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Current Status of Gadolinium Toxicity in Patients with Kidney Disease

Mark A. Perazella
CJASN February 2009, 4 (2) 461-469; DOI: https://doi.org/10.2215/CJN.06011108

Article Figures & Data

Figures

  • Figure 1.
    Figure 1.

    Structures of various GBC agents. The agents vary on the basis of linear versus macrocyclic structure and ionic versus nonionic charge.

  • Figure 2.
    Figure 2.

    The process of transmetallation. A nonionic linear chelate binds Gd3+ less tightly than other chelates, allowing endogenous cations such as copper (Cu2+), iron (Fe3+), zinc (Zn2+), and calcium (Ca2+) to compete with Gd3+ for chelate binding. This allows free Gd3+ to be released into the circulation, where it may bind other anions such as phosphate.

  • Figure 3.
    Figure 3.

    On the basis of the published literature, GBC is less nephrotoxic than iodinated radiocontrast; however, when GBC agents are used in high dosage with arterial injection in patients with advanced kidney disease, AKI can occur.

Tables

  • Table 1.

    FDA-approved GBC agents and iodinated radiocontrast agentsa

    AgentMolecular StructureChargeOsmolality (mOsm/L)Viscosity (mPa · S)Stability ConstantExcess Chelate (mg/ml)
    GBC formulation
        gadodiamide (Omniscan)LinearNonionic9001.41014.912.00
        gadopentetate (Magnevist)LinearIonic19602.91018.10.40
        gadoversetamide (OptiMARK)LinearNonionic11102.01015.028.40
        gadobenate (MultiHance)LinearIonic19705.31018.40.10
        gadoteridol (Prohance)CyclicNonionic6301.31017.10.23
    Iodinated contrast
        diatrizoateMonomerIonic19806.0N/AN/A
        iopamidal, iohexolMonomerNonionic600 to 10005.0 to 10.0N/AN/A
        iodixanolDimerNonionic28011.0N/AN/A
        iosmenolDimerNonionic2807.0N/AN/A

    • ↵a FDA, Food and Drug Administration; GBC, gadolinium-based contrast.

  • Table 2.

    Studies supporting renal safety of GBC agentsa

    ReferenceStudyContrast AgentDosage (mmol/kg)Renal Function ([Cr] in mg/dl)Result
    Niendorf et al. (18), 1993Phase III trial, n = 1171 [Cr] at 24 h, subgroup with [Cr] at 5 dGadopentetate0.10[Cr] <1.3, [Cr] >1.3 to 1.4, [Cr] >1.4No change in [Cr], Subgroup of patients: GFR 20 to 40: [Cr] ↑ 0.25 GFR <20: [Cr] ↑ 0.25
    Arsenault et al. (20), 1996Retrospective, n = 136, n = 90 with pre/post [Cr] at 3 dGadopentetate0.10[Cr] >2.0, mean [Cr] 2.5No change in [Cr] baseline (2.5) to day 3 (2.3)
    Prince et al. (21), 1996Retrospective, n = 64, [Cr] 2 d pre and 2 d post, CIN ≥0.5 mg/dlGadopentetate, gadodiamide, gadoteridol0.20 to 0.40[Cr] >1.5, mean [Cr] 2.0 ± 1.4CIN: RC- 11/64 (17%) Gado- 0/64 (0%)
    Swan et al. (16), 1999Prospective, double-blind random, 32 patients (2:1), CIN >0.5 mg/dlGabobenate dimeglumine0.20CrCl 10 to 30, CrCl 31 to 60, 24-h urineNo CIN
    Hammer et al. (22), 1999n = 31, 34 DSAs, mean age 53.1, CIN >0.5 mg/dlGadopentetate0.40[Cr] >1.5CIN: 1/34 (3%)
    Spinosa et al. (23), 2000n = 40, LE angiograms, 42 procedures RC- 15, Gado- 20 CIN ≥0.5 mg/dl at 48 hGadodiamideup to 0.40[Cr] >1.5, mean [Cr] 2.2, range [Cr] 1.6 to 3.6RC- 6/15 (40%) GBC- 1/20 (5%)
    Spinosa et al. (24), 2001Consecutive patients treated with Gado + CO2, CIN > 0.5 mg/dl at 48 hGadodiamide<0.30[Cr] >1.5, mean [Cr] 2.7CIN: 3/95 (3%)
    Sancak et al. (25), 2001n = 16, intravenous Gado for upper extremity or SVCGadodiamide0.30Mean [Cr] 1.5, range [Cr] 1.2 to 1.8Largest increase in [Cr] 0.2 mg/dl
    Rieger et al. (26), 2002Prospective, n = 29, 32 procedures (IA and intravenous) CIN >0.5 mg/dl at 72 hGadopentetate0.34 ± 0.06[Cr] >1.5 mean [Cr] 3.6AKI: 1/29 (atheroemboli)
    TotalN/AN/AAverage dosage ∼0.26 (0.10 to 0.40)Average mean [Cr] ∼2.36; range 1.2 to 3.6CIN: GBC: 0 to 5% RC: 17 to 40%

