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What Nephrologists Need to Know About Gadolinium: Laboratory Abnormalities Associated With Gadolinium


Laboratory Abnormalities Associated With Gadolinium

Gadolinium chelates interfere with a wide variety of assays. The most widely reported laboratory artifact associated with gadolinium is pseudohypocalcemia.[84-89] Gadolinium can also reduce ACE levels, alter serum iron concentration (reduce or elevate, depending on the assay), increase total iron-binding capacity, and lower serum zinc levels.[89]

Pseudohypocalcemia was first reported to be associated with gadolinium in 1995.[90] It is most common for gadolinium to affect colorimetric assays that employ orthocresolphthalein (OCP), the agent most frequently used to measure calcium concentration. Pseudohypocalcemia does not occur when assays that employ atomic emission spectroscopy or ion-selective electrodes are used. Artifactual reduction of calcium concentration is thought to result either from binding of gadolinium to OCP, which prevents OCP from binding calcium, or from binding of calcium to the excess chelate that is included in some (but not all) gadolinium chelate preparations. Gadodiamide has 0.025 mmol/ml of excess chelate and gadopentetate dimeglumine 0.001 mmol/ml; gadoterate meglumine contains no excess chelate. The purpose of including excess chelate in gadolinium preparations is to maintain gadolinium binding during storage.

In a study by Prince et al. of 896 patients whose serum calcium level was measured within 24 hours of gadodiamide administration, 165 developed pseudohypocalcemia.[88] Calcium concentration declined by more than 0.5 mmol/l (2 mg/dl) in 42 patients, and in 25 patients was less than 1.5 mmol/l (6 mg/dl). Oral or intravenous calcium was administered to 18 patients for what was mistakenly interpreted as 'true' hypocalcemia, even though the patients had no clinical symptoms of the disorder. The pseudohypocalcemic effect persisted for up to 4.5 days in patients with CKD, and was more pronounced at high doses of gadodiamide. In patients with a normal GFR who had received low-dose gadodiamide, pseudohypocalcemia lasted 4-6 hours. In those whose GFR was reduced, the artifact persisted for more than 24 hours. Recommended minimum waiting times from administration of contrast medium to collection of plasma sample have been established for the Roche OCP assay (Hitachi 747 analyzer; Roche Diagnostics, Indianapolis, IN) on the basis of GFR (Table 4).[91]

Kang et al.[91] also examined the effect of several different gadolinium chelates on in vitro calcium concentrations. Gadodiamide and gadoversetamide both reduced calcium levels, whereas gadoteridol and gadopentetate dimeglumine did not. Interestingly, both the gadolinium chelates that cause pseudohypocalcemia in vitro are packaged with higher concentrations of excess chelate-- 331 mg/ml for gadoversetamide and 12 mg/ml for gadodiamide versus 0.2 mg/ml for gadoteridol and 0.4 mg/ml for gadopentetate dimeglumine. This fact indicates that pseudohypocalcemia might be the result of calcium binding to excess infused chelate, rather than of dissociation of gadolinium from chelate in vivo.[40]

The reduction in ACE levels observed after gadolinium administration is thought to result from binding of zinc by the chelate; measurement of ACE is zinc dependent. Iron concentration is increased by gadolinium when the Vitros® 950 (Ortho-Clinical Diagnostics, Raritan, NJ) and Synchron LX® 20 (Beckman Coulter, Brea, CA) assays are used.[89] Likewise total iron-binding capacity is increased by gadolinium when either the Modular P or Dimension RxL (Roche Diagnostics, Indianapolis, IN, and Dade Behring, Deerfield, IL, respectively) methods are used to quantify this parameter. The formazan dye employed in the zinc assay probably binds gadolinium, resulting in a falsely low concentration of zinc being detected.

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