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The Gadolinium Controversy--An Update.

Introduction

Gadolinium-based contrast agents (GBCA) are intravenously administered drugs used in diagnostic imaging procedures to enhance the quality of magnetic resonance imaging (MRI) and are commonly used for enhancement of vessels as in MR angiography (MRA) or for solid tumor enhancement, including brain tumors associated with the degradation of the blood-brain barrier.

Gadolinium (Gd)-based contrast agents have not proved safer than the iodinated hydrophilic radiocontrast agents used in X-ray radiography or computed tomography; and because these gadolinium contrast agents pass the blood-brain barrier, increased awareness has focused on their toxicity. According to the FDA, patients who have received four or more MRIs involving Gd-based contrast agents showed traces of Gd in brain tissue. Consequently, the FDA revised its class warnings for all gadolinium-based contrast media and advised that the use of gadolinium-contrast agents must be based on careful consideration. As of now, extra care must be taken with patients requiring multiple doses, including pregnant and pediatric patients, and those with inflammatory conditions.

The FDA (Food and Drug Administration) updated its Medication Guide, May 16, 2018, stating that all MRI centers should provide a Medication Guide the first time an outpatient receives a GBCA injection or when the information is substantially changed. However, hospital inpatients are not required to receive a Medication Guide unless the patient or caregiver requests it. A health care professional who determines that it is not in a patient's best interest to receive a Medication Guide because of significant concerns about its effects may direct that it not be provided to that patient; however, the Medication Guide should be provided to any patient who requests the information. FDA also states:
Health care professionals should consider the retention characteristics
of each agent when choosing a GBCA for patients who may be at higher
risk for gadolinium retention. These patients include those requiring
multiple lifetime doses, pregnant women, children, and patients with
inflammatory conditions. Minimize repeated GBCA imaging studies when
possible, particularly closely spaced MRI studies. However, do not
avoid or defer necessary GBCA MRI scans.


Chemical Structure and Use of Gd-Contrast Agents

According to their chemical structure, Gd-based contrast agents are subdivided into ionic and nonionic, macrocyclic and linear contrast agents (see Table 1). The cyclic structure creates a stronger bond to gadolinium. Macrocyclic agents have a cage-like structure that is less likely to release the Gd(III) ion. In contrast, linear agents have an elongated molecular structure, making them more likely to release gadolinium. Linear contrast agents are so-called Gd chelates with open, mobile chains that have no strong binding to the toxic Gd3+ ion. (Hemsen 2012, Marckmann 2006).

Risks and Side Effects

According to information from the European Medicines Agency (EMA) and the Federal Institute for Drugs and Medical Devices (January 2018), the long-term risks of gadolinium contrast agent administration are still unknown. In the EU, the intravenous use of specific linear gadolinium-containing contrast agents has been suspended (see Table 2). The linear agents in question are gadobenic acid, gadodiamide, gadopentetic acid and gadoversetamide. In lieu of the information available, it would seem reasonable to delay the use of any linear GBCA. However, after gadolinium producers and imaging societies raised objections, the EMA will reexamine its decision regarding these agents.

"While there is clear evidence that all types of [gadolinium contrast agents], both linear and macrocyclic, may result in trace amounts of gadolinium in the brain, there exists no clinical evidence that this leads to an increase in risk or harm to patients," a press release from GE Healthcare defended the company's MRI contrast agent Omniscan; and continued stating that "Omniscan has a specific cardiac indication in several European Member States; removing it would limit clinical choice."

In patients with impaired renal function (i.e. an impaired elimination of the drug), gadolinium-based contrast agents (GBCAs) may increase the risk for nephrogenic systemic fibrosis (NSF), a rare and serious syndrome involving fibrosis of skin, joints, eyes and internal organs. In these patients, the use of GBCAs must be avoided unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. The risk for NSF appears highest among patients with chronic, severe kidney disease (GFR <30 mL/min/1.73m2) or acute kidney injury. Before GBCAs are administered to patients with chronically reduced renal function, including diabetics, hypertensive and older patients (>60 years), the estimation of the glomerular filtration rate (GFR) is essential.

