Nephrogenic systemic fibrosis (NSF) is a severe skin condition seen in patients with kidney failure exposed to gadolinium-based contrast agents. The document discusses the clinical features and pathogenesis of NSF and provides recommendations to minimize the risk of NSF in patients with kidney disease requiring gadolinium imaging. It is recommended that gadolinium be avoided in patients with eGFR <30 mL/min or on dialysis unless absolutely necessary. For patients who must receive gadolinium, a macrocyclic agent at the lowest possible dose is preferred, and hemodialysis should be performed within hours after administration.

2.  Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder seen only in
patients with kidney failure. It is characterized by two primary features:
 Thickening and hardening of the skin overlying the extremities and trunk.
 Marked expansion and fibrosis of the dermis in association with CD34-
positive fibrocytes.

3.  NSF occurs exclusively in patients with kidney failure.
 The first cases were noted between 1997 and 2000 in hemodialysis
patients or patients with failed renal allografts who developed severe skin
induration that was histologically thought to be scleromyxedema.

4. Fibrosing skin condition among patients with renal disease--United States and Europe, 1997-2002.Centers for Disease Control and Prevention (CDC),MMWR Morb Mortal Wkly Rep.2002;51(2):25.

5. Fibrosing skin condition among patients with renal disease--United States and Europe, 1997-2002.Centers for Disease Control and Prevention (CDC),MMWR Morb Mortal Wkly Rep.2002;51(2):25.

6.  Subsequent reports have:
 Mostly involved patients on hemodialysis.
 Peritoneal dialysis.
 Renal transplant recipients (typically with reduced allograft function).
 Advanced chronic kidney disease (CKD).
 Acute renal failure not requiring dialysis.

7.  The number of cases has declined dramatically since initial reports, most
certainly due to the avoidance of gadolinium-containing agents among at-
risk patients.
 As of January 2013, over 400 cases of NSF had been reported to the
International NSF Registry at Yale University.
 Almost all cases were in adults, but children were also affected .

8.  There is no predilection to NSF by gender, race, or age, etiology of
kidney disease; or duration of renal failure.
 The relationship between time of dialysis initiation to diagnosis of NSF
can vary, ranging from 2 months to 15 years in one series of 12 cases.

9.  However, patients undergoing peritoneal dialysis, compared with
hemodialysis, may be at higher risk.
 As an example, a case-control study found that, over a four-year period,
the attack rate after exposure to gadolinium was higher for peritoneal
dialysis than for hemodialysis patients (4.6 cases per 100 peritoneal
dialysis patients versus 0.61 cases per 100 hemodialysis patients) [27].
Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents--St. Louis, Missouri, 2002-2006, Centers for Disease Control and
Prevention (CDC), MMWR Morb Mortal Wkly Rep. 2007;56(7):137.

10.  Gadolinium(Gd):
 is a nonradioactive, paramagnetic element in the lanthanide series.
 Gd+3 ions closely approximate Ca2+ ions in size, and, consequently,
gadolinium ions are effective (and toxic) calcium channel blockers.
 Gadolinium is hyperosmolal (650 mosmol/kg) contrast agents that are
primarily administered during magnetic resonance imaging (MRI) or MR
angiography studies.
 Because of its toxicity, Gd+3 is bound to a proprietary ligand (or chelate).
 The chelates can be ionic or nonionic and linear or cyclical.
 Binding of Gd+3 ions reduces their interaction with tissues and facilitates
their excretion.

11.  Gadolinium(Gd):
o Gadolinium-containing contrast agents differ by biochemical
structure and charge and can be divided into three groups based on
thermodynamic and kinetic stability.
o Most stable are ionic linear, then nonionic linear, and macrocyclic.
o Higher values of the stability constant indicate a lower rate of
dissociation of free gadolinium ion (Gd3+) from its ligand.

13.  Most gadolinium-containing contrast agents are excreted
unchanged almost exclusively by the kidney.
 Their half-life is 1.3 hours in healthy volunteers, 10 hours at an
estimated glomerular filtration rate (eGFR) of 20 to 40 mL/min, and
34 hours in patients with end-stage renal disease (ESRD).
 For patients with ESRD, the half-life is reduced dramatically to
between 1.9 to 2.6 hours if hemodialysis follows the administration
of gadolinium.

14.  One agent, gadoxetic acid (Eovist or Primovist) undergoes
significant biliary clearance, which may make it desirable for
patients with mild to moderated reduced kidney function.

15.  In a small pharmacokinetic study of patients with a creatinine
clearance of 30 to 50 mL/min, the elimination half-life of gadoxetic
acid was 2.8 hours as compared with 1.8 hours in healthy controls.
 There was a nonsignificant trend towards a greater fractional
excretion via the biliary system in these respective patient groups
(41 versus 31 percent) [34].
 However, similar to other gadolinium-based contrast agents, the
half-life of gadoxetic acid in ESRD patients was markedly elevated
at 20 hours, and, thus, dialysis would still be needed if it were to be
administered to an ESRD patient.

