Calciphylaxis is a serious condition characterized by necrosis of the skin and adipose tissue. It is seen mainly in patients with end-stage renal disease (ESRD) on maintenance dialysis. Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), carries a high mortality rate, mainly due to secondary infections, sepsis, and ischemia.
Seyle1 first described in 1962 a syndrome in the experimental animal and postulated that two steps are required to produce ectopic systemic calcifications. First, a systemic sensitization induced by agents such as parathyroid hormone (PTH), vitamin D, or a diet high in calcium (Ca) and phosphorus (P). Second, after a time interval (the "critical period"), exposure to appropriate challenging agents by subcutaneous injections resulted in macroscopically visible deposits of calcium salts (hydroxyapatite) systemically, and at the site of injection within two to three days. Challenging agents included local trauma, iron salt, egg albumin, polymyxin, and glucocorticoids. Selye named the syndrome "calciphylaxis." A few years later a syndrome characterized by peripheral ischemic tissue necrosis, vascular calcification, and cutaneous ulcerations was reported in uremic patients.2 Because of its resemblance to Selye's animal model, it was also named "calciphylaxis"2. However, the syndrome described in the uremic patient only resembles Selye's model. Though a useful concept, the analogy to Selye's model may not be warranted because the term "calciphylaxis" has pathogenic implications that have not been confirmed in humans. Thus, significant differences exist between Selye's model and uremic calciphylaxis. The former was characterized by metastatic systemic calcifications that developed after significant invasive manipulations of the animal model, but vascular calcifications were not present. The latter occur primarily in the presence of uremia with abnormalities in divalent ions (i.e., hypercalcemia, hyperphosphatemia, and high PTH), and most importantly, vascular calcifications were noted at the lesions. Retrospectively, it appears that uremic soft tissue calcification (tumoral calcinosis) is the syndrome most analogous to Selye's. It should be emphasized that Selye's model did not exhibit the histology consistently described with uremic calciphylaxis (i.e., small-vessel calcification and intimal hypertrophy in association with panniculitis and small-vessel thrombosis)2.
PATHOGENIC CONSIDERATIONS
It is important to review certain pathogenic factors. First, the presence of a uremic milieu together with a high Ca x P product has been in the majority of reports2,3,4,5. Diffuse vascular calcifications were frequently noted in the early days of maintenance dialysis6. Extraskeletal calcifications were noted in 20% of dialysis patients with secondary hyperparathyroidism (HPT)6; this number increased to 58% in patients with clinical evidence of HPT, and to 75% in patients with severe overt HPT7. Still, even in the early days, at a time when secondary HPT was common, calciphylaxis was uncommon.
Second, the Ca content of the skin was an important pathogenic factor because it was noted to be high in dialysis patients developing calcific uremic arteriolopathy (CUA)8. CUA also appeared to occur when a high dialysate Ca concentration of 4.0 mEq/L was used.9 In addition, a decrease in dialysate Ca dramatically improved CUA in some patients, whereas a high dialysate Ca concentration aggravated soft tissue calcification9. Furthermore, CUA was associated with hypercalcemia induced by large oral doses of calcium carbonate, and it was reversed by discontinuing Ca carbonate10. It is worth emphasizing that the use of Ca-containing binders is common, and that many dialysis patients still ingest large doses of elemental Ca. The long-term effect of this large Ca load on the dialysis population remains to be established. It is striking that almost all patients described in recent years who developed CUA were ingesting Ca-containing binders.
A third important pathogenic factor was the presence of high PTH levels. Earlier, it appeared that HPT was an important risk factor in the development of CUA4. Gipstein et al4 reported a series of patients with CUA, most with peripheral digital ulcers, in whom parathyroidectomy (PTx) resulted in dramatic healing of the ulcers and total disappearance of the syndrome in 61% of the patients. A period of marked hyperphosphatemia was present in each patient at some point prior to the appearance of CUA. Later, hyperphosphatemia was also associated with CUA6,11. In these patients, who had relatively low PTH levels, appropriate phosphorus restriction was shown to reverse CUA5,11.