GBCAs were first considered as a cause of NSF as early as 2006 (Agarwal 2009, Grobner 2006). Reports indicated that NSF developed within days or months after administration in patients with renal insufficiency (Dawson 2008).

Prof. Detlef Moka, MD, and Chief Executive Officer of BDN stated in interview: "If gadolinium stays in the body longer in patient with renal insufficiency, Gd can accumulate in the skin and organs and cause the severe connective tissue disease NSF."

Toxicity

Gadolinium(III) ions occurring in water-soluble salts are toxic to mammals. Chelated gadolinium(III) compounds (i.e. gadolinium bound to a chelate) are far less toxic because the chelate carries the tightly bound gadolinium ions through the kidneys and out of the body before free ions can be released. Because of its paramagnetic properties, solutions of chelated gadolinium complexes are used intravenously in magnetic resonance imaging.

Theory and Practice

With healthy kidney function, Gd contrast agents should be excreted within a short time. Gadodiamite, for example, is a linear and thus less stable Gd chelate. One milliliter of gadodiamide contains 287 mg (0.5 mmol) of the Gd drug. The pharmaceutical manufacturer GE Healthcare states, "the recommended dose is usually 0.1 mmol / kg BW (equivalent to 0.2 ml / kg BW) up to a body weight (BW) of 100 kg. If the body weight is more than 100 kg, then 20 ml is usually sufficient to obtain a desired contrast for diagnosis."

Consider the theoretical reduction of contrast agent after administration of 20 ml gadodiamide as shown in Table 3. About 32.5 hours after the intravenous injection of 20 ml Omniscan, only 0.2 [micro]g gadodiamide should remain in the system. After three days, no gadolinium should be detected in urine.

Data from 550 randomized urinary specimens before chelation showed a mean Gd concentration of 5.76 [micro]g/l with a standard deviation of 128 [micro]g/l. The maximum value was 2990 [micro]g/l (Source: Micro Trace Minerals Laboratory (MTM 2006). The detection limit for gadolinium in urine is currently 0.05 [micro]g/l.

Further surveillance carried out in 2011, 2017, and 2018, showed a similar Gd mean concentration, and again a high standard deviation. In 2018, another statistical evaluation of more than 12,000 baseline urine measurements showed a mean gadolinium concentration below the detection limit with a high standard deviation of 2605 [micro]g/l, indicating the presence of some urine samples with very high gadolinium concentrations. Of the 12,000 baseline urines tested, 80 urine samples showed a Gd concentration of more than 100 [micro]gGd/l. In 11 of these samples, Gd values greater than 1000 [micro]g/l were detected.

The highest gadolinium concentration was 290,000 [micro]g/l (two-hundred and ninety-thousand). The urine creatinine value of this sample was inconspicuous, reflecting normal renal function. The second-highest Gd urine concentration was 57,000 [micro]g/l with a urine creatinine value of 2.56 g/l, indicating renal stress. In both cases, available patient information did not provide information regarding the time the contrast agent was administered, nor did we receive the contrast agent's product name.

It is of specific interest that none of the extreme values outlined above came from a urine sample following chelation. This demonstrates that the renal clearance of the above-mentioned urine tests is due to the body's own excretion mechanism. It shows that gadolinium is continuously eliminated over a given time without the use of chelating agents.

Chelation

Chelation therapists debate if chelating agents such as DMPS, DTPA, EDTA, or DMSA are useful in de-chelating GBCAs. Our evaluation of data suggests otherwise. The problem we noticed is that provocation urine test results were not compared with urine test results of unprovoked (baseline) urines, leading to misinterpretation.

