Gadolinum Induced Nephrogenic Systemic Fibrosis

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• Gadolinum Induced Nephrogenic Systemic Fibrosis

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INTRODUCTION

• Nephrogenic systemic fibrosis (NSF), formerly
  known as nephrogenic fibrosing dermopathy (NFD),
  is now a major concern for nephrologists
• This entity was first described in 1997 in renal
  transplant recipients with poor graft function
• Ref Lancet356 1000 1001,2000

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Curr Opin Rheumatol18 614 617,2006

• NSF is a fibrosing disorder that involves
  predominantly the skin but also affects systemic
  organs such as the liver, heart, lungs,
  diaphragm, and skeletal muscle
• It is associated with severe physical disability
  and death when multisystem disease supervenes
• The cause of NSF is unknown however, underlying
  kidney dysfunction is present in all cases

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Clin J Am Soc Nephrol2 264 267,2007 Clin J Am
Soc Nephrol2 258 263,2007

• The trigger for NSF is unknown, but the magnetic
  resonance imaging (MRI) contrast agent gadolinium
  (Gd3) has become the leading suspect
• Ttwo articles describe Gd3 exposure before the
  development of NSF in patients who had ESRD and
  were on dialysis

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Invest Radiol 34 443 448,1999

• Gd3 may act as a trigger for NSF in patients
  with kidney disease on the basis of its reduced
  clearance and possibly its chelate-binding
  characteristics
• Gd3 contrast is eliminated almost entirely (97)
  by the kidneys
• Reduced renal function significantly increases
  the half-life of Gd3 from 1.96 h in healthy
  individuals to 5.61 and 9.18 h in stages 4 and 5
  CKD, respectively

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Top Magn Reson Imaging12 309 314,2001

• For prevention of toxicity, Gd3 is sequestered
  by binding it to a chelate
• Gd3 is classified into four major categories on
  the basis of chelate structure (macrocyclic
  versus linear) and chelate charge (ionic versus
  nonionic)
• Macrocyclic chelates bind Gd3 more tightly than
  linear chelates, are more stable both in vitro
  and in vivo, and have lower dissociation rates

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Clin J Am Soc Nephrol2 264 267,2007

• Gadodiamide, the agent that most commonly is
  associated with NSF, is a nonionic contrast agent
  that uses a linear chelate
• Gadopentetate, described in one of the NSF cases
  in this issue also uses a linear chelate
• It is possible that the linear chelate
  characteristic makes certain Gd3 formulations
  less stable and more likely to dissociate

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Invest Radiol41 272 278,2006

• Compared with gadoteridol, a macrocyclic chelate,
  gadodiamide leaves two to four times more Gd3 in
  bone tissue of patients with normal kidney
  function
• The relative instability of gadodiamide may
  underlie its excess association with NSF

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• Prolonged tissue exposure occurs in patients with
  CKD/ESRD which may allow free Gd3 to extravasate
  from abnormal vessels (e.g., from vascular
  trauma, endothelial dysfunction, chronic edema)
  and deposit in tissues
• Once in tissues, Gd3-containing macrophages
  produce profibrotic cytokines that act locally
  and attract cF, which promote the fibrotic
  response (Figure 1).

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Figure 1. Speculative mechanism by which
gadolinium (Gd3) might trigger nephrogenic
systemic fibrosis
Perazella, M. A. Clin J Am Soc Nephrol
20072200-202
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• Although cause and effect have not been proven
  with Gd3 exposure and development of NSF, there
  is compelling associative evidence to recommend
  limiting Gd3 exposure to patients with kidney
  disease
• Dialysis patients are clearly at risk and should
  avoid Gd3 at all costs

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• If MRI with Gd3 is to be avoided, then iodinated
  radiocontrast-based imaging may be the only
  alternative when other noninvasive studies are
  insufficient
• Because radiocontrast-induced nephropathy is
  generally reversible and NSF is not, exposure to
  radiocontrast is probably preferable.

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• For the time being, it is best to avoid
  administration of Gd3 to patients with AKI and
  stage 4/5 CKD (including transplant patients) and
  those who are on dialysis
• Judicious use of iodinated radiocontrast with
  standard prophylaxis may be a better choice
• If an MRI study with contrast is absolutely
  required, then a nongadodiamide contrast using
  the lowest possible dosage is preferable

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Clin J Am Soc Nephrol2 264 267,2007

• In patients in whom NSF has developed,
  intravenous sodium thiosulfate may provide some
  benefit (in addition to aggressive physical
  therapy)
• Sodium thiosulfate may act by chelating Gd3 and
  improving endothelial function through its
  antioxidant effects.

