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Nr. 3 - 29 January 2009

Scand J Prim Health Care Physician 2009; 129:180-2

doi: 10.4045/tidsskr.09.33117

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MEDICINE AND SCIENCEOverview Article

Nephrogenic systemic fibrosis using MRI contrast agent R E L Christiansen Sviland In Sekse E Svarstad

Summary Background. Nephrogenic systemic fibrosis is a new and probably iatrogenic disease. The condition was first described in 2000 and in 2006 was put in context with the use of MRI contrast agents with gadolinium in patients with impaired renal function.

Materials and methods. We give an overview of nephrogenic systemic fibrosis based on a non-systematic literature review and own clinical experience.

Results. Nephrogenic systemic fibrosis is a severe systemic disease with active inflammation and fibrosis formation, especially in the skin but also in several other tissues such as skeletal muscle, heart and esophagus.

Interpretation. The condition is very difficult to treat. The detection of disease has led to changes in policies regarding the use of gadoliniumkontrastmidler in patients with impaired renal function.

Nephrogenic systemic fibrosis is a rare disease, and there is no previously published cases in Norway. We have at Haukeland University Hospital had a patient who has received this diagnosis.

The incidence of chronic renal failure is increasing (1), And associated comorbidity, particularly cardiovascular disease, is common in patients who need dialysis or transplantation (2). In connection with studies of, for example. karstrukturer will be a need for contrast studies with iodinated contrast fluids (CT angiography or conventional angiography), and this gives a high risk of acute renal failure (kontrastnefropati) in patients with impaired renal function.

By the introduction of MRI and MRI contrast (gadoliniumkontrastmidler) Mon perceived risk of kontrastnefropati in patients with impaired renal function as very low. This enabled the use of assumed less risky and increasingly more accessible radiological investigations in this patient group. Examples of current studies are of MR angiography nyrekar suspected renal artery stenosis and aortic MRI in the assessment of kidney disease patients in preparation for kidney transplantation.

A man in his 30s was transplanted kidney after many years of IgA nephritis. He was employable until he was receiving disability benefits Seven years after transplantation. Due. transplantatsvikt he started peritoneal dialysis, one year after transplantation, with gradual transition to hemodialysis.

In connection with the investigation of new kidney transplant was carried out MR angiography of the renal and pelvic arteries, ten years after he got the renal graft. During the following month, he lamented over the clamping feeling in both forføtter and gradually more pronounced numbness up the legs. Three months after the contrast study, he was hospitalized due. fatigue, hypotension, and arthritis. It was proven indurert thickened skin around the ankles. He was hospitalized again a month later due. hypotension, stiffness in the ankles / feet and failing again function.

Eventually, he is now more pronounced hyperpigmentation around add / ankles (Fig. 1) and indurert tissue proximal to the knees and in both hands. After several skin biopsy without a representative material, it was about. one year after an MRI taken a deep skin biopsy from the forearm with the detection of histological changes consistent with nephrogenic fibrosis rendering dermopati (Fig. 2).

Microscopic was there upåfallende epidermis, but significant increase of cell-rich connective tissue in the reticular dermis and into the septa. There were scattered CD34-positive spolformede cells, many CD68-positive cells and a few small multicore cells. Septa were clearly thickened with increased collagen formation of calcium deposits in tissue and the vessel wall.

The patient was at this point treatment with regular hemodialysis. It was tried a number of measures against his new illness. It was changed to hemodiafiltrasjon without significant effect. Photodynamic therapy was tried, but due. pain patients completed only one session. He conducted four sessions with extracorporeal fotoforese, also without significant effect.

He became progressively more wheelchair dependent, needy, some nursing home patients and had multiple hospital admissions. The general condition was deteriorating and he died at home 13 years after transplant was completed, probably by cardiac arrest.

Figure 1 a) Image of indurert skin lesions from the patient's left leg. b) "Pinch Test" which shows loss of elasticity in the skin and subcutaneous Show: a new window Powerpoint

Figure 2 a) Cell Erik dermis and subcutis with increased connective tissue formation. b) Expanded septa with increased

connective tissue and scattered small multi-core cells. c) CD34-positive dendritic processes in the dermis. d) CD68-positive cells in the septa Show: a new window Powerpoint

Materials and methods We give an overview of the disease based on non-systematic literature review and own clinical experience.

The use of MRI contrast by reduced renal function In 2006, the published data that continued use of gadoliniumkontrastmidler in patients with significant renal impairment in conjunction with a new, severe systemic disease called nephrogenic systemic fibrosis (3). This led to the development of new recommendations for use by manufacturers, the Food and Drug Administration (FDA) in U.S. and eventually the Norwegian health authorities. Gadodiamid (Omniscan) is now contraindicated when the glomerular filtration rate (GFR) is below 30 ml/min/1, 73 m2In

addition to before and after liver transplantation. Other available gadoliniumkontrastmidler should only be used after careful consideration by similar severe renal failure (4).