The contrast agent's molecular structure determines its stability and if it can be re-chelated by a given chelating agent. The molecular formula of GdDTPA and ZnDTPA are similar, as is the Log K (thermodynamic stability constant). For ZnDTPA the stability constant is 18.40 and for GdDTPA it is 18.25 (at pH 7.4), which indicates that binding ability and stability constant of DTPA with Zn and Gd are similar. Whether ZnDTPA is a suitable chelating agent for GBCAs is to be determined.

We compared the gadolinium concentration of urine samples before and after chelation. Selected pairs came from the same patient and had been taken at the same day. Samples were submitted by various clinics and the results, as shown in Table 4, seem to indicate that chelation is not as successful as proclaimed.

Most importantly, if the gadolinium excretion value before and after provocation are not compared, post chelation results are most likely misinterpreted.

We evaluated data received from chelation with Dimaval (DMPS, Sodium 2,3-dimercaptopropane-l-sulfonate), the chelator of choice for many European physicians. Dimaval is produced by Heyl, Berlin, and in talking with the responsible scientist Dr. J. Ruprecht, we learned that this chelator is not likely to bind gadolinium. Our evaluation of available data confirmed his statement (see Table 4).

Some physicians claim treatment success by using combination treatments such as DMPS+CaEDTA or DMPS+ZnDTPA. In our database, we could find few pairs of pre and post chelation samples involving such pre and post test results. Those located did not prove that gadolinium binding happened with chelation (Table 5 and 6).

We also evaluated the binding ability of the oral chelator DMSA with gadolinium. Of the 34 pairs, 24 of the unchallenged urine samples showed slightly higher Gd concentrations than the samples after chelation.

Note: Urine creatinine levels are used to mathematically convert mcg/l values to mcg/g creatinine. This conversion is commonly used today because it reduces the potentially great margin of error that result from an incorrect sample volume given. A low urine creatinine level of 0.3 g/l or less affects the mathematical conversion factor, elevating test results. Low urine creatinine levels are generally the result of overhydration. High urine creatinine levels above 2 g/l are either due to dehydration or renal stress.

Summary

Our data clearly indicates that a Gd provocation urine test value can only be judged after it has been compared with a Gd-test result from an unprovoked urine.

As expected, DMPS is not able to bind and detoxify gadolinium compounds, and our data indicates that combination treatments involving the chelating agents DMPS, DTPA, EDTA or DMSA seem equally unsuccessful in increasing the elimination of gadolinium via the renal system. The use of oral DMSA may support the thought that Gd-binding could possibly happen, leading to increased renal elimination, but this is highly unlikely as DMSA is a chelator that is chemically similar to, but much weaker than DMPS.

Our data indicates that none of the chelating agents discussed here sufficiently binds and eliminates gadolinium via the renal system. However, just recently, a preliminary case report on 25 patients demonstrated that CaDTPA and ZnDTPA may be useful for the treatment of patients with gadolinium deposition disease (Semelka RC 2018). For that study, 24-hour urine samples were analyzed before and after chelation treatment, showing treatment success. However, not all pre-urine samples were taken immediately prior to treatment. Urine creatinine levels were not specified, which could lead to misinterpretation of results.

Our results are based on urine creatinine levels, but chelation treatment protocols did not involve a 24-hour urine collection. Instead, urine collection was based on the chelator's half-life plus time of administration. For a ZnDTPA injection or an EDTA infusion, that would be 45 minutes plus time of administration.

Clearly, more studies are needed. In future studies, test results should be supported by precise clinical information regarding the contrast agent name, the amount and time of the GBCA given, plus the amount and time of chelating agent administration. Protocols must be determined and followed, including urine collection times.

It would be of interest to find out if linear and macrocyclic GBCAs are retained, and if chelation treatment is an option for linear and macrocyclic GBCAs. Furthermore, it should be cleared if patient reactions are due to gadolinium toxicity or immune reactions, or both, and to which degree renal support such as orthomolecular treatments increase the body's own detoxification ability.

For more information, contact ebb@microtrace.de.

