Evidence Suggesting a Role of Iron in a Mouse Model of Nephrogenic Systemic Fibrosis.

Nephrogenic systemic fibrosis is associated with gadolinium contrast exposure in patients with reduced kidney function and carries high morbidity and mortality. We have previously demonstrated that gadolinium contrast agents induce in vivo systemic iron mobilization and in vitro differentiation of peripheral blood mononuclear cells into ferroportin (iron exporter)-expressing fibrocytic cells. In the present study we examined the role of iron in a mouse model of nephrogenic systemic fibrosis. Chronic kidney disease was induced in 8-week-old male Balb/C mice with a two-step 5/6 nephrectomy surgery. Five groups of mice were studied: control (n = 5), sham surgery control (n = 5), chronic kidney disease control (n = 4), chronic kidney disease injected with 0.5 mmol/kg body weight of Omniscan 3 days per week, for a total of 10 injections (n = 8), and chronic kidney disease with Omniscan plus deferiprone, 125 mg/kg, in drinking water (n = 9). Deferiprone was continued for 16 weeks until the end of the experiment. Mice with chronic kidney disease injected with Omniscan developed skin changes characteristic of nephrogenic systemic fibrosis including hair loss, reddening, ulceration, and skin tightening by 10 to 16 weeks. Histopathological sections demonstrated dermal fibrosis with increased skin thickness (0.25±0.06 mm, sham; 0.34±+0.3 mm, Omniscan-injected). Additionally, we observed an increase in tissue infiltration of ferroportin-expressing, fibrocyte-like cells accompanied by tissue iron accumulation in the skin of the Omniscan-treated mice. The deferiprone-treated group had significantly decreased skin thickness (p<0.05) and significantly decreased dermal fibrosis compared to the Omniscan-only group. In addition, iron chelation prevented tissue infiltration of ferroportin-expressing, fibrocyte-like cells. Our in vitro experiments demonstrated that exposure to Omniscan resulted in the release of catalytic iron and this was prevented by the iron chelator deferiprone. Deferiprone inhibited the differentiation of human peripheral blood mononuclear cells into ferroportin-expressing cells by immunohistochemical staining and western blot analysis. Our studies support an important role of iron in the pathophysiology of gadolinium chelate toxicity and nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis in a gadolinium-naïve patient: successful treatment with oral sirolimus.

A 52-year old woman with chronic renal failure presented with tender buttock nodules, bilateral non-tender periocular papules and yellow scleral plaques. The patient then developed sclerodermoid changes of the hands, as well as woody induration, oedema and hyperpigmentation of lower limbs. There was no previous exposure to gadolinium contrast. Her histology and clinical features were consistent with nephrogenic systemic fibrosis. Treatment with oral sirolimus resulted in a marked reduction of induration and oedema, and an improvement in distal upper limb and lower limb joint mobility.

Evaluation of imatinib mesylate as a possible treatment for nephrogenic systemic fibrosis in a rat model.

INTRODUCTION: The purpose of the study was to evaluate the efficacy of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF) in a rat model administered high-dose gadodiamide, erythropoietin (Epo) and intravenous iron (IV iron). MATERIALS AND METHODS: The local committee for animal research approved this study. Four groups of six Hannover-Wistar rats were studied. Group A received normal saline; Group B, IV iron and Epo; Group C, gadodiamide, IV iron and Epo; and Group D, gadodiamide, IV iron, Epo and imatinib. Gadodiamide was administered at 10 mmol/kg of body weight for 5 consecutive days. Imatinib was administered at 50 mg/kg starting 3 days before gadodiamide injections and was continued for 50 days afterwards. Biopsies were taken 3 and 7 weeks after gadodiamide injection, and dermal histology was analyzed as well as gadolinium deposition as measured by inductively coupled plasma mass spectrometry. Additionally, rats treated with gadodiamide were observed for a total of 16 weeks. For comparison of cellularity, a linear mixed-effects model was used, and for metal deposition, an analysis of variance was used, which was corrected with a Tamhane correction for unequal variances. RESULTS: Rats treated with gadodiamide in addition to IV iron and Epo (group C) had worse skin lesions on histology (P<.001) compared to control animals (groups A and B). Treatment with imatinib resulted in decreased cellularity (group D vs C, P<.001), although there was no difference in the amount of deposited gadolinium (P>.5). Histology at 16 weeks demonstrated increased fibrosis and dermal calcifications, consistent with the clinical presentation of NSF. CONCLUSIONS: The administration of imatinib to rats treated with high-dose gadodiamide resulted in decreased lesion severity.

Antifibrotic effect after low-dose imatinib mesylate treatment in patients with nephrogenic systemic fibrosis: an open-label non-randomized, uncontrolled clinical trial.

