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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 5  |  Page : 1068-1071
Subcutis calcinosis caused by injection of calcium-containing heparin in a chronic kidney injury patient

1 Department of Nephrology, La Rabta Hospital, Tunis, Tunisia
2 Department of Anatomo-pathology, La Rabta Hospital, Tunis, Tunisia
3 Laboratory of Renal Pathology, LR001SP, Tunisia

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Date of Web Publication2-Sep-2014


Subcutis calcinosis, characterized by abnormal calcium deposits in the skin, is a rare complication of using calcium-containing heparin occurring in patients with advanced renal failure. We report the case of an 83-year-old female, a known case of chronic kidney disease (CKD) for four years with recent worsening of renal failure requiring hospitalization and hemodialysis. She developed subcutis calcinosis following injection of calcium-containing heparin. Biochemical tests showed serum parathormone level at 400 pg/dL, hypercalcemia, elevated calcium-phosphate product and monoclonal gammopathy related to multiple myeloma. She developed firm subcu­taneous nodules in the abdomen and the thighs, the injection sites of Calciparin ® (calcium nadroparin) that was given as a preventive measure against deep vein thrombosis. The diagnosis of subcutis calcinosis was confirmed by the histological examination showing calcium deposit in the dermis and hypodermis. These lesions completely disappeared after discontinuing calcium nadro-parin injections. Subcutis calcinosis caused by injections of calcium-containing heparin is rare, and, to the best our knowledge, not more than 12 cases have been reported in the literature. Pathogenesis is not well established but is attributed to the calcium disorders usually seen in advanced renal failure. Diagnosis is confirmed by histological tests. Outcome is mostly favorable. The main differential diagnosis is calciphylaxis, which has a poor prognosis. Even though rarely reported, we should be aware that CKD patients with elevated calcium-phosphorus product can develop subcutis calcinosis induced by calcium-containing heparin. When it occurs, fortunately and unlike calci-phylaxis, outcome is favorable.

How to cite this article:
Fatma LB, El Ati Z, Azzouz H, Rais L, Krid M, Smaoui W, Maiz HB, Béji S, Zouaghi K, Zitouna M, Moussa FB. Subcutis calcinosis caused by injection of calcium-containing heparin in a chronic kidney injury patient. Saudi J Kidney Dis Transpl 2014;25:1068-71

How to cite this URL:
Fatma LB, El Ati Z, Azzouz H, Rais L, Krid M, Smaoui W, Maiz HB, Béji S, Zouaghi K, Zitouna M, Moussa FB. Subcutis calcinosis caused by injection of calcium-containing heparin in a chronic kidney injury patient. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Dec 3];25:1068-71. Available from: https://www.sjkdt.org/text.asp?2014/25/5/1068/139943

   Introduction Top

Low molecular weight heparin containing so­dium or calcium is widely used for the pre­vention and treatment of deep vein thrombosis. Subcutis calcinosis, characterized by abnormal calcium deposition in the skin, is a rare complication of using calcium-containing heparin in patients with advanced stages of chronic kidney disease (CKD). Herein, we report a case who developed marked subcutis calcinosis at the injection sites of calcium-containing heparin.

   Case Report Top

An 83-year-old woman was admitted to the hospital in January 2009 for management of renal failure. She had arterial hypertension for the previous 20 years and CKD for four years related to nephroangiosclerosis. Ultrasonography revealed small-sized kidneys, each measuring 8 cm in length.

Fifteen days after receiving thrombosis pro­phylaxis with subcutaneous calcium-containing heparin for 10 days, several asymptomatic sub­cutaneous nodules at the injection sites were noted.

These multiple nodules were firm, colorless, indolent, round to oval shaped and measuring up to 3 cm in diameter. It emerged at the sites where calcium-containing heparin had been injected, such as the abdomen and the ventral thighs. Laboratory investigations revealed serum creatinine at 6 mg/dL and creatinine clearance at 7 mL/min using the Cockroft-Gault formula, hypercalcemia at 109 mg/L, hyperphosphatemia at 70 mg/L, elevated serum levels of calcium- phosphate product at 7630 mg²/L² and hyper-parathyroidism with serum parathormone level at 400 pg/mL. Hemoglobin was 7 g/dL and immunoelectrophoresis showed a monoclonal gammapathy. Bone marrow aspirate revealed a diffuse plasmocyte infiltration of 16%. X-rays of the skeleton showed no lytic lesions. Based on the clinical and laboratory findings, multiple myeloma of Durie Salmon stage IIIB was diagnosed. The renal involvement was an acute exacerbation of renal failure most probably related to multiple myeloma tubulopathy. Echo-cardiography showed calcifications and narro­wing of aorta. Ultrasonography at the injection sites of calcium-containing heparin showed heterogenous, hypo-echogenic, focal dermal oval deposits [Figure 1].
Figure 1: Ultrasonography of the abdomen and ventral thighs showing heterogenous, hypoechogenic and hypodermic oval formations.

