Nephrology Dialysis Transplantation

NDT Advance Access published online on May 4, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm261

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Case-control study of gadodiamide-related nephrogenic systemic fibrosis

Peter Marckmann¹, Lone Skov², Kristian Rossen³, James Goya Heaf¹ and Henrik S. Thomsen⁴

¹Department of Nephrology and ⁴Department of Diagnostic Radiology, Herlev Hospital, DK-2730 Herlev and ²Department of Dermatology and ³Department of Pathology, Gentofte Hospital, DK-2900 Hellerup, Denmark

Correspondence and offprint requests to: Peter Marckmann, Department of Nephrology, Herlev Hospital, DK-2730 Herlev, Denmark. Email: peter.marckmann{at}dadlnet.dk

	Abstract

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Background. Nephrogenic systemic fibrosis may be caused by gadolinium (Gd)-containing magnetic resonance imaging contrast agents. Most reported cases were associated with one particular agent, gadodiamide. Yet, unidentified cofactors might explain why only a minority of renal failure patients exposed to gadodiamide develop nephrogenic systemic fibrosis.

Methods. We conducted a case-control study of 19 histologically verified cases and 19 sex- and age-matched controls. All subjects had chronic renal failure when exposed to gadodiamide. Clinical, biochemical and pharmacological data were retrieved from medical records.

Results. Cases had been exposed to a mean gadodiamide dose of 0.29 mmol/kg (range 0.18–0.50) shortly before first signs of nephrogenic systemic fibrosis. Controls had been exposed to 0.28 mmol/kg (0.13–0.49). Cumulative gadodiamide exposure while in chronic kidney disease stage 5 was significantly higher among cases compared with controls (0.41 vs 0.31 mmol/kg, P = 0.05) and among severe cases (n = 9) compared with non-severe cases (0.49 vs 0.33 mmol/kg, P = 0.02). Severe cases developed primarily among patients in regular haemodialysis therapy at exposure. Cases had higher serum concentrations of ionized calcium and phosphate than controls and tended to receive higher doses of epoietin-ß than controls at time of exposure. Severe cases were treated with higher doses of epoietin-ß than non-severe cases at exposure (10.8 vs 4.4 10³ IU/week, P = 0.02).

Conclusions. Increasing cumulative gadodiamide exposure, high-dose epoietin-ß treatment, and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamide-related nephrogenic systemic fibrosis in renal failure patients. Severe cases seem to develop primarily among patients in regular haemodialysis therapy at exposure.

Keywords: case-control study; chronic renal failure; cofactors; gadodiamide; gadolinium; nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF), known for only 10 years, was until recently a mysterious, idiopathic scleroderma-like disease [1,2]. It only affects patients with renal failure. Although some patients experience mild courses of NSF, a large proportion of affected patients progress into contractures, severe immobility, cachexia and in some cases even death occurs [3–5].

In 2006, the first reports of a suspected link between one particular gadolinium(Gd)-containing magnetic resonance imaging (MRI) contrast agent, gadodiamide (Omniscan, GE Health Diagnostics, Amersham, UK) and NSF were published [4–6]. The probability of a causal link between gadodiamide and NSF was strongly supported by the finding of Gd in skin biopsies of NSF patients [7,8]. Other linear Gd-containing MRI contrast agents have also been associated with NSF development, but gadodiamide-associated NSF has been reported far more frequently [9]. The kinetic and thermodynamic stability of gadodiamide is poor compared with other Gd-containing MRI agents, except gadoversetamide [10,11]. Gadodiamide (and gadoversetamide) is therefore particularly likely to disintegrate in the human body and to liberate ionic Gd from the gadodiamide complex. Gd is replaced in the complex by other available cations, such as Ca++, Cu++ or Zn++, in the process of transmetallation [10–14]. The risk of Gd liberation is significantly increased in kidney failure, where gadodiamide is retained in the body for markedly prolonged periods of time [15]. Once liberated, the highly toxic ionic form of Gd might initiate the processes leading to NSF. The toxic profile of Gd described in ex vivo and animal studies [16], could indicate that NSF developing after exposure to Gd-containing MRI contrast agents is a matter of human Gd intoxication.

