Saudi Journal of Kidney Diseases and Transplantation

CASE REPORT
Year
: 2017  |  Volume : 28  |  Issue : 1  |  Page : 154--157

Denosumab for the treatment of bisphosphonate resistant hypercalcemia in a hemodialysis patient


Omar Dahmani1, Christine Sophoclis2, Malika Kebir2, Djemai Bouguern1, Aboubacry Sakho2, Pascale Demarchi1,  
1 Department of Nephrology and Dialysis, Hospital Louis Jaillon, Saint-Claude, France
2 Secondary Care, Hospital Louis Jaillon, Saint-Claude, France

Correspondence Address:
Omar Dahmani
Department of Nephrology and Dialysis Hospital Louis Jaillon, Saint-Claude
France

Abstract

The acronym of malignancy, iatrogenic, intoxication and immobilization, sarcoidosis, hyperparathyroidism and hyperthyroidism, milk-alkali syndrome, and paget is very helpful in diagnosing hypercalcemia. We report on a 94-year-old patient with history of end-stage renal failure secondary to benign nephroangiosclerosis, who was on maintenance hemodialysis during dialysis, his blood chemistry revealed mild hypercalcemia (2.66 mmol/L) with normal level of intact primary hyperparathyroidism (32.37 ng/mL) mandating the discontinuation of Vitamin D[3]. In view of persisting hypercalcemia, denosumab 60 mg/mL was administrated subcutaneously. The serum calcium level showed a decrease and stabilized at near upper limit (2.57 mmol/L). Three weeks later, the serum calcium remained mildly elevated fluctuating between 2.66 and 2.80 mmol/L.



How to cite this article:
Dahmani O, Sophoclis C, Kebir M, Bouguern D, Sakho A, Demarchi P. Denosumab for the treatment of bisphosphonate resistant hypercalcemia in a hemodialysis patient.Saudi J Kidney Dis Transpl 2017;28:154-157


How to cite this URL:
Dahmani O, Sophoclis C, Kebir M, Bouguern D, Sakho A, Demarchi P. Denosumab for the treatment of bisphosphonate resistant hypercalcemia in a hemodialysis patient. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2022 Sep 27 ];28:154-157
Available from: https://www.sjkdt.org/text.asp?2017/28/1/154/198239


Full Text

 Introduction



The acronym of malignancy, iatrogenic, intoxication and immobilization, sarcoidosis, hyperparathyroidism and hyperthyroidism, milkalkali syndrome, and paget is very helpful in diagnosing hypercalcemia. In patients with normal renal function, 90% of cases of hypercalcemia are mainly related to cancers and primary hyperparathyroidism (PTH). In endstage renal failure (ESRF), iatrogenic, secondary hyperparathyroidism, and cancers are responsible for 90% of cases of hypercalcemia.[1] ,[2] Hypercalcemia is classified as mild, moderate, and severe, and PTH-mediated and non-PTH- mediated.[3] The most common cause of nonPTH-mediated hypercalcemia is malignancy, usually observed in hospitalized patients. The mechanism of tumor-induced hypercalcemia includes (a) paraneoplastic syndrome secreting PTH-related peptide, (b) osteolytic metastasis by releasing cytokines and lymphokines that promote osteoclastic activity, and (c) tumor producing 1,25(OH) Vitamin D. Hypercalcemia is classified as absorptive, resorptive, and renal and in some circumstances, all three mechanisms are involved. The treatment of such condition is usually based on the suppression of the etiologic factors, symptomatic, and by increasing the removal of the excess calcium. Combined approaches are often needed to overcome this overwhelming condition.

