Early recognition and treatment of calciphylaxis. (Case Report).

Abstract: Calciphylaxis is a condition with a high mortality rate that is often found in patients with renal failure. It is characterized by soft tissue calcification and painful skin ulceration. A serum calcium-phosphorus product of more than 60 [mg.sup.2]/[dl.sup.2] indicates great risk for calciphylaxis. The diagnosis is made on the basis of an incisional biopsy showing calcification of the small, subcutaneous arteries.

Key Words: aged, calciphylaxis, diabetes mellitus

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Calciphylaxis (CPX) is a relatively rare condition characterized by soft tissue calcification and calcification in the medial layer of the small and medium-sized arteries. (1) This calcification of small and medium-sized arteries results in painful, indurated lesions that progress to the necrotic cutaneous ulcerations that are characteristic of CPX. If left untreated, CPX will progress to sepsis and death. Almost 90% of cases are seen in patients with chronic renal failure. (2,3) It has a mortality rate as high as Outcomes are thought to be improved by early recognition and treatment.

Case Report

A 69-year-old, nondiabetic native Mexican woman had developed end stage renal failure of unknown etiology 10 months before admission. Hemodialysis was initiated in Mexico twice per week and after 9 months was changed to peritoneal dialysis because of repeated episodes of hypotension during hemodialysis.

Three weeks after the initiation of peritoneal dialysis, she presented to the emergency department with chills, nausea, weakness, and shortness of breath. She was alert, oriented, and afebrile. Her body mass index was 32. A Grade 3/6 systolic murmur was heard at the apex. The abdomen was tender without rebound or guarding. A 2-cm indurated ulcer was noted on the lower abdomen. A peritoneal catheter was in place. There were scattered 1-cm necrotic ulcerations on the patient's lower extremities that were indurated and tender. There were also tender, indurated nodules on her legs.

Laboratory data showed the following abnormalities: blood urea nitrogen (BUN), 121 mg/dl (normal, 5-22 mg/dl); creatinine, 12.1 mg/dl (normal, 0.5-1.3 mg/dl); calcium, 7.7 mg/dl (normal, 8.7-10.6 mg/dl); phosphorus, 11.6 mg/dl (normal, 2.7-4.5 mg/dl); albumin, 2.7 g/dl (normal, 3.9-5 g/dl); alkaline phosphatase, 428 IU/L (normal, 3-36 IU/L); and intact parathyroid hormone, 517 pg/ml (normal, 10-65 pg/ml). The calcium-phosphate product was 89.3 [mg.sup.2]/[dl.sup.2] (normal, <60 [mg.sup.2]/[dl.sup.2]).

The patient was hospitalized and received hemodialysis with the use of temporary vascular access. After this dialysis, laboratory test values improved as follows: phosphorus, 6.2 mg/dl; calcium, 7.2 mg/dl; calcium- phosphorus product, 44.6 [mg.sup.2]/[dl.sup.2]; BUN, 43 mg/dl; and creatinine 5.5 mg/dl. During this hospitalization, she tolerated hemodialysis three times per week without any episodes of hypotension. The test for hepatitis B surface antigen (HBsAg) was positive, but the tests for antihepatitis C virus antibody (anti-HCV Ab) and anti-hepatitis A virus immunoglobulin M (anti-HAV IgM) were negative. A diagnostic peritoneal tap for suspected peritonitis returned purulent peritoneal fluid. Treatment with piperacillin/tazobactam (3.375 g/6 h) was started. On the day after admission, the peritoneal catheter was removed and the 2-cm abdominal wall ulcer was debrided. Pseudomonas aeruginosa was isolated from the peritoneal fluid cultures, and ciprofloxacin was substituted for piperacillin/tazobactam in the treatment regimen. Because of the characteristic nature of the painful, indurated skin ulcers, the diagnosis of CPX was entertained. An incisional biopsy of a l esion on the right leg showed necrotic skin with fibrinoid necrosis and thrombosis of the blood vessels with little inflammation. Serial sections failed to identify calcium within the vessels, however. Because the biopsy did not confirm the diagnosis of CPX, treatment with parathyroidectomy was not considered.