Although NSF can no longer be considered totally mysterious and unexplained, several important questions remain unanswered. In particular, it is not understood why gadodiamide (and other Gd-containing MRI contrast agents) leads to NSF in only a minority of exposed patients [4,5,17]. Cofactors might be in play. The current case-control study aimed at identifying such clinical, biochemical and pharmacological factors having an impact on the risk of NSF after gadodiamide exposure. The focus of the present study was on gadodiamide, because this contrast agent was the preferred Gd-containing contrast agent at our institution and the only agent used for renal failure patients during the time period of interest.

	Materials and methods

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During November and December 2006, we conducted a case-control study of 19 histologically confirmed cases of NSF and an equal number of sex- and age-matched renal failure patients with no medically recorded or current signs of NSF. All cases and controls had stage 5 chronic kidney disease (CKD5), had been exposed to gadodiamide while in stage CKD5 and were seen at the Nephrology Department of Herlev Hospital, Denmark. The matched controls were randomly selected from a file of gadodiamide-exposed patients provided by the Department of Diagnostic Radiology.

Data were extracted from medical records and the Radiology Information System of the Department of Diagnostic Radiology. Primary renal diagnosis and date of NSF-eliciting gadodiamide exposure (cases)/latest gadodiamide exposure (controls) were identified. The NSF-eliciting gadodiamide exposure was defined as the first gadodiamide exposure of the patient followed by medically recorded signs of NSF. Age, time on dialysis, current therapy [conservative treatment/haemodialysis (HD)/peritoneal dialysis (PD)], estimated glomerular filtration rate (eGFR, millilitres/minute) of predialytic patients, NSF-eliciting dose of gadodiamide (NSF dose, millimol/kilogram) in cases and dose of gadodiamide at latest MRI procedure in controls, cumulative gadodiamide dose while in category CKD5 (CKD5 dose, millimol/kilogram), lifetime cumulative gadodiamide dose irrespective of kidney function (lifetime dose, millimol/kilogram), current dosing of epoietin-ß (Neorecormon, Roche, Basel, Switzerland; it was the only erythropoietin (EPO) analogue used in the department during the studied time period)(IU/week), current treatment with angiotensin-converting enzyme inhibitors (ACEI +/–), calcium supplements (+/–), calcium antagonists (+/–) and oral iron supplements (+/–) and biochemical variables (S-bicarbonate (millimol/litre), S-ionized calcium (millimol/litre), S-phosphate (millimol/litre), S-ferritin (micrograms/litre), (S-PTH (nanograms/litre)) at the time of gadodiamide exposure were extracted from patient files. The timing of blood samplings was recorded.

Selected clinical events (antibiotic treatment, bacteraemia, intravenous iodine-contrast agent exposure, scintigraphy, venous or arterial thrombosis, intravenous iron therapy, major surgery, general anaesthesia) during the last 6 months before gadodiamide exposure were extracted from patient records.

NSF cases were classified into two categories according to their current NSF symptoms: non-severe (skin changes without or with only minor associated disability) or severe (skin changes causing major disabilities having an impact on daily life and leading to need of aiding equipment). Deceased NSF cases (n = 4) were categorized according to their NSF status at death.

Statistics
Parametric (mean, SD/SEM, range) and non-parametric (median, 1st–3rd quartile, range) descriptive statistics were employed as appropriate. Cases and controls were compared with paired or unpaired parametric (t-test) and non-parametric (Wilcoxon's matched pairs test, Mann–Whitney's U-test) tests as appropriate. Categorical data were compared with Fisher's exact test or ²-test. The unadjusted odds ratio was calculated for serum phosphate after dichotomization. A significance level of 0.05 was chosen. We used Graphpad software, version 3.05 (GraphPad Software, San Diego, CA, USA) for all statistical analyses.

	Results

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The study included 19 cases (9 males, 10 females, mean age 52 years, SEM 2.1) and 19 controls (mean age 51 years, SEM 2.0). Cases and controls characteristics are presented in Table 1. The distribution of renal diagnoses did not differ significantly between cases and controls (²-test; P = 0.17). There was no significant difference between cases and controls with respect to current treatment modality (²-test; P = 0.43) and previous time on dialysis treatment (unpaired t-test; P = 0.85). Cases exposed to gadodiamide in their pre-dialytic stage tended to have lower eGFR than pre-dialytic controls (unpaired t-test, P = 0.06).

View this table: [in this window] [in a new window]   Table 1. Characteristics of 19 cases with gadodiamide-related nephrogenic systemic fibrosis and 19 sex- and age-matched gadodiamide-exposed control patients (n,%)

 
All cases were exposed to gadodiamide more than 10 months before the present study was conducted. Among controls, gadodiamide exposure had taken place a median of 26 months previously (range 12–61 months). In our experience, NSF develops within <3 months after gadodiamide exposure if at all [5]. The absence of signs of NSF in controls thus indicated that they were true controls that would not turn into NSF-cases with longer follow-up time.

