Progressive tumoral calcinosis as the presenting feature of sarcoidosis in a patient on haemodialysis treatment

Takashi Naito1, Kosaku Nitta1, Naoki Kimata1, Kazuho Honda1, Takumi Yoshida1, Miyuki Koinuma1, Yoko Ikeda1, Yoshiharu Kato2 and Hiroshi Nihei1

1 Department of Medicine, Kidney Centre and 2 Department of Orthopedics, Tokyo Women's Medical University, Tokyo, Japan

Correspondence and offprint requests to: K. Nitta MD, Department of Medicine, Kidney Centre, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.

Keywords: etidronate disodium; haemodialysis; sarcoidosis; tumoral calcinosis



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
Periarticular tumoral calcification is an infrequent, but severe, complication in uraemic patients. The genesis of tumoral calcification has generally been explained by a high calcium–phosphorus product (CaxP) and/or advanced secondary hyperparathyroidism after long-term haemodialysis (HD) treatment [1]. We observed a male patient who developed rapidly progressive tumoral calcinosis less than 1 year after the beginning of HD. He had sarcoidosis and a high CaxP product, but not severe hyperparathyroidism.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 39-year-old man was admitted in September 1995, because of appetite loss and general fatigue. Physical examination revealed marked uraemia, and HD was started three times a week on 26 September. However, bilateral ankle pain appeared immediately from the beginning of HD and the ankles gradually developed swelling and hyperaemia. Right wrist pain also developed in April 1996, and similar signs were noted bilaterally in knees, elbows and hips in succession from June to August 1996. Elevated CaxP product (>=70) and C-reactive protein (CRP) values were documented from the beginning of 1996 despite discontinuation of vitamin D therapy. In December 1996, systemic high fever and painful bilateral shoulder swelling appeared. Finally, because of large-joint involvement, he could no longer walk and lost 10 kg body weight in 1 year. He underwent regular HD for 4 h three times weekly using a conventional cuprophane hollow-fibre dialyser (1.6 m2). The composition of dialysate was as follows (mmol/l): Na 140, K 2.0, Ca 1.5, Mg 1.0, Cl 111, HCO3 25, acetate 10, glucose 1 g/l, Osmo 296 mosm/l.

He was admitted to our centre on 21 January 1997. Physical examination revealed cachexia, anuria, high fever of 38.7°C, systemic lymphadenopathy, hepatosplenomegaly and periarticular tumoral calcinosis of all large joints. Bilateral ocular fundi were unremarkable. A bone survey showed multinodular soft-tissue calcification in the area of the shoulders (20x30 cm), elbows, wrists, hip (30x40 cm), knees and ankles. A serum chemical analysis showed the following concentrations: BUN, 49.7 mg/dl; creatinine, 8.6 mg/dl; calcium 10.1 mg/dl; phosphorus, 7.3 mg/dl; albumin, 3.0 g/dl; total bilirubin, 0.5 mg/dl; aspartate aminotransferase, 15 IU/l (normal range, 6–25); alkaline phosphatase, 547 IU/l (bone type, 123 IU/l; normal range of total alkaline phosphatase, 80–260); leucine aminopeptidase, 180 IU/l (normal range, 80–170) and CRP, 5.3 mg/dl (normal range, <0.4).

The peripheral blood leucocyte count was 7600/µl (eosinophils, 1%; normal range, <7), haematocrit 27.8% and platelet count 16.0x104/µl. Intact parathyroid hormone (PTH) was 41 pg/ml; mid- region specific PTH, 5096 pg/ml; intact-osteocalcin, 16 ng/ml; tartrate-resistant acid phosphatase, 12.2 U/l; aluminium, <1.0 g/dl; PTH-related peptide, <1.1 pmol/l; 25-hydroxyvitamin D3, 7.5 ng/ml (normal range, 9–34); and 1,25-dihydroxyvitamin D3, 33.0 ng/ml (normal range, 15–50).

Radionuclide bone and gallium scintigrams demonstrated intense bilateral radiotracer uptake in the hip, shoulder, elbow, wrist, knee and ankle regions. Dual-energy X-ray absorptiometry showed low bone-mineral density in lumbar spine and radius forearm (lumbar 0.669 g/cm2, age matched -2.44; forearm 0.627 g/cm2, age matched -3.39).

Chest X-ray showed cardiomegaly, but no other abnormality. Echocardiogram showed mitral valve calcification and marked left ventricle (LV) hypertrophy (18 mm), LV contraction was normal. The abdominal and pelvic computed tomography (CT) showed bilaterally contracted kidney, diffuse gall bladder and pancreas swelling, marked hepatosplenomegaly, as well as para-aortic and celiac lymph node swelling and moderate numbers of ascites (Fig. 1Go).



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Fig. 1. The abdominal CT shows the swelling of paraaortic and celiac lymphnodes (A). They were significantly reduced after about 1 month of therapy (B).

