Dynamic Serial Cytokine Measurements During Intravenous Ca-DTPA Chelation in Gadolinium Deposition Disease and Gadolinium Storage Condition: A Pilot Study

Abstract

Purpose: The aim of this study was to investigate the feasibility of measuring early changes in serum cytokine levels after intravenous diethylenetriaminepentaacetic acid (Ca-DTPA) chelation in patients manifesting either gadolinium deposition disease (GDD) or gadolinium storage condition (GSC) and the possible usefulness of this method in further research.

Methods: Four patients with recent-onset GDD (≤1 year) and 2 patients with long-standing GSC (4 and 9 years) underwent chelation with intravenous bolus administration of Ca-DTPA. Multiple blood draws were performed to measure serum cytokines: at T = 0 (before Ca-DTPA injection) and 1, 5, 10, 30, 60 minutes, and 24 hours after Ca-DTPA injection. Patients rated the severity of GDD symptom flare at 24 hours. The 24-hour urine Gd amounts were measured prechelation and for the 24 hours after chelation. Serum samples were analyzed blind to whether patients had GDD or GSC but with knowledge of the time points characterizing each sample.

Results: Urine samples for both GDD and GSC patients showed increases in Gd postchelation. All GDD patients experienced flare reactions postchelation; the 2 GSC patients did not. Two cytokines, EGF and sCD40L, peaked at 30 minutes postchelation in at least 4 of the 6 participants. Three cytokines, ENA78/CXCL5, EOTAXIN/CCL11, and LEPTIN, peaked at 24 hours in at least 4 of the 6 participants. Two participants were high outliers for a large number of cytokines across time points. No clear distinction between GDD and GSC was apparent from the cytokine patterns, although differences were present.

Conclusions: This pilot study describes precise temporal resolution (in the range of minutes) after a cytokine-inciting event. Select cytokines exhibited peak values at different time points. At this preliminary stage of investigation, peak cytokine release seems to reflect the amount of Gd mobilized rather than the severity of the patient symptomatic reaction. Too few subjects were studied to support statistical analysis between GDD and GSC groups, although differences were observed through visual data analysis.

Conflict of interest statement

Conflicts of interest and sources of funding: none declared.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1.. Cytokines that peak at 30 min post-DTPA administration.

A peak is defined as an increase at 30 min of at least 20% vs. the value at 10 min. The two cytokines shown are those with peaks in at least 4 participants; 3 of the 4 are GDD patients. Patient 05 is missing a 10 min measurement and was therefore excluded from developing a definition of “peak’; his available data is included in the Figure. MFI = median fluorescence intensity for the cytokine in Luminex assay. Open purple shapes represent GDD patients; solid green shapes represent GSC controls.

Figure 2.. Cytokines that peak at 24 h post-DTPA administration.

A peak is defined as an increase at 24 h (1440 min) of at least 20% vs. the value at 60 min. The three cytokines shown are those with peaks in at least 4 participants; 3 of the 4 are GDD patients. MFI = median fluorescence intensity for the cytokine in Luminex assay. Open purple shapes represent GDD patients; solid green shapes represent GSC controls.

Figure 3.. Representative cytokines with high outliers.

44 of 76 cytokines measured had one or more participants who were “high outliers.” VEGF, lower right, was the only cytokine with a low outlier; it also had two high outlier participants.

Figure 4.. High outlier cytokines by participant.

A dot indicates that participant was a high outlier for the given cytokine (defined as > Q3 + 3 × IQR, see Methods). Cytokines denoted with * are those previously shown to be elevated in GDD. Two participants (04 and 01) were high outliers for many more cytokines than the others. 04 was a GDD patient, while 01 was a GSC control, but both had far higher post-chelation urine Gd levels than other participants (55 and 33 μg/ml, respectively, vs. 0.24 −15 μg/ml for other participants).