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A light microscopic study of a nodule revealed multiple foci of microcalcifications. Only the hematoxylin and eosin stain was used, as von Kossa staining was not available to us. These calcifications formed a palisade in the dermis and subcutis, obviously marking the area of subcutaneous injection. There was diffuse lymphomononuclear inflammation in the dermis and focal foreign body reaction in the subcutis [Figure 2] and [Figure 3]. The diagnosis of subcutis calcinosis was confirmed. Seven weeks after discontinuation of treatment with calcium-con­taining heparin, the lesions disappeared gra­dually without any specific treatment. No im­provement of renal failure was noted and the patient was continued on regular hemodialysis.
Figure 2: Skin biopsy showing nodule in the abdominal wall (HE ×10) with intact hypodermal layer.

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Figure 3: Skin biopsy with the nodule on the abdomen (HE ×30): Fragmented calcium deposits in the deep dermis surrounded by inflamatory cells corresponding to a focal foreign body reaction in the subcutis. Diffuse lymphomononuclear inflam-mation is seen in the dermis.

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   Discussion Top

Low molecular weight heparin containing calcium is routinely used for the prevention and treatment of thrombotic events. However, low molecular weight heparin is generally avoided in advanced CKD, when creatinine clearance is less than 30 mL/min. Local side-effects at the injection sites of calcium-containing heparin are rare and can be related to immunologic or non-immunologic origin, and may occur in various circumstances. To the best of our know­ledge, not more than 12 cases have been reported in the literature. No patient had plasma cell dis­order like in our case. This local side-effect presents as painful plaques and subcutaneous nodules, which may undergo necrosis. [1],[2] Le­sions predominantly involve regions rich in adipose tissue, such as the abdomen and thighs. [3] Delay for the lesions to appear may range from a few days, like in our case, to a few weeks.

The subcutis calcinosis has almost invariably been described in association with underlying disease, resulting in disturbed calcium-phos­phate balance such as CKD and hyperparathyroidism. Our patient had CKD, hyperparathyroidism and elevated calcium-phosphate pro­duct.

Depending on the pathophysiologic mecha­nisms, subcutis calcinosis has been classified as metastatic, dystrophic, idiopathic or iatrogenic. [4],[5] The first form includes metastatic calcifications that usually appear in the context of secondary hyperparathyroidism with abnormal calcium and/or phosphate metabolism. Calcifications predominantly affect the cardiovascular system, kidney, lung and the gastrointestinal tract. Cuta­neous metastatic calcifications are uncommon and are localized at the periarticular sites and fingertips. [6] Dystrophic calcifications are the result of calcium salt deposits in previously damaged or inflamed or necrotic tissue without disturbance of calcium or phosphate metabo­lism. This form is commonly seen in auto­immune connective tissue diseases such as sys­temic scleroderma. Some studies suggest that tissue necrosis caused by inflammation or in­jury may result in the release of alkaline phosphatase by damaged lysosomes. Alkaline phosphatase acts on organic phosphate, which usually inhibits crystal formation. This pheno­menon allows calcium precipitation. [2],[7] Idiopathic calcinosis is an uncommon disorder, spora­dic or associated with Down's syndrome, and it appears more often in childhood or adole­scence. Finally, iatrogenic calcification is due to the extravasation of calcium salts within the skin after intravenous administration of calcium or phosphate or after electroencephalography and electromyography. [8],[9],[10]

Light microscopy shows calcium deposits in both the dermis and the subcutis, like in our case, without necrosis or thrombosis. The dif­ferential diagnoses that should be considered include calciphylaxis, such as calcifying panniculitis that is a skin necrosis and may be seen in CKD patients with abnormal calcium-phos­phorous product, and calcification in hematoma occurring as a local side-effect of heparin or calcification of allergic reactions such as urti­caria and eczema. [11],[12],[13]

There is no specific therapy for subcutis calcinosis. All reported cases, as in our case, have resolved after discontinuation of the treatment with a mean delay of three months. [14],[15]

   Conclusion Top

Although rarely reported, subcutis calcinosis in patients with advanced CKD may occur as other heparins, such as fondaparinux or other low-weight molecular heparins, are avoided in patients with chronic kidney injury, resulting in a higher degree of use of calcium-containing heparin among them. The main differential diagnosis is calciphylaxis, which has a poor prognosis, unlike subcutis calcinosis, in which the outcome is generally favorable.

