiple specialty providers (dermatology, cardiology, nephrology, hematology, palliative care, pulmonology, hematology and pharmacy, depending on the patientʼs unique circumstances). Transportation to and from physicians in each specialty who can deal with organ-specific manifestations of calciphylaxis is daunting, and is often impossible if the clinic is outside the range of where a skilled nursing facility or LTAC can transport the patient.
Conclusions
Calciphylaxis is an ischemic small-vessel vasculopathy with a controversial, multifactorial pathogenesis often seen in patients with ESRD on HD. Additional comorbidities and the administration of certain medications, chief among them warfarin, can accelerate lesion formation and complicate attempts at treatment. This report reviews the pathogenesis, risk factors, clinical history, physical examination findings, diagnostic evaluation and treatment of calciphylaxis as it is currently understood. In doing so, we hope to illustrate the far-reaching scope of the disease, the complex interaction that results in multiple organ systems, and the many dilemmas clinicians can face when managing this disease. Ultimately, successful treatment of calciphylaxis is a multidisciplinary effort, and should involve close collaboration between dermatology, cardiology, nephrology, hematology, palliative care, pulmonology, hematology, pharmacy and the primary treatment team as necessary depending on the unique manifestations of disease in individual patients.
References
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Kirkland G.S.
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Cutaneous necrosis from calcific uremic arteriolopathy.
Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy.
Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD.
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