NDT Advance Access published online on April 24, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn217
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Possibly enhanced Gd excretion in dialysate, but no major clinical benefit of 3–5 months of treatment with sodium thiosulfate in late stages of nephrogenic systemic fibrosis
1 Department of nephrology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark 2 National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark
Correspondence and offprint requests to: Peter Marckmann, Brovej 5, DK-4000 Roskilde, Denmark. Tel +45-46757980; E-mail: peter.marckmann{at}dadlnet.dk
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Abstract |
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Background. Gd-related nephrogenic systemic fibrosis was successfully treated with intravenous sodium thiosulfate according to a recent case report.
Methods. Four haemodialysis patients with severe Gd-related nephrogenic systemic fibrosis were treated with intravenous sodium thiosulfate for 3–5 months. Symptoms and patients’ experiences were investigated. The dialysate Gd content was monitored.
Results. We observed no major clinical improvements in any patient. In one patient, we found slightly improved joint motion. Two patients had a subjective impression of slight improvements of joint motion and skin abnormalities. The dialysate Gd content was raised by the treatment, up to fivefold.
Conclusions. We could not confirm that sodium thiosulfate treatment results in marked and rapid improvement in late stages of Gd-related nephrogenic systemic fibrosis. However, dialysate contents of Gd seemed to increase. It is unknown whether increased Gd excretion will lead to long-term clinical improvements in late stages of nephrogenic systemic fibrosis.
Keywords: gadodiamide; gadolinium
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Introduction |
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Nephrogenic Systemic Fibrosis (NSF) is a newly identified, frightened disease of renal failure patients [1]. It leads frequently to severe disability including the loss of walking function and dependence on aiding devices [2]. The disease is thought to be caused by Gd deposition in tissues of vulnerable patients with moderate to severe renal insufficiency who have been exposed to gadodiamide or one of the other less stable Gd-based contrast agents used for magnetic resonance imaging (MRI) [3,4].
Anecdotical reports have described NSF symptom regression in patients after spontaneous recovery of renal function and after successful kidney transplantation, but otherwise there is no known curative treatment for NSF. It was therefore of utmost interest, when Yerram et al. recently published a case story of successful NSF treatment with sodium thiosulfate (STS) [5]. They described a young female patient who had been treated with regular haemodialysis for several years. In 2003, she had five separate gadodiamide-enhanced MR examinations made. In early 2004 she developed severe NSF-like symptoms. She also had large arterial calcifications and these calcifications were the primary reason for starting a treatment trial with STS, which is increasingly being used for calciphylaxis. The STS treatment was begun in May 2006. Within 1 month, the patient had dramatic improvements in her NSF symptoms (skin discoloration, pain, joint stiffness). A skin biopsy taken in July 2006 after 2 months of STS treatment showed that she was suffering from NSF, while there was no histological sign of calciphylaxis. The case report was submitted for publication in September 2006. Late results of her STS treatment have not been published. Nevertheless, these promising preliminary data prompted us to offer STS treatment to four severely affected gadodiamide-related NSF patients (NSF grade 3–4 [2]).
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Subjects and methods |
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We offered STS treatment to four severely affected biopsy-verified gadodiamide-related NSF patients who were in regular haemodialysis treatment at the nephrological department of Copenhagen University Hospital Herlev in the summer of 2007. All accepted the invitation. Baseline characteristics are presented in Table 1. The patients had had NSF symptoms for 26–52 months when the STS treatment was initiated. They all had had classical early NSF symptoms (swelling, pain, itching and skin discoloration of lower legs), and now were partly (patients 3 and 4) or fully disabled (patients 1 and 2) due to classical late NSF symptoms (skin stiffness, joint contractures, with or without advanced neuropathy). Early NSF symptoms predominate within the first 2 months after an NSF-eliciting Gd exposure, whereas late NSF symptoms have been defined as the NSF symptoms that predominate >6 months after the NSF-eliciting exposure [2].
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Two patients (patients 1 and 2) began the STS treatment in late June 2007. Patients 3 and 4 started in late August 2007. The treatment protocol was similar to the one used by Yerram et al. [5]: 12 g of STS (Pharmacy of the Capitol Region of Denmark, Copenhagen, Denmark) was infused intravenously over 16 min after each haemodialysis session.
The patients were examined and questioned about NSF symptoms just before start and again in early December 2007 after 3–5 months of STS treatment. Dialysate samples (10 mL sampled 10 min after initiation of the haemodialysis session) were collected before initiation of STS treatment (n = 2), at the first haemodialysis session following the first STS infusion (n = 2), and after 8–10 weeks of STS treatment (n = 4). Dialysate samples from two control patients unexposed to Gd-based contrast agents were also collected.