    • ↵a CIN, contrast-induced nephropathy; [Cr], serum creatinine concentration; CrCl, creatinine clearance; RC, iodinated radiocontrast; DSA, digital subtraction angiogram; IA, intra-arterial; LE, lower extremity; SVC, superior vena cava.

  • Table 3.

    Studies supporting nephrotoxicity of GBC agentsa

    ReferenceStudyContrast AgentDosage (mmol/kg)Renal Function ([Cr] in mg/dl)Result
    Sam et al. (27), 2003n = 195 with CKD, no control group CIN >1.0 mg/d at 48 h with oligoanuriaGadopentetate0.28CrCl <80 ml/min, CG 38.2 ± 16 ml/min, mean [Cr] 2.6CIN: 7/195, MRA: 3/153 (1.9%), DSA: 4/42 (9.5%)
    Erley et al. (28), 2004Randomized prospective, n = 21, CIN >50%, decrease in GFRGadobutrol = 10 Iohexol = 110.57 ± 0.17[Cr] >1.5 or CrCl <50 ml/min per 1.73 m2, mean [Cr] 3.4CIN: GBC: 5/10 (50%) RC: 5/11 (45%)
    Briguori et al. (30), 2006Retrospective, n = 25 (historical controls, n = 32), CIN ≥0.5 mg/dl within 48 h or dialysis within 5 dGadodiamide = 8 Gadobutrol = 17 3:1 mixture with RC0.60 ± 0.30 0.28 to 1.23[Cr] >2 mg/dl or CrCl <40 ml/min, mean [Cr] 2.3CIN: GBC: 7/25 (28%); RC: 2/32 (6.5%)
    Ergun et al. (29), 2006Retrospective, n = 91, [Cr] measured pre-GBC, days 1, 3, and 7, and 1 mo, CIN ≥0.5 mg/dl within 72 hGadopentetate, gadodiamide, dotarem0.20Stages 3 and 4 CKD mean [Cr] 33 ml/min, range CrCl 15 to 58, mean [Cr] 4.0CIN: 11/91 (12.1%); CKD Stage 4: 9/11 with CIN
    Kane et al. (31), 2008Retrospective, n = 163, [Cr] measured pre-GBC and within 7 d, CIN ≥0.5 mg/dl within 7 dGBC agent, GBC + RC mixture, RC aloneGBC-76 ml, GBC + RC mixture-55 + 37 ml, RC-102 mlStages 3 to 5 CKD GBC [Cr] 2.77, GBC + RC [Cr] 2.63, RC [Cr] 2.48CIN: GBC: 5.3% GBC + RC: 10.5%; RC: 20.6%
    TotalN/AN/AAverage dosage ∼0.41 (0.20 to 0.60)Average mean [Cr] ∼3.02, range 2.60 to 4.00CIN: GBC: 5.3 to 50.0%; RC: 6.5 to 45.0%

    • ↵a MRA, magnetic resonance angiography.

  • Table 4.

    Case-control studies with odds ratio for patients who had ESRD/CKD and were exposed to GBC agents

    ReferenceNo. of NSF CasesNo. of Patients with ESRD and Exposure to GBCOdds Ratio
    Broome et al. (4)12 (ESRD 8)25841.3
    Collidge et al. (36)14 (12 biopsy-proven)141846.6
    Deo et al. (32)338031.5
    Othersen et al. (37)458820.6
    Marckmann et al. (35)13 (ESRD 8)43032.5
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Current Status of Gadolinium Toxicity in Patients with Kidney Disease
Mark A. Perazella
CJASN Feb 2009, 4 (2) 461-469; DOI: 10.2215/CJN.06011108
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