Background
Calciphylaxis (also referred to as calcific uremic arteriolopathy) is a poorly understood and highly morbid syndrome of vascular calcification and skin necrosis. Bryant and White first reported it in association with uremia in 1898. However, the significance of this relationship became uncertain when vascular calcification was subsequently shown to be prevalent in uremia, yet the syndrome of vascular calcification with cutaneous necrosis was less common. [1]
In a 1962 experimental study, Selye was able to precipitate systemic calcification, somewhat analogous to this syndrome, in nephrectomized rats. He was the first to coin the term calciphylaxis to characterize this enigma. Over the years, many other names have been suggested to characterize the pathogenic process, which has remained elusive. The clinical importance of this syndrome was not recognized until the mid-1970s. Since then, a multitude of case reports of calciphylaxis have documented data outlining its morbidity and therapeutic dilemmas. Efforts to achieve a better understand of the etiology and pathogenesis of calciphylaxis have continued. Unfortunately, this syndrome remains a conundrum. [2]
Pathophysiology
The pathogenesis of calciphylaxis remains obscure and is likely the result of a multiplicity of comorbid factors or events. Disorders that are most often implicated in the pathogenesis of calciphylaxis include chronic kidney disease (CKD; or chronic renal failure), obesity, diabetes mellitus, hypercalcemia, hyperphosphatemia, an elevated calcium-phosphate product, secondary hyperparathyroidism, and a variety of hypercoagulable states. Yet, although these abnormalities are extremely common in patients with end-stage renal disease (ESRD), calciphylaxis is relatively rare.
Using a rat model, Selye [3] demonstrated that a series of events might be necessary for the formation of calciphylaxis. He defined calciphylaxis as a condition of hypersensitivity induced by a set of "sensitizing" agents, in which calcinosis occurred only in those subsequently subjected to a group of "challengers" and only after a critical lag time. Experimental sensitizing events and agents included nephrectomy and exposure to parathyroid hormone (PTH) and vitamin D. Substances used as challengers included egg albumin and metallic salts. Calciphylaxis was the end result.
Although extrapolation of animal data to humans is conjectural, it seems to be true that serial events, most consistently involving renal failure–induced abnormalities in calcium homeostasis, are required to occur over time for calciphylaxis to develop. The cause of calciphylaxis has been elusive, most likely because it is the common endpoint of a heterogeneous group of disorders.
Many molecular and cytochemical factors have been identified as crucial in bone metabolism. The receptor activator of nuclear factor-kB (RANK), RANK ligand, and osteoprotegerin appear to regulate skeletal and extraskeletal mineralization. [4, 5] Uremia-induced defects in this system may predispose to calciphylaxis. [6]
Corticosteroids, aluminum, hyperparathyroidism, liver disease, warfarin therapy, and various inflammatory processes all can alter this balance and promote vascular calcification. [7, 8] Chronic inflammatory conditions may predispose to calciphylaxis by reducing serum levels of fetuin-A, an important inhibitor of calcification produced in the liver. [9, 10, 11] Some authors have suggested that calciphylaxis is an active form of osteogenesis with upregulation of bone morphogenic protein 2 (BMP-2), Runx2, its target gene, and its indirect antagonist sclerostin. [12]
Most investigators have noted that the common endpoint of calciphylaxis is vascular occlusion and thrombosis, which results in cutaneous ischemia [13, 14, 15] ; however, the factors associated with thrombosis are not uniform.
Etiology
Disorders associated with the development of calciphylaxis include the following [4, 16, 17, 18] :
-
Common associations - CKD, hypercalcemia, hyperphosphatemia, elevated calcium-phosphate product, hyperparathyroidism, and vascular calcification
-
Noted associations - Aluminum toxicity, coagulation abnormalities, and iron dextran infusion
-
Associations suggested from clinical observations - Renal transplantation, immunosuppressive agents, corticosteroid use, and obesity
The cause of calciphylaxis remains obscure. Most cases occur in the setting of CKD, abnormal calcium-phosphate homeostasis, and hyperparathyroidism. Both hypercalcemia and hyperphosphatemia may be present, and the calcium-phosphate product frequently exceeds 60-70 mg2/dL2. However, calciphylaxis may occur in the setting of normal, or minimally elevated, calcium and phosphate levels.
Case reports exist of calciphylaxis occurring in primary hyperparathyroidism, cirrhosis, Crohn disease, malignancy, and rheumatoid arthritis, without renal disease. The pathogenesis of calciphylaxis in these cases is uncertain. [19, 16, 20, 21] The exact role of PTH is uncertain because calciphylaxis may occur after total parathyroidectomy, in the absence of measurable PTH levels.
