Medial arterial calcification mimicking temporal arteritis

CASE REPORT

Medial Arterial Calcification Mimicking Temporal Arteritis Ahmed I. Al-Absi, MD, Barry M. Wall, MD, and C. Robert Cooke, MD ● Medial arterial calcification, which has been increasingly recognized in end-stage renal disease (ESRD) patients, has been associated with acutely symptomatic vascular complications including calcific uremic arteriolopathy (calciphylaxis) and ischemic changes in the extremities. This report describes a 50-year-old ESRD patient on maintenance hemodialysis in whom medial arterial calcification developed with features mimicking the findings of temporal arteritis. He complained of persistent bilateral temporal area headaches with associated symptoms of blurred vision; pain in his shoulders, hips, and knees; and intermittent symptoms consistent with jaw claudication. He was not receiving calcium or vitamin D supplements. Superficial temporal arteries were dilated, tortuous, nodular, and tender to palpation. Ophthalmologic examination was unremarkable, except for the presence of peripapillary atrophy. Temporal artery biopsy results showed medial arterial calcification with mild inflammatory changes. No giant cells were identified. Additional long-term complications of medial arterial calcification have included the development of painful ischemic ulceration of the glans penis and extensive mitral annulus calcification detected by echocardiography. The findings in this patient show that clinical manifestations of medial artery calcification associated with ESRD can mimic those seen with other vascular diseases. Am J Kidney Dis 44: E73-E78. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Medial arterial calcification; calcific uremic arteriolopathy; hemodialysis; giant cell arteritis; end-stage renal disease (ESRD).

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ONCKEBERG’S SCLEROSIS (medial arterial calcification), first described in diabetic patients, has been increasingly recognized in patients with end-stage renal disease (ESRD, both diabetic and nondiabetic), and has been associated with calcific uremic arteriolopathy.1-6 Calcific uremic arteriolopathy, which has been reported to occur in up to 4% of ESRD patients receiving hemodialysis, is a life-threatening condition characterized by progressive skin lesions that typically include tender firm plaques or subcutaneous nodules.4-6 Skin biopsy specimens obtained from involved areas of skin show vascular calcifications in the tunica media, predominantly in the subcutaneous fat and dermis. These lesions typically progress to occlusion of the arteriole leading to skin infarctions.6 In addition to calcific uremic arteriolopathy, medial arterial calcification has also been associated with ischemic changes in the distal extremities leading to necrosis of digits and to penile calciphylaxis leading to necrosis of the glans penis.7 In this report, we describe a patient on hemodialysis in whom the symptoms of medial arterial calcification mimicked the clinical findings of temporal arteritis. The findings in this patient show that clinical manifestations of medial artery calcification associated with ESRD can mimic those seen with other vascular diseases.

CASE REPORT A 50-year-old African-American man on hemodialysis complained of bilateral temporal area headaches that had persisted over 2 months and were associated with the more recent onset of blurred vision. He had also noted the occurrence of jaw claudication with chewing and arthralgias that involved both shoulders, hips, and knees. He denied fever, weight loss, dysarthria, diplopia, vertigo, or claudication in his extremities. He was not receiving calcium or vitamin D analogues. Compliance with medications and dialysis had been erratic. Medical history included hypertension leading to ESRD requiring hemodialysis in 1990, cadaveric kidney transplantation in 1994, and return to hemodialysis in 1998 after allograft failure owing to chronic rejection. His blood pressure was often poorly controlled because of noncompliance and cocaine abuse. Funduscopic examination found peripapillary atrophy but no papilledema, exudates, or hemorrhages. Visual acuity was intact. Temporal arteries were dilated, tortuous, and tender on palpation (Fig 1). Radial arteries were thickened and firm, with bilaterally positive findings with Osler’s maneuver. No skin lesions were present.

From the Department of Nephrology, University of Tennessee Health Science Center, Veterans Affairs Medical Center, Memphis, TN. Received May 18, 2004; accepted in revised form June 30, 2004. Address reprint requests to Barry M. Wall, MD, VAMC, Nephrology Section (111B), 1030 Jefferson Ave, Room G410, Memphis, TN 38104. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4404-0031$30.00/0 doi:10.1053/j.ajkd.2004.06.017

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Fig 1. Prominent dilated tortuous temporal artery.