In spite of intensive wound care and continued hemodialysis, the patient's condition progressively deteriorated, and she had episodes of confusion and hallucinations. The parathyroid hormone level was measured and found to be 517 pg/ml (normal, 10-65 pg/ml). At that time, a parathyroidectomy was performed; postoperatively, the parathyroid hormone level was 7 pg/ml, and the ionized calcium level was 1.03 mg/dl (1.11-1.29 mg/dl). In spite of aggressive therapy, she developed sepsis and eventually died.

Discussion

The incidence of CPX is approximately 1% in patients with end-stage renal disease. It is more common in whites and seems to be three times more frequent in females. CPX has been reported in all age groups, in patients from 6 months to 83 years of age, with the average age of onset at 48 years. Renal failure is not the only clinical setting in which CPX occurs. (5) At least 10% of cases are associated with primary hyperparathyroidism, multiple myeloma, lymphoma, leukemia, and the milk-alkali syndrome.

Two distinct clinical patterns of CPX lesions have been described. The first is the centrally occurring pattern, which demonstrates lesions over the abdomen, thighs, and buttocks, and is associated with a mortality rate as high as 86%. This centrally occurring form is the most common form, occurring in 68% of cases. (6) The second form is the peripheral pattern, which demonstrates lesions below the knees and elbows. This peripheral pattern typically involves the digits and penis (prepuce and glans penis) (7) and has a reported mortality rate of 32%.

The typical patient at risk to develop CPX is obese (often morbidly obese), female, is undergoing dialysis for longstanding end-stage renal disease, and has secondary hyperparathyroidism, diabetes, hyperphosphatemia, and an elevated calcium-phosphate product (in the range of 60-70 [mg.sup.2]/[dl.sup.2]). In a case-control study of proximal CPX, the only factors associated with patients with CPX compared with other hemodialysis patients were white race, morbid obesity, and low serum albumin level. (8) A few CPX cases without elevated calciumphosphate products or elevated parathyroid hormone levels have been reported, but they are rare. An elevated calcium-phosphorus product of more than 60 [mg.sup.2]/[dl.sup.2] seems to be one of the more sensitive findings in considering the diagnosis of CPX. Although CPX is associated with calcium deposition in subcutaneous tissues, only 20% of patients with CPX have hypercalcemia.

In the clinical presentation of CPX, skin lesions appear suddenly as painful, indurated nodules, which may be associated with or preceded by livedo reticularis or bullae. The lesions quickly progress to central necrosis with eschar formation. They occur predominantly over fatty areas such as the abdomen, buttocks, and inner thighs. The lesions of CPX do not typically occur over the usual pressure points.

A generous incisional biopsy, rather than a punch biopsy, is the preferred method of diagnosis. The characteristic histologic findings are medial calcification of small vessels (0.1 mm in diameter), intimal proliferation, stenosis, and, frequently, intraluminal clotting. These findings are by no means absolute, because vascular calcification frequently occurs in end-stage renal disease.

The differential diagnosis of diseases that can cause tissue necrosis and simulate CPX is extensive. They include bullous pemphigoid, erythema nodosum, vasculitis, bullous lupus, Wegener's granulomatosis, dermatomyositis, warfarin necrosis, cryoglobulinemia, cryofibrinogenemia, antiphospholipid syndrome, proteins C and S deficiencies, cholesterol emboli, polyarteritis nodosa, peripheral vascular disease, and subacute bacterial endocarditis. Thus, diagnosis requires careful integration of the clinical findings, laboratory data, and pathologic findings.

