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This is a good overall presentation but dated as a woman was presented as having acquired non-nephrogenic systemic fibrosis with normal functioning kidneys at the 5th Annual NSF conference.
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Teaching Module IVNephrogenic Systemic Fibrosis (NSF)
Astana, November 5, 2010
Delayed adverse reactions to GBCA
Nephrogenic Systemic FibrosisThis slide deck was prepared by:
Gertraud Heinz-Peer, MDDept. of Radiology, Medical University of Vienna, [email protected]
November 5th, 2010
• General considerations on GBCA
• Delayed adverse reactions to GBCA
• Update knowledge on NSF
• Physicochemical properties of GBCA
• Guidelines and recommendations
Learning objectives
• Expanded intrinsic tissue contrast
• Improved signal-to-noise ratio (SNR)
• Improved contrast-to-noise ratio (CNR)
• Increased sensitivity, specificity, and accuracy of MRI
Gadolinium-based contrast agents (GBCA)
• Supposed to be very safe in general
• No deterioration of renal function in early studies
• Preferably CE-MRI studies performed in patients with renal dysfunction
• Bold off-label applications in MRA and myocardial viability studies
Gadolinium-based contrast agents (GBCA)
GBCA in clinical use
Gd chelate (trade name) Body regions approved Approval
Gadopentetate dimeglumine (Magnevist®)
CNS, whole body EU, USA, Jap
Gadodiamide (Omniscan®) CNS, whole body EU, USA, Jap
Gadoterate meglumine (Dotarem®)
CNS, whole body EU
Gadoteridol (Prohance®) CNS, whole body EU, USA, Jap
Gadobutrol (Gadovist®) CNS, liver, kidney, MRA EU
Gadobenate dimeglumine (MultiHance®)
CNS, liver EU, USA
Gadoversetamide (OptiMARK®) CNS, liver EU, USA
Gadoxetic acid disodium (Primovist®)
Liver EU, USA
Gadofosveset (Vasovist®) Vessels (abd., limbs) EU
Generally most MR contrast agents are safe
but
they are not a 100% safe
MR contrast agents
• Anaphylactoid/anaphylactic reactions (requiring immediate intervention)
• Side effects
• Nephrogenic systemic fibrosis (NSF)
• Nephrotoxicity
MR contrast agents safety considerations
NSF affects patients with advanced or acute renal insufficiency
• Severe fibrosis scleroderma like skin lesions
• Flexion contractures of joints
• Fibrosis may also affect liver, lung, heart, muscles
Nephrogenic Systemic Fibrosis (NSF)
• Progressive skin disease
• Erythematous papules, brownish plaques
• Symmetric distribution
• Peau d’orange
• Thickening of cutis – “woody texture”
• Pains
• Pruritus
• Burning sensation (neuropathic pain)
Clinical presentation of NSF
NSF
• Gold Standard = deep skin biopsy
• Cells resembling fibroblasts
• CD 34 and procollagen I positive
• TGF-β1 expression
• Dendritic cells
• CD68, F XIIIa positive
• Thickened, chaotic collagen bundles
• Mucin deposits in the skin
Histopathologic findings in NSF
• Natural history - not well understood
• Sometimes gradual improvement in mobility
• Complete spontaneous healing in patients with ongoing kidney disease has not yet been reported
• 5% or less have an exceedingly rapid and fulminate disease course that may result in death
Prognosis of NSF
• Circulating fibrocytes
• Leave the circulation
• Endothelial damage
• Fibrocytes differentiate into cells that resemble normal dermal fibroblasts
• Circulating cells → deposit in other organs → multi-system fibrosis
Pathophysiology of NSF
• Strong evidence of GBCA to trigger NSF
• Mostly affected patients with severe renal insufficiency (grade 4 and 5) i.e. eGFR < 30 mL/min per 1.73 m2 or ARF
• Higher cumulative doses
• Proinflammatory or profibrotic conditions
• Linear GBCA ↑ risk compared to macrocyclic agents
NSF and GBCA
Pathophysiology – not well known stability?