References

Agarwal R, et al. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: a systematic review and meta-analysis. Nephrol Dial Transplant. 2009;24(3): 856-63.

Dawson P, Punwani S. NSF: What We Know and What We Need to Know. Semin Dial. January 23, 2008.

Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006. 21:1104-1108.

Hemsen J. Einfluss der MR-Kontrastmittel MultiHance, Omniscan und Teslascan auf humane embryonale Lungenfibroblasten und humane Nabelschnurenendothelzellen. Dissertation zur Erlangung des Doktorgrades der Medizin. Med. Fakultat Erlangen 2012.

Marckmann P, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhancing magnetic resonance imaging. J Am Soc Nephrol. 2006; 17(9):2359-62.

Semelka RC, et al. Intravenous Calcium/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients with Presumed Gadolinium Deposition Disease. Investigative Radiology. 2018.

by E. Blaurock-Busch, PhD
Table 2: Overview of Gadolinium-based Contrast Agents

Product                        Structure/Application

Artirem/Dotarem/Dotarem        Macrocyclic / intra-articular
Arthro (Gadoterate meglumine)

Gadovist (Gadobutrol)          Macrocyclic / i.v.

Prohance (Gadoteridol)         Macrocyclic / i.v.

Magnevist (Gd-DTPA)            Linear / intra-articular

Magnevist (Gd-DTPA)            Linear / i.v.

Multihance                     Linear / i.v.
(Gadobenat dimeglumine)

Omniscan (Gadodiamid)          Linear / i.v.

Optimark (Gadoversetamide)     Linear / i.v.

Primovist or Eovist (GdDTPA)   Linear / i.v.

Product                        Indication

Artirem/Dotarem/Dotarem        For MRI in brain (intracranial), spine
Arthro (Gadoterate meglumine)  and associated tissues in adult and
                               pediatric patients (including term
                               neonates) to detect and visualize areas
                               with disruption of the blood brain
                               barrier (BBB) and/or abnormal
                               vascularity.

Gadovist (Gadobutrol)          For adults and children of all ages
                               including full-term newborns for contrast
                               enhancement in cranial and spinal MRI.
                               This includes differentiation of intra-
                               and extramedullary tumors, demonstration
                               of solid tumor areas in known syrinx,
                               determination of intramedullary tumor
                               spread.

Prohance (Gadoteridol)         For use in MRI in adults and children
                               over 2 years of age to visualize lesions
                               with abnormal vascularity in the brain
                               (intracranial lesions), spine and
                               associated tissues, including lesions in
                               the head and neck.

Magnevist (Gd-DTPA)            Used for MRI in adults, and pediatric
                               patients (2 years of age and older) to
                               visualize lesions with abnormal
                               vascularity in the brain (intracranial
                               lesions), spine and associated tissues.
                               Contraindicated in patients with severe
                               kidney disease

Magnevist (Gd-DTPA)            Use suspended in EU. Contraindicated in
                               patients with severe kidney disease

Multihance                     Use suspended in EU. In USA, used for MRI
(Gadobenat dimeglumine)        of CNS in adults and pediatric patients
                               to visualize abnormal blood-brain barrier
                               or abnormal vascularity of brain, spine
                               and associated tissue. Also used in
                               adults with known or suspected renal or
                               aorto-ilio-femoral occlusive vascular
                               disease

Omniscan (Gadodiamid)          Use suspended in EU. Can cause spurious
                               hypocalcemia, particularly at doses of
                               0.2 mmol/kg or higher in patients with
                               renal insufficiency. Used in MRI to
                               visualize lesions with abnormal
                               vascularity (or those thought to cause
                               abnormalities in the blood-brain barrier)
                               in the brain (intracranial lesions),
                               spine, and associated tissues, also used
                               to facilitate the visualization of
                               lesions with abnormal vascularity within
                               the thoracic (noncardiac), abdominal,
                               pelvic cavities, and the retroperitoneal
                               space (FDA)

Optimark (Gadoversetamide)     Use suspended in EU.