The disease was first described in 2000 (5) For a case from 1997 was identified. Initially conceived Mon that the condition was limited to the skin and named it nephrogenic fibrosis rendering dermopati. As more case reports were published, it appeared clear that this was a systemic disease that could also involve other tissues such as. lungs, esophagus, skeletal muscle, heart, and dura mater (6, 7), And the disease now called nephrogenic systemic fibrosis so far registered 271 cases (October 2007) of the disease worldwide, and it created an international research center at Yale University, Connecticut, USA - International Center for Nephrogenic Fibrosing Dermopathy.

System Disease Nephrogenic systemic fibrosis is a severe fibrosis rendering system disease with significantly increased morbidity and mortality. There is described an acute phase (8), But most cases are clearly defined by a chronic phase which debuts weeks to months after gadoliniumeksponering (frame 1) (9).

Box 1

Nephrogenic systemic fibrosis was first described in 2000 and later in 2006 set in the context of the use of gadoliniumkontrastmidler in chronic renal failure.

The disease was first perceived to be limited to the skin, but it is now clear that in the case of a disease with inflammation and increased fibrosis formation in several tissues such as skin, lung, esophagus, heart and skeletal muscle.

Still unresolved is a lot about the disease pathophysiology, but the activation of fibrocytter and transforming growth factor β is involved together with a likely release and deposition of gadolinium in tissues.

The condition typically affects distal areas of the feet, hands and arms, and often proves to be more generalized edema followed by plaque-like erythema and papules indurerte with a woody texture. The skin is often thickened and hard, and the changes can sometimes be severe painful. Alopecia and hyperpigmentation of the extremities can follow, while the involvement of the facial skin occurs very rarely. Systemic involvement includes conditions such as acute pancreatitis, thrombosis, and frequent infections. The disease is often disabling and can lead to wheelchair dependence / bed rest caused by among other things, reduced general condition and leddkontrakturer.

Differential Diagnostic must consider skleromyksødem, systemic sclerosis, Morfeas, eosinophils fasciitis, eosinophilia-myalgia syndrome (EMS) and "Spanish toxic oil" syndrome. The clinical findings are important. The diagnosis of nephrogenic systemic fibrosis based on a typical clinical picture and histological examination of deep skin biopsy from the affected area. Histological seen a proliferation of spolformede cells, with scattered monocyttære cells and small multi-core cells in the dermis and subcutaneous

septa. Immunohistochemistry showed that the cells are spolformede CD34-positive dendritic cells, while the monocyttære and multicore cells are positive for CD68 (macrophages). Also seen an increased amount of collagen, mucin and elastic fibers. Histologically it can be difficult to differentiate nephrogenic systemic fibrosis from skleromyksødem but skleromyksødem seen as a rule "lakes" of mucin with plasma cells and fragmented elastic fibers that are not detected in patients with this disease. Biopsies from systemic sclerosis or Morfeas showing bundles of homogenized collagen and no proliferation of spolformede cells that are so characteristic of nephrogenic systemic fibrosis.

Discussion Nephrogenic systemic fibrosis is a relatively new disease which causes, mechanisms of disease development and the incidence has not yet been clarified. Gadoliniumeksponering in patients with impaired renal function have been identified as a significant risk factor, which has led to changed guidelines for use of the drug in this patient group. In addition, it eventually found a number of other risk factors for the development of the disease (10), But the most compelling etiological factor is the continued association with exposure to gadolinium in patients with impaired renal function (9, 11, 3). The association was strengthened after gadolinium has been detected in skin lesions (12).

Most cases described initially were related to the use of gadodiamid, but it is now clear that it is likely the case of a class effect of gadoliniumholdige contrast fluids, although it is likely that the problem is more or less with some preparations. This applies to the gadoliniumholdige MRI contra funds in the Norwegian market: gadopentetat (Magnevist), gadodiamid (Omniscan), gadoteridol (ProHance) gadotersyre (Dotarem) gadobutrol (Gadovist) dinatriumgadoksetinsyre (Primo Viewed) gadofosveset (Vasovist) and gadobensyre (Multihance ).

The risk of developing the disease is associated with reduced GFR value and especially when the estimated GFR <30 ml / min, ie, chronic kidney disease in stage 4 and 5 (13). The trend can be seen both in acute and chronic renal failure and regardless of the cause of kidney failure. In addition to gadoliniumeksponering find additional risk factors, such as høydosert erythropoietin, elevated PTH and widespread disease play a role in the development of the disease (10, 14).

When the pathophysiology of the disease is still a lot unclear. The skin is thickened as a result of increased local collagen synthesis secondary to fibrocyttaktivering and activation of transforming growth factor β (trans-forming growth factor β, TGF-β) (4). The image is characterized by persistent inflammation-like response.

