Extracellular Gd-CA: differences in prevalence of NSF

Until recently it was believed that extracellular gadolinium-based contrast agents were safe for both the kidneys and all other organs within the dose range up to 0.3 mmol/kg body weight. However, in 2006, it was demonstrated that some gadolinium-based contrast agents may trig the development of nephrogenic systemic fibrosis, a generalized fibrotic disorder, in renal failure patients. As no prospective studies can be performed we must rely on retrospective data. From those data it is obvious that the prevalence of NSF is significantly higher after the unstable agent gadodiamide than after any other gadolinium-based agent (3–7% versus 0–1% per injection) in patients with reduced renal function. Prevalence after exposure to two gadodiamide injections is as high as 36% in patients with chronic kidney disease (CKD) stage 5. No report of NSF after the most stable agents has been reported in the peer-reviewed literature documenting that there is a difference between the various agents regarding triggering NSF.     

Prevalence of NSF following intravenous gadolinium-contrast media administration in dialysis patients with endstage renal disease

Purpose

To evaluate the prevalence of nephrogenic systemic fibrosis (NSF) in a patient population being at highest risk for developing this disease and to evaluate possible risk factors.

Materials and methods

The radiological records of 552 patients with ESRD being on hemodialysis (HD) or peritoneal dialysis (PD) were retrospectively reviewed to identify whether the patients underwent MR-examinations with or without intravenous administration of GBCA. In case of exposure to GBCA, the number of contrast injections, the benchmark and the cumulative doses of GBCA, and possible cofactors regarding pathogenesis of NSF were recorded. Diagnosis of NSF was confirmed either by deep skin biopsy or by review of medical and histopathological records. Data of NSF patients were compared with data of dialysis patients who did not develop NSF after MR-examinations.

Results

146 dialysis patients underwent MRI without i.v.-administration of GBCA. No case of NSF was observed in this patient population. 195/552 patients proved to have a total number of 325 well-documented exposures to GBCA. Seven different types of GBCA were used during these MR-examinations. NSF prevalence rate was 1.6%. One patient died of NSF. Three different types of GBCA were involved in 6 NSF cases. 4/6 proved to be confounded cases. The cumulative dose of GBCA, history of thrombosis, recent surgery, and the combination of HD and PD proved to be significant cofactors for the development of NSF (p < .05). No significant difference regarding residual renal clearance (p = .898) and residual urine volume (p = .083) was found between NSF and non-NSF patients.

Conclusion

The prevalence of NSF proved to be much lower in this high risk patient group being exposed to GBCA compared to the literature. NSF was not observed in ESRD patients undergoing MRI without administration of GBCA. Our data support a positive association between cumulative dose of GBCA and development of NSF. No positive association was found between residual renal clearance and residual urine volume and NSF.     

Gadolinium-Based Contrast Agents in Kidney Disease: Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists

Use of gadolinium-based contrast agents (GBCAs) in renal impairment is controversial, with physician and patient apprehension in acute kidney injury (AKI), chronic kidney disease (CKD), and dialysis because of concerns regarding nephrogenic systemic fibrosis (NSF). The position that GBCAs are absolutely contraindicated in AKI, CKD stage 4 or 5 (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) and dialysis-dependent patients is outdated, and may limit access to clinically necessary contrast-enhanced MRI examinations. Following a comprehensive review of the literature and reported NSF cases to date, a committee of radiologists and nephrologists developed clinical practice guidelines to assist physicians in making decisions regarding GBCA administrations. In patients with mild-to-moderate CKD (eGFR ≥30 and <60 mL/min/1.73 m²), administration of standard doses of GBCA is safe and no additional precautions are necessary. In patients with AKI, with severe CKD (eGFR <30 mL/min/1.73 m²), or on dialysis, administration of GBCAs should be considered individually and alternative imaging modalities utilized whenever possible. If GBCAs are necessary, newer GBCAs may be administered with patient consent obtained by a physician (or their delegate), citing an exceedingly low risk (much less than 1%) of developing NSF. Standard GBCA dosing should be used; half or quarter dosing is not recommended and repeat injections should be avoided. Dialysis-dependent patients should receive dialysis; however, initiating dialysis or switching from peritoneal to hemodialysis to reduce the risk of NSF is unproven. Use of a macrocyclic ionic instead of macrocyclic nonionic GBCA or macrocyclic instead of newer linear GBCA to further prevent NSF is unproven. Gadopentetate dimeglumine, gadodiamide, and gadoversetamide remain absolutely contraindicated in patients with AKI, with stage 4 or 5 CKD, or on dialysis. The panel agreed that screening for renal disease is important but less critical when using macrocyclic and newer linear GBCAs. Monitoring for and reporting of potential cases of NSF in patients with AKI or CKD who have received GBCAs is recommended.     