16.  There is strong evidence that the risk of NSF is greater with linear
than with macrocyclic preparations.
 As an example, in the United States, among cases in which the
type of gadolinium preparation was reported, gadodiamide
causes more than 80 percent of cases.
How should nephrologists approach gadolinium-based contrast imaging in patients with kidney disease?, Perazella MA, Clin J Am Soc Nephrol. 2008;3(3):649. Epub 2008 Apr 2.

17.  The reported risk has ranged between 2.5 and 5 percent in studies of
approximately 400 to 500 dialysis patients.
 Cases have been reported in patients with AKI.
 The risk in individuals with eGFR of 15 to 59 mL/min/1.73 m2 remains
undefined, but cases have been reported.
 The risk is felt to be low among patients with eGFR 15 to 29
mL/min/1.73 m2 (ie, stage 4) and very low in individuals with eGFR 30 to
59 mL/min/1.73 m2 (ie, stage 3).

18.  The pathogenesis of NSF is not fully understood.
 The resemblance of NSF to a tissue injury reaction and the
presence of myofibroblasts in the tissue specimens suggest that
fibrogenic cytokines may be important, possibly resulting in a
cascade of events similar to wound healing .
 Two proposed contributors to the exaggerated tissue fibrosis are:
1. Activation of the transforming growth factor (TGF)-beta-1 pathway.
2. An increase in circulating fibrocytes.

19. A low magnification image of a skin biopsy from a patient
with nephrogenic systemic fibrosis shows subcutaneous
septa that are widely expanded by collagen deposits
(arrow). The asterisk highlights an area of normal septal
thickness, and S indicates the skin surface
A high magnification image with immunohistochemical
staining reveals abundant elongated cells that express the
cell surface antigen CD34 (brown) and produce the protein
procollagen I (magenta). This combination of findings
identifies the cells as circulating fibrocytes.

20.  Skin involvement:
 Skin disease in NSF typically presents as symmetrical, bilateral, fibrotic, indurated papules,
plaques, or subcutaneous nodules that may or may not be erythematous.
 The lesions first develop on the ankles, lower legs, feet, and hands and then move
proximally to involve the thighs, forearms, and, less often, the trunk or buttocks.
 Common distribution patterns involve the ankles to below the knees, the mid-thighs, and
the skin between the wrists and mid-upper arms, bilaterally.
 Systemic involvement:
 The prevalence of systemic involvement is unknown.
 Muscle induration.
 Joint contractures.
 Fibrosis of internal organs, including the lungs and diaphragm (with respiratory failure),
myocardium, pericardium, pleura, and dura mater.
 Yellow asymptomatic scleral plaques are common.

21. The major preventive measure for NSF that can be
currently recommended to patients with advanced kidney
failure is the avoidance of gadolinium.

22.  The US Food and Drug Administration (FDA) recommends in
patients with estimated glomerular filtration rate (eGFR) <30
mL/min/1.73 m2, receiving dialysis, or with acute kidney injury (AKI):
 Gadolinium-containing contrast agents should be used only if
clearly necessary. Gadolinium should be avoided in patients with a
diagnosis or clinical suspicion of NSF.
 Gadodiamide (Omniscan), gadoversetamide (OptiMARK), and
gadopentetate dimeglumine (Magnevist) should be avoided.
 Although there are no data that support the following approach, it
may prompt hemodialysis after the imaging study is completed if
gadolinium is given.

23. Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines, Wang Y, Alkasab TK, Narin O, Nazarian RM, Kaewlai R,
Kay J, Abujudeh HH, Radiology. 2011 Jul;260(1):105-11. Epub 2011 May 17.

25.  Among patients with an eGFR <30 mL/min/1.73 m2 who it is felt must
receive a gadolinium contrast study, suggest the following approach:
 The patient should be informed of the benefits, risks, and alternatives.
 Avoid linear chelates such as gadodiamide, gadoversetamide, and gadopentetate
dimeglumine.
 Per Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest,
among such patients, macrocyclic chelate preparations (such as gadoteridol,
gadobutrol, or gadoterate) preferred to use.
 Gadolinium should be given in the lowest dose deemed necessary to provide the
desired diagnostic information (preferably no more than one-half the standard
dose).