As the disease develops only in patients with impaired renal function, it is tempting to imagine a toxic effect of endogenous or exogenous material. Gadolinium is excreted almost exclusively via renal excretion, accumulates in renal failure and renal failure-association gadolinium-nephrogenic systemic fibrosis is well documented (3, 9).

Gadoliniumkontrastmidler is water-soluble contrast agents which contain base metal gadolinium (Gd). Gadolinium is basically toxic and are therefore naturally in a reversible complex structure (chelators) in the solution. One thinks that the toxic gadolinium released including a trans-metallization of free iron (4, 14). Gadolinium deposited in tissues and initiate inflammation / fibrosis. Different incidence of nephrogenic systemic fibrosis related to the different gadoliniumkontrasmidlene is likely related to the drug physicochemical properties and thus vary in their ability to free gadolinium.

There is currently no clear consensus about which treatment is best for patients with nephrogenic systemic fibrosis. Improvement of renal function (such as. By kidney transplantation), however, seems to be able to stop the development. Otherwise, it tried a variety of treatment measures, but with only a few patients or single cases described. Man has tried steroids, photodynamic therapy (15) Fotoforese, plasma exchange and UV treatment without clearly documenting the beneficial effect. In addition, because pentoksyfyllin used. antifibrotisk effect and TNF-ɑ-blockade and cell poison cyclophosphamide. But there is no evidence that drugs help. Acute deposits of gadolinium can be removed by dialysis. If patients with significant renal insufficiency (chronic renal failure, stage 3-5), however, must undergo gadoliniumbaserte contrast studies, recommended dialysis treatment immediately after exposure and new treatment after 24 hours (16).

The Norwegian policy is now updated about renal failure and use of gadoliniumkontrastmidler (17).

Conclusion Nephrogenic systemic fibrosis is a recently discovered illness related to kidney failure and the likely use of gadoliniumkontrastmidler. We have described a case of the disease at the Haukeland University Hospital in a patient with severe renal failure. Gadodiamid is contra-indicated by GFR <30 ml/min/1, 73 m2And other available gadoliniumkontrastmidler should only be used after careful consideration by similar severe renal failure.

The patient's relatives have given permission for the article is published.

We thank Lene Sandvik Frøyen and Day Sollesnes Holsen at the Department of Dermatology, Haukeland University Hospital, for loan of images of skin lesions.

Declared conflicts of interest:No

Key Messages

Nephrogenic systemic fibrosis is a fibrosis rendering system disease with high morbidity and mortality

Use of gadoliniumholdige MRI contrast agents in patients with severe renal failure is the most important risk factor

It has recently developed more restrictive guidelines for the use of gadoliniumkontrastmidler of renal failure

Literature

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2. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998; 9: 16-23.

3. Grobner T. Gadolinium - a as the specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic Systemic fibrosis? Nephrol Dial Transplant 2006; 21: 1104-6.

4. Nortier JL, del Marmol V. Nephrogenic Systemic fibrosis - the need for a multidisciplinary approach. Nephrol Dial Transplant 2007; 22: 3097-101.

5. Cowper SE, Robin HS, Steinberg SM et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356: 1000-1.

6. What WW, Stone MS, Madison KC et al. Nephrogenic fibrosing dermopathy with Systemic involvement. Arch Dermatol 2003; 139: 903-6.

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9. Marckmann P, Skov L, Rossen K et al. Nephrogenic Systemic fibrosis: suspected causative role of gadodiamide unusual for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006; 17: 2359-62.

10. Swaminathan S, Leung N. Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 2006; 145: 234-5.

11. Collidge TA, Thomson PC, Mark PB et al. Gadolinium-enhanced MR imaging and nephrogenic Systemic fibrosis: Retrospective study of a renal replacement therapy cohort. Radiology 2007; 245: 168-75.

12. High WA, Ayers RA, Cowper SE. Gadolinium is quantifiable Within the Tissue of Patients with Systemic nephrogenic fibrosis. J Am Acad Dermatol 2007; 56: 710-2.

13. Sadowski EA, Bennett LK, Chan MR et al. Nephrogenic Systemic fibrosis: risk factors and incidence estimation. Radiology 2007; 243: 148-57.

14. Kanal E, Barkovich AJ, Bell C et al. ACR guidance document for Safe MR Practices: 2007. AJR Am J Roentgenol 2007; 188: 1447-74.

15. Schmook T, Budde K, Ulrich C et al. Successful treatment of nephrogenic fibrosing dermopathy in a kidney transplant recipient with photo dynamic therapy. Nephrol Dial Transplant 2005; 20: 220-2.

16. Swaminathan S, Shah SV. New insights Into nephrogenic Systemic fibrosis. J Am Soc Nephrol 2007; 18: 2636-43.

17. Buajordet I, Madsen S. Serious side effects of Omniscan and Magnevist in patients with renal failure. Oslo: Norwegian Medicines Agency, 2008.

The manuscript was received 9.2. 2008 and approved 30.5. 2008. Medical Editor Ms Helland.

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