Using radiography to detect a biliary stent fracture and related bowel obstruction

Calciphylaxis: Necrotizing Skin Ulcers in End-Stage Renal Disease

Hani Bleibel, MD, Meharry Medical College, Nashville; Stephen Kim, MD, University of Pennsylvania, Philadelphia; and Nikhil Hemady, MD, FAAFP, Wayne State University, Pontiac

Published Online: March 2, 2008 - 6:14:16 PM (CST)

Hani Bleibel, MD

Resident
Internal Medicine Residency Program
Meharry Medical College
Nashville, Tenn

Stephen Kim, MD

Resident
Department of Internal Medicine
University of Pennsylvania
Philadelphia, Pa

Nikhil Hemady, MD, FAAFP

Associate Director
Family Medicine Residency Program
Assistant Professor and Vice-Chair
Department of Family Medicine
North Oakland Medical Centers
Wayne State University
Pontiac, Mich

Calciphylaxis (also known as calcific uremic arteriolopathy) is an uncommon necrotizing skin condition that mainly affects patients with chronic renal failure and often leads to fatal consequences. Chronic renal failure, hyperparathyroidism, hypercalcemia, and hyperphosphatemia are often implicated as sensitizing mechanisms that trigger the precipitation of calcium-phosphate crystals in the arterioles of the dermis and soft tissues, leading to ischemia and skin ulcerations. The diagnosis of calciphylaxis is mainly based on clinical judgment and is suggested by the characteristic ischemic skin lesions. Although skin biopsy can establish the diagnosis in most cases, biopsy is infrequently done, because of the risk of poor healing and secondary infections. Early recognition and multidisciplinary treatment of calciphylaxis are imperative, given the associated morbidity and mortality. Collaboration between the medical and surgical specialties is warranted. Despite aggressive treatment regimens, mortality continues to be high.

Calciphylaxis, also known as calcific uremic arteriolopathy, is an uncommon necrotizing skin condition characterized by excessive calcification of soft tissue and small arteries, leading to ischemic ulceration of the skin.¹ It most often affects patients with chronic renal failure or with secondary hyperparathyroidism. Early studies suggested that the prevalence of calciphylaxis among the dialysis population was about 1%; however more recent reports indicate it may be as high as 4%, possibly as a result of the greater use of calcium salts and vitamin D for the treatment of hyperphosphatemia in these patients.^2,3 If left untreated, calciphylaxis is associated with considerable morbidity and a mortality rate ranging from 60% to 80%.⁴

Pathophysiology

In 1962, Seyle first coined the term "calciphylaxis" after demonstrating a series of events that produced ectopic systemic calcification in a rat model.⁵ Two steps were required for the process. First, the rats were systemically sensitized with high doses of parathyroid hormone and vitamin D. After a critical time interval, challenging agents administered subcutaneously induced soft-tissue calcification.

In subsequent years, a syndrome characterized by systemic vascular calcification with ischemic necrosis and cutaneous ulcers was observed in uremic patients. Because of its resemblance to Seyle's animal model, it was named calciphylaxis. Since then, studies have shown that the pathologic findings in the animal model are not consistent with the clinical syndrome seen in humans.⁶ Still, the term "calciphylaxis" has persisted.

The pathogenesis of calciphylaxis has yet to be fully elucidated. Chronic renal failure, hyperparathyroidism, hypercalcemia, and hyperphosphatemia are often implicated as sensitizing factors that trigger the precipitation of calcium-phosphate crystals. Vascular calcification of the media of smallto medium-sized arteries leads to secondary ischemic epidermolysis and ulceration.⁷ However, even though abnormalities in parathyroid hormone (PTH), calcium, and phosphate levels are common among patients with chronic renal failure and hyperparathyroidism, few patients develop calciphylaxis. In addition, calciphylaxis has also been reported to occur in patients with normal renal function and normal PTH levels.⁸