 
We analysed periarticular fluid and the calcific mass located in the left shoulder. They were composed almost entirely of calcium phosphate and contained neither crystals of oxalate or calcium pyrophosphate nor amyloid deposition. Histological findings showed the typical features of tumoral calcinosis, i.e. histiocytic infiltration of connective tissue around central necrotic, calcarious masses. A bone biopsy obtained from the iliac crest demonstrated evidence for both increased bone reabsorption and impaired mineralization. Neither bone surface aluminium nor amyloid deposition were detected.

The lymph node retained its structure, although it showed atrophy of lymph follicles and sinus histiocytosis with erythrophagocytosis. At high-power noncaseating granulomas were found with Langhans-type giant cells and asteroid body in sinuses (Fig. 2Go). These findings were consistent with the diagnosis of sarcoidosis. Indeed, the patient had an increased serum angiotensin converting enzyme activity (48.9 IU/l; normal range 8.3–21.4).



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Fig. 2. Light-microscopic finding of PAS staining on a specimen of left inguinal lymph node. At high-power magnification, it shows noncaseating granuloma with polynuclear and Langhans-type giant cells in sinus. x400.

 
On 21 February we began treatment for tumoral calcinosis with oral etidronate disodium (EHDP) 300 mg/day (Didronel, Sumitomo Pharm. Co., Tokyo, Japan) and intravenous elcatonin 40 U (Elcitonin, Asahikasei Pharm. Co., Tokyo, Japan) every other day. On 10 March, oral prednisolone (PSL) therapy at an initial dose of 40 mg/day was also started for systemic lymphadenopathy and high fever. High fever and periarticular pain disappeared during PSL therapy, and CRP was negative in April 1997. PSL therapy also resulted in a gradual decrease in surface and/or abdominal lymphadenopathy. The follow-up CT on 26 March showed that para-aortic lymph nodes and ascites had decreased gradually under PSL therapy. Furthermore, the size of calcium deposits close to large joints was reduced after 3 months of combined therapy (Fig. 3Go). The patient was able to walk and drive a car in April 1997.



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Fig. 3. Radiographic appearance of periarticular tumoral calcification in the patient. Tumoral calcification was markedly reduced in the right shoulder. (A) Before therapy (23 January), (B) after therapy (19 May).

 


   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
We describe an unusual patient who had rapidly progressive tumoral calcinosis less than 1 year from the beginning of HD. Tumoral calcinosis had already occurred at the initiation of HD when both serum Ca and P concentrations were normal. Six months after initiation of HD, Ca and P, concentrations were continuously high. Schenkier and Gertner [2] reported tumoral calcinosis in a patient receiving continuous ambulatory peritoneal dialysis for only 7 months. Tezelman et al. [3] reported that recently tumoral calcinosis tends to be more frequent in uraemic patients with secondary hyperparathyroidism because of recent changes in the medical treatment of these patients.

As a rule calcitrol deficiency is found in patients with end-stage renal diseases because of diminished activity of the renal enzyme 25-hydroxyvitamin D3-1-hydroxylase, which catalyses calcitriol synthesis [4]. Occasionally, however, calcitriol is synthesized in extrarenal tissues. There is evidence of abnormal calcitriol production because 25-hydroxyvitamin D3-1-hydroxylase activity is abnormally regulated, in patients with tumoral calcinosis [5,6] including the hereditary form of tumoral calcinosis, [1,2,7].

Cases of tumoral calcinosis associated with sarcoidosis have been reported since the 1960s [8,9] and this was explained by extrarenal production of calcitriol by sarcoid granuloma [1012]. Adams et al. [12] demonstrated that cultured pulmonary alveolar macrophages from patients with active pulmonary sarcoidosis synthesized 1,25-(OH)2-D3 from 25-OH-D3 in vitro. Kalantar-Zadeh et al. [13] also reported hypercalcaemia in an anephric haemodialysis patient with sarcoidosis.

To treat tumoral calcinosis and systemic sarcoidosis reaction we used EHDP and elcatonin on the one hand, and steroids on the other hand. Russell et al. [14] demonstrated that bone reabsorption and soft-tissue calcification in experimental renal osteodystrophy is alleviated by diphosphonates [15]. Diphosphonates, such as EHDP, are synthetic analogues of pyrophosphate which inhibit soft-tissue calcification [16,17]. The effect of diphosphonates is not clearly understood, but several mechanisms have been proposed. They bind strongly onto crystal surfaces, prevent further crystal growth and increase dissolution of crystals by blocking bone reabsorption [18]. We also used elcatonin, a calcitonin analogue. Previous reports have shown that calcitonin had some effects on soft-tissue calcification [19]. Finally, the patient received steroids. This combined approach reduced soft-tissue calcification, fever and lymphadenopathy.



   References
 Top
 Introduction
 Case
 Discussion
 References
 

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Received for publication: 15. 7.98
Accepted in revised form: 22.12.98





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