• GBCA with linear molecular structure
• GBCA with macrocyclic molecular structure
NSF and GBCA
In vitro and in vivo studies
Linear GBCA are less stable compared to macrocyclic agents
Stability of GBCA
Possible mechanism
• Transmetallation may play a role in the pathophysiology of NSF
• Peripherally deposited Gd might be a target for circulating fibrocytes
NSF and GBCA
• Leads to release of free Gd3+ which is extremely toxic. Gd replaced by endogenous metals such as zinc or copper
• Transmetallation is more likely with linear chelates and when GBCA remains in the body for a long period
• Transmetallation is more likely in acidotic condition
GBCA - Transmetallation
• Thermodynamic stability (Ktherm) – describes affinity of Gd for the ligand at pH 14
• Conditional stability (Kcon) – describes equilibrium considering all protonated forms of the ligand at pH 7.4
• Variable amounts of free ligands or calcium complexes in some agents to ensure chelation of any free Gd3+
GBCA - Stability
• Kinetic stability describes speed of dissociation
• Assessed by measuring dissociation half-life under acidic conditions
GBCA – Stability
• More likely to occur with unstable molecules as indicated by:
• Low Ktherm value
• Low Kcon value
• Low kinetic stability
• Presence of large amount of excess chelate
• Linear molecules are less stable compared to macrocyclic agents
• Non-ionic linear molecules are thermodynamically less stable than ionic ones
GBCA - Transmetallation
Kimura et al., Radiation Medicine 2005; 23:322-326
• Non-ionic molecules are thermodynamically less stable in comparison to ionic chelates
• [Kcon]
• Gadoversetamide (Optimark) non-ionic (15.0)
• Gadodiamide (Omniscan) non-ionic (14.9)
• Gadoteridol (ProHance) non-ionic (17.1)
• Gadobutrol (Gadovist) non-ionic (15.5)
• Gd-DTPA (Magnevist) ionic (18.1)
• Gadobenate (MultiHance) ionic (18.4)
• Gd-DOTA (Dotarem) ionic (18.8)
GBCA - StabilityMolecular structure
• [Ktherm]
• Gadoversetamide (Optimark) 16.6
• Gadodiamide (Omniscan) 16.9
• Gd-DTPA (Magnevist) 22.1
• Gadobutrol (Gadovist) 21.8
• Gadobenate (MultiHance) 22.6
• Gadoteridol (ProHance) 23.8
• Gd-DOTA (Dotarem) 25.8
GBCA - Stability
• Excess chelates
• Gadoversetamide (Optimark) 28.40
• Gadodiamide (Omniscan) 12.00
• Gd-DTPA (Magnevist) 00.40
• Gadoteridol (ProHance) 00.23
• Gadobutrol (Gadovist) 00.00
• Gadobenate (MultiHance) 00.00
• Gd-DOTA (Dotarem) 00.00
GBCA - Stability
• Macrocyclic agents are kinetically much more stable than linear chelates
• Gadoversetamide (Optimark) Linear
• Gadodiamide (Omniscan) Linear
• Gd-DTPA (Magnevist) Linear
• Gadobenate (MultiHance) Linear
• Gadobutrol (Gadovist) Cyclic
• Gadoteridol (ProHance) Cyclic
• Gd-DOTA (Dotarem) Cyclic
GBCA - StabilityMolecular structure
ExtracellularGd-CM
Type
Thermo-dynamic stability constant
Condition stability
Excess chelate (mg/ml)
Dissociation half-life at pH 1.0
Gadoversetamide (OptiMark)
Non-ionic linear
16.6 15 28.4 Not available
Gadodiamide (Omniscan)
Non-ionic linear
16.9 14.9 12 35 sec
Gadobutrol (Gadovist)
Non-ionic cyclic
21.8 15.5 Not available 18h*
Gadoteridol (ProHance)
Non-ionic cyclic
23.8 17.1 0.23 4h*
Gadopentetate (Magnevist)
Ionic linear 22.1 18.1 0.4 10 min
Gadobenate (MultiHance)
Ionic linear 22.6 18.4 None Not available
Gadoterate (Dotarem)
Ionic cyclic 25.8 18.8 None 85h*
* pH=1.2, 37°C Port Br J Radiol 2008; 81: 258-259
In-vitro stability measurements in native human serum
Frenzel et al. Invest. Radiol. 2008
• Differences within the group of non-ionic and the ionic linear class, but no differences within the macrocyclic class
• For the macrocyclic agents, Gadovist, Dotarem and Prohance,
no (< 0.1%) release was observed within 15 days