   References Top

1.Koch P, Munssinger T, Rupp-John C, Uhl K. Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: Tolerance of a new recombinant hirudin. J Am Acad Dermatol 2000;42:612-9.  Back to cited text no. 1
2.Eich D, Scharffetter-Kochaneck K, Weihrauch J, Krieg T, Hunzelmann N. Calcinosis of the cutis and subcutis: An unusual nonimmunologic adverse reaction to subcutaneous injections of low-molecular-weight calcium-containing heparins. J Am Acad Dermatol 2004;50:210-4.  Back to cited text no. 2
3.Buchet S, Blanc D, Humbert P, et al. Calcifying Panniculitis. Ann Dermatol Venereol 1992;119: 659-66.  Back to cited text no. 3
4.Bhatia S, Silverberg NB, Don PC, Weinberg JM. Extensive calcinosis cutis in association with systemic lupus erythematosus. Acta Derm Venereol 2001;81:446-7.  Back to cited text no. 4
5.Reiter N, El-Shabrawi L, Leinweber B, Berghold A, Aberer E. Calcinosis cutis: Part I. Diagnostic pathway. J Am Acad Dermatol 2011;65:1-12.  Back to cited text no. 5
6.Touart DM, Sau P. Cutaneous deposition diseases. Part II. J Am Acad Dermatol 1998; 39:527-44.  Back to cited text no. 6
7.Boulman N, Slobodin G, Rozenbaum M, Rosner I. Calcinosis in rheumatic diseases. Semin Arthritis Rheum 2005;34:805-12.  Back to cited text no. 7
8.Ahn SK, Kim KT, Lee SH, Hwang SM, Choi EH, Choi S. The efficacy of treatment with triamcinolone acetonide in calcinosis cutis following extravasation of calcium gluconate: A preliminary study. Pediatr Dermatol 1997;14: 103-9.  Back to cited text no. 8
9.Handschin AE, Trentz O, Kock HJ, Wanner GA. Low molecular weight heparin-induced skin necrosis-a systematic review. Langenbecks Arch Surg 2005;390:249-54.  Back to cited text no. 9
10.Giorgini S, Martinelli C, Massi D, Lumini A, Mannucci M, Giglioli L. Iatrogenic calcinosis cutis following nadroparin injection. Int J Dermatol 2005;44:855-7.  Back to cited text no. 10
11.Bonnecarrère L, Templier I, Carron PL, et al. Two cases of iatrogenic cutis and subcutis calci-nosis after calcium-containing heparin injection. J Mal Vasc 2009;34:366-71.  Back to cited text no. 11
12.Richens G, Piepkorn MW, Krueger GG. Calcifying panniculitis associated with renal failure. A case of Selye's calciphylaxis in man. J Am Acad Dermatol 1982;6:537-9.  Back to cited text no. 12
13.Foo CC, Wong SN. Calciphylaxis with a pro­tracted course in a patient with end-stage renal failure. Am J Clin Dermatol 2007;8:55-8.  Back to cited text no. 13
14.Campanelli A, Kaya G, Masouyé I, Borradori L. Calcifying panniculitis following subcutaneous injections of nadroparin-calcium in a patient with osteomalacia. Br J Dermatol 2005;153: 657-60.  Back to cited text no. 14
15.Boccara O, Prost-Squarcioni C, Battistella M, Brousse N, Rongioletti F, Fraitag S. Calcinosis cutis: A rare reaction to subcutaneous injections of calcium-containing heparin in patients with renal failure. Am J Dermatopathol 2010;32:52-5.  Back to cited text no. 15

Correspondence Address:
Dr. Lilia Ben Fatma
Nephrology Department, La Rabta Hospital, Jabbari, 1007, Tunis
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DOI: 10.4103/1319-2442.139943

PMID: 25193911

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