Laboratory Evaluation

Hospital Course

Hematocrit value was 33%, white blood cell count was 9.1/mm3 (67% neutrophils, 19% lymphocytes, 11% monocytes, 0.4% eosinophils), platelet count was 258,000, and erythrocyte sedimentation rate was 101 mm/h. Serum calcium concentration was 8.0 mg/dL (2.00 mmol/L), phosphorus concentration was 7.5 mg/dL (2.42 mmol/L), and intact parathyroid hormone was 1,128 pg/mL (ng/L; normal, ⬍65 pg/ml [ng/L]). Time averaged calcium phosphorus products were 70 to 80 (Figs 2 and 3). Results of tests for antinuclear antibodies and antineutrophil cytoplasmic antibodies were negative.

Based on the clinical, ophthalmologic, and laboratory findings, methylprednisolone was administered and temporal artery biopsy was performed. Histologic sections showed the presence of diffuse medial arterial calcification with mild inflammatory changes. No giant cells or panarteritic changes were identified (Fig 5). Based on these findings, steroid therapy was discontinued, and daily hemodialysis was performed to lower the serum phosphorus concentration and calcium ⫻ phosphorus product. Parathyroidectomy was recommended but declined by the patient. During long-term follow-up, headaches have decreased in frequency, and there has been no deterioration in visual acuity. Additional complications, however, have included the development of painful ischemic ulceration of the glans penis and the presence of extensive mitral annulus calcification, detected by echocardi-

Radiologic Evaluation Extensive soft tissue vascular calcifications were present in both hands (Fig 4).

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Fig 2. Serum calcium concentration (solid line) increased and serum phosphorus concentration (dashed line) decreased after successful kidney transplantation. Serum calcium concentrations were decreased mildly, and phosphorus concentrations were increased markedly after failure of the allograft and return to hemodialysis. To convert calcium and phosphorus in mg/dL to mmol/L, multiply by 0.2495 and 0.3229, respectively.

ography. Discomfort in the shoulders and hips has persisted, consistent with clinical manifestations of hyperparathyroidrelated bone disease.

DISCUSSION

Giant cell arteritis, a disease of persons greater than 50 years of age, is characterized clinically by symptoms reflecting end-organ ischemia owing to involvement of branches of the external and internal carotid arteries.8,9 This involvement

leads to the classical manifestations of headache, scalp tenderness, jaw claudication, and visual impairment. The diagnosis of giant cell arteritis is confirmed by biopsy of the temporal arteries, showing panarteritis with mononuclear cell infiltrates penetrating all layers of the arterial wall.8-10Activated T cells and macrophages often are aggregated in granulomas in association with multinucleated giant cells. The intimal layer

Fig 3. The markedly increased calcium phosphorus products (solid line) and intact parathyroid hormone levels (dashed line) normalized after successful kidney transplantation. After failure of the allograft and return to hemodialysis, severe secondary hyperparathyroidism and markedly elevated calcium phosphorus products recurred. To convert intact parathyroid hormone in pg/mL to ng/L, multiply by 1.

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Fig 4. Radiograph of the hand shows extensive vascular calcifications.

of the vessels is hyperplastic, leading to concentric occlusion of the vascular lumen. Vascular calcifications are uncommon. Castillo et al11 described the occurrence of focal vascular calcifications in only 6% of temporal artery biopsy specimens in a large series of patients with giant cell arteritis. Our patient’s symptoms closely mimicked those associated with giant cell arteritis. However, temporal artery biopsy showed the presence of medial arterial calcification with minimal inflammation. Plain radiographs of the

hands documented extensive small vessel medial arterial calcification (Fig 4). Medial arterial calcification occurs predominantly in muscular-type conduit arteries, including femoral, tibial, radial, coronary, cerebral, and visceral vessels, leading to increased arterial stiffness.1,2,12 Whereas the majority of patients are asymptomatic, medial arterial calcification contributes to the high cardiovascular morbidity and mortality of ESRD patients.1-3 The presence and extent of medial arterial calcification in

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Fig 5. Temporal artery biopsy with mild inflammatory changes, absence of giant cells, and extensive medial arterial calcification.

