B.N. is a 71-year-old African American female with significant medical history of chronic kidney disease (CKD) stage 6, who has been on hemodialysis since March 2003. She was previously treated with peritoneal dialysis (PD), which was discontinued secondary to peritonitis. She has multiple myeloma (controlled and stable on thalidomide), a propensity for intravascular clotting with associated deep venous thrombosis/pulmonary embolus (DVT/PE), and a Greenfield (inferior vena cava/IVC) filter placement. The clotting problem is currently controlled with warfarin therapy. B.N. has a history of diabetes mellitus that has not required treatment since the initiation of hemodialysis. She also has frequent lower extremity ulcerations that rarely heal completely in spite of hyperbaric oxygen therapy. Considering the return of auto-glycemic control, the etiology of these cutaneous ulcers comes into question.

B.N.’s first 15 months of hemodialysis were plagued with complications and frequent thrombosis, which eventually resulted in the failure of one arteriovenous (AV) fistula  and subsequently, one AV polytetrafluorethylene (PTFE) graft. She experienced new onset leg ulcers and exacerbation of existing ischemic ulcers. Following the failure of her second AV access, B.N. underwent an MRI/MRA with gadolinium contrast agent for vein mapping. Approximately 2 weeks later, she returned to the dialysis center from vacation reporting bilateral lower extremity parasthesias and muscle tightness. The initial medical evaluation described the symptoms as “brawny” muscular edema (edema believed to involve deep tissues in addition to fascia). Subsequent aggressive ultrafiltration (UF) with removal of fluid did not improve the condition. Over the following week, B.N. reported worsening muscular tightness in the lower extremities, which progressed rapidly to rigid flexion contractures and a pronounced tightening of the skin with peau d’orange texture on the right hand and bilaterally in the legs.
 
Although of doubtful clinical significance, it is interesting to note that the patient’s bio-intact parathyroid hormone (PTH) level increased substantially from 497 ng/L to 1552 ng/L over this period of time. By the end of the second week of symptoms, B.N. was reduced from an independent ambulatory status to being wheelchair-bound and requiring much assistance in the completion of her activities of daily living. Upon the onset of dermatologic symptoms, the patient was referred to dermatology. Skin biopsies were consistent with nephrogenic systemic fibrosis (NSF), which is also know as nephrogenic fibrosing dermopathy (NFD). A referral was made to the Yale University International Center for NFD research, where B.N.’s diagnosis of NSF/NFD was confirmed.

Intervention
NSF, in essence, produces a chain reaction in which affected dendritic cells release transforming growth factor-B (TGF-B), causing affectation and accumulation of previously non-pathologic dendritic cells within the tissues in question. As hypothesized by Mendoza et al. (2006, p. 248), “…it is possible that the causative agent(s) resulted in increased expression of the growth factor as part of the response of the dendritic cells to this noxious agent. The transforming growth factor-B (TGF-B) produced by these dendritic cells in turn would be responsible for the fibrotic process and the expansion and enhancement or initiation of antigen presenting functions of further dendritic cell.”

The physical removal of TGF-B by means of therapeutic plasma exchange (TPE) appears to be a logical means of breaking the cycle. This connection, however, is merely hypothesized and needs further evaluation. Limited success in the treatment of NSF skin lesions has been reported following TPE in three patients with NSF post liver transplantation (Baron et al. 2003). Follow-up studies with a larger sample group have not been completed to date. Additionally, two of the surviving subjects regained kidney function over the course of their NSF treatment. Thus, as of now, there have been no consistently effective treatments documented for NSF.

It is also important to note that several other patients had NSF resolve spontaneously following the return of renal function and the discontinuation of renal replacement therapy, further confounding the report of successful treatment with TPE. The remission of NSF in the presence of returning renal function should not be considered a cure. As reported by Mendoza et al. (2006), 6 of a 12-patient sample group received transplants and all failed. Whether the failure was related to the NSF is unknown.

Circulating fibrocytes (CFs) are also believed by many investigators to play an important role in the development of NSF. CFs are produced in the bone marrow and are involved in the repair of wounds and remodeling of tissues. Cowper and Bucala (2003) suggested that the dendritic cells found within NSF lesions are in fact CFs that had been recruited by an unknown pathologic means. Considering the role of the CFs as a wound healing mediator, it is interesting to note that a patient who had a “minor dermal abrasion” at the time of NSF onset developed “a remarkable fibroproliferative reaction…with a large hypertrophic and neovascularized scar” (Mendoza et al. 2006, p. 241). Further research is required to examine the link between the wound healing characteristics of the CFs and the aberrant wound healing reported by Mendoza in the presence of NSF pathogenesis. The presence of B.N.’s leg ulcerations at the time of NSF onset and her lack of hypertrophic scarring should not necessarily be discounted considering the essential differences in inflammation and perfusion of ischemic wounds versus traumatic wounds. Furthermore, other mechanisms may be in place considering the persistence of the leg ulcerations despite the return of B.N.’s inherent glycemic control.

