Recent topics related to nephrogenic systemic fibrosis associated with gadolinium-based contrast agents
This article is corrected by:
- Errata: Corrigendum Volume 19, Issue 12, 1127, Article first published online: 26 November 2012
Kazuhiro Kitajima M.D., Ph.D., Department of Radiology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Email: email@example.com
Nephrogenic systemic fibrosis is a progressive, potentially fatal, multiorgan-system fibrosing disease related to exposure of patients with renal failure to gadolinium-based contrast agents used in magnetic resonance imaging. Between 1997 and 2007, more than 500 cases of nephrogenic systemic fibrosis in patients with severe renal insufficiency (glomerular filtration rate less than 30 mL/min/1.73 m2) were reported, and no known cases of nephrogenic systemic fibrosis have occurred in patients with a glomerular filtration rate of more than 30 mL/min/1.73 m2 without acute kidney injury. Additional major risk factors are use of high-dose and specific gadolinium-based contrast agents, a pro-inflammatory state. Although the mechanism of nephrogenic systemic fibrosis is unclear and there is no consistently-effective therapy, nephrogenic systemic fibrosis is an entity that can be eliminated by observing recent recommended guidelines for gadolinium-based contrast agents and nephrogenic systemic fibrosis. This article reviews current knowledge about nephrogenic systemic fibrosis and focuses mainly on how to prevent it.
Abbreviations & Acronyms
- CIN =
- ESUR =
European Society of Urogenital Radiology
- FDA =
US Food and Drug Administration
- GBCA =
gadolinium-based contrast agents
- GFR =
glomerular filtration rate
- MRI =
magnetic resonance imaging
- NSF =
nephrogenic systemic fibrosis
The prevalence of kidney disease is increasing, and selection of appropriate contrast material-enhanced imaging modalities for affected patients with renal disease is challenging, leading to an increasing clinical problem. Historically, CIN has limited the use of contrast CT, and until 2006, MRI using GBCA was carried out at ever-increasing doses in patients with renal failure and patients undergoing dialysis. However, the recent discovery of an association between GBCA treatment and NSF has changed the way that GBCA are used.
NSF is a progressive, potentially fatal, multiorgan-system fibrosing disease related to exposure of patients with renal failure to the GBCA used in MRI. Because current treatment options are limited, there has recently been an emphasis on prevention, and the FDA now recommends that specific types of GBCA should not be used for patients with acute or chronic severe renal insufficiency with a GFR less than 30 mL/min/1.73 m2 or acute kidney injury of any severity associated with hepatorenal syndrome, or during the perioperative period after liver transplantation.1
For the practising urologist, we review current knowledge about NSF and suggest approaches to contrast material-enhanced imaging studies in patients with renal dysfunction.
NSF was first noted in 1997 and reported to the medical community in 2000 as a scleromyxedema-like cutaneous disease seen in patients with renal failure, predominantly those on hemodialysis.2 That series included 15 patients on dialysis who presented with extensive thickening and hardening of the skin with brawny hyperpigmentation primarily affecting the extremities. Initially, NSF was named nephrogenic fibrosing dermopathy, because it was believed that the fibroses were limited to the skin. Later, however, when autopsies showed involvement of other organs including the lungs, myocardium, skeletal muscle and tendons, nephrogenic fibrosing dermopathy was recognized as a systemic condition and renamed NSF.3 In early 2006, the relationship between NSF and the GBCA used in MRI was first reported.4 This relationship was confirmed in subsequent studies, and gadolinium has even been discovered in skin biopsy samples from patients with NSF.5 NSF can also cause respiratory failure as a result of diaphragmatic involvement, which might be life-threatening, and an estimated 5–31% of cases show a more fulminant course resulting in death.6,7
The incidence of NSF in patients with severe renal insufficiency after exposure to GBCA appears to be approximately 2–5%, irrespective of sex, race or age.7–9 Thanks to several guidelines pertaining to GBCA and NSF,10–12 a virtual absence of new cases with onset in 2008–2011 suggests that several preventive measures have been successful, allowing safe judicious use of GBCA in patients with renal failure and those receiving dialysis, whenever clinical necessity arises.