Imaging patients with chronic kidney disease: CIN or NSF?

Patients with chronic kidney disease (CKD) frequently require contrast-enhanced imaging studies in order to manage their condition. Radiologists are often confronted with selecting the best imaging modality for each patient based on the patient's degree of renal impairment. In the past, when patients required a contrast-enhanced imaging study, the tendency was to select magnetic resonance (MR) imaging with a gadolinium (Gd)-based contrast agent over computed tomography (CT) with iodinated contrast media (CM) due to the known nephrotoxic nature of iodinated CM, which is associated in some patients with the development of contrast-induced nephropathy (CIN). However, recently, the administration of Gd-based contrast agents has been associated with a severe, potentially fatal, adverse reaction, termed nephrogenic systemic fibrosis (NSF), in patients with moderate-to-severe renal insufficiency. Therefore, this same patient population is now at risk for developing either CIN or NSF. In order to optimise patient outcomes, imaging of patients with CKD requires an understanding of the risk factors for both CIN and NSF.     

Risk factors for NSF: A literature review

Emerging evidence linking gadolinium‐based contrast agents (GBCAs) to nephrogenic systemic fibrosis (NSF) has changed medical practice patterns toward forgoing GBCA‐enhanced magnetic resonance imaging (MRI) or substituting other imaging methods, which are potentially less accurate and often radiation‐based. This shift has been based on reports of high NSF incidence at sites where a confluence of risk factors occurred in patients with severe renal dysfunction. This review article explores the factors that affect NSF risk, compares risks of alternative imaging procedures, and demonstrates how risk can be managed by careful selection of GBCA dose, timing of injection with respect to dialysis, and other factors. Nearly half of NSF cases are a milder form that does not cause contractures or reduce mobility. It appears that eliminating even a single risk factor can reduce NSF incidence/risk at least 10‐fold. Elimination of multiple risk factors by using single‐dose GBCA, dialyzing dialysis patients quickly following GBCA administration, avoiding GBCA in acute renal failure while serum creatinine is rising, and avoiding nonionic linear GBCA in renal failure patients may reduce NSF risk more than a thousand‐fold, thereby allowing safe GBCA‐enhanced MRI in virtually all patients. J. Magn. Reson. Imaging 2009;30:1298–1308. © 2009 Wiley‐Liss, Inc.     

Nephrogenic systemic fibrosis—Implications for nephrologists

Nephrogenic systemic fibrosis (NSF) is a debilitating disorder seen in-patient with advanced chronic kidney disease (CKD). Recent evidence suggests a link between NSF and the administration of gadolinium-based contrast agents (Gd-CA). In addition, other risk factors have also been suggested to facilitate the development of NSF in this population after Gd-CA. These include metabolic acidosis, high-dose erythropoietin therapy, and the altered mineral metabolism of CKD. While it is possible that these factors may increase the risk of NSF after Gd-CA exposure, they may also simply reflect conditions that increase the risk of getting exposed to Gd-CA, particularly at high doses. Furthermore, given the risk of NSF in CKD, physicians must weigh the risks of NSF versus the risk of contrast-induced nephropathy (CIN) with iodinated agents in this population. In this review, we will provide a nephrologist's perspective on these issues and the nephrologist's role in the prevention of NSF.     