BACKGROUND: Nephrogenic systemic fibrosis is a disease affecting the connective tissue of the skin and internal organs in patients with renal failure. No effective treatments are available. OBJECTIVES: To investigate if the tyrosine kinase inhibitor, imatinib mesylate was effective in patients with moderate to severe nephrogenic systemic fibrosis. METHODS: Among 25 patients with nephrogenic systemic fibrosis evaluated for the study from 1 October 2009 to 1 December 2010, four were included. They were treated with oral imatinib mesylate at a start dose of 400 mg/day. MAIN OUTCOME MEASURE: Reduction of skin fibrosis and increase in joint mobility evaluated by the modified Rodnan skin score and a goniometer. RESULTS: In two patients, the imatinib mesylate dose was reduced to 200 mg/day and in one patient to 100 mg/day. Two patients were treated for 24 weeks, one patient for 16 weeks and one patient for 4 weeks. Three patients experienced tethering of their skin which lessened with reduction in modified Rodnan skin score from 24 to 20, 24 to 17 and 21 to 14 but with very limited changes in joint mobility. The fourth patient discontinued the treatment due to a complicating infection. CONCLUSION: Imatinib mesylate may be an effective drug in the treatment of skin fibrosis in moderate to severe NSF cases, even at reduced doses. We found a positive clinical effect on the skin, but no convincing improvement of the joint mobility. Only few patients could be recruited limiting the interpretation and conclusions of the results.

Extracorporeal photopheresis: clinical use so far.

Extracorporeal photopheresis (ECP or photopheresis) is an advanced therapeutic apheresis procedure in which blood is separated into its various components and the isolated buffy coat is treated with 8-methoxypsoralen (a photoactivating drug), exposed to ultraviolet light and returned to the patient. All other remaining blood components are also returned to the patient. The purpose of this procedure is immunomodulation. The treated leukocytes, specifically T-cells, are returned to the patient's circulation and will induce cytotoxicity and reduce proliferation of new T-cells. In the United States, ECP was initially approved for the treatment of cutaneous T-cell lymphoma by the US Food and Drug Administration in the late 1980s. Since that time, it has been used as an "off-label" therapy to treat several other autoimmune diseases in the United States and even more extensively in Europe and Asia. The following review is limited to the current clinical use of ECP in cutaneous T-cell lymphoma, Crohn's disease, systemic sclerosis, graft versus host disease, and emerging data on nephrogenic systemic fibrosis.

Alefacept therapy for nephrogenic systemic fibrosis: a case series.

Nephrogenic systemic fibrosis (NSF) is a recently described systemic fibrosing disorder that develops in the setting of renal insufficiency. Exposure to gadolinium has been implicated in its development. While the primary manifestations are cutaneous, systemic fibrosis can also occur. Several anecdotal reports of successful treatment have been reported, but there is no consistently efficacious therapy. We report the improvement or stabilization of cutaneous disease in three patients with NSF using alefacept therapy.

Liposomes radiolabeled with (159)Gd: in vitro antitumoral activity, biodistribution study and scintigraphic image in Ehrlich tumor bearing mice.

PEG-coated pH-sensitive and PEG-folate-coated pH-sensitive liposomes containing the Gd-DTPA-BMA complex were prepared and radiolabeled by neutron activation. The radiolabeled liposomes presented significant in vitro cytotoxic activity against Ehrlich tumor cells when compared with controls. The biodistribution profile of these liposomes and free (159)Gd-DTPA-BMA were studied in mice bearing a previously-developed solid Ehrlich tumor. The results demonstrated an important uptake of the formulations by the tumor tissue, with a tissue/blood partition coefficient (Kp) 3.88 and 14.16 times higher than that of the free complex for pH-sensitive PEG-coated and PEG-folate-coated liposomes containing the (159)Gd-DTPA-BMA complex, respectively. Both formulations accumulated in the liver and spleen, thereby revealing some difficulty in escaping the action of the MPS cells. The formulation without folate presented a lower renal uptake, which is desirable in patients with chronic renal failure due to the potential risk of nephrogenic systemic fibrosis (NFS). The scintigraphic study revealed that the target/non-target ratio is always greater than three for pH-sensitive PEG-coated liposome formulations and above nine for pH-sensitive PEG-folate-coated liposome formulations. The results obtained in this study demonstrated that the formulations employed can be considered to be a potential alternative for the treatment of cancer, including patients with chronic renal failure.

Osseous metaplasia late in the course of nephrogenic systemic fibrosis.

Osseous metaplasia has recently been described in several cases of nephrogenic systemic fibrosis, sometimes in association with unusual clinical features such as painful hyperkeratotic spicules, palpable bony masses, and disease regression. Some authors have suggested that it may mainly occur late in the disease course or even be a marker for involuting nephrogenic systemic fibrosis. Here, we present a 27-year-old woman with a 7-year history of nephrogenic systemic fibrosis, who developed cutaneous osseous metaplasia.