CLINICAL CONSIDERATIONS
The skin lesions of calciphylxis usually begin as painful nodules or violaceous mottling similar to livedo reticularis, or as painful panniculitis. The lesions may be found in the distal extremities, involving the toes, fingers, or ankles (acral lesions), or they may be localized proximal to the knees and elbows, typically in areas rich in adipose tissue [e.g., the thighs, buttocks, abdominal wall, and breasts (proximal lesions)]. Occasionally they are bilateral and symmetrical. As the lesions progress and expand, they may become hemorrhagic, and deep ulcers and eschars may develop. Dry gangrenous digits can occur.
Histologically, the lesions are characterized by calcification of small subcutaneous arteries and arterioles, and infarctions of the adjacent subcutis and skin. The primary lesion appears to be the accumulation of calcium salts in the media of the small arteries and arterioles. Subsequently, the intima is thickened by loose connective tissue, which narrows the lumen, sometimes markedly, and compromises perfusion.
The clinical picture of calciphylxis has evolved over the last three decades, and from the increase in number of cases reported, the incidence of calciphylaxis may be on the rise. In the first descriptions in the late 1960s and early 1970s, calciphylaxis was noted to predominantly involve distal sites in uremic patients with clinically significant hyperparathyroid bone disease and elevated Ca x P product. A link between calciphylaxis and HPT was further supported by the early observation that PTx dramatically improved the syndrome4. Thus, ulcerations that had persisted for months healed dramatically within weeks following PTx4.
In the last 10 years, the clinical features of CUA have changed. At present, the great majority of the cases describes the lesions proximally, particularly in Caucasian women. Obesity has been recently described as a predisposing factor. Hypoalbuminemia and diabetes may be increased risk factors for calciphylaxis. With the advent of calcitriol and better control of HPT, other factors have surfaced and become more relevant in the triggering of CUA. As reported by Coates et al3 and Bleyer et al5, the presence of obesity is an important predisposing factor to developing CUA, especially in white women. Morbid obesity was present in 11 of our 14 patients (79%) with CUA12. Supposedly, areas rich in adipose tissue may be more prone to small-vessel damage, which may promote calcification before cutaneous lesions and necrosis of the skin become clinically apparent. Coates et al3 noticed a significant weight loss preceding the development of the skin lesion in 7 of 16 patients. Furthermore, Bleyer et al5 in a logistic regression analysis identified obesity and low serum albumin as highly predictive of CUA. Others have noted an association with insulin-dependent diabetes mellitus and CUA. Interestingly, in four patients the lesions developed in areas that had served as sites of insulin injection5.
The evolving nature of CUA is reflected in our clinical observations over the last five years of 22 patients with CUA 12]. Twenty patients were on HD and two had renal transplantations. All patients developed painful livido retucularis. Eighteen patients had proximal skin lesions (proximal CUA) and four had distal lesions (acral CUA). Sixteen patients were morbidly obese. All patients had elevated Ca x P product in the past, but only four patients had an elevated PTH (870 
234 pg/mL). On presentation, serum Ca, P, and PTH (<250) were seemingly controlled in some patients; however, when compared with a matched (for comorbid factors) ESRD population (100 patients), CUA patients had a higher serum Ca (corrected for serum albumin), phosphorus (P), and Ca x P product. Most importantly, in the 16 patients with proximal CUA, PTH levels were significantly lower (P> 0.01) than the control ESRD patients. Ten patients had previous parathyroidectomy (PTx) 1 to 3 years prior to presentation. All patients were ingesting large doses of Ca-containing phosphate binders (4.2 2.1 g/elemental Ca). Two patients were taking oral caltriol (.5 
g/day) and 15 were on intravenous calcitriol (1–3 g), despite the relatively low PTH (mean 250 pg/mL). Fourteen patients had skin biopsies that showed panniculitis, extensive Ca deposits within arteriole size and small vessel wall with endovascular fibrosis and fat necrosis. The four patients with high PTH levels (mean PTH> 800 pg/mL) underwent PTx, which resulted in resolution of the lesions in two patients, and improvement in one. In 10 patients with proximal CUA and relatively low PTH, Ca-containing binders were switched to Renagel and HD was performed five days/week using a low dialysate Ca (1 or 2 mEq/L). Five patients had significant improvement in CUA lesions and two patients had complete resolution of the lesions.