ESRD patients are independently predictive of subsequent cardiovascular disease and mortality, even after adjustment for conventional risk factors.1,2 Medial arterial calcification has also been associated with acute vascular complications, including calcific uremic arteriolopathy and ischemic changes in the distal extremities.4-7 Risk factors that have been associated with medial arterial calcification in ESRD patients include increasing age, duration of dialysis therapy, severity of hypertension, serum phosphorus concentrations, calcium ⫻ phosphorus product, and oral calcium intake.1,2,13 In contrast to the focal intimal calcifications that are associated with atherosclerotic lesions and are discontinuous along the course of arteries, medial arterial calcification in patients with chronic and/or ESRD occurs diffusely in the tunica media of muscular arteries.1,2 The process of vascular calcification in these patients resembles new bone formation. Vascular smooth muscle cells have been shown to be capable of differentiation into phenotypically distinct cells capable of mineralization and production of bone matrix proteins including osteopontin, bone sialoprotein, matrix GLA protein, osteocalcin, and bone morphogenic protein, in vitro.1,13-17 Stimuli that have been shown to induce this process of differentiation include oxidized low-density lipoprotein, parathyroid hormone, vitamin D, and

phosphorus.13-17 Hyperphosphatemia, in ranges typically present in ESRD, has been shown to independently induce calcification of vascular smooth muscle cells in vitro in a dose-dependent manner.15 Therapy of acute vascular complications related to medial arterial calcification is primarily supportive, including aggressive wound care, an intensive dialysis schedule to maximize phosphate removal, and minimizing dietary phosphate intake.5,17 In patients with hypercalcemia or markedly elevated calcium ⫻ phosphorus products, the use of noncalcium containing PO4 binders and discontinuation of vitamin D analogues may also be indicated. Parathyroidectomy should only be recommended in those patients with documented medically refractory secondary hyperparathyroidism.17 ACKNOWLEDGMENT The authors thank T.A. Mangold for her assistance with the production of the figures.

REFERENCES 1. Goodman WG, London G: Vascular calcification in chronic kidney disease. Am J Kidney Dis 43:572-579, 2004 2. London GM, Guerin AP, Machais SJ, Metivier F, Pannier B, Adda H: Arterial media calcification in end stage renal disease: Impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731-1740, 2003

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3. Blacher J, Guerin AP, Pannier B, et al: Arterial calcifications, arterial stiffness, and cardiovascular risk in endstage renal disease. Hypertension 38: 938-942, 2001 4. Shanahan CM, Cary NRB, Salisbury JR, et al: Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: Evidence for smooth muscle cell-mediated vascular calcification. Circulation 100: 2168-2176, 1999 5. Russell R, Brookshire MA, Zekonis M, Moe SM: Distal calcific uremic arteriolopathy in a hemodialysis patient responds to lowering Ca x P product and aggressive wound care. Clin Nephrol 58:238-243, 2002 6. Angelis M, Wong LL, Myers SA, Wong LM: Calcifylaxis in patients on hemodialysis: A prevalence study. Surgery 122:1083-1090, 1997 7. Karpan E, Das S, Kurzrock EA: Penile calciphylaxis: Analysis of risk factors and mortality. J Urol 169:22062209, 2003 8. Weyand CM, Goronzy JJ: Medium- and large-vessel vasculitis. N Engl J Med 349:160-169, 2003 9. Brack A, Martinez-Taboada V, Stanson A, et al: Disease pattern in cranial and large-vessel giant cell arteritis Arthritis Rheum 42:311-317, 1999

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10. Weyand CM, Goronzy JJ: Arterial wall injury in giant cell arteritis. Arthritis Rheum 42:844-853, 1999 11. Castillo BV Jr, Orczynski E, Edward DP: Monckeberg’s sclerosis in temporal artey biopsy specimens. Br J Ophthalmol 83:1091-1092, 1999 12. Guerin AP, London GM, Marchais SJ, et al: Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 15:1014-1021, 2000 13. Reslerova M, Moe SM: Vascular calcification in dialysis patients: Pathogenesis and consequences. Am J Kidney Dis 4:S96-S99, 2003 (supp 1) 14. Ahmed S, O’Neill KD, Hood AF, et al: Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis 37:1267-1276, 2001 15. Chen NX, O’Neill KD, Duan D, et al: Phosphorous and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int 62:1724-1731, 2002 16. Moe SM, O’Neill KD, Duan D, et al: Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 61:638-647, 2002 17. Moe SM: Calcific uremic arteriolopathy: A new look at an old disorder. Nephrology Self-Assessment Program 3:77-83, 2004