It has been documented that certain gadolinium-based magnetic resonance contrast agents injected for enhancement of magnetic resonance imaging (MRI) or for angiography in selected patients, i.e. gadodiamide (Omniscan®) and gadoversetamide (Optimark®), can cause spurious hypocalcaemia, due to interference with colorimetric assays in a dose-dependent way [14]. Three other agents approved for clinical use, gadopentetate dimeglumine (Magnevist®), gadoterate meglumine (Dotarem®) and gadoteridol (Prohance®), do not cause this interference [2].
A 69-year-old female patient underwent contrast-enhanced vascular MRI of the vertebrobasilar system with gadodiamide (20 ml, 287 mg/ml, intravenous injection) and presented to the outpatient pulmonary clinic 1 h later for a routine check-up. Afterwards she went home, though was urgently called back 60 min later because laboratory results revealed a total serum calcium level of 2.87 mg/dl (0.7 mmol/l) with an albumin level of 4.47 g/dl (44.7 g/l). Serum calcium was measured by colorimetric method using ortho-cresolphtalein (OCP) (Roche® Diagnostics) as reagent on a Modular P800 Analyzer (Roche® Diagnostics).
The patient had a history of proven Gilbert syndrome [homozygosity for the A(TA)7TAA-sequence in the promoter region of the UGT1A1-gene] and pulmonary arterial hypertension secondary to an atrial septal defect type II. She had moderate chronic renal insufficiency of unknown aetiology with a calculated creatinine clearance (Cockcroft and Gault formula) of 37 ml/min. There was no previous history of chronic hypocalcaemia. Her treatment consisted of furosemide 40 mg once daily, spironolactone 50 mg once daily, atorvastatin 10 mg once daily, sitaxsentan 100 mg once daily and fenprocoumon with a target INR of 2.5.
Three hours after the first serum sample, a second sample yielded a total calcium level of 6.9 mg/dl (1.68 mmol/l). The ionized calcium level at that time, measured by ion-selective electrode-technology, was 4.88 mg/dl (1.19 mmol/l). The patient was asymptomatic and there were no clinical signs of hypocalcaemia. No treatment was initiated. She returned home and a control serum calcium level determined 6 days later was 9.05 mg/dl (2.2 mmol/l). Given the relationship in time with the administration of a gadolinium-chelate, her normal ionized calcium level and the absence of symptoms, it was concluded that this had to be a laboratory error.
Gadolinium-related spurious hypocalcaemia in colorimetric assays, such as the Arsenazo Dye III and OCP assays, is caused by binding of gadolinium ions to the colorimetric agent, removing the gadolinium from the chelate [3]. The free chelate then binds to serum calcium thereby causing it to be falsely low. The administration of gadodiamide or gadoversetamide in higher doses, in particular when given to patients with chronic renal insufficiency, increases measurement inaccuracy and prolongs the duration of artifactual hypocalcaemia [4].
Since the use of colorimetric assays to determine total calcium levels is widespread, this laboratory artifact is a potentially dangerous cause of unnecessary and possibly harmful medical interventions. Due to the nature of their illness, patients with renal disease face the double risk of being injected with higher doses of contrast agent (i.e. for vascular MRI) while being least able to excrete it. Based on our own experience, we feel that, certainly among clinicians, this cause of spurious hypocalcaemia is still largely unknown. We suggest drawing the attention of clinicians and radiologists to the potential interference of gadodiamide with total calcium measurement, especially when high drug doses are used, or when it is administered to patients with impaired renal function.
Conflict of interest statement. None declared.
[see related Teaching Point by Mark et al. (doi:10.1093/ndt/gfh836)]
Department of Nephrology and Renal Transplantation University Hospitals Leuven Belgium Email: Kathleen.Claes{at}uz.kuleuven.ac.be
References
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