Nephrogenic Systemic Fibrosis


Table 3: Essential Clinical Features of Patients with Nephrogenic Systemic Fibrosis


Have or have had severe acute or chronic renal insufficiency (glomerular filtration rate less than 30 ml/minute/1.73 m2) Have been exposed to gadolinium-based contrast agent(s) while renally impaired


Develop skin changes ranging from minor elements of fibrosis to extensive hardening of large skin areas causing disabilities


Table 4: Co-factors Increasing the Risk for Nephrogenic Systemic Fibrosis After Exposure to Gadolinium-based Contrast Agent


Increasingly poor renal function


Increasing cumulative exposure to Gd-based contrast agent Inflammatory conditions Hyperphosphataemia


Erythropoietin treatment and high dosing


stability profile quite similar to Omniscan, seems to be as risky. Magnevist® (gadopentetate dimeglumine) is the GdBCA that has been associated with the second highest number of cases of NSF. Magnevist has an intermediate stability profile, but has had a very large market share, in particular in the US, which explains the relatively high number of NSF cases related to Magnevist exposure. Two recent case reports have described three NSF cases caused by one of the presumably very stable and safe macrocyclic agents, Gadovist® (gadobutrol).41,42 However, these reports have been questioned.43


To the author’s


knowledge, there have been no scientific reports on NSF caused by the remaining GdBCAs.


The absolute incidence or prevalence of NSF after GdBCA exposure has been the subject of several studies. They differ grossly in their design: from closely monitored studies of small, well-defined groups exposed to precisely described types and amounts of GdBCAs, to registry studies of large, inhomogeneous populations with poor data quality on GdBCA exposure. Therefore, it is not surprising that prevalence estimates vary enormously. In some studies, NSF prevalence was reported to be zero.44,45


At the other end of the scale,


we find studies such as Grobner’s report on nine Omniscan-exposed haemodialysis patients, where five patients developed signs of NSF (prevalence 56 %, 95 % confidence interval [CI] 26–81 %);34


the study


by Todd et al., where the prevalence of NSF among haemodialysis patients after Magnevist exposure was 30 % (95 % CI 19–43 %);13


and


the study by Rydahl et al., where NSF prevalence in patients with CKD stage 5 was 18 % (95 % CI 11–27 %) after Omniscan exposure.46


Gadolinium-based Contrast Agents and Nephrogenic Systemic Fibrosis – Causality The repeatedly observed temporal relationship between GdBCA exposure and the development of NSF symptoms does not suffice to prove causation. However, several other lines of evidence have convincingly confirmed the causal link. First, it was demonstrated that NSF patients – in contrast to patients unexposed to GdBCAs – have Gd deposits in the dermis and subcutis of skin biopsies from affected areas.47–49


other tissues of NSF patients.11,50,51


Later studies reported the finding of Gd deposits in several Second, animal studies have shown


that exposure of rats to GdBCAs with relatively poor stability profiles led to skin Gd deposition and fibrotic changes resembling NSF.52,53 Third, studies on cell cultures have demonstrated that Gd and


124


unstable GdBCAs induce pro-fibrotic alterations in cell structure and function.53–56


Among GdBCA-exposed patients with poor renal function, there is a varying but considerable proportion that does not develop NSF, even after exposure to high doses of unstable agents. This fact illustrates the existence of co-factors in NSF pathogenesis. Several studies have examined the role of possible co-factors.32,38,57,58 essence of such studies.


Table 4 lists the


Prevention and Treatment of Nephrogenic Systemic Fibrosis


Prevention has been the key to stopping the NSF epidemic. Currently, the reporting of newly developed cases is approaching zero. This favourable situation is the result of the change in the use of GdBCAs in patients with renal insufficiency that has taken place since 2006. Supported by the guidelines for GdBCA use published by medical authorities worldwide, the use of the most unstable, linear GdBCAs (Omniscan, OptiMark, Magnevist) in kidney patients seems to have stopped, and the other GdBCAs seem to be used more cautiously. In addition, haemodialysis patients are now dialysed shortly after completion of GdBCA-enhanced MRI to reduce the duration of GdBCA exposure. This practice has not been proved to prevent NSF, but is a result of common sense.


There is still no proved curative medical treatment for NSF patients. The poor clinical condition of many NSF patients has forced physicians to try numerous treatment modalities including extracorporal photopheresis, plasmapheresis, intravenous sodium thiosulphate, imatinib, steroids and ultraviolet A phototherapy. Currently, there is some hope that imatinib may be helpful, but the number of reported positive outcomes after imatinib treatment is still low and it seems premature to draw conclusions about its efficacy.59 So far, the cornerstones in NSF treatment are painkillers, physiotherapy to maintain or restore muscular power and joint mobility, psychological support, and supply of aiding devices such as wheelchairs or nursing personnel in severely disabled cases.


Some reports indicate that NSF patients who regain renal function as a result of remission of acute renal failure or kidney transplantation may experience a marked regression of their NSF symptoms.60,61 However, not all NSF patients improve after kidney transplantation.61 It is probable that severe cases with fully developed joint contractures and calcifications of soft tissues cannot expect to improve with restoration of normal kidney function. Nevertheless, it should be considered whether such patients might be given high priority on kidney transplantation waiting lists: the restoration of normal kidney function would mean an improved quality of life despite continued NSF symptoms and could be seen as a compensation for their iatrogenic NSF problems.


Conclusions


Certain relatively unstable GdBCAs have caused hundreds, maybe even thousands of NSF cases among renal patients. These agents (Omniscan, OptiMark, Magnevist) should not be used in patients with impaired renal function in the future. The toxicity of GdBCAs is explained by their content of the highly toxic heavy metal Gd, which is liberated in intolerable amounts when the more unstable GdBCAs are used in patients with impaired renal function. It is important to note that even the more stable GdBCAs may lead to the deposition of


EUROPEAN NEPHROLOGY


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