The treatment of CPX consists of reducing the calcium-phosphate product by using various oral phosphate binders, using a low-calcium dialysate in hemodialysis, and treating any underlying hypercoagulable state with low-molecular-weight heparin. (9) Parathyroidectomy is an effective treatment for those patients with elevated levels of parathyroid hormone (10,11) and provides a 2:1 survival advantage. (12) Aggressive wound debridement and wound care are essential for the treatment of ulcerated lesions. Finally, hyperbaric oxygen has been reported to be effective in the wound healing of two cases of CPX skin ulcers. (13,14)

Conclusion

Because the overall mortality rate of patients with CPX is approximately 60%, early recognition is important, and early treatment to prevent ulcer occurrence appears to reduce the mortality rate. CPX occurs more commonly than reported, because the number of dialysis patients is increasing and the duration of dialysis is longer. Therefore, wider awareness and greater knowledge of this syndrome are necessary before the mortality rate can be reduced.

Accepted November 12, 2001

References

(1.) Hafner J, Keusch G, Wahl C, Burg G. Calciphylaxis: A syndrome of skin necrosis and acral gangrene in chronic renal failure. Vasa 1998;27:137-143.

(2.) Essary LR, Wick MR. Cutaneous calciphylaxis: An underrecognized clinicopathologic entity. Am J Clin Pathol 2000;113:280-287.

(3.) Mozcg D, Salsal J. Calciphylaxis: A review of pathogenesis, diagnosis and treatment. Univ Tor Med J 2000;77:98-102.

(4.) Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: Study of three cases with literature review. Hum Pathol 1995;26:1055-1064.

(5.) Fader DJ, Kang S. Calciphylaxis without renal failure. Arch Dermatol 1996;132:837-838.

(6.) Chan YL, Mahony JF, Turner JJ, Posen S. The vascular lesions associated with skin necrosis in renal disease. Br J Dermatol 1983;109:85-95.

(7.) Jhaveri FM, Woosley JT, Fried FA. Penile calciphylaxis: Rare necrotic lesions in chronic renal failure patients. J Urol 1998;160:764-767.

(8.) Bleyer AJ, Choi M, Igwemezie B, de la Torre E, White WL. A case control study of proximal calciphylaxis. Am J Kidney Dis 1998;32:376-383.

(9.) Coates T, Kirkland GS, Dymock RB, et al. Cutaneous necrosis from calcific uremie arteriolopathy. Am J Kidney Dis 1998;32:384-391.

(10.) Khafif RA, Delima C, Silverberg A, Frankel R, Groopman J. Acute hyperparathyroidism with systemic calcinosis: Report of a case. Arch Intern Med 1989;149:681-684.

(11.) Kane WJ, Petty PM, Sterioff S, McCarthy JT, Crotty TB. The uremic gangrene syndrome: Improved healing in spontaneously forming wounds following subtotal parathyroidectomy. Plast Reconstr Surg 1996;98:671-678.

(12.) Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): A complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954-962.

(13.) Vassa N, Twardowski ZJ, Campbell J. Hyperbaric oxygen therapy in calciphylaxis-induced skin necrosis in a peritoneal dialysis patient. Am J Kidney Dis 1994;23:878-881.

(14.) Dean SM, Werman H. Calciphylaxis: A favorable outcome with hyperbaric oxygen. Vasc Med 1998;3:115-120.

RELATED ARTICLE: Key Points

* Calciphylaxis occurs in up to 1% of patients on chronic hemodialysis and has approximately an 80% mortality rate.

* When the calcium-phosphate product ([Ca.sup.2+] [PO.sub.4]) is greater than 60 [mg.sup.2]/[dl.sup.2], the patient is at substantial risk for calciphylaxis developing.

* A generous incisional biopsy of the indurated ulcer is preferred for diagnosis rather than punch biopsy, which is often nondiagnostic.

* Treatment consists of reducing the calcium-phosphate product with phosphate binders, using a low calcium dialysate, and aggressive wound care.

* Parathyroidectomy is effective treatment in patients with elevated parathyroid hormone.

From the Division of Community Geriatrics, Department of Family and Community Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX.

Reprint requests to Robert W. Parker, MD, MC 7795, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9601-0053-0053