Iron-mobilizing properties of the gadolinium-DTPA complex: Clinical and experimental observations

Department of Nephrology, Soroka Medical Center, Ben Gurion University of the Negev, Faculty of Health Sciences, PO Box 151, Beer Sheva 84101, Israel.
Nephrology Dialysis Transplantation (Impact Factor: 3.58). 06/2003; 18(5):884-7. DOI: 10.1093/ndt/gfg064
Source: PubMed


Gadolinium (Gd) magnetic resonance imaging (MRI) contrast agents are considered to be safe in patients with impaired renal function. Our study investigates a mechanism of severe iron intoxication with life-threatening serum iron levels in a haemodialysis patient following MRI with Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) administration. His previous history was remarkable for multiple blood transfusions and biochemical evidence of iron overload. We hypothesized that Gd-DTPA may have an iron-mobilizing effect in specific conditions of iron overload combined with prolonged exposure to the agent.
For the in vitro study, Gd-DTPA was added to mice liver homogenate and iron metabolism parameters were measured after incubation in comparison with the same samples incubated with saline only. For the in vivo study, an experimental model of acute renal failure in iron-overloaded rats was designed. Previously iron-overloaded and normally fed rats underwent bilateral nephrectomy by renal pedicle ligation, followed by Gd-DTPA or saline injection. Iron and iron saturation levels were checked before and 24 h after Gd-DTPA or vehicle administration.
Significant mobilization of iron from mice liver tissue homogenate in mixtures with Gd in vitro was seen in the control (saline) and in the experimental (Gd) groups (513+/-99.1 vs 1117.8+/-360.8 microg/dl, respectively; P<0.05). Administration of Gd-DTPA to iron-overloaded rats after renal pedicle ligation caused marked elevation of serum iron from baseline 143+/-3.4 to 570+/-8 microg/dl (P<0.0001). There were no changes of the named parameter, either in iron-overloaded anuric rats after saline injection or in normal diet uraemic animals, following Gd-DTPA administration.
The combination of iron overload and lack of adequate clearance of Gd chelates may cause massive liberation of iron with dangerous elevation of free serum iron. It is highly recommended that after Gd contrast study, end-stage renal disease patients with probable iron overload should undergo prompt and intensive haemodialysis for prevention of this serious complication.