Local trauma, such as subcutaneous injections of heparin or iron dextran, may also be precipitating factors in the local development of CUA.5. The relative risk of CUA increased as weight increased. This is important because severe morbid obesity is uncommon in dialysis patients and these patients may be easily identified. The impression is that patients with proximal calciphylaxis have a poorer prognosis than those with acral CUA. Thus, Hafner et al13 evaluated the role of PTx in 38 of 58 patients who had survived, compared with 13 of 37 patients who did not undergo PTx13. Most importantly, 40 of the 53 patients (75%) with distal location of necrosis survived, compared with 11 of 42 patients (26%) with proximal CUA (P = 0.00001).
MANAGEMENT OF CALCIPHYLAXIS
The prognosis of patients with CUA is poor, with most dying of sepsis and ischemic events. The fact that we do not have a clear understanding of this syndrome makes therapy extremely difficult. In patients with CUA, the following therapy is recommended: (1) stop oral calcium, use non–Ca-containing binders, and try to control serum P to less than 6.0 mg/dL; (2) if the patient has laboratory evidence of overt HPT (intact PTH above 600 pg/mL), PTx should be performed on an emergent basis; (3) if laboratory evidence of significant HPT is not present, daily (5 or 6 days a week) dialysis with a low Ca dialysate may be beneficial12; (4) debridement, local wound care, and treatment of sepsis are crucial.
It is important to note that PTx should be performed only in selected cases. Early reports recommending PTx mostly described patients with severe HPT4. Later reports indicated PTx was not successful in many patients13. Chan et al14 reviewed 47 cases with CUA and noted that the survival rate of patients who underwent PTx was similar to those who did not. Not only did patients with low PTH levels develop CUA unresponsive to PTx, but CUA was also described in patients after PTx. Thus, the available data strongly suggest that PTx should not be performed in patients with low PTH. In a review of 47 patients with CUA, Budisavijevic et al15 described 31 patients who had PTx performed after the development of CUA. Fifty percent of those patients died within an average period of 9 weeks after PTx.
CONCLUSION
Factors associated with triggering CUA should be minimized. Thus, local injections in adipose areas where the lesions usually develop should be avoided whenever possible. Other potential factors in triggering CUA (e.g., blood products, corticosteroids, immunosuppressants) should be avoided. Hyperbaric oxygen therapy has improved CUA in continuous ambulatory peritoneal dialysis (CAPD) patients16.
References
- Selye H: Calciphylaxis, 1962 Chicago, University of Chicago Press, pp 15–40
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- Coates, T, Kirkland, GS, Dymock, RB, et al: Ischemic tissue necrosis (calciphylaxis) in renal failure. Am J Kidney Dis 1998 32: 384–391, | PubMed | ISI | ChemPort |
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- Bleyer, AJ, Choi, M, Igwenezie, B, et al: A case control study of proximal calciphylaxis. Am J Kidney Dis 1998 32: 376–383, | PubMed | ISI | ChemPort |
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- Llach, F, Goldblatt, M, Freundlich, RE, et al: The evolving pattern of calcific uremic arteriolopathy (calciphylaxis). J Amer Soc of Nephrol 2000 11: 685A,
- Hafner, J, Keusch, G, Wahl, C, et al: Uremic small artery disease with medial calcification and intimal hypertrophy (so-called calciphylaxis): A complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995 33: 954–962, | Article | PubMed | ISI | ChemPort |
- Chan, YL, Mahoney, JF, Turner, JJ, Posen, S: The vascular lesions associated with skin necrosis in renal disease. Br J Dermatol 1983 109: 85–95, | PubMed | ISI | ChemPort |
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