Dialysates were analysed for their Gd content in duplicate by inductively coupled plasma mass spectrometry (ICPMS) following simple dilution 1 + 1 with 2% subboil distilled nitric acid (Merck, Darmstadt, Germany). The method of addition calibration was used for quantification of the Gd content using the mean of the three isotopes 156Gd, 158Gd and 160Gd, which all gave similar results. The accuracy was verified by the quantitative recovery of added spike to one of the samples. The limit of detection (0.005 µg/L) was defined as three times the standard deviation from replicate measurements of blank samples.
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Results |
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Clinical assessments. We found no improvements in three of four patients after 3–5 months of STS treatment. One patient (patient 2) had some improved motion of her fingers and slightly improved motion of her ankles, but was still severely disabled and wheelchair bound.
Patients’ experiences. Two patients (patients 1 and 2) perceived that STS treatment had led to slightly improved joint motion and partial skin normalisation (less discoloration, less stiffness) and wished to continue the treatment.
The dialysate Gd content is presented in Table 2. Apparently, the Gd content increased with the STS treatment. The dialysate Gd content increased from 0.017 to 0.026 (50% increase) in patient 3 and from 0.08 to 0.44 (450% increase) in patient 4 over 8–10 weeks’ treatment. Baseline samples were not available from patients 1 and 2, but their dialysate Gd content was at a level comparable to that of patients 3 and 4 after 8–10 weeks’ treatment. The number of studied patients was too small to justify any statistical analyses of the data. The two Gd-unexposed control patients had Gd contents below the limit of detection in their dialysates.
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The STS treatment was well tolerated. We observed a tendency to acidosis in some patients, but the acidosis was moderate and was left untreated. One patient complained of nausea after STS infusions.
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Discussion |
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To our disappointment we did not see any dramatic clinical improvements in our four severely disabled NSF patients with the STS treatment. Our observations contrast with the promising findings reported by Yerram et al. [5]. We have no explanation for the discrepancy. Similar to the patient in Yerram et al.'s report, our patients had been in regular dialysis treatment for several years and had had NSF symptoms for more than a year. Maybe, their observations represent successful STS treatment of extensive calcifications rather than of NSF as discussed by the authors themselves.
Although our observations did not support that STS treatment results in marked and rapid clinical benefits, we found minor clinical improvements in one patient and also observed an increase in the dialysate Gd content with the treatment. STS treatment thus seems to accelerate the excretion of Gd from NSF patients. Assuming that 1% of the total Gd load (3.6 g, see Table 1) of the average patient was deposited in the patient's tissues, that the dialysate Gd content averaged 0.01 µg/L without and 0.04 µg/L with STS treatment and that the average patient used 500 L of dialysate every week, it could be calculated that the average patient would need almost 160 years without and 40 years with STS treatment to get rid of his/her Gd deposits. These assumptions are all very speculative, but nevertheless indicate that freeing the body of a renal failure patient from any Gd deposits is a very difficult and lengthy task. Accordingly, Abraham et al. recently reported clear evidence for long-term persistence of Gd in the skin of NSF patients [6].
We conclude that STS treatment seems to accelerate Gd excretion in dialysates of haemodialysed NSF patients. However, a 3- to 5-month treatment course was not associated with convincing clinical improvements in the present small and preliminary series of patients with late stages of NSF. It is unknown whether longer treatment periods might lead to clinically significant improvements. It remains to be investigated whether STS treatment initiated shortly after NSF debut might be effective in preventing severe NSF.
Conflict of interest statement. None to declare. The results presented in this paper have not been published previously in whole or part.
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References |
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- Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet (2000) 356:1000–1001.[CrossRef][Web of Science][Medline]
- Marckmann P, Skov L, Rossen K, Thomsen HS. Clinical manifestations of gadodiamide-related nephrogenic systemic fibrosis. Clin Nephrol (2008) 69:161–168.[Web of Science][Medline]
- Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol (2006) 17:2359–2362.
[Abstract/Free Full Text] - Thomsen HS, Marckmann P, Logager VB. Nephrogenic systemic fibrosis (NSF): a late adverse reaction to some of the gadolinium based contrast agents. Cancer Imaging (2007) 7:130–137.[CrossRef][Medline]
- Yerram P, Saab G, Karuparthi PR, et al. Nephrogenic systemic fibrosis: a mysterious disease in patients with renal failure—role of gadolinium-based contrast media in causation and the beneficial effect of intravenous sodium thiosulfate. Clin J Am Soc Nephrol (2007) 2:258–263.
[Abstract/Free Full Text] - Abraham JL, Thakral C, Skov L, et al. Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol. 158:273–280.
Accepted in revised form: 27. 3.08
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