Nephrogenic systemic fibrosis: A survey of the use of gadolinium-based contrast agents in Ghana

IntroductionThe aim of this study is to identify current practice of administration of gadolinium-based contrast agents (GBCAs) in Ghana.MethodA total of 13 MRI (magnetic resonance imaging) facilities were sent a survey questionnaire to request information on their current practice with the use of GBCAs.ResultsGadodiamide, a high risk GBCA accounted for 67% of first line agents. 5 (42%) had a departmental protocol on the administration of GBCAs with regards to its association with nephrogenic systemic fibrosis (NSF). Of the 8 that use gadodiamide, 3 check kidney function in all patients, 2 check in selected patients, and 3 do not check at all. All 3 that screen all patients do not use contrast if the patient has an eGFR (estimated glomerular filtration rate) of 30–59 ml/min, 1 considers other modality; and if the patient has an eGFR of <30 ml/min, 2 do not use contrast but consider other modality, however 1 continues with the high risk agent.ConclusionGadodiamide is widely used, with varied practice in screening for renal function, and risk factors associated with NSF. Current evidence shows that it is advisable to administer macrocyclic agents in patients with compromised renal function. It is also imperative to establish local guidelines in line with international guidelines in order to minimize the incidence of NSF.     

Gadolinium-containing contrast media for radiographic examinations: a position paper

Recently, it has been suggested that gadolinium-based contrast media could be used for radiological examinations in patients with significant renal impairment, previous severe generalized reaction to iodinated contrast media or thyroid disease about to undergo radioactive iodine treatment; however, the indications for and risks of using gadolinium agents in this way are not well known; hence, the Contrast Media Safety Committee of The European Society of Urogenital Radiology reviewed the literature to issue a position paper on this subject. A comprehensive literature review was performed and the resulting report was discussed at the Ninth European Symposium on Urogenital Radiology in Genoa, Italy, June 2002. Review of the literature indicates that according to experimental data on animals gadolinium-based contrast media have more nephrotoxic potential than iodinated contrast media in equivalent X-ray attenuating doses; therefore, gadolinium-based contrast media should not replace iodinated contrast media in patients with renal insufficiency for radiographic examinations. For patients with previous severe generalized reactions to iodinated contrast media, and in patients about to undergo thyroid treatment with radioactive iodine gadolinium-based contrast media in approved intravenous doses, up to 0.3 mmol/kg body weight will not give diagnostic radiographic information in most cases. Gadolinium-based contrast media are not approved for radiographic examinations.     

Nephrogene systemische Fibrose

A scleromyxedema-like disease was recognized in 1997. In 2000 this disorder was first published and termed nephrogenic fibrosing dermopathy because all patients had advanced renal failure. In 2006 it was discovered that the patients had a history of a preceding contrast-enhanced magnetic resonance imaging (MRI). All patients had acute or chronic severe renal insufficiency with a glomerular filtration rate (GFR) <30 ml/min per 1.73 m(2). So far a total of about 215 patients with this new skin disorder have been reported to international registries. The skin thickening has a typical histology and begins in the peripheral extremities and progresses proximally, including also the abdominal wall and the head in some patients. NSF involves not only the skin, but also the muscles and other organs (e.g., lungs, heart, eyes) in some patients. Therefore the term nephrogenic systemic fibrosis (NSF) was introduced. Skin fibrosis and sclerosis are usually progressive with disabling contractures of involved joints (knees, hands, feet). NSF may be lethal in up to 28% of patients. Spontaneous remissions are rare. No generally accepted treatment is available. So far, the pathogenesis is not well understood. One hypothesis supposes a role of gadolinium liberated from the contrast agents. As patients with acute or chronic advanced renal failure (GFR <30 ml/min per 1.73 m(2)) including those with hepatorenal dysfunctions are at high risk to develop NSF after exposure to gadolinium-based contrast agents, contrast-enhanced MRI should be avoided in this group and alternative diagnostic procedures should be used whenever possible.     

In an animal model nephrogenic systemic fibrosis cannot be induced by intraperitoneal injection of high-dose gadolinium based contrast agents

Aim and objective

Nephrogenic systemic fibrosis (NSF) has been reported in humans to be most likely induced by gadolinium based contrast agents (GBCA), namely by gadodiamide, gadopentetate dimeglumine, and gadoversetamide, rarely by other GBCA. The pathogenesis of NSF remains unclear; different hypotheses are under discussion. The objective of the study is to assess if in the animal model human-like NSF changes can be induced by high-dose, intraperitoneal GBCA injections over four weeks.