In-vitro stability measurements in human serum + phosphate
• Addition of phosphate enhances release of Gd from linear agents, but class differences prevail• For the macrocyclic agents, Gadovist, Dotarem and ProHance, no (< 0.1%) release was
observed within 15 days. Phosphate had no effect on stability.• No difference between Gadovist, Dotarem, and ProHance
Frenzel et al. Invest. Radiol. 2008
Up to October 2009 in peer-reviewed literature
Estimated # of appl. (Dec. 09)*
• Omniscan 48 mio. 347 patients
• Magnevist 100 mio. 89 patients
• OptiMark 9 mio. 5 patients
• Unspecified Gd-CM 151 patients
• Gadovist 4 mio. one patient
Epidemiology of NSF published case reports
* Company data presented at FDA Advisory Board Dec. 09, Gadovist data from BSP
• Patients with GFR <30 ml/min including those on dialysis should not receive non-ionic linear chelates or Magnevist
• The most stable Gd-CM should be used in these patients (macrocyclic Gd-CA)
• The lowest possible dose
• Allow at least one week before giving more Gd-CM
• Patients on haemodialysis can be scheduled to have the dialysis session shortly after the MRI examination
• Patients on peritoneal dialysis should be asked to do several rapid exchanges after the examination
How to reduce the risk of NSF
• FDA
• EMA
• ESUR
Current guidelines
• Package insert with black box warning on the risk of NSF
• Risk groups for NSF: acute and chronic kidney disease grades 4 and 5 and every grade of ARF
• Check for renal dysfunction before administration of GBCA (medical history, laboratory tests)
• No off-label use
FDA
FDA (September 2010)
• Omniscan, OptiMark and Magnevist no longer allowed in CKD grade 4 and 5
• Other GBCA may be carefully used in these patients
FDA
It may be prudent to institute prompt dialysis in patients with advanced kidney dysfunction who receive GBCA. Although there are no data to determine the utility of dialysis to prevent or treat
NSF in patients with decreased kidney function, average excretory rates of gadolinium are 78%, 96%, and 99% in the first
to third haemodialysis sessions, respectively.
• Package insert with black box warning on the risk of NSF
• Omniscan, OptiMark and Magnevist no longer allowed in CKD grade 4 and 5
• Other GBCA may be carefully used in these patients
• Check for renal dysfunction before administration of GBCA (medical history, laboratory tests)
EMA
ESUR guidelines on NSF
Patients at risk of NSF
• Patients with CKD (GFR < 30 ml/min)
• Patients on dialysis
• Patients suffering from acute renal failure
• Patients with reduced renal function who have had or are awaiting liver transplantation
ESUR guidelines on NSF
Do not use in patients at risk of NSF
• Omniscan
• Magnevist
• OptiMark
ESUR guidelines on NSF
In high-risk patients
• Use a GD-CM with high stability
• Give the lowest dose possible to achieve a diagnostic examination
• Allow at least one week before giving more Gd-CM
Note: Do not deny at risk patients clinically important MR examinations
Ethical issue
Don’t go into panic because of NSF
NSF - a complication that could be avoided
At the centre which reported the largest series of cases with NSF:
Since they have stopped gadodiamide in March 06 and switched to a macrocyclic MRI-CM, they have not seen a single new case of NSF.
Thomsen et al., ACTA Radiologica 2007; 48:593-596
No cases of NSF were identified in dialysis patients who received ProHanceReilly RF, Clin J Am Soc Nephrol 2008
A recent study documented that no cases of NSF were seen in 135 patients with advanced renal impairment (GFR < 30 ml/min) who received the ionic macrocyclic agent Dotarem between July 05 to July 06
Janus et al., The FINEST study, Eur J Radiol 2009
Thank you!