 Case Report



We report on a 94-year-old patient with history of ESRF secondary to benign nephro angiosclerosis, who was on maintenance hemodialysis. He had a history of aortic valve replacement, hypothyroidism, gouty arthritis, left retinal vein thrombosis, and prostatectomy for adenocarcinoma. He had dialysis through a right tunneled catheter after a failed vascular access creation. During this period of observation, he developed two episodes of bronchopneumonia and severe gastroenteritis on top of diverticular sigmoiditis. Three months earlier, he presented with left submandibular lymph node enlargement consistent with nonspecific inflammation after fine needle aspiration. Computerized tomography (CT) scan of the neck and thorax did not show any catheterrelated complications. The patient had stable hemodynamic parameters and was afebrile. He had lost weight, which was attributed to poor appetite and difficulty in swallowing both solids and liquids. He presented with sluggish pain during neck rotation. Initial laboratory testing showed raised urea and creatinine, normal liver function tests, and calcium level at the upper limit. Serum protein electrophoresis showed no abnormality apart of hypoalbuminemia. Further testing revealed elevated ionized calcium of 1.35 mmol/L (range 1.09- 1.30), elevated lactate dehydrogenase of 237 U/L (range 91-223), elevated intact PTH of 187.7 pg/mL (range 15-65), low Vitamin D2+D3 of 35.4 nmol/L (>75), and normal 1,25(OH)2 Vitamin D of 35 pg/mL (20-60). Zinc, aluminum, folic acid, and B[12] levels were within the normal range. Liver function tests were normal, and prostate-specific antigen was 0.003 ng/mL (<4). He was negative for hepatitis C, B, and human immunodeficiency virus. During his stay, upper gastrointestinal endoscopy showed the presence of patchy pharyngeal and upper esophagus candidiasis that was resistant to fluconazole. On the 3rd day of stay, he fell down from his bed and had minor trauma with ecchymosis of the front and worsening neck pain. The painkiller was changed to paracetamol/tramadol supplemented by Vitamin D3 (UVEDOSE) 100,000 IU every two months. The other treatment included high-dose darbepoetin alpha targeting a hemoglobin level between 10.5 and 12 g/dL despite thrombocytopenia, pantoprazole, alfuzosin, and zolpidem. Unfortunately, his pain became worse and initial plain X-ray failed to show any fracture. However, CT scan of cervical spine showed type II odontoid vertebral fracture requiring external immobilization for three months. By the end of the 1st month, blood chemistry revealed mild hypercalcemia (2.66 mmol/L) mandating the discontinuation of Vitamin D3. Despite using dialysate bath containing low calcium (calcium 1.25 mmol/L), the serum calcium continued to rise reaching 3.64 mmol/L by the 6th month. Repeat blood test showed a normal level of intact PTH of 32.37 ng/mL, Vitamin D[2]+D[3] level of 57.84 nmol/L, increased level of 1,25(OH)[2]D[3] at 92 pg/mL, and elevated alkaline phosphatase at 248 IU/L. Thoracoabdominal and pelvis CT scan revealed signs of pulmonary fibrosis with mild pulmonary artery hypertension. There were multiple lymph nodes in the mediastinum. He was started on weekly 60 mg of pamidronate disodium administrated at the end of dialysis for four weeks without any significant modification of his serum calcium. In view of persisting hypercalcemia, denosumab 60 mg/mL was administrated subcutaneously. The serum calcium level showed a decrease and stabilized at near upper limit (2.57 mmol/ L). Three weeks later, the serum calcium remained mildly elevated fluctuating between 2.66 and 2.80 mmol/L.