Materials and methods

After approval by the institutional animal ethics committee, six rats each were randomly assigned to groups, and treated with seven different GBCA. Intraperitoneal (IP) injections – proven in the animal model to be effective – were chosen to prolong the animals’ exposure to the respective GBCA. GBCA doses of previous intravenous (IV) animal studies were applied. After five weeks all rats were sacrificed. Sham controls were treated with IP saline injections, employing the same regimen.

Results

No findings comparable with human NSF were observed in all animals after IP treatment with all seven GBCA at daily doses of 2.5 and 5.0 mmol/kg body weight (BW). No histopathological abnormalities of all examined organs were noted. Weight loss was stated in weeks three and four with GBCA injections at doses of 5.0 mmol/kg BW, but rats regained weight after cessation of GBCA treatment.

Conclusions

NSF-comparable pathological findings could not be induced by high dose intraperitoneal injection of seven GBCA.     

Magnetic resonance angiography (MRA) in renally impaired patients: when and how

Magnetic resonance angiography (MRA) and NSF in renally impaired patients have a close relationship due to the frequent coincidence of vascular and renal pathologies, the relatively large amount of contrast media applied and the delayed excretion. The date of the first NSF cases described in literature falls into the development of multi-stationary MRA—an investigation that requested multiple bolus injections or one large bolus of the contrast agent. It is therefore easily understood that NSF was regarded initially as possible complication of MRA.

A review on the history of MRA is presented and various techniques for MRA are described. While many neuroradiological indications can be solved by native MRA, most angiographic indications throughout the body rely on the application of intravenous contrast agents.

The paper discusses options for alternative methods in vascular imaging and offers guidelines for patients with renal impairment. NSF must always be balanced versus the outcome of an investigation, respectively versus the outcome of a denied MRA. Moreover, in patients with chronic kidney disease (CKD) and a proper justification for a vascular investigation, neither CT angiography nor DSA should replace MRA. Restrictions in contrast media dose for CKD patients are mandatory and obviously reduce the risk of NSF. Gadolinium-based contrast agents with lower stability are now contraindicated in patients with reduced renal function. The role of blood pool agents is under evaluation.

Since the awareness of the new disease grew over the last year, radiologists were able to reduce the number of newly diagnosed NSF cases by more careful consideration of contrast application and agent in renally impaired patients, which gives hope that NSF can be avoided by respecting some easy rules.     

Occurrence of adverse reactions to gadolinium-based contrast material and management of patients at increased risk: a survey of the American Society of Neuroradiology Fellowship Directors

RATIONALE AND OBJECTIVES: The authors attempted to determine the frequency and severity of adverse reactions to gadolinium-based magnetic resonance (MR) contrast agents and to identify strategies for management of patients at increased risk. MATERIALS AND METHODS: American Society of Neuroradiology program directors were surveyed about adverse reactions at their institutions to gadolinium-based contrast agents, the contrast agents responsible, and the management of patients with allergy-like reactions to iodinated or gadolinium-based agents who required MR contrast agent administration. RESULTS: Fifty-three (50.5%) surveys were received from 105 centers. Of 687,255 gadopentetate dimeglumine injections, 314 (0.046%) nonallergic reactions and 107 (0.016%) mild, 28 (0.004%) moderate, and five (0.001%) severe allergy-like reactions occurred. Of 74,275 gadodiamide injections, 11 (0.015%) nonallergic and 12 (0.016%) mild allergy-like reactions occurred. Of 64,005 gadoteridol administrations, 171 (0.267%) nonallergic reactions and 49 (0.077%) mild, 29 (0.047%) moderate, and 11 (0.017%) severe allergy-like reactions occurred. Twenty-six departments took no precautions for patients with previous allergy-like reactions to iodinated contrast material. Nineteen did not premedicate patients who previously had reactions to gadolinium-based agents before repeat administration of MR contrast agents. CONCLUSION: Although MR contrast agents are safe, adverse reactions occur. Many centers have not adopted policies for the OFF     

