Dynamic Serial Cytokine Measurements During Intravenous Ca-DTPA Chelation in Gadolinium Deposition Disease and Gadolinium Storage Condition: A Pilot Study (2022).

GDD/ToxicityTreatment Options
Written By Kate

Article Link: https://pubmed.ncbi.nlm.nih.gov/34120127/

Journal: Investigative Radiology

Authors and Affiliations: Holden T Maecker 1, Janet C Siebert 2, Yael Rosenberg-Hasson 1, Lorrin M Koran 3, Miguel Ramalho, Richard C Semelka 4

  • 1From the Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA.

  • 2CytoAnalytics, Denver, CO.

  • 3Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.

  • 4Richard Semelka Consulting, PLLC, Chapel Hill, NC.

Main Theme: This pilot study investigates the changes in serum cytokine levels following intravenous Ca-DTPA chelation therapy in patients with Gadolinium Deposition Disease (GDD) and Gadolinium Storage Condition (GSC) to explore the potential role of cytokines in the pathophysiology of GDD.

Key Findings:

  • Increased Gd Excretion: Both GDD and GSC patients showed increased gadolinium (Gd) excretion in urine post-chelation, confirming the chelator's efficacy in mobilizing retained Gd.

  • Symptom Flare in GDD: All GDD patients experienced symptom flare reactions after chelation, while GSC patients remained asymptomatic. This aligns with previous observations that symptom manifestation distinguishes GDD from GSC.

  • Early Cytokine Peaks: Two cytokines, EGF and sCD40L, peaked at 30 minutes post-chelation in most participants (including GDD and GSC), suggesting an immediate immune response to mobilized Gd.

  • Late Cytokine Peaks: Three cytokines, ENA78/CXCL5, EOTAXIN/CCL11, and LEPTIN, peaked at 24 hours post-chelation in most participants, indicating a delayed response potentially involving non-immune cells.

  • Individual Variability: High outlier cytokine levels across all time points were observed primarily in two participants (one GDD, one GSC) who also exhibited the highest urine Gd excretion and received the most GBCA injections. This highlights the significant individual variability in cytokine response to Gd mobilization.

  • Cytokine Peaks and Gd Mobilization: The study suggests that the amount of Gd mobilized, rather than the severity of the flare reaction, may be the primary driver of cytokine elevation. This is supported by the observation of similar cytokine peaks in both symptomatic GDD and asymptomatic GSC patients.

Implications:

  • This study provides preliminary evidence of a dynamic and complex interplay between Gd mobilization, immune response, and symptom manifestation in GDD.

  • The temporal resolution of cytokine measurements reveals distinct early and late responses, potentially involving different cell types and signaling pathways.

  • The significant individual variability in cytokine profiles underscores the need for personalized approaches to GDD diagnosis and treatment.

  • The study methodology offers a valuable model for investigating the immediate biological effects of therapeutic interventions in other disease contexts, particularly those involving heavy metal toxicity.

What is Gadolinium and what are GBCAs?

Gadolinium (Gd) is a rare earth metal used in Gadolinium-Based Contrast Agents (GBCAs). GBCAs are injected into patients undergoing Magnetic Resonance Imaging (MRI) scans to enhance the visibility of internal organs and tissues.

What is the difference between Gadolinium Deposition Disease (GDD) and Gadolinium Storage Condition (GSC)?

While essentially all patients retain trace amounts of gadolinium after a GBCA-enhanced MRI, most experience no adverse effects.

  • GSC (Gadolinium Storage Condition) is the term used for individuals who have retained gadolinium but remain asymptomatic.

  • GDD (Gadolinium Deposition Disease) is diagnosed in symptomatic patients who experience specific clinical signs following GBCA administration.

What are the symptoms of GDD?

GDD symptoms typically include:

  • Cognitive disturbances

  • Extremity pain

  • Joint pain (arthralgia)

  • Chest wall pain

  • Skin pain

  • Headaches

  • Skin induration

  • Skin hyperpigmentation

How is GDD diagnosed?

GDD diagnosis involves several factors:

  • Presence of at least three of the eight characteristic GDD symptoms

  • Normal or near-normal kidney function

  • Elevated 24-hour urine gadolinium levels exceeding laboratory norms at least 28 days after the GBCA-enhanced MRI

What is a "Flare reaction" in GDD?

A "Flare reaction" refers to a temporary intensification of existing GDD symptoms or the emergence of new, related symptoms following chelation therapy with Ca-DTPA. This therapy aims to remove retained gadolinium from the body.

What is the role of cytokines in GDD?

Cytokines are signaling molecules involved in immune responses. Research suggests that gadolinium mobilization, whether triggering symptoms or not, is associated with the release of specific cytokines. Early cytokine peaks observed after chelation suggest an immediate immune response. Later peaks indicate potential involvement of non-immune tissues, possibly triggered by the initial immune activation.

How does the amount of gadolinium retained relate to cytokine levels?

This pilot study suggests that the amount of gadolinium mobilized and excreted may be a stronger factor influencing circulating cytokine elevations than the severity of GDD symptoms. Individuals with higher gadolinium retention, regardless of GDD diagnosis, exhibited higher outlier levels for numerous cytokines.

What are the implications of this research for understanding and treating GDD?

This study emphasizes the importance of measuring dynamic cytokine changes over time to understand GDD pathophysiology fully. Larger studies are needed to investigate the relationship between gadolinium retention, cytokine profiles, and symptom severity. Further research on cytokine responses to chelation therapy may contribute to improved GDD treatment strategies.

Glossary of Key Terms

Gadolinium (Gd): A rare earth metal used as a contrast agent in magnetic resonance imaging (MRI).

Gadolinium-Based Contrast Agent (GBCA): A chemical compound containing gadolinium used to enhance the visibility of internal organs and tissues in MRI scans.

Gadolinium Deposition Disease (GDD): A recently proposed diagnostic label for patients who experience symptoms after receiving a GBCA, characterized by various symptoms such as pain, cognitive disturbances, and skin changes.

Gadolinium Storage Condition (GSC): A proposed term for individuals who have received a GBCA and retain gadolinium but do not exhibit any associated symptoms.

Chelation Therapy: A medical procedure that employs a chelating agent, such as Ca-DTPA, to bind to and remove heavy metals like gadolinium from the body.

Ca-DTPA (Calcium Diethylenetriaminepentaacetic Acid): A chelating agent used to remove gadolinium from the body.

Cytokine: Small proteins that play a crucial role in cell signaling and immune responses.

Cytokine-Inciting Event (CIE): An event that triggers the release of cytokines, such as the administration of Ca-DTPA for gadolinium chelation.

Flare: A temporary worsening of symptoms experienced by some patients with GDD after chelation therapy.

Tissue-Resident Memory T cells (Trm): A subset of memory T cells that reside in tissues and provide localized immune surveillance and response.

Kate
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