Gadolinium-containing contrast medium associated with fibrosing nephrogenic dermopathy and systemic fibrosis [Classics Series]

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials

1. In patients with end-stage renal disease (ESRD), gadolinium (Gd) containing MRI contrast agents has been shown to trigger nephrogenic fibrosing dermopathy (NFD) or nephrogenic systemic fibrosis (NSF) within one month depending on administration.

2. Gadolinium half-life is significantly prolonged in ESRD and, when associated with metabolic acidosis, may contribute to the dissociation of the Gd-ligand complex, allowing tissue precipitation of Gd salts.

Original publication date: June 2006

Summary of the study: Gadolinium-containing contrast agents are used in MRI examinations to reduce the T1 relaxation time of water molecules as they intermittently bind to the paramagnetic metal center, providing an increased MR signal. They are generally considered very safe agents, even in people with kidney failure, with a low rate of adverse effects and a half-life of around 2 hours in people without kidney disease. However, in patients with impaired renal function, this half-life can extend up to 120 hours, and it has been proposed that this prolonged exposure may lead to Gd salt deposition in body tissues and subsequent complications. , such as NFD or NSF . NFD is an acquired idiopathic disease of people with renal failure characterized by painful thickening and induration of the skin, particularly in the distal extremities. NSF is a variant of the same disease in which there is systemic involvement beyond the skin, affecting the joints, lungs, heart, or liver. The present study described a case-control series in which patients with ESRD underwent Gd-enhanced magnetic resonance angiography (MRA) and developed symptoms of NFD or NSF, and were among the first publications to describe the association between Gd and these diseases. Of the 9 patients who underwent Gd-enhanced MRA for 2 years, 5 developed cutaneous symptoms suggestive of DNF with characteristic histopathological changes. The most significant differences between those who developed symptoms and those who did not were the presence of significant metabolic acidosis and a prolonged history of dialysis in those affected compared to those unaffected. Despite the inherent limitations of a series of case-control studies examining a rare disease entity with limited sampling, this study introduced a now common association between Gd contrast agents and NFD or NSF in patients with IRT.

Click to read the study in Nephrology Dialysis Transplantation

In depth [prospctive cohort]: This series identified 9 dialysis-dependent patients (mean age 58 ± 10.3 years) over a 2-year period who underwent Gd-enhanced ARM with gadopentetic acid, 5 of whom developed cutaneous symptoms suggestive of NFD with characteristic histopathological changes. Baseline characteristics of affected individuals were compared to those unaffected in an effort to identify potential risk factors for the development of NFD or NSF. In each index case, skin changes occurred 2-4 weeks after initial administration of gadopentetic acid, and the clinical course was uneventful. Only two major differences were identified between the two groups of patients: their mean time on dialysis and their pH values. Affected people had a mean time on dialysis of 36 ± 16.5 months versus 23.75 ± 12.5 months for unaffected people. Additionally, affected individuals uniformly exhibited metabolic acidosis with a mean pH of 7.29 ± 0.04 and serum bicarbonate of 19.5 ± 1.7 mmol/L versus 7.39 ± 0.01 and 22.95 ± 0.58 mmol/L respectively, for unaffected persons. Laboratory examination including antinuclear antibodies, antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, immune complexes, anti-glomerular basement membrane antibodies, and complement factors revealed nothing in affected and unaffected individuals. Only one affected patient had decreased protein C levels and increased factor VIII levels. No drugs were identified in common between any of the nine patients. In individuals with ESRD, the half-life of Gd-containing compounds is significantly prolonged and multiple metabolic disorders are often present, including metabolic acidosis. This may predispose the Gd ion to dissociation from its contrast complex, allowing the formation of Gd salts with free anions such as phosphate, the concentration of which is often increased in dialysis patients. It has been proposed, although without direct evidence, that these salts may precipitate in the tissues and trigger the symptoms of NFD or NSF in susceptible patients.

Grobner T. Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation. 2006 Jan 21: 1104–08.

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