NSF risk factors
Major risk factors are renal failure, resulting from the use of specific types and high doses of GBCA.
NSF is observed only in patients with severe renal dysfunction, primarily undergoing or approaching the need for dialysis, hence use of the nephrogenic. The published literature includes more than 500 cases of NSF, all in patients with severe renal dysfunction with an estimated GFR of less than 30 mL/min/1.73 m2.13 No known cases of NSF have occurred in patients with an estimated GFR of more than 30 mL/min/1.73 m2 without acute renal failure. The recommendation is to avoid GBCA administration in patients with acute renal failure in whom the serum creatinine level is increasing.14
Extracellular GBCA are linear or macrocyclic chelates, and both are available as ionic or non-ionic preparations (Table 1). Linear agents have an advantage over macrocyclic agents in that they are simpler and less expensive to synthesize. Macrocyclic agents, in contrast, have greater kinetic stability as a result of complete enclosure of the Gd3+ ion with covalent bonds. Non-ionic linear compounds are also less stable than ionic ones, because the binding between Gd3+ and the negatively-charged catrboxyl groups in the latter is stronger than that with amides or alcohol in the former. Stability constants and kinetic measurements indicate that the least stable agents are the non-ionic linear chelates, such as gadodiamide and gadoversetamide.
Table 1. Various gadolinium-based agents
|MultiHance||Gadobenate dimeglumine||Gd-BOPTA||Linear||Ionic||97% Kidney 3% Bile||Very low|
|Primovist||Gadoxetic acid disodium salt||Gd-EOB-DTPA||Linear||Ionic||50% Kidney 50% Bile||Very low|
|Vasovist||Gadofosveset trisodium||Gd-DTPA||Linear||Ionic||91% Kidney 9% Bile||Very low|
|Dotarem||Gadoterate meglumine||Gd-DOTA||Cyclic||Non-ionic||Kidney||Very low|
Looking at all the available data, just three agents (gadodiamide, gadoversetamide and gadopentetate dimeglumine) have been associated with NSF.10–12,15 Gadodiamide has been the GBCA most often associated with NSF, being associated with NSF in 68∼85% of NSF cases.16,17 Other safer agents are acceptable for use in patients with severe renal impairment, and the incidence of NSF can be lower simply by using one of these safer agents.18 The most recent FDA guidelines stipulate that gadodiamide, gadoversetamide and gadopentetate dimeglumine should be labeled as “inappropriate” for use among patients with acute kidney injury or chronic severe kidney disease.15 The ESUR guidelines on NSF recommend against using gadodiamide, gadoversetamide and gadopentetate dimeglumine in patients with a GFR of less than 30 mL/min/1.73 m2 and patients with reduced renal function who are awaiting liver transplantation.11 The ESUR further recommend that other safer agents should be used only with caution in patients with an estimated GFR of 30∼60 mL/min/1.73 m2, pregnant women and children younger than 1 year-of-age. The 2010 American College of Radiology guidelines on NSF contraindicate use of the three “inappropriate” agents for patients who are receiving chronic dialysis treatment and/or have an estimated GFR lower than 60 mL/min/1.73 m2,12 whereas the staff of one American hospital have shown that gadopentetate dimeglumine can be safely given to patients with a GFR of 30∼60 mL/min/1.73 m2.19
Many authors have concluded that high doses (e.g. double or triple doses) of GBCA contribute to an increased risk of NSF. Broome et al. reported zero cases of NSF among 94 dialysis patients receiving the standard dose, 0.1 mmol/kg, of gadodiamide, whereas 12 of 207 dialysis patients receiving a high dose of gadodiamide developed NSF, with an odds ratio of 12:1.8 In a larger, but still retrospective, study, investigators found no cases of NSF among approximately 74 000 unscreened patients receiving a standard dose of a GBCA (80% receiving gadodiamide), but 15 cases of NSF were documented among approximately 9000 patients receiving a high dose.20