Nephrogenic systemic fibrosis: risk factors and incidence estimation

PURPOSE: To retrospectively review data in 13 patients with biopsy-confirmed nephrogenic systemic fibrosis (NSF), assess the associated risk factors, and report the incidence of NSF at the authors' institution. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; informed consent was waived. Statistical analysis was performed for all available clinical and laboratory data in patients with biopsy-confirmed NSF. The data from the patients with NSF were compared with data from a control population of patients with renal insufficiency but who did not develop NSF. RESULTS: There were eight male and five female patients, aged 17-69 years, with a diagnosis of NSF. Within 6 months of diagnosis, all 13 patients had been exposed to gadodiamide and one had been exposed to gadobenate dimeglumine in addition to gadodiamide. At the time of contrast material-enhanced magnetic resonance (MR) imaging, all 13 patients had renal insufficiency (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m(2)) and were hospitalized for a proinflammatory event (major surgery, infection, or vascular event). The group with NSF had significantly decreased eGFR (P = .01), more proinflammatory events (P < .001), and more contrast-enhanced MR examinations per patient (P = .002) than did the control group. CONCLUSION: A combination of factors, including altered kidney function, inflammatory burden, and exposure to gadolinium-based contrast agents may all play a role in development of NSF. Alternative imaging should be considered in patients with these factors. If use of a gadolinium-based agent is clinically indicated, the referring physician and patient should be informed of the potential risk of developing NSF.     

Biodistribution of gadolinium‐based contrast agents,including gadolinium deposition

The biodistribution of approved gadolinium (Gd)‐based contrast agents (GBCAs) is reviewed. After intravenous injection GBCAs distribute in the blood and the extracellular space and transiently through the excretory organs. Preclinical animal studies and the available clinical literature indicate that all these compounds are excreted intact. Elimination tends to be rapid and, for the most part, complete. In renally insufficient patients the plasma elimination half‐life increases substantially from hours to days depending on renal function. In patients with impaired renal function and nephrogenic systemic fibrosis (NSF), the agents gadodiamide, gadoversetamide, and gadopentetate dimeglumine have been shown to result in Gd deposition in the skin and internal organs. In these cases, it is likely that the Gd is no longer present as the GBCA, but this has still not been definitively shown. In preclinical models very small amounts of Gd are retained in the bone and liver, and the amount retained correlates with the kinetic and thermodynamic stability of the GBCA with respect to Gd release in vitro. The pattern of residual Gd deposition in NSF subjects may be different than that observed in preclinical rodent models. GBCAs are designed to be used via intravenous administration. Altering the route of administration and/or the formulation of the GBCA can dramatically alter the biodistribution of the GBCA and can increase the likelihood of Gd deposition. J. Magn. Reson. Imaging 2009;30:1259–1267. © 2009 Wiley‐Liss, Inc.     

Updated Clinical Practice Guideline on Use of Gadolinium-Based Contrast Agents in Kidney Disease Issued by the Canadian Association of Radiologists

In 2017, the Canadian Association of Radiologists issued a clinical practice guideline (CPG) regarding the use of gadolinium-based contrast agents (GBCAs) in patients with acute kidney injury (AKI), chronic kidney disease (CKD), or on dialysis due to mounting evidence indicating that nephrogenic systemic fibrosis (NSF) occurs with extreme rarity or not at all when using Group II GBCAs or the Group III GBCA gadoxetic acid (compared to first generation Group I linear GBCAs). One of the goals of the work group was to re-evaluate the CPG after 24 months to determine the effect of more liberal use of GBCA on reported cases of NSF in patients with AKI, CKD Stage 4 or 5 (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²), or those that are dialysis-dependent. A comprehensive review of the literature was conducted by a subcommittee of the initial CPG panel between the dates of January 1, 2017-December 31, 2018 to identify new unconfounded cases of NSF linked to Group II or Group III GBCAs and an updated CPG developed. To our knowledge, when using a Group II or Group III GBCA between 2017-2018, only a single unconfounded case report of a fibrosing dermopathy has been reported in a patient who received gadobenate dimeglumine with Stage 2 CKD. No other unconfounded cases of NSF have been reported with Group II or III agents in during this timeframe. The subcommittee concluded that the main recommendations from the 2017 CPG should remain unaltered, but agreed that screening for renal disease in the outpatient setting is no longer justifiable, cost-effective or recommended. Patients on hemodialysis (HD) should, however, be identified prior to GBCA administration to arrange timely HD to optimize gadolinium clearance, although there remains no evidence that HD reduces the risk of NSF. When administering Group II or III GBCAs to patients with AKI, on dialysis or with severe CKD, informed consent relating to NSF is also no longer explicitly recommended.     