Rapid improvement of nephrogenic systemic fibrosis with rapamycin therapy: possible role of phospho-70-ribosomal-S6 kinase.

Nephrogenic systemic fibrosis (NSF) is a fibrosing disorder that occurs in some patients with renal insufficiency. Exposure to gadolinium-based contrast agents (GdCA) has been associated with the development of NSF. No uniformly effective treatment options exist. We present immunohistochemical evidence to show that the proliferating fibrocytes of NSF express phospho-70-s6 kinase (PI-3-K), a protein downstream of PI-3-K, and the target of the drug rapamycin. In our patient, use of rapamycin resulted in rapid clinical improvement marked by reduced edema, reduced skin induration, and decreased pain. This suggests a possible role for PI-3-K and rapamycin (mTOR) pathways in the pathogenesis of NSF. Drugs that inhibit these pathways may be a target for future therapy. While our patient did attribute disease onset to GdCA exposure, used on a single occasion for abdominal imaging, he was also exposed to iron, calcium, and darbepoetin alpha at the time of imaging.

Nephrogenic systemic fibrosis: what the hospitalist needs to know.

Nephrogenic systemic fibrosis (NSF) has now been linked to gadolinium-based contrast (GBC) exposure in those with compromised kidney function, particularly those with end-stage renal disease (ESRD). When ESRD is present, symptoms can be quite devastating for the patient including severe pain and immobility and even death. For those at risk, avoidance of GBC exposure, whenever possible, is absolutely essential to prevent this potentially devastating complication. Identifying those at risk depends in some circumstances on appropriate recognition of renal dysfunction and understanding appropriate use of glomerular filtration rate (GFR) estimation formulas. Although hemodialysis (but not peritoneal dialysis) removes gadolinium, the availability of dialysis should never be used as a justification for GBC use in this high-risk population. Unfortunately there is a lack of a universally effective therapy. Resolution of acute kidney injury (AKI) appears to attenuate disease in most cases, while kidney transplantation has been associated with variable success.

Nephrogenic fibrosing dermopathy.

An adult female patient on hemodialysis for chronic renal failure presented with large, brownish, and indurated plaques with bound-down skin on both lower limbs and abdomen along with difficulty in movement of the legs. Histopathological features revealed thick collagen bundles admixed with mucin and intercalating spindle-like cells characteristic of nephrogenic fibrosing dermopathy (NFD). Immunohistochemical study showed prominent CD68 positivity and weak CD34 positivity suggesting that the plaques were more than 20-weeks old. NFD in patients with chronic renal failure of unknown cause is a poor prognostic indicator. Early detection before the development of contracture and prompt treatment of NFD and underlying renal failure may reverse this disabling condition.

Imatinib in the treatment of nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis is a disabling progressive condition that is being reported with increased frequency in patients with kidney disease. Treatment is extremely limited and largely supportive. We report a case of severe nephrogenic systemic fibrosis in a dialysis patient exposed to multiple doses of gadolinium who improved clinically and histologically with treatment with imatinib.

Nephrogenic systemic fibrosis associated with gadoversetamide exposure: treatment with sodium thiosulfate.

Nephrogenic systemic fibrosis (NSF) is a debilitating fibrosing disorder of patients with kidney disease that is associated with gadolinium-based contrast exposure. Most cases are linked to gadodiamide. Gadoversetamide, an agent with chelate characteristics similar to gadodiamide, has rarely been described to cause NSF. With the exception of normalization of kidney function, there are no consistently effective therapies for patients with NSF. We describe 3 cases of NSF in patients with end-stage renal disease after gadolinium-based contrast exposure. Two patients received gadoversetamide and the third received gadodiamide. All 3 patients were treated early in their disease course with intravenous sodium thiosulfate and responded with improved skin changes and joint mobility.

Nephrogenic systemic fibrosis and the use of gadolinium-based contrast agents.

Nephrogenic systemic fibrosis (NSF) is a disease seen exclusively in patients with decreased renal function. The use of gadolinium-based contrast agents (GBCAs) has a strong association with NSF. Linear non-ionic GBCAs that are more prone to release free gadolinium are the more likely to cause NSF. The number of reported cases has increased recently, and there are currently nine pediatric cases, the patients ranging in age from 8 years to 19 years, and the oldest adult patient is 87 years of age. The most successful treatment is improvement of renal function with renal transplantation or with recovery of acute kidney injury. NSF can be severely debilitating and even fatal. Avoidance of a GBCA in patients at risk, or limitation of the dose in the patients who need gadolinium enhancement, is recommended.

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.

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.