Several studies have shown that the cumulative dose of GBCA over the lifetime of patients who have compromised renal function increases the risk of NSF, whereas standard doses over many years might pose less of a problem than a single high-dose injection.9,14
Other factors that have been suggested as predisposing patients to NSF include metabolic acidosis, increased iron, calcium and/or phosphate levels, high-dose erythropoietin therapy, immunosuppression, vasculopathy (including hypercoagulability and/or vascular injury as a result of surgery or endovascular catheterization), and other pro-inflammatory conditions.14
The diagnosis of NSF should consider patient history, clinical presentation and biopsy findings.21 Most cases of NSF become evident weeks to months after GBCA exposure. Excisional deep skin biopsy including the fascia is essential for the diagnosis of NSF, as superficial biopsy might not show fibrosis involving deep dermal tissues, underlying fat, fascia and muscle.22 Recently, a multi-institutional meeting was convened to review the criteria for NSF, and a scoring system based on clinical and histological findings, which assigns a pre-established score to each finding, was proposed. The clinical and histological scores are summarized in Tables 2 and 3, respectively. From the sum of the scores, it is possible to clarify cases in relation to the risk of NSF. The scoring system is the same for both clinical and histological findings, and uses a scale from 0 to 4 (Table 4). This scoring system might allow more accurate diagnosis in the future, and enable comparisons between studies to improve patient care.21,22
Table 2. Clinical findings of NSF
| Patterned plaques|
| Joint contractures|
| Marked induration/peau d'orange|
| Puckering/linear banding|
| Superficial (plaque/patch)|
| Dermal papules|
| Scleral plaques (patient <45-years-old)|
Table 3. Histological findings of NSF
|1. Increased cellularity (spindle and/or epithelioid) with few other inflammatory cells|
|2. CD34 + spindle or epithelioid cells in a reticular or parallel arrangement with “tram-tracking” (CD34+ dendritic processes on either side of elastic fibers)|
|3. Presence of both fine collagen and ropey collagen surrounded by clefts|
|4. Elastic fibers preserved|
|5. Septal Involvement|
Table 4. Possible diagnosis based on clinical or histological score system
| 4 = Consistent with NSF (>1 major criteria)|
| 3 = Suggestive of NSF (1 major criteria)|
| 2 = Inconsistent with NSF (>1 minor criteria)|
| 1 = NSF ruled out (0–1 criteria)|
| 0 = Diagnostic of an entity other than NSF|
| 4 = Consistent with NSF (4 or 5 criteria)|
| 3 = Suggestive of NSF (3 criteria)|
| 2 = Inconsistent with NSF (2 criteria)|
| 1 = NSF ruled out (1 criteria)|
| 0 = Another diagnosis can be made|
There is no consistently effective therapy for NSF. Improvement of renal dysfunction as a result of any cause appears to slow or arrest the progression of NSF. Some investigators have reported instances of cure or a reduction of symptoms after successful renal transplantation or recovery from acute kidney injury.4 Physical therapy should be started early to maintain and improve the range of motion of contracted joints. Extracorporeal photopheresis, plasmapheresis, photodynamic therapy, pentoxifylline therapy, high-dose intravenous immunoglobulin therapy, thalidomide therapy, steroid therapy, imatinib mesylate and other immunosuppressive therapies have been attempted.20–25
Because of the lack of effective treatment for NSF, prevention is important. Careful evaluation of renal function is mandatory in every patient with renal insufficiency and at risk of chronic kidney disease or acute kidney injury before GBCA exposure.