Histopathology

Biopsy specimens typically demonstrate calcification within the media of small- and medium-sized arteries, with extensive intimal hyperplasia and fibrosis. A mixed inflammatory infiltrate is frequently seen. Subcutaneous calcium deposits with panniculitis and fat necrosis may sometimes be found. Vascular microthrombi are frequently evident. The classic finding is intimal proliferation with endovascular calcification and fibrosis, thus demonstrating a form of obliterative vasculopathy. Verhoeff-van Gieson (von Kossa's) stains, which are specifically used to stain calcium, can help identify calcium deposition within the tissues (Figure 1).^9,10

Figure 1 Calcium deposition. (A) Hematoxylin-and-eosin staining shows calcifications (purple color) in the walls of arterioles and inflammatory changes in the adipose tissue as a result of ischemia. (B) Calcium deposits can be confirmed by von Kossa's staining, which reveals calcium (black color) in the intima of small- and medium-sized arterioles. Arteriolar wall thickening can be seen in some small vessels; others have intraluminal fibrin clots.

Epidemiology

Calciphylaxis is an uncommon condition that affects 1% to 4% of patients with end-stage renal disease (ESRD).³ Reports suggest that the incidence may have increased during the last decade, possibly related to the more widespread use of parenteral vitamin D and iron dextran in patients with ESRD. The incidence of calciphylaxis in the general population is not known but is believed to be exceedingly low.⁷

Calciphylaxis affects whites more than blacks. The female-to-male ratio is approximately 3:1. The female predominance may be explained in part by increased fat mass.² This condition occurs in all age-groups, with cases reported in patients as young as 6 months and as old as 85 years.⁷ In one study, the incidence was higher in younger persons with ESRD who had a longer duration of dialysis therapy.³ The mean patient age is approximately 48 years.³

Clinical Presentations

The majority of patients with calciphylaxis have ESRD and are chronically on dialysis. On rare occasions, the condition occurs in a patient with chronic renal failure before the initiation of replacement therapy. Many patients with calciphylaxis have undergone renal allograft transplantation, and their allograft may still be functional when calciphylaxis develops. Recent noncompliance with dietary, medical, and/or dialysis recommendations is common in this patient population.^2,9,11

There is often a precipitating event or a characteristic risk factor, such as recent weight loss, obesity, dextran infusion, immune suppressive therapy, warfarin use, hyperphosphatemia, hyperparathyroidism, and hypoalbuminemia. Patients typically present with the sudden development of intensely painful, rapidly progressive cutaneous lesions. Such lesions may be singular or multiple; 90% are on the legs (Figure 2), typically involving the thighs and/or buttocks.¹² Infrequently, lesions may also be seen on the hands and torso.

Figure 2 Calciphylaxis. The patient in Panel A suffers from end-stage renal disease and has been treated with hemodialysis for more than 4 years. She has had ischemic, nonhealing necrotic ulcerations on her calves for more than 4 months. The patient in Panel B, who was on peritoneal dialysis, presented with a 2-month duration of well-demarcated erythema, hemorrhagic bullae, ulcers, and ecchymoses surrounded by skin thickening and tender subcutaneous indurations.

The early lesions of calciphylaxis have a nonspecific appearance, manifesting as violaceous mottling, livedo reticularis, erythematous papules, plaques, or nodules. Later, these lesions develop into a stellate purpuric configuration, with central cutaneous necrosis surrounded by firm cutaneous and subcutaneous indurations. Multiple lesions of variable duration may be present at the same time. Less often, calciphylaxis presents as bullae or as subcutaneous erythematous nodules resembling erythema nodosum.^7,13

Diagnosis

The diagnosis of calciphylaxis is based on clinical findings of the characteristic ischemic skin lesions, most often in a patient with chronic renal failure. Bone scanning showing abnormal uptake in the clinically apparent areas has a reported sensitivity of 97%.²

Figure 3 Plain radiograph of the thigh of the patient shown in Figure 2B, demonstrating densely calcified tissues and a lead, pipelike artery (arrow).