In the absence of a curative therapy, the goal with B.N.’s therapy has been palliation of her symptoms. Following her diagnosis with NSF, multiple treatment options were employed to reduce the debilitating effects of her physical symptoms. These included topical and systemic corticosteroids, sirolimus (Rapammune®) therapy and aggressive physical therapy.

In light of conflicting evidence regarding the efficacy of TPE in the treatment of NSF, B.N. has not received TPE therapy. She has had many hyperbaric oxygen treatments in an effort to heal the lower extremity ischemic ulcers. Although these treatments continue to demonstrate measurable, albeit limited, success in the treatment of her wounds, hyperbaric therapy seems to have had no confirmed effect on the NSF. Despite the myriad of treatments B.N. has received, none has improved her skin lesions or significantly improved her range of motion.

Discussion
Following the initial report of symptoms in 1997 and the identification of NSF/NFD by Cowper, Robin, Steinberg, Gupta, and LeBoit (2000), NSF has been an etiological mystery to the nephrology community. Theories abound regarding a causative agent; ranging from vitamin D analogs to dialyzer membrane reactions. In May 2006, the Danish Medicines Agency reported 20 cases in Denmark and 5 cases in Austria of new onset NSF/NFD in which development had occurred within 3 months of the receipt of gadolinium-containing MRI contrast agent (Grobner, 2006). In June 2006, the FDA released a caution to limit the exposure of patients with CKD to gadolinium contrast (U.S .Food & Drug Administration, 2006). As noted previously, B.N. had received a bolus dose of gadolinium for diagnostic imaging. Additionally, she had the associated risk factors of hypercoagulability and volume overload (related to inability to undergo dialysis secondary to access thrombosis). Despite the absence of irrefutable clinical evidence linking gadolinium dye to NSF, the proximity of B.N.’s gadolinium exposure to her onset of symptoms should not be discounted. Granted, a large number of patients with ESRD have received gadolinium without any deleterious effect. However, given the correlation between NSF and contrast exposure, it would be auspicious to avoid gadolinium within this population unless the risk of NSF is significantly less than the risks associated with alternate imaging methods.

Summary
Nephrogenic systemic fibrosis is a severely physically disabling phenomenon experienced by a specific subset of patients with renal disease. Several of the 200 reported cases worldwide are currently treated within the author’s facility. My colleagues and I have witnessed first-hand the life altering effects of NSF on our patients’ physical, psychological, and social health, not to mention the unseen effects on family dynamics and changes in the interpretation and function of individual roles. Outside of the ESRD community, NSF is a largely unknown entity, likely due to the infrequency of incidence and relatively cohorted population. Despite the infrequency, we in the nephrology specialty must spread awareness of this condition and share our common knowledge and experiences to help those suffering from NSF to maintain their quality of life.

In collaboration with the Centers for Disease Control (CDC), the Yale University International Center for NSF Research has established a website (www.icnfdr.org) for reporting of new cases of NSF/NFD. Until a causative agent is irrefutably identified, it is of the utmost importance that new cases be reported immediately. We expend a great deal of effort and gain valuable experience in helping our patients live their lives as richly as possible. If we as professional nurses share our knowledge and experience in managing the life-altering effects of NSF, our patients as a collective whole will benefit. It is, therefore, our responsibility to collaborate within and outside of the profession to reduce the number of new cases of NSF and help existing patients live their lives with the highest quality standard possible.

References

Baron, P.W., Cantos, K., Hillebrand, D.J., Hu, K.Q., Ojogho, O.N., & Nehlsen-Cannarella, S. (2003). Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. American Journal of Dermatopathology 25, 204-209.

Cowper, S.E., Robin, H.S., Steinberg, S.M., Gupta, S, & LeBoit, P.E. (2000). Scleromyxoedema – Like cutaneous disease in renal-dialysis patients. Lancet, 356, 1000-1001.

Cowper, S.E., & Bucala, R. (2003). Nephrogenic fibrosing dermopathy: Suspect identified, motive unclear. American Journal of Dermatopathology, 25, 358.

Cowper, S.E. (2006). Nephrogenic fibrosing dermopathy. Retrieved August 15, 2006 from http://www.icnfdr.org.

Grobner, T. (2006). Gadolinium - A specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis. Nephrology Dialysis Transplantation, 21(4), 1104-1108.

Mendoza, F., Artlet, C., Sandorfi, N., Latinis K, Piera-Velazquez, S., & Jimenez, S. (2006). Description of twelve cases of nephrogenic fibrosing dermopathy and review of the literature. Seminars in Arthritis and Rheumatism, 35(4), 238-249.

U.S. Food and Drug Administration. (2006). Public health advisory. Retrieved August 15, 2006 from http://www.fda.gov/cder/drug/advisory/gadolinium agents.htm.￿