Primovist or Eovist (GdDTPA)   To diagnose certain liver disorders and
                               to visualize blood vessels, organs, and
                               other non- bony tissues

Table 3: Theoretical Reduction after Administration of 20 ml Omniscan
(Gadodiamide)

Hours after iv-admin  [micro]g Contrast agent

          0.0               5740000
          1.3                287000
          2.6               1435000
          3.9                717500
          5.2                358750
          6.5                179375
          7.8                 89687.5
          9.1                 44843.8
         10.4                 22421.9
         11.7                 11210.9
         13.0                  5605.5
         14.3                  2802.7
         15.6                  1401.4
         16.9                   700.7
         18.2                   350.3
         19.5                   175.2
         20.8                    87.6
         22.1                    43.8
         23.4                    21.9
         24.7                    10.9
         26.0                     5.5
         27.3                     2.7
         28.6                     1.4
         29.9                     0.7
         31.2                     0.3
         32.5                     0.2

Table 4: Gadolinium in Urine Before and After Chelation with DMPS iv,
250 mg (1 Ampule)

Urine Test Value  Urine concentration
before Chelation    after DMPS iv,
    in mcg/g        250 mg in mcg/g     Chelation
   Creatinine         Creatinine        Assessment

      3096               2340          unsuccessful
       563                536             ditto
       525                507             ditto
       766                574             ditto
      3703               2186             ditto
       238                 63             ditto
        11                 10             ditto
        97                 97             ditto
        91                 65             ditto
        40                 35             ditto
       112                 76             ditto
       230                138             ditto
        31                 32             ditto
        74                 52             ditto
        21                 20             ditto
       189                178             ditto
        21                 21             ditto
       109                101             ditto
        77                 60             ditto
        15                 13             ditto
       494                449             ditto
       383                318             ditto
        63                 29             ditto
        11                 10             ditto
        97                 97             ditto

Table 5: Gd in Urine Before and After Chelation with DMPS+CaEDTA

Urine Test Value    Urine concentration
before Chelation  after DMPS iv, 250 mg +
    in mcg/g         CaEDTA, 1.9 g iv
   Creatinine       in mcg/g Creatinine     Assessment

       189                  178            Unsuccessful
      1424                 1284               ditto
        46                   29               ditto
       586                  281               ditto
      1865                 1788               ditto
       189                  178               ditto

Table 6: Gd in Urine Before and After Chelation with DMPS+ZnDTPA

Urine Test Value  Urine concentration
before Chelation  after DMPS+ZnDTPA,
    in mcg/g        1 Amp, each iv
   Creatinine     in mcg/g Creatinine   Assessment

       696                512          Unsuccessful
         8                  5             ditto

Table 7: Gd in Urine Before and After Chelation with DMSA

Urine Test Value  Urine concentration
before Chelation   after DMSA oral,
    in mcg/g        500-1 000mg in
   Creatinine      mcg/g Creatinine     Assessment

       696                550          Unsuccessful
       735                552             Ditto
       768                610             Ditto
        37                 11             Ditto
         9                  5             Ditto
        20                 21            See note
        24                 19          Unsuccessful
         6                  6             Ditto
        13                  8             Ditto
       293                187             Ditto
        40                 30             Ditto
       108                 80             Ditto
         9                  9             Ditto
        29                 30             Ditto
       195                174             Ditto
       696                551             Ditto
       303                317            See note
       104                 87          Unsuccessful
        93                 97            See note
         9                  7          Unsuccessful
       344                328             Ditto
        23                 17             Ditto
         9                 10            See note
         9                 10            See note
        16                 17            See note
        11                 12            See note
        10                  7          Unsuccessful
         9                 10            See note
       189                217            See note
        13                  8          Unsuccessful
         8                  6             Ditto
        21                 17             Ditto
        18                 11             Ditto
         7                  8            See note
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Author:Blaurock-Busch, E.
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Article Type:Report
Date:May 1, 2019
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