Plain films uniformly demonstrate vascular calcification within the dermis and subcutaneous tissue (Figure 3). However, this is a common finding in many patients with ESRD and is not specific to calciphylaxis.⁷

Biopsy of a skin lesion can confirm the diagnosis, if it shows the appropriate calcification of small arteries. In many cases, punch biopsies may not be adequate, because the depth of tissue obtained may not be sufficient for diagnosis. Thus, an incisional cutaneous biopsy is usually necessary. Nevertheless, skin biopsy in a patient with calciphylaxis is risky, because the biopsy site, which is subject to poor healing, may become infected. Therefore, a biopsy should only be performed when other means of attaining a diagnosis have been exhausted.⁹

The following laboratory values should be obtained when calciphylaxis is suspected:

Serum blood urea nitrogen
Creatinine
Serum calcium
Phosphate
PTH
Alkaline phosphatase
Albumin levels.

Hypercoagulable states should be excluded by measuring prothrombin time, activated partial thromboplastin time, protein C, protein S, anticardiolipin antibody, lupus anticoagulant antibody, factor V Leiden, and homocysteine levels. Cryoglobulinemia workup includes checking for serum cryoglobulin and rheumatoid factor, testing for hepatitis C antibody, and determining cryofibrinogen level.^2,7,9

Keep in mind that laboratory test results can only support the clinical diagnosis. There are no diagnostic threshold levels for PTH, calcium, or phosphate. Thus, these measurements are merely useful for excluding other pathologies and for supporting the diagnosis of calciphylaxis.¹¹

Treatment

Early recognition and multidisciplinary treatment of calciphylaxis are imperative, given the high morbidity and mortality associated with this condition. Collaboration between the medical and surgical specialties is warranted.⁴ Medical management should include an attempt to identify and eliminate the triggering event. Measures to correct the plasma calcium and phosphate concentration levels should be initiated.

For patients on dialysis, a low sodium calcium dialysate is appropriate. A recent report suggests that increasing the frequency of hemodialysis will optimize clearance and reduce plasma calcium and phosphate concentrations.¹⁴

Surgery should be consulted for diligent wound care, frequent debridement, and skin grafting or revascularization, if necessary. In many cases, aggressive wound care and debridement may be necessary to avoid infection and sepsis. In a recent study of 64 patients, the 12-year survival rate was 62% in patients receiving surgical debridement and only 27% in those who did not.¹⁵ Reports have shown that the use of a vacuum-assisted closure device and hyperbaric oxygen can be helpful in some patients with calciphylaxis, after extensive debridement and before skin grafting.^2,9

Parathyroidectomy for the treatment of calciphylaxis remains a controversial issue. Studies have shown equivocal results. Some studies have reported the resolution of pain, wound healing, and longer survival times when the parathyroid gland is removed.^16,17 The most recently published study, however, found no difference in survival rate between patients who underwent parathyroidectomy and those who did not.¹⁵ Further studies are needed to prove the efficacy of parathyroidectomy in these patients.

Novel therapies have been attempted. Within the past few years, several successful reports have shown success using maggot therapy and oral pentoxyfyllin (not currently available in the United States),¹⁸ bisphosphonates,¹⁹ and sodium thiosulfate.²⁰

Prognosis

The prognosis for a patient with calciphylaxis is generally poor, with a mortality rate ranging from 60% to 80%.⁴ Most patients succumb to sepsis from wound infection or organ failure caused by internal involvement. Survivors often undergo limb amputation and reconstructive surgery and are consequently severely disabled.

The location and progression of the skin lesions are significant factors in predicting the likely outcome. Proximal involvement lesions located on the trunk and areas proximal to the elbows and knees carries a poorer prognosis (63% mortality) than distally located lesions (23% mortality).² In addition, the presence of ulceration on the skin lesions is associated with a greater mortality rate.³ Early detection and treatment are essential to prevent further disease progression and possible fatality.

Conclusion

Calciphylaxis is an uncommon necrotizing skin disease that mainly affects patients with chronic renal failure and carries high mortality and morbidity rates. The mechanisms of this disease are not yet clear, and the diagnosis is established based on clinical data in the majority of cases. Deep-tissue biopsy can confirm the diagnosis of calciphylaxis but has a high rate of complications and should therefore be avoided when possible. Early recognition and a multidisciplinary approach to treatment are warranted. Despite aggressive management regimens, calciphylaxis continues to be associated with high mortality.

PRACTICE POINTS

Calciphylaxis occurs mainly in patients with end-stage renal disease.

