Possible involvement of gadolinium chelates in the pathophysiology of nephrogenic systemic fibrosis: A critical review

doi:10.1016/j.tox.2008.03.012

Toxicology

Volume 248, Issues 2–3, 27 June 2008, Pages 77-88

https://doi.org/10.1016/j.tox.2008.03.012 Get rights and content

Abstract

Nephrogenic systemic fibrosis (NSF) is a recently described, highly debilitating scleroderma-like disease occurring in patients with severe or end-stage renal failure. NSF is characterized by cutaneous papules and coalescing plaques (“peau d’orange” appearance) and a wooden consistency. It may ultimately cause disabling contractures of several joints, thus making many patients wheelchair-dependent. NSF has been associated to prior administration of gadolinium chelates (GC) used as contrast agents for magnetic resonance imaging. The best available treatment option at the present time is renal transplantation. The mechanism of NSF has not been fully elucidated. Several hypotheses have been proposed so far and are critically discussed in the present review article. Gadolinium has been found in skin biopsy samples of patients. The most widely accepted hypothesis is related to dechelation of less stable GC, progressively releasing free Gd³⁺ which may subsequently lead to the attraction of CD34+, CD45+, pro-collagen+ circulating fibrocytes via the release of chemokines, thereby inducing systemic fibrosing disorders. Pre-existing renal failure may facilitate the process by delaying the excretion of GC. A complex interplay between gadolinium and co-factors (pro-inflammatory status, vascular injury, high dose of erythropoietin, high levels of calcium, phosphorus, etc.) may occur in patients with impaired renal function. This and other hypotheses remain to be investigated, as well as the role and independence of co-factors.

Introduction

Nephrogenic systemic fibrosis (NSF) is a recently described, highly debilitating and sometimes fatal disease occurring in patients with renal failure (Cowper et al., 2000). A causal link between NSF and gadolinium chelates (GC) used as contrast agents for magnetic resonance imaging has recently been proposed, on the basis of retrospective analyses (Grobner, 2006, Marckmann et al., 2006). GC are small molecular weight, extracellular space markers that enhance tissue contrast on MR T1-weighted images by shortening the T1 relaxation time. They are widely used to enhance the diagnostic efficacy of MRI for the detection and characterisation of lesions and for the evaluation of perfusion and flow-related abnormalities (Bellin et al., 2003). Two categories of GC are currently used: (a) “macrocyclic” chelates where Gd is “caged” in a pre-organized cavity of the polyamino-polycarboxylic ligand, and (b) “open-chain” (or “linear”) chelates (Fig. 1). GC are currently administered in about 30% of clinical MRI procedures. It is estimated that about 20 millions of procedures involving injected CA were performed worldwide in 2005 (Idée et al., 2006). These agents are administered intravenously concomitantly with the MRI procedure and are excreted unchanged by passive glomerular filtration. Their plasma elimination half-life is about 1.5 h in healthy volunteers but may exceed 30 h in patients with renal insufficiency (Joffe et al., 1998).

The link between NSF and GC has raised a considerable amount of interest. This review of the literature is designed to critically discuss the numerous hypotheses that have been proposed to explain the mechanism of NSF and to propose other putative pathways.

The classical Medline and Excerpta Medica databases were used to prepare this review.

Section snippets

Nephrogenic systemic fibrosis: clinical and histopathological aspects

NSF was first recognized in 1997 in 15 dialyzed patients and was described in 2000 (Cowper et al., 2000). This rare and highly disabling disorder is characterized by extensive thickening and hardening of the skin associated with skin-coloured to erythematous papules that coalesce into erythematous to brawny plaques with a peau d’orange appearance. Nodules are sometimes also described. Joint contractures may develop, with patients progressively becoming wheelchair-dependent. Patients often

Hypotheses for pathophysiological mechanisms involved in NSF

No validated mechanism for NSF has been established to date. NSF patients frequently have numerous co-morbidity factors such as coagulation abnormalities and deep vein thrombosis, endothelial damage due to vascular surgery or renal/liver transplantation. Several case–control clinical studies have investigated the clinical conditions associated with development of the disease. These co-factors are listed in Table 3. When compared to age- and sex-matched renal failure patients with no signs of