14 Reads
  • Source
    • "The lanthanides are known to form insoluble hydroxides, phosphates, or carbonates in blood and tissues (Wedeking and Tweedle, 1988; Luckey and Venugopal, 1977). These complexes are deposited in liver, bone, and muscle tissues (Vorobiov et al., 2003). In both rats and mice GdCl 3 has been demonstrated to cause necrosis in the liver and spleen, and mineral deposition in these organs as well as in the kidney (Spencer et al., 1997, 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The feasibility of using the McMaster University in vivo prompt gamma neutron activation analysis system for the detection of gadolinium has been investigated. Phantoms have been developed for the kidney, liver, and the leg muscle. The initial detection limits are determined to be 7.2 ± 0.3 ppm for the kidney, 3.0 ± 0.1 ppm for the liver, and 2.33 ± 0.08 ppm for the lower leg muscle. A few system optimizations have been tested and show significant detection limit reduction from these initial values. The technique is promising and shows feasibility for in vivo studies of gadolinium retention.
    Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 01/2011; 69(1):105-11. DOI:10.1016/j.apradiso.2010.07.023 · 1.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) is a recently described disease, occurring only in patients with variable degrees of renal failure (RF) previously exposed to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. Public advisories are consistent on some key points including that no cases of NSF/NFD have been reported in patients with normal renal function, and GBCAs may be toxic in patients with RF due to the prolongation of the half-time allowing dissociation and extravasation of highly toxic gadolinium-free ions, potentially linked to the scleroderma-like NSF/NFD, a systemic disabling disease with a mortality rate of up to 30%. The most intriguing feature remains which cofactor might be at play to explain why the disease occurs only in a minority of exposed patients. Therefore, renal dysfunction (substrate) and gadolinium chelates (trigger agent) are necessary but not sufficient. The challenge for nephrologists includes (a) evidence of transmetallation, such as gadolinium deposits in bone, increased urinary zinc excretion, iron-transferrin dissociation or "spurious hypocalcemia" in exposed people; (b) research for uremic cofactors such as increased serum calcium/phosphate, acidosis, use of phosphate-chelating agents able to act as efficient competitor ligands or other drugs; and (c) identification of at-risk patients (with moderate to severe renal dysfunction) and definition of the role of dialysis in removing gadolinium chelates, if any. Nephrologists are called to action to collect and organize information to identify cofactors for NSF/NFD, and therefore they must be aware of this new pathology, as the eye sees only what the mind knows.
    Journal of nephrology 01/2008; 21(3):324-36. · 1.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with end stage renal disease (ESRD) have a 20-100 fold risk of premature cardiovascular death compared to age matched controls from the general population. These patients have many ‘conventional’ cardiovascular risk factors such as diabetes, ischaemic heart disease, hypertension, cigarette smoking and hyperlipidaemia. However, the relationship between the presence of these risk factors and cardiovascular outcomes is less clear in ESRD than in the general population. In the cases of hyperlipidaemia and hypertension a paradoxical relationship has been demonstrated where lower cholesterol or blood pressure is associated with an increased risk of cardiovascular events. One factor previously demonstrated to be associated with poor prognosis is the presence of uraemic cardiomyopathy, found in approximately 70% of ESRD patients at initiation of dialysis therapy, usually defined echocardiographically as the presence of left ventricular (LV) abnormalities, including left ventricular hypertrophy (LVH), LV dilatation and LV systolic dysfunction. However, echocardiography makes assumptions regarding LV geometry, which is frequently distorted in patients with ESRD. Furthermore any errors in measurements are amplified by the changes in hydration status which occur during the dialysis cycle, leading to changes in LV chamber dimensions. For these reasons, cardiac magnetic resonance imaging (CMR), by providing high fidelity measurements, potentially offers a ‘volume independent’ method of quantifying LV dimensions. Furthermore, by using gadolinium based contrast agents, tissue abnormalities particularly myocardial fibrosis, indicated by late gadolinium enhancement (LGE) may by identified. The work contained in this thesis examines the relationship between cardiac dimensions, as defined by CMR and cardiovascular risk factors (both conventional and specific to uraemia). In a study of 145 patients with ESRD using CMR with gadolinium, two specific pathological processes were demonstrated. First, the presence of subendocardial LGE indicating previous myocardial infarction was associated with the presence of conventional cardiovascular risk factors such as previous ischaemic heart disease and diabetes. Patients with subendocardial LGE frequently had LV systolic dysfunction. Second, diffuse LGE, representing fibrosis throughout the LV wall was identified in patients with LVH. This was an unexpected finding and appears specific to uraemia. Using CMR, isolated LV dilatation was rare. These findings suggest that in uraemia two forms of cardiomyopathy exist- LV systolic dysfunction due to underling myocardial ischaemia and LVH which is a true ‘uraemic cardiomyopathy’ associated with diffuse myocardial fibrosis. Attempts were made to reassess the relationship between CMR and echocardiographic measures of cardiac dimensions. In keeping with a previous study, it was demonstrated that M-mode echocardiography overestimates LV mass compared to CMR in this population. Thus, CMR may be used to optimise echocardiographic formulae to calculate LV mass. Furthermore, it appeared that either by echocardiography or by CMR the chief determinant of LVH in this population was blood pressure, in particular systolic blood pressure. This has implications for treatment as recent studies aimed at correcting anaemia, previously associated with LVH, either to reduce LV mass or to improve survival, have generally demonstrated increased cardiovascular events with higher haemoglobin. Therefore, if LV mass is a goal of treatment, attempts should be made to reduce blood pressure further in this population. The patients studied in these investigations were candidates for renal transplantation, the definitive treatment for chronic renal failure. Cardiovascular disease is the leading cause of death both in patients on the renal transplant list, as well as post successful transplantation. There is a great deal of interest in identifying patients at high cardiovascular risk, to allow strategies to be adopted to minimise this risk, frequently by undertaking invasive investigation such as coronary angiography. In a survival study of 300 potential renal transplant recipients, factors associated with increased risk of mortality were increased age, ischaemic heart disease whilst receipt of a renal transplant was protective. Although the presence of LGE was associated with poorer outcome, this finding was not independent of other variables. One interesting finding was that patients with greater exercise tolerance, measured objectively using the full Bruce exercise test had better outcomes. This observation represents a simple pragmatic method to risk-stratify such patients. A study using the biomarker brain natriuretic peptide (BNP) a peptide released from the LV in response to stretch and hypertrophy, in 114 patients, demonstrated that whilst BNP has potential as a diagnostic tool for the presence of uraemic cardiomyopathy, in particular LVH, this peptide added little prognostic value. As familiarity with CMR techniques developed, it became clear that vascular function could be investigated with this imaging modality. Previous studies using alternative measures of vascular function have suggested that arterial stiffness is an important predictor of long term outcome in patients with ESRD. A study of 147 uraemic patients using aortic distensibilty and aortic volumetric arterial strain as CMR measures of aortic stiffness demonstrated that both these parameters were associated with an increased risk of cardiovascular events and mortality. To date there do not appear to be any similar outcome studies using these measures, although a number of authors have noted an association between aortic distensibilty and cardiovascular risk factors. These factors may represent potential targets for therapy aimed at reduction of cardiovascular risk in patients with ESRD. One unfortunate development during the period during which these studies were undertaken, was the emergence of a link between exposure to gadolinium based contrast agents and nephrogenic systemic fibrosis (NSF), a potentially life threatening skin disorder in patients with advanced renal failure. This finding lead to the cessation of contrast CMR studies. A retrospective investigation of factors present in patients in North Glasgow affected by NSF, confirmed that patients with NSF were more likely to have undergone contrast based imaging than unaffected patients, frequently undergoing multiple scans, with high doses of gadodiamide used. Until this issue is clarified, future scans using these agents in this population should be undertaken with caution. These studies have characterised for the first time the relationship between both uraemic cardiomyopathy and uraemic arterial stiffness and both cardiovascular risk factors and long term outcome. CMR measures of cardiac dimensions and vascular function represent future targets for interventions aimed at reducing cardiovascular risk in patients with advanced renal failure.
Show more


14 Reads