If MRI using GBCA must be carried out for patients with renal insufficiency, especially for those with a GFR of less than 30 mL/min/1.73 m2, care should be taken to use the lowest possible dose of GBCA and avoid the three “inappropriate” agents (gadodiamide, gadoversetamide and gadopentetate dimeglumine). It is unknown whether hemodialysis prevents NSF, and the effect of prompt dialysis after exposure to GBCA is controversial for patients receiving hemodialysis. Furthermore, two or three dialysis sessions separated by 1 day are recommended. Okada et al. estimated that 78% of circulating gadolinium chelates are eliminated during a single session of hemodialysis, and that 95% are eliminated after a second session.26 Saitoh et al. showed that it requires three dialysis sessions to remove more than 98% of 0.1 mmol/kg bodyweight of gadodiamide (average removal rates are 73.8%, 92.4% and 98.9% for successive dialysis sessions, at 1, 3 and 5 days later, respectively).27 However, initiating hemodialysis solely to prevent NSF is not recommended.10
Because peritoneal dialysis might not eliminate GBCA efficiently,28 it is not recommended. Patients undergoing peritoneal dialysis appear to be at the highest risk, with an incidence of 4.6 cases per 100 patients (vs 0.61 cases per 100 patients undergoing hemodialysis).29
NSF versus CIN
Selection of an appropriate contrast-enhanced imaging modality (CT or MRI) for patients with renal insufficiency is challenging. It is necessary to decide which type of study should be carried out and the type of contrast agent, if any, that should be given. Recent recommendations are detailed as follows (Table 5):11,12
Table 5. Indications for the use of gadolinium-based versus iodinated contrast material
|Contrast material||>60||30–60||15–29||<15 or Dialysis|
|Gadolinium-based||Safe||Minimal or no risk||Great risk||Not safe|
|Iodinated||Safe||Risk||Moderate risk||Great risk (okay if undergoing dialysis)|
- 1Patients with an estimated GFR of less than 30 mL/min/1.73 mIodinated contrast media appears to have the advantage, and it would be reasonable to consider giving iodinated contrast media and carrying out CT rather than MRI when such a substitution is deemed possible. The risk of NSF as a result of GBCA treatment actually exists. It is necessary to refrain from GBCA, especially in patients with renal failure. The effect of prompt hemodialysis is controversial and inadequate. If the benefits of GBCA treatment clearly outweigh the potential risk, and administration of GBCA is absolutely essential, then judicious use of the lowest possible dose of safe GBCA (to allow a diagnostic study) is probably the safest option. In this setting, the patient and the referring physician must be informed of the risks of NSF and must give their consent to proceed.If iodinated contrast material must be given to these patients who not undergoing hemodialysis, the judicious use of minimum dose and sufficient hydration is necessary. In patients undergoing dialysis, there is no risk of worsening the renal function with iodinated contrast material, and therefore iodinated contrast material can be given with impunity. We do not have to restrict the use of iodinated contrast material in those patients regardless of when the next dialysis is scheduled.
- 2Patients with an estimated GFR 30∼59 mL/min/1.73 m2GBCA appears to have the advantage. As long as a GBCA dose of 0.2 mL/kg or less is utilized, this group can be considered to have an extremely low or no risk of developing NSF. Because the risk of CIN clearly exists, it would therefore be reasonable to consider carrying out contrast-enhanced MRI rather than contrast-enhanced CT.
- 3Patients with an estimated GFR 60∼119 mL/min/1.73 m2All GBCA can be given safely to these patients, as long as a dose of 0.2 mL/kg or less is used. Both iodinated contrast media for CT and GBCA for MRI can be given as indicated.
NSF is a progressive, potentially fatal, multiorgan system fibrosing disease related to exposure of patients with renal failure to the GBCA used in MRI. In patients with severe renal insufficiency (estimated GFR less than 30 mL/min/1.73 m2), it is recommended that GBCA treatment be avoided if at all possible. If the benefits of GBCA administration clearly outweigh the potential risk, and contrast-enhanced MRI must be carried out, care should be taken to use the lowest possible dose and to avoid the three “inappropriate” agents (gadodiamide, gadoversetamide and gadopentetate dimeglumine).
Conflict of interest