The impact of gadodiamide dosing
The NSF-eliciting MRI procedures in cases were iliac and lower extremity arteriography (n = 16), graft arteriography (n = 2) and thoracic phlebography (n = 1). The corresponding MR procedures in controls were iliac and lower extremity arteriography (n = 17), cerebral (n = 1) and abdominal (n = 1) imaging. The dosing of gadodiamide in cases and controls is presented in Table 2. Individual gadodiamide doses varied from 0.13 to 0.50 mmol/kg in our material. The minimum NSF-eliciting gadodiamide dose was 0.18 mmol/kg. The volume of infused gadodiamide varied from 15 to 60 ml. The maximal per protocol gadodiamide dose of the Department of Diagnostic Radiology was 0.3 mmol/kg. The observed higher dosing in some cases appeared to be due to use of incorrect body weight data.

View this table: [in this window] [in a new window]   Table 2. Gadodiamide exposures (millimol/kilogram) of 19 patients with nephrogenic systemic fibrosis and 19 sex- and age-matched control patients. Mean, SEM (range)

 
According to Table 2, there was no significant difference between dosing at the NSF-eliciting MRI procedure in cases and the latest MRI examination of controls. However, the cumulative gadodiamide exposure while being in stage CKD5 (the CKD5 dose) was significantly higher among NSF cases than controls (P = 0.05). Furthermore, the cumulative CKD5 and lifetime gadodiamide exposures were significantly higher in severe NSF cases compared with non-severe cases (Table 2).

Other possible contributing factors
Data on medication and biochemical variables in cases and controls are presented in Table 3. We found a borderline statistically significant higher epoietin-ß dosing and significantly higher serum concentrations of ionized calcium and phosphate in cases compared with controls. Three of the NSF cases had never been treated with an erythropoietin (EPO) analogue. We found no difference in serum bicarbonate (a marker of metabolic acidosis) between cases and controls.

View this table: [in this window] [in a new window]   Table 3. Prescribed drugs and biochemical variables at the time of gadodiamide exposure eliciting nephrogenic systemic fibrosis in cases (n = 19) and at latest gadodiamide exposure in controls (n = 19). Mean, SEM, (range); median, 1st–3rd quartile, (range); or % of population

 
In a post-hoc analysis, serum phosphate was dichotomized into high and low levels arbitrarily at 2.00 mmol/l. The unadjusted odds ratio for developing NSF after gadodiamide exposure was estimated to be 7.04 (95% CI 1.6–31.0)(P = 0.01) for patients having a serum phosphate 2.00 mmol/l compared with patients with lower levels.

In a comparison between severe and non-severe NSF cases, we observed a significantly higher frequency of patients in regular HD treatment at exposure among severe cases (seven HDs, one PD and one conservatively treated patient) than among non-severe cases (two HDs, two PDs and six conservatively treated patients at exposure)(²-test; P = 0.04). Correspondingly, we found a significantly higher treatment dosage of epoietin-ß in severe cases (unpaired t-test; 10.8 vs 4.4 10³ IU/week, P = 0.02) at the time of gadodiamide exposure. Furthermore, there was a trend for more patients being treated with calcium supplements among severe cases (Fischer's exact test; 8 of 9 vs 5 of 10, P = 0.09). No other biochemical or pharmacological data varied significantly between severe and non-severe cases.

The blood sampling on which the earlier results were based was the latest blood test made before the culprit gadodiamide exposure. On average, cases had samples taken 16 days (SEM 2.6) and controls 14 days (SEM 3.9) before exposure (no significant difference).

Counting and comparing clinical events occurring during the last 6 months before gadodiamide exposure gave no hints as to important etiological cofactors in NSF. Among cases (number of controls in parenthesis), 10 [4] had been treated with antibiotics, one [2] had a bacteraemia, two [2] had an iodine-contrast radiography, four [5] had a scintigraphy, two [3] had a thrombotic event, five [7] had been treated with intravenous iron, three [5] had had major surgery and two [5] had been anaesthesized. The proportion of patients having been exposed to these clinical events did not differ significantly between cases and controls.