 Discussion



The most common abnormality of mineral bone disease encountered in dialyzed patients is renal osteodystrophy. It has skeletal and extraskeletal manifestations. The occurrence of hypercalcemia in ESRF is related to medications, secondary hyperparathyroidism, or malignancy. Suppression of the offending agent including calcium-containing phosphate binders and Vitamin D derivatives usually leads to the correction of this metabolic derangement. Secondary hyperparathyroidism could be challenging in the presence of normal calcium level and mild elevated intact PTH. There is great discrepancy between clinical, biochemical, and bone morphology findings. A diagnosis can be established easily by measuring corrected serum calcium, ionized total calcium, alkaline phosphatase, 25(OH) Vitamin D, 1,25(OH)[2] Vitamin D, and PTH concentrations.[1] Our patient had initial laboratory workup suggestive of mild secondary hyperparathyroidism with reduced 25(OH) Vitamin D2+D3 but with normal 1,25(OH)2 Vitamin D level. This alerted us to the existence of a possible extrarenal hydroxylation associated with granulomatous disease due to gouty arthritis and tophaceous lesions or hematological tumors. Such conditions have been reported in patients having granulomatous diseases (tuberculosis, leprosy, scabies, fungal infection, berylliosis, and silicone, AIDS- related, pneumocystis carinii, Wegener granulomatosis, extensive granulomatous foreign body reaction, Crohn's disease, and sarcoidosis) and cancer.[4] ,[5] ,[6] ,[7] Extrarenal 1 alphahydroxylation is due to activated macrophage and dendritic cells surrounding the granuloma. Our patient was not receiving calcium compounds or Vitamin D derivatives. He developed severe hypercalcemia after the introduction of 25(OH)D[3] to relieve bony pain in the presence of odontoid fracture. In contrast to Deluca et al, [8] high level of 1,25(OH)[2] Vitamin D was probably the mainstay of the observed toxicity. Our patient was having low level of PTH-related peptide that is reportedly elevated in malignancy-associated hypercalcemia. Hypercalcemia associated malignancy has been described to respond well to bisphosphonates.[9] ,[10] The co-existence of severe symptomatic hypercalcemia with a PTH level within the reference range suggested the presence of conditions producing an increase in serum calcium,[11] but opposite effects on PTH (PTH-dependent and PTH-independent hypercalcemia). All measures failed to correct this severe hypercalcemia, including pamidronate infusion. To avoid dialyzability of pamidronate, it was prescribed at the end of dialysis. Clodronate, pamidronate, and ibandronate are also readily dialyzable, enabling them to be used in dialysis patients according to Bergner study.[12] Persisting-resistant hypercalcemia usually responds well to either denosumab or gallium nitrate.[13] The former has proven to be better than bisphosphonates for the prevention of skeletal-related events in patients with solid tumor malignancy or multiple myeloma, tumor parathyroid gland, and all situations wherever extrarenal hydroxylation of Vitamin D is accelerated. Denosumab is a novel, fully human monoclonal antibody which prevents the receptor activator of nuclear factor kappa B ligand from binding to its receptor and inhibits osteoclast development, activation, and survival. It is easy to administer, without dose adjustment for renal impairment, and has lower incidence of renal failure and acute phase reactions. Hypocalcemia has been described as a major side effect.[14] After the initiation of denosumab, the calcium level fell rapidly to normal levels within two days, which was stable for at least one month.

In summary, this case demonstrates that patients with ESRF could have, rarely, an elevated 1,25(OH)[2] Vitamin D. Accordingly, correction of 25(OH) Vitamin D might unmask preexisting hypercalcemia. The presence of severe hypercalcemia with normal intact PTH level should suggest the co-existence of multiple hypercalcemic diseases. Denosumab offers an alternative attempt to overcome resistance that has to be confirmed by controlled studies.

Conflict of interest: None declared.

References

1Olgaard K. How to evaluate hypercalcaemia in the patient with chronic renal failure. Nephrol Dial Transplant 1996;11:2509-12.
2Carroll MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician 2003;67:1959-66.
3Malberti F. Treatment of immobilizationrelated hypercalcaemia with denosumab. Clin Kidney J 2012;5:491-5.
4Hewison M, Burke F, Evans KN, et al. Extrarenal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 2007;103:316-21.
5Kallas M, Green F, Hewison M, White C, Kline G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab 2010;95: 3111-7.
6Sachdeva A, Goeckeritz BE, Oliver AM. Symptomatic hypercalcemia in a patient with chronic tophaceous gout: a case report. Cases J 2008;1:72.
7Ueckermann V. A challenging case of hypercalcaemia. JEMDSA 2013;18:68-70.
8Deluca HF, Prahl JM, Plum LA. 1,25- dihydroxyvitamin D is not responsible for toxicity caused by Vitamin D or 25-hydroxyvitamin D. Arch Biochem Biophys 2011;505: 226-30.
9Trimarchi H, Lombi F, Forrester M, et al. Disodium pamidronate for treating severe hyper-calcemia in a hemodialysis patient. Nat Clin Pract Nephrol 2006;2:459-63.
10Rosner MH, Dalkin AC. Onco-nephrology: the pathophysiology and treatment of malignancy- associated hypercalcemia. Clin J Am Soc Nephrol 2012;7:1722-9.
11Pellicciotti F, Giusti A, Gelli MC, Foderaro S, Ferrari A, Pioli G. Challenges in the differential diagnosis of hypercalcemia: A case of hypercalcemia with normal PTH level. World J Clin Oncol 2012;3:7-11.
12Bergner R. Bisphosphonate therapy in renal osteodystrophy - a review. J Nephrol 2013; 26:450-5.
13Hu MI, Glezerman I, Leboulleux S, et al. Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst 2013;105:1417-20.
14McCormick BB, Davis J, Burns KD. Severe hypocalcemia following denosumab injection in a hemodialysis patient. Am J Kidney Dis 2012;60:626-8.