Nephrogene systemische Fibrose als unerwünschte Arzneimittelwirkung gadoliniumhaltiger Kontrastmittel für die Magnetresonanztomographie

Nephrogenic systemic fibrosis (NSF) was first described as nephrogenic fibrosing dermopathy (NFD), a disease occurring exclusively in patients with severe renal insufficiency. Recently NSF was recognised to be a very rare adverse drug reaction (ADR) of gadolinium-based contrast media for magnetic resonance imaging (MRI). Over 200 million applications of gadolinium-based contrast agents have been performed worldwide, including about 80 million of Magnevist and 33 million of Omniscan. Cases of NSF have been reported so far only for Omniscan (180 including 77 from the EU), for Magnevist (78 including 9 from the EU, 4 of which were also exposed to Omniscan) and for OptiMARK, which is not authorized in the EU. Because of this risk an EU-wide contraindication was ordered for patients with severe renal failure for the use of Omniscan (gadodiamid), which is one of eight gadolinium-based substances authorized in Germany and the EU and which has the highest risk potential, and just recently also for Magnevist (gadopentetate-dimeglumine). Whether similar measures will be implemented for other gadolinium-based substances, for which no cases of NSF have been reported, but a risk potential may exist, is still under discussion.     

Safe use of iodinated and gadolinium-based contrast media in current practice in Japan: a questionnaire survey

Purpose

To help establish consensus on the safe use of contrast media in Japan.

Materials and methods

Questionnaires were sent to accredited teaching hospitals with radiology residency programs.

Results

The reply rate was 45.4 % (329/724). For contrast-induced nephropathy (CIN), chronic and acute kidney diseases were considered a risk factor in 96.7 and 93.6 %, respectively, and dehydration in 73.9 %. As preventive actions, intravenous hydration (89.1 %) and reduction of iodinated contrast media dose (86.9 %) were commonly performed. For nephrogenic systemic fibrosis (NSF), chronic and acute kidney diseases were considered risk factors in 98.5 and 90.6 %, respectively, but use of unstable gadolinium-based contrast media was considered a risk factor in only 55.6 %. A renal function test was always (63.5 % in iodinated; 65.7 % in gadolinium) or almost always (23.1; 19.8 %) performed, and estimated glomerular filtration rate (eGFR) was the parameter most frequently used (80.8; 82.6 %). For the patients with risk factors for acute adverse reaction (AAR), steroid premedication or/and change of contrast medium were frequent preventive actions, but intravenous steroid administration immediately before contrast media use was still performed.

Conclusion

Our questionnaire survey revealed that preventive actions against CIN were properly performed based on patients? eGFR. Preventive actions against NSF and AAR still lacked consensus.

     

Nephrogenic systemic fibrosis: risk factors suggested from Japanese published cases