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Two patients with nephrogenic systemic fibrosis
(NSF) that developed after gadodiamide injection

• Broome, D. R. et al. Am. J. Roentgenol.
  2007188586-592

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59-year-old man with nephrogenic systemic
fibrosis (NSF) with both skeletal muscle and skin
findings
Broome, D. R. et al. Am. J. Roentgenol.
2007188586-592
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59-year-old man with nephrogenic systemic
fibrosis (NSF) with both skeletal muscle and skin
findings
Broome, D. R. et al. Am. J. Roentgenol.
2007188586-592
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30-year-old woman with nephrogenic systemic
fibrosis with predominant skin finding
Broome, D. R. et al. Am. J. Roentgenol.
2007188586-592
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30-year-old woman with nephrogenic systemic
fibrosis with predominant skin finding
Broome, D. R. et al. Am. J. Roentgenol.
2007188586-592
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Flow diagram for identification and selection of
studies
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Relationship between gadolinium and NSF. Results
indicate a significant increase in the risk of
NSF with gadolinium. The odds of developing NSF
were 27 times greater in patients exposed to
gadolinium compared to those who were not
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Relationship between gadodiamide and NSF. Results
indicate a significant increase in the risk of
NSF with gadodiamide. The odds of developing NSF
were 20 times greater in patients exposed to
gadodiamide compared to those who were not
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Funnel plots for publication bias. The
symmetrical distribution of studies in an inverse
funnel shape suggests the absence of publication
bias
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Exclusion sensitivity plots (A) all studies and
(B) studies exclusively examining gadodiamide.
Each diamond represents the pooled estimate after
exclusion of individual studies in the order
shown in the meta-analyses in the corresponding
meta-analyses in Figures 2 and 3. The similarity
among the pooled estimates suggests that no
single study disproportionately influenced the
results of the meta-analyses
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a. Patient with NSF presented with area of
edema, induration, and erythema on the forearm
Sadowski E A et al. Radiology 2007243148-157
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b. Patient with NSF presented with an
erythematous appearance to the skin over the
thigh, which spared the groin
Sadowski E A et al. Radiology 2007243148-157
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(a, b) Patient with NSF presented with area of
edema, induration, and erythema on (a) the
forearm and (b) an erythematous appearance to the
skin over the thigh, which spared the groin.
Sadowski E A et al. Radiology 2007243148-157
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(a, b) Patient with NSF presented with area of
edema, induration, and erythema on (a) the
forearm and (b) an erythematous appearance to the
skin over the thigh, which spared the groin.
Sadowski E A et al. Radiology 2007243148-157
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Chart shows 1-year incidence of NSF in patients
undergoing contrast-enhanced MR (CE-MR) imaging.
Sadowski E A et al. Radiology 2007243148-157
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Bar graphs show relevant clinical and laboratory
data in 13 patients with NSF (gray bars) and 125
control patients (white bars) without NSF but
with renal insufficiency and ongoing
proinflammatory condition at time of
contrast-enhanced MR (CE-MR) examination.
Sadowski E A et al. Radiology 2007243148-157
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Bar graphs show relevant clinical and laboratory
data in 13 patients with NSF (gray bars) and 125
control patients (white bars) without NSF but
with renal insufficiency and ongoing
proinflammatory condition at time of
contrast-enhanced MR (CE-MR) examination.
Sadowski E A et al. Radiology 2007243148-157
32
Bar graphs show relevant clinical and laboratory
data in 13 patients with NSF (gray bars) and 125
control patients (white bars) without NSF but
with renal insufficiency and ongoing
proinflammatory condition at time of
contrast-enhanced MR (CE-MR) examination.
Sadowski E A et al. Radiology 2007243148-157
33
Bar graphs show relevant clinical and laboratory
data in 13 patients with NSF (gray bars) and 125
control patients (white bars) without NSF but
with renal insufficiency and ongoing
proinflammatory condition at time of
contrast-enhanced MR (CE-MR) examination.
Sadowski E A et al. Radiology 2007243148-157
34
Bar graphs show relevant clinical and laboratory
data in 13 patients with NSF (gray bars) and 125
control patients (white bars) without NSF but
with renal insufficiency and ongoing
proinflammatory condition at time of
contrast-enhanced MR (CE-MR) examination.
Sadowski E A et al. Radiology 2007243148-157
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