Biopsy can confirm the diagnosis but is associated with increased risk of infection and should therefore be avoided when not absolutely necessary.

Risk factors include recent weight loss, obesity, dextran infusion, immune suppressive therapy, warfarin use, hyperphosphatemia, hyperparathyroidism, and hypoalbuminemia.

Diagnosis is based on clinical findings of the characteristic ischemic skin lesions in a patient presenting with a sudden, rapidly progressing and intensely painful lesion.

SELF-ASSESSMENT TEST

Which of the following findings is most characteristic of the ulcers of calciphylaxis?
1. Asymmetry
2. Painless
3. Slow developing
4. Well-demarcated

Which statement about calciphylaxis is true?
1. Women are more often affected than men
2. Blacks are more often affected than whites
3. It is a condition of old age
4. Incidence has decreased during the past few years

All the following situations have been identified as triggers for calciphylaxis, except:
1. Emotional stress
2. Obesity
3. Recent noncompliance with dietary recommendations
4. Warfarin use

All the following features are diagnostic of calciphylaxis, except:
1. Calcification of small arteries on biopsy
2. Vascular calcification in the subcutaneous tissue on x-ray
3. Hypophosphatemia
4. Hypercalcemia

Which lesion location is associated with the worst prognosis?
1. Trunk
2. Calves
3. Hands
4. Feet

(Answers at end of references list)

References

Hafner J, Keusch G, Wahl C, et al. Calciphylaxis: a syndrome of skin necrosis and acral gangrene in chronic renal failure. Vasa. 1998;27:137-143.
Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int. 2002;61:2210-2217.
Angelis M, Wong LL, Myers SA, et al. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery. 1997;122:1083-1090.
Bardsley S, Coutts R, Wilson C. Calciphylaxis and its surgical significance. ANZ J Surg. 2005;75:356-359.
Selye H. Calciphylaxis. Chicago, IL: University of Chicago Press; 1962.
Llach F. Calcific uremic arteriolopathy (calciphylaxis): an evolving entity? Am J Kidney Dis. 1998;32:514-518.
Mathur RV, Shortland JR, el-Nahas AM. Calciphylaxis. Postgrad Med J. 2001;77:557-561.
Goyal S, Huhn KM, Provost TT. Calciphylaxis in a patient without renal failure or elevated parathyroid hormone: possible aetiological role of chemotherapy. Br J Dermatol. 2000;143:1087-1090.
Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002;15:172-186.
Nikko AP, Dunningan M, Cockerell CJ. Calciphylaxis with histologic changes of pseudoxanthoma elasticum. Am J Dermatopathol. 1996;18:396-399.
Milas M, Bush RL, Lin P, et al. Calciphylaxis and nonhealing wounds: the role of the vascular surgeon in a multidisciplinary treatment. J Vasc Surg. 2003;37:501-507.
Budisavljevic MN, Cheek D, Ploth DW. Calciphylaxis in chronic renal failure. J Am Soc Nephrol. 1996;7:978-982.
Dear J, Brookes J, Mansell M, et al. Calciphylaxis. Lancet. 2003; 362:1707.
Don BR, Chin AI. A strategy for the treatment of calcific uremic arteriolopathy (calciphylaxis) employing a combination of therapies. Clin Nephrol. 2003;59:463-470.
Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56:569-579.
Girotto JA, Harmon JW, Ratner LE, et al. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130:645-651.
Arch-Ferrer JE, Beenken SW, Rue LW, et al. Therapy for calciphylaxis: an outcome analysis. Surgery. 2003;134:941-945.
Tittelbach J, Graefe T, Wollina U. Painful ulcers in calciphylaxis combined treatment with maggot therapy and oral pentoxyfillin. J Dermatolog Treat. 2001;12:214.
Monney P, Nguyen QV, Perroud H, et al. Rapid improvement of calciphylaxis after intravenous pamidronate therapy in a patient with chronic renal failure. Nephrol Dial Transplant. 2004;19:2130-2132.
Cicone JS, Petronis JB, Embert CD, et al. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis. 2004;43:1104-1108.

Answers: 1. D; 2. A; 3. A; 4. C; 5. A.