The aim of this article is to review the published cases of nephrogenic systemic fibrosis (NSF) in Japan. The Japanese medical literature database and MedLine were searched using the keywords NSF and nephrogenic fibrosing dermopathy (January 2000 to March 2009). Reports in peer-reviewed journals and meeting abstracts were included, and cases with biopsy confirmation were selected. 14 biopsy-verified NSF cases were found. In seven of eight patients reported after the association between gadolinium-based contrast agent (GBCA) and NSF was proposed, GBCA administration was documented: five received only gadodiamide; two received both gadodiamide and gadopentetate dimeglumine. In four cases, the amounts of contrast agent were registered: two received only a single dose (0.1 mmol kg⁻¹ body weight) whereas the other two received 7–15 ml (the body weight was not disclosed) for each MR examination. Five patients had multiple injections of GBCA before NSF developed. Except for one patient in whom renal assessment was not reported, none of the patients had an estimated glomerular filtration rate >30 ml min⁻¹ 1.73 m⁻² and all received dialysis. 5 of the 8 patients (63%) in whom GBCA exposure was confirmed were treated with peritoneal dialysis. Skin lesion of the lower extremity was the first symptom in 12 patients (86%), whereas 2 patients had primarily symptoms from the upper extremity. In three cases, GBCA was administered even after onset of the NSF symptoms because of the physicians'' lack of knowledge about the possible association between GBCA and NSF. NSF is found among Japanese end-stage renal failure patients even after examinations using a single dose.Nephrogenic systemic fibrosis (NSF) is a rare disease that occurs in patients with renal failure; it can be devastating and usually initially appears as skin thickening and hardening, and occasionally progresses to limb contractures, leading to severe disability and even death [1–9]. It can be very painful. The disease was first diagnosed in 1997 and a report first published in 2000 [10]. A confident diagnosis requires a combination of clinical history, physical examination and pathological assessment of the skin biopsy specimen [1–9]. The exact pathophysiology of NSF remains uncertain, but the possible association between gadolinium-based contrast agent (GBCA), which is widely used for MRI, and NSF was proposed in 2006 [7, 11]. The leading hypothesis for the aetiology of NSF due to GBCA is that free gadolinium may be released from the chelates and bound by phosphate, which prevents reassociation with the chelates; patients with end-stage renal failure are exposed to the agents longer than patients with normal renal function owing to their slower excretion.A total of 190 biopsy-proven cases had been published in the peer-reviewed literature by 1 February 2008 [12]; 83% had received gadodiamide (Omniscan®, Daiichi Sankyo, Tokyo, Japan). No one had reported development of NSF after exposure to the macrocyclic agents, i.e. gadoteridol or gadoterate meglumine alone. The NSF-associated warnings concerning GBCA use were first released in May 2006 in Europe [13], June 2006 in the USA [14] and March 2007 in Japan [15]. Most NSF cases have been reported in the USA and Europe. There are only a few Asian cases reported in the English literature [16–19], despite approximately 20% of GBCAs in the world being used in Japan (personal communication with employees of Daiichi Sankyo, Tokyo, Japan; Bayer Yakuhin, Osaka, Japan; Eisai, Tokyo, Japan). It has been suggested that there is no race difference in NSF occurrence [1, 12]. Therefore, we undertook a review of the Japanese literature.     

Are intravenous injections of contrast media really less nephrotoxic than intra-arterial injections?

We oppose the opinion that the intra-arterial administration of iodine-based contrast media (CM) appears to pose a greater risk of contrast medium-induced nephropathy (CIN) than intravenous administration since 1) in intra-arterial coronary procedures and most other intra-arterial angiographic examinations, CM injections are also intravenous relative to the kidneys, 2) there is a lack of comparative trials studying the risk of CIN between intra-arterial and intravenous procedures with matched risk factors and CM doses, 3) a bias selection of patients with fewer risk factors may explain the seemingly lower rate of CIN after CT in comparison with coronary interventions, 4) the rate of CIN following intra-arterial coronary procedures may also be exaggerated owing to other causes of acute kidney failure, such as haemodynamic instability and microembolisation, 5) roughly the same gram-iodine/GFR ratio (≈1:1) as a limit of relatively safe CM doses has preliminarily been found for both intravenous CT and intra-arterial coronary procedures and 6) the substantially higher injected intravenous CM dose rate during CT relative to an intra-arterial coronary procedure might actually pose a higher risk of CIN following CT.

Key Points

• Most intra-arterial injections of contrast media are intravenous relative to the kidneys.

• No evidence that intravenous CM injections should be less nephrotoxic than intra-arterial.

• Considerably higher dose rates of CM are used for CT relative to intra-arterial procedures.

• Higher dose rates may pose higher nephrotoxic risk for intravenous based CT studies.