26.  Among patients with an eGFR <30 mL/min/1.73 m2 who it is felt must
receive a gadolinium contrast study, suggest the following approach:
 Hemodialysis immediately after gadolinium exposure results in significant
removal of the contrast agent.
 As an example, in a review of 70 hemodialysis patients who underwent
gadolinium contrast MRI, the average rates of gadolinium removal were 78, 96,
and 99 percent in the first, second, and third every-other-day dialysis sessions,
respectively [82].
 In a second study of 13 anuric patients, the average elimination of gadodiamide
(1 mmol/kg) with hemodialysis initiated at 1 to 4.5 hours after exposure was 73,
93, and 99 percent with one, two, and three treatments, respectively [33].

28.  Although there is NO evidence that hemodialysis immediately after
exposure lowers the risk or severity of NSF, recommend the following
approach since NSF is such a severe disease:
 Among patients who are on maintenance hemodialysis, suggest an additional
treatment session just after the imaging study. the dialysis session should
optimally be performed as soon as possible after gadolinium administration
(within hours, not days).
 A second dialysis session at 24 hours should be considered, if clinically safe.

29.  Gadolinium is cleared much more slowly with continuous
ambulatory peritoneal dialysis (69 percent after 22 days, in one
report).
 Thus, among patients on maintenance peritoneal dialysis,
recommend hemodialysis after the procedure.
 If hemodialysis cannot be performed, we suggest more frequent
peritoneal dialysis cycles, for at least 48 hours after exposure, with
no periods with a dry abdomen.

30.  Among patients not on dialysis who have an eGFR <30 mL/min and
a functioning chronic hemodialysis vascular access, we would also
perform hemodialysis as soon as possible after gadolinium
administration (within hours, not days).

31.  Among patients not on dialysis who have an eGFR <15 mL/min and
do not have a functioning vascular access, the possible benefits
associated with gadolinium removal must be weighed against the
possible adverse effects associated with placement of a large
vascular catheter and performance of hemodialysis.
 Despite the risks, we suggest initiating hemodialysis according to
the above regimen. An attempt should be made to schedule elective
imaging studies at a time at which the patient has a functioning
access so that hemodialysis can be performed soon after the
gadolinium is administered.

32.  The approach to patients with an eGFR between 15 and 29 mL/min
who do not have a functioning vascular access is unclear. We do
not perform hemodialysis in this setting, given the unknown benefit
of gadolinium removal in these patients and the risk associated with
placement of a temporary hemodialysis catheter.
 We do not perform hemodialysis after gadolinium exposure in
patients with an eGFR between 30 and 60 mL/min.

33.  Despite the indirect evidence in a single study suggesting a
possible link between erythropoietin and NSF, we suggest that
erythropoietin NOT be discontinued. Erythropoietin doses should be
given to attain current recommended hemoglobin target levels.

34. There is no proven medical therapy for NSF other than recovery of
renal function.

35. Several treatments and combinations of treatments have been
evaluated, but none have shown consistent benefit.
Because NSF is a new and uncommon disorder, most studies have
involved a small number of patients, with limited follow-up.

36.  Kidney transplantation:
 Extracorporeal photopheresis:
 Ultraviolet A phototherapy:
 Plasmapheresis:

37.  Possible efficacy has been noted with imatinib, photodynamic
therapy, pentoxifylline, intravenous sodium thiosulfate, alefacept,
and high-dose intravenous immune globulin.
 Topical, intralesional, or oral glucocorticoid therapy and
cyclophosphamide have generally shown no benefit.

38. Among patients with an estimated glomerular filtration rate (eGFR) <30
mL/min/1.73 m2 or those on dialysis, recommend NOT administering
gadolinium-containing contrast agents (Grade 1B), unless clinical
conditions make gadolinium-based imaging absolutely necessary.

39. There is no consensus among the authors and reviewers of this topic
as to whether or not gadolinium-based contrast agents should be
administered to patients with an eGFR of 30 to 60 mL/min/1.73 m2. In
general, it seems advisable to limit exposure of any patient with
marginal renal function to the three gadolinium-based contrast agents
deemed the highest risk

40. Given that the great majority of cases of NSF have followed imaging
with gadodiamide (Omniscan), gadoversetamide (OptiMARK), and
gadopentetate dimeglumine (Magnevist), suggest giving one of the
other commercially available gadolinium preparations (such as
gadoteridol) (Grade 2C).
The lowest dose that is deemed necessary should be given.

41. Among patients undergoing chronic or acute dialysis (both
hemodialysis and peritoneal dialysis) and patients not on dialysis who
have an eGFR <30 mL/min and a functioning chronic hemodialysis
vascular access, we recommend initiating a hemodialysis session as
soon as possible (within hours, not days) after gadolinium
administration (Grade 1C).
Placement of a temporary hemodialysis catheter should be performed
in peritoneal dialysis patients without a functioning vascular access.

42. Among patients with chronic or acute kidney failure who have an
eGFR <15 mL/min, are not on dialysis, and do not have a functioning
vascular access, we suggest initiating a hemodialysis session as soon
as possible after gadolinium administration (Grade 2C).