Conclusion

The mechanism of NSF remains speculative and the exact role of GC is still unknown, although numerous clinical studies strongly suggest the involvement of certain GC. GC differ in terms of thermodynamic and kinetic stability, as both the macrocyclic structure and ionicity confer higher stability to the molecule, thereby minimizing the risk of free Gd³⁺ release in vivo. The higher incidence of NSF is associated with the less stable, open-chain agent Gd-DTPA-BMA (Kanal et al., 2008), which is

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The purpose of this study was to systematically search for long-term complications, including Nephrogenic Systemic Fibrosis (NSF), in patients who were previously administered the gadolinium-based contrast agent Gadofosveset at our institute.
All patients who were administered Gadofosveset at our institute between 2006 and 2009 were identified in our Radiological Information System (RIS). Clinical data such as cause of death during follow-up, and dermatological or nephrological diseases were systematically searched for in electronic patient records (EPR).
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ReviewPossible involvement of gadolinium chelates in the pathophysiology of nephrogenic systemic fibrosis: A critical review

Abstract

Introduction

Section snippets

Nephrogenic systemic fibrosis: clinical and histopathological aspects

Hypotheses for pathophysiological mechanisms involved in NSF

Conclusion

Inorg. Chim. Acta

J. Am. Acad. Dermatol.

Magn. Reson. Imaging

Adv. Dermatol.

Lancet

J. Am. Acad. Dermatol.

J. Am. Acad. Dermatol.

Am. J. Pathol.

Magn. Reson. Imaging

J. Am. Acad. Dermatol.

J. Am. Acad. Dermatol.

J. Comp. Pathol.

Acad. Radiol.

J. Alloys Comp.

Kidney Int.

Semin. Arthritis Rheum.

J. Am. Acad. Dermatol.

Forensic Sci. Int.

Peripheral blood fibrocytes: differentiation pathway and migration to wound sites

J. Immunol.

Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis

Br. J. Dermatol.

Basic experimental studies and clinical aspects of gadolinium salts and chelates

Cardiovasc. Drugs Rev.

Advisory about gadolinium calls for caution in the treatment of uremic patients with lanthanum carbonate

Kidney Int.

Currently used non-specific extracellular MR contrast media

Eur. Radiol.

Imaging in the time of NFD/NSF: do we have to change our routines concerning renal insufficiency?

Magma

Response to “Gadodiamide-associated nephrogenic systemic fibrosis”

Am. J. Roentgenol.

Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned

Am. J. Roentgenol.

Kinetic stability of gadolinium (III) chelates used as MRI contrast agents

Stability and toxicity of contrast agents

Fibrocytes: discovery of a circulating connective tissue cell progenitor

Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair

Mol. Med.

The peripheral blood fibrocytes is a potent antigen-presenting cell capable of priming naive T cells in situ

Proc. Natl. Acad. Sci. U.S.A.

Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort

Radiology

Structure–activity relationship of macrocyclic and linear gadolinium chelates: investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme

J. Magn. Reson. Imaging

Nephrogenic fibrosing dermopathy: the first 6 years

Curr. Opin. Rheumatol.

Nephrogenic systemic fibrosis: an update

Curr. Rheumatol. Rep.

Zinc and immune function

Eur. J. Clin. Nutr.

Can the risk of gadolinium be extrapolated to lanthanum?

Semin. Dial.

Nuclear magnetic resonance spectroscopy of lanthanide complexes with a tetraacetic-tetraaza macrocycle. Unusual conformation properties

Inorg. Chem.

Preclinical safety evaluation of Gd-EOB-DTPA (Primovist)

Invest. Radiol.

Cutaneous mucinosis associated with dermatomyositis and nephrogenic fibrosing dermopathy: fibroblast hyaluronan synthesis and the effect of patient serum

Br. J. Dermatol.

Gadodiamide contrast agent ‘activates’ fibroblasts: a possible cause of nephrogenic systemic fibrosis

J. Pathol.

Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure

Nephrol. Dial. Transplant.

Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair

Stem Cells

Erythropoietin: physiology and pharmacology update

Exp. Biol. Med.

Stability of gadolinium-based contrast agents in human serum

Eur. Radiol.

Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy)

Curr. Opin. Rheumatol.

Transglutaminases: nature's biological glues

Biochem. J.

Review
Possible involvement of gadolinium chelates in the pathophysiology of nephrogenic systemic fibrosis: A critical review