Patients at an increased risk appear to be those who are obese and those who have been exposed to immunosuppressive agents, including glucocorticoids. [16] Calciphylaxis occurs more frequently in areas where body fat is most abundant (eg, thighs, buttocks, and lower abdomen). [17, 18] Fatty areas may be at higher risk for thrombosis, owing to lower blood flow, increased potential for vascular kinking, or, more likely, involvement of adipocytes in the pathogenesis of calciphylaxis. [22]
Persons with diabetes mellitus may also be at an increased risk [16, 17, 18] ; insulin injections may pose an independent risk through trauma to the subcutis.
The clinical appearance of the lesions of calciphylaxis (livedo reticularis and stellate purpura) suggests that the common endpoint of the process is small-vessel occlusion. Indeed, microthrombi are found in most cases.
Hypercoagulable conditions, including protein C and protein S deficiencies, vitamin K deficiency, and the presence of a circulating anticoagulant have been described in a number of patients. [23, 24, 25, 26, 27, 22] However, conditions of hypercoagulability are not found uniformly. If they do exist, they could possibly precipitate or exacerbate calciphylaxis in a predisposed patient.
Vascular calcification is a constant finding in cases of calciphylaxis. Theoretically, various pathologic roles may be attributed to this vascular calcification, including the following:
-
First, calcification of the vascular endothelium may alter the local interaction of procoagulant and anticoagulant factors, predisposing to a microenvironment of hypercoagulability
-
Alternatively, extensive endothelial calcification and intimal hyperplasia, which are known to compromise the luminal size of vessels in calciphylaxis, may result in vascular occlusion
-
Finally, data suggest that the uremic milieu may promote calcification through inhibition of various endogenous inhibitors of calcification, such as alpha2-Heremans-Schmid glycoprotein/fetuin A (AHSG), osteopontin, and matrix Gla protein
Epidemiology
United States and international statistics
Calciphylaxis is an uncommon condition that affects 1-4% of the population with ESRD. [28, 29] A concern exists that the incidence has increased during the last decade because of a number of possible factors, including more widespread use of parenteral vitamin D and iron dextran.
In a study using data from the Australia and New Zealand Dialysis and Transplant Registry, the incidence of calciphylaxis episodes among patients on dialysis was found to be 4.5 (range, 4.1-5.1) per 1000 patient-years on dialysis. [30]
The incidence of calciphylaxis in the general population without ESRD is not known with certainty, but it is even lower. Nonuremic disease is being identified more commonly, especially in patients with rapid weight loss. Some cases are associated with warfarin use, but that association does not appear to alter prognosis. [31]
Age-, sex-, and race-related demographics
Calciphylaxis has been reported in individuals ranging in age from 6 months to 83 years. From a large series of patients, a mean patient age of 48 (± 16) years has been calculated. Individuals seemingly more predisposed are younger patients who have had a longer duration of renal replacement therapy.
Females are affected more often than males, with a female-to-male ratio of approximately 3:1. Females also appear to be more commonly affected with nonuremic calciphylaxis.
Although the disease may affect persons of any race, it appears to be more prevalent in Whites.
Prognosis
The prognosis is generally not good, with mortality as high as 60-80% having been reported in patients with ulcerative disease. [7] In a retrospective cohort study (N = 302) by Tan et al, the 1-year mortality was 36.70% for nephrogenic calciphylaxis and 30.77% for nonnephrogenic calciphylaxis. [32] Mortality is higher in patients with proximal disease than in those with only distal or acral disease.
Patients who do not die of sepsis or organ failure frequently undergo amputation of an involved limb. Vascular calcification is theoretically reversible with aggressive management, but many patients have numerous comorbid diseases, and intervention may be too late. [7] A multidisciplinary approach with wound debridement, possible parathyroidectomy, and aggressive medical management may improve survival. [4] The impact of sodium thiosulfate on the overall survival rate remains to be determined. [33]
Patient Education
It is essential to emphasize compliance with the dialysis prescription. Patients must be educated regarding dietary restrictions and the need for phosphate binders. If anticoagulation is chosen, the risks and the benefits of this therapy must be explained to the patient.
-
Several lesions of calciphylaxis that occurred on the lower extremity of a patient undergoing dialysis. These lesions developed in areas of livedo reticularis and followed the path of the vasculature.
-
An isolated lesion of calciphylaxis manifesting as an enlarging necrotic plaque on the lower extremity of a patient undergoing dialysis. The stellate purpuric morphology can be appreciated surrounding the area of necrosis.
-
Calciphylaxis may manifest as rapidly progressive, diffuse and extensive, cutaneous necrosis, as is seen in this patient with chronic renal failure. Bullae may also be seen as a rare manifestation of calciphylaxis.
-
Radiologic findings of a hand in a patient with calciphylaxis. Extensive calcification of the radial and ulnar arteries is readily visible.
-
Calcification of capillaries within the subcutaneous fat, characteristic of calciphylaxis. Image courtesy of Dirk Elston, MD.
