A dialysis-dependent 48-year-old white man with polycystic kidney disease was admitted to the hospital for a living-related renal transplantation. In the immediate post-op course he was evaluated for arrhythmias via cardiac magnetic resonance imaging (MRI) with gadolinium contrast. Three weeks post-op he underwent a renal biopsy for an elevated serum creatinine, which showed acute tubular necrosis (ATN). At that time he developed a painful, erythematous sclerotic plaque with a small erosion in the center of his abdominal wall. Skin biopsies were consistent with nephrogenic systemic fibrosis (NSF).
Rare systemic fibrosing disorder presenting as symmetrical, thickened, fibrotic skin leading to flexion contractures and immobility.1,2
Skin involvement is the predominant feature, leading to its former description as nephrogenic fibrosing dermopathy (NFD). However, increased understanding of this disorder as a systemic process with systemic manifestations has necessitated changing the nomenclature to NSF.
95% of cases occur in patients with advanced stages of renal dysfunction.
This represents mostly hemodialysis, but also includes peritoneal dialysis, reduced transplant allograft function, and acute kidney injury (AKI) not requiring dialysis.
Rate of incidence is estimated between 1% and 5% of dialysis-dependent patients.
Risk is higher in peritoneal dialysis versus hemodialysis.
Gadolinium dose-response relationship has been suggested in a study comparing double dose versus single dose. Odds ratio comparing the two doses was found to be 22.3 for the double dose versus single dose.
First published case series chronicled patients from 1997 to 2002.
Gadolinium-based contrast agents3,4,5, and 6
Gadolinium is a cationic contrast agent used in MRI. Free gadolinium is relatively water insoluble and toxic to tissue. Thus it is chelated for use in humans. There are various molecular structures used to accomplish this with varying degrees of binding strength. Ionic and cyclical compounds are more stable, compared to nonionic, linear structures.
Chelates are excreted unchanged through the kidney, thus diminished renal function significantly prolongs the half-life of gadolinium, from 1.5 to 2 hours with normal renal function, to greater than 30 hours in renal failure.
One US/FDA registry of 75 cases revealed an exposure to gadolinium 2 days to 18 months prior to diagnosis of NSF. An international registry noted more than 95% of cases reported fell within 2 to 3 months of exposure.
The acidosis, hyperphosphatemia, and abnormal iron metabolism associated with renal failure may contribute to destabilization of the gado-linium-chelate complex causing the release of free gadolinium into circulation.
Erythropoietin therapy
Postulated because of its fibrogenic properties, bone marrow stimulation, and iron mobilization.
An association has been described, suggesting that high and escalated doses of erythropoietin are an additional risk factor for NSF.
Infection
One single center, retrospective study found that the presence of infection at the time of gadolinium administration markedly increased the risk of NSF in dialysis patients (odds ratio [OR] 25, 95% confidence interval [CI] 3.9-264).
Light microscopy7
Early disease is characterized by subtle proliferation of dermal fibrocytes.
Late disease is characterized by marked thickening of the dermis with florid proliferation of fibrocytes with long dendritic processes.
Thick collagen bundles with surrounding clefts are prominent, while there is a variable increase in dermal mucin and elastic fibers.
Immunohistochemical staining
Abundance of CD34+ dermal cells typically associated with tissue injury and wound healing.
Dendritic processes align with elastic fibers and around collagen bundles in dense networks.
Special stainings may reveal gadolinium in tissue; however, at this time chelated versus nonchelated gadolinium cannot be distinguished.
Two proposed mechanisms involve activated transforming growth factor beta 1 (TGF-β1) pathway and increased circulating fibrocytes:6,7
TGF-β1
Upregulated messenger ribonucleic acid (mRNA) levels discovered in skin and fascia of affected tissue.
TGF-β1 produced by local CD68+/factor IIIa+ dendritic cells on activation by noxious stimuli.
TGF-β1 in turn regulates dendritic cell maturation and antigen presentation, leading to a vicious cycle responsible for generating tissue fibrosis.
Increased circulating fibrocytes
Toxin directly stimulates bone marrow to produce CD34+ fibrocytes.
Accumulate in affected tissue and produce collagen.
Superimposed on these two postulates are the roles of proinflammatory cytokines and gadolinium itself:
Proinflammatory/profibrotic cytokines
NSF tissue found to have accumulation of macrophages, fibroblasts, TGF-β expression.
In vitro studies of human peripheral blood monocytes (PBMCs) exposed to gadolinium chelates showed marked expression of interleukin (IL)-13, IL-4, IL-6, IL-13, TGF-β, and vascular endothelial growth factor (VEGF).
Free gadolinium
Believed to be the initial toxin/stimuli that initiates the above mechanisms.
In vivo studies have demonstrated precipitation in tissue, disruption of calcium movement through nerve and muscle cells, and displacement of endogenous metals thus interfering with intracellular enzymes and cell membranes.
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