	Discussion

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In our view, there is convincing scientific evidence that gadodiamide may cause NSF [4–9,17–19]. This opinion is shared by official drug authorities in Europe and the US, and by the producer of gadodiamide (Omniscan) according to very recent statements (first months of 2007) from these sources. The focus of the present study was to investigate the impact of gadodiamide dosing and the putative existence of cofactors explaining why far from all gadodiamide-exposed renal failure patients develop NSF. We made several important observations that may contribute to the understanding of gadodiamide-related NSF pathogenesis.

Somewhat surprisingly, the dose received by cases just before their first signs of NSF did not differ from the dose given to controls at their latest examination. All cases had been exposed to 0.18 mmol/kg or more at the NSF-eliciting examination, but NSF-development after as little as 0.11 mmol/kg was recently published by others [17,18]. Importantly, we observed that the cumulative gadodiamide exposure, particularly while in stage 5 CKD, was higher among cases than controls, and among severe vs non-severe NSF cases. That result indicates that once liberated, Gd has a very long half-life in the human body and that Gd-intoxication may build up over periods of months to years. It therefore seems essential to keep files on Gd-exposure for all patients with renal insufficiency in order to avoid extreme cumulative doses similar to the doses some of our patients received (up to 1 mmol/kg over <30 months).

Although treatment modalities did not differ between cases and controls, there was a remarkable overrepresentation of patients in regular HD treatment among severe cases compared with non-severe cases. This finding suggests that loss of residual renal function in CKD5 patients increases the risk of severe NSF.

We tested several published and unpublished hypotheses regarding NSF pathogenesis in our case-control study. The hypothesis that NSF is caused by EPO analogues could be rejected: three NSF-cases had never been treated with such drugs. However, there was a stronger trend towards higher EPO dosing in cases than in controls. Also, severe cases had been treated with significantly higher doses of EPO than non-severe NSF cases. These findings could indicate that EPO analogues may be an important cofactor in NSF development, increasing the Gd toxicity and causing a more aggressive progression of the disease.

Based on their clinical experience and experimental evidence that ACEI may protect against fibrotic processes, Fazeli et al. [20] suggested that NSF might develop only in patients not treated with ACEI. In our material, 32% of cases were taking ACEI. A similar proportion of controls took ACEI (37%). Fazeli's hypothesis, therefore, can be rejected. Other hypotheses on NSF pathogenesis include causative roles of intravenous iron therapy, thrombotic events and infections. They were all rejected by our observations.

Reports [10,16] on the possibility of in vivo interaction (transmetallation) between gadodiamide and bodily cations, including Ca⁺⁺ and Fe⁺⁺ and on competition between the Gd-ligand in gadodiamide and bodily anions, including , prompted us to extract data on serum concentrations of ionized calcium, phosphate and ferritin from medical records of all cases and controls. Data were achieved from the last relevant blood sampling before the intravenous gadodiamide infusion in question. Our finding that cases had significantly higher serum concentrations of ionized calcium and phosphate at exposure are in line with the chemical theories: higher levels of ionized calcium would be expected to increase the risk of transmetallation and higher phosphate levels would increase the chance of retaining ionized Gd outside the gadodiamide complex. Both situations would tend to lead to retention of the highly toxic ionized Gd in the body and would allow Gd ions to cross membranes and enter cells with serious consequences [10,16]. In line with these biochemical data, we found a borderline higher frequency of calcium supplement use among severe cases compared with non-severe NSF cases.

The overall evidence relating gadodiamide exposure to NSF is sufficiently strong to justify the ban against the use of gadodiamide in renal failure patients that was recently declared by drug authorities in Europe and the US. It remains to be proven whether any Gd-containing MRI agents can be used safely as alternatives to gadodiamide in renal failure patients. In our view, cautious use of the chemically most stable, cyclic agents may be acceptable (see reference [10] for details about agent stabilities). However, MRIs with Gd-containing agents should only be performed after carefully weighing clinical benefits against the risk of NSF and repeated examinations should be avoided if possible.

The present report suggests that the risk of gadodiamide-related NSF is increased with increasing cumulative gadodiamide exposure and with higher EPO-dosing, and higher serum concentrations of calcium and phosphate at the time of exposure. Severe cases develop primarily among patients in regular haemodialysis therapy at exposure.

	Acknowledgements

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The Research Council of Herlev Hospital supported Peter Marckmann with a research grant.

Conflict of interest statement. None declared.

	References

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Received for publication: 26. 2.07
Accepted in revised form: 4. 4.07

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