Nephrogenic systemic fibrosis (NSF) is a new fibrotic skin disease entity that was first recognized in 1997 in 15 patients receiving hemodialysis.
Early reports noted that NSF closely resembled scleromyxedema, but had a number of differentiating features. The entity was initially termed nephrogenic fibrosing dermopathy, and a case definition was established based on its characteristic clinical and histopathologic features. The name was later changed to NSF in view of the systemic nature of the disorder and recognition of the role circulating fibrocytes play in mediating NSF.
Underlying renal impairment is a prerequisite for the diagnosis of NSF, and 90% of patients with NSF have end-stage renal disease (ESRD). The age of the patients with NSF has ranged from 8-87 years with equal gender distribution. Cases of NSF have been reported in many countries and no race predilection has been observed. In a recent case-control study of 19 patients with NSF, 58% and 32% received hemodialysis and peritoneal dialysis respectively in the six months preceding the diagnosis.
Clinical, histologic features
NSF is associated with cutaneous lesions that are typically distributed in a symmetrical fashion on the limbs and trunk; the face is usually spared. The primary lesions consist of skin-colored to erythematous papules coalescing into brawny patches with a peau d’orange surface appearance.
The patient’s involved skin typically becomes markedly thickened and develops a woody texture. Yellow scleral plaques have been observed in some patients with NSF. Intense pain and pruritis are commonly reported in affected areas.
As NSF progresses, patients may experience significant decrease in the function of their hands and feet, with the development of joint contractures. Some may require wheelchair use and assistance with activities of daily living. Severe disability and mortality have been reported in patients with NSF.
NSF is a clinical and histopathological diagnosis. Lesions show an increase in dermal spindle cells which are bland and have long dendritic processes. Most of these spindle cells are immunohistochemically positive for CD34 and procollagen I. This immunologic profile is identical to circulating fibrocyte, a bone-marrow derived leukocyte. Thick collagen bundles with surrounding clefts are also prominent findings with a variable amount of mucin and elastic fibers noted.
No etiologic agent or intervention has been identified as causing or being associated with NSF until recently. The observations that vascular surgery and thrombotic episodes were common preceding events prompted speculation that NSF may be triggered by an imaging contrast agent. Five out of nine ESRD patients in an Austrian dialysis center who underwent MR angiography with gadodiamide had developed NSF two to four weeks later. Gadolinium was thought to be a trigger for NSF under certain conditions based on above observations. This theory was further supported by the findings of a study of 13 confirmed cases of NSF, all of whom had been exposed to gadodiamide before the onset of NSF. The odds ratio was calculated at 32.5 with these 13 NSF cases identified among 370 ESRD patients exposed to gadolinium-based contrast agents (GBCA) and none among 430 non-exposed ESRD patients. The time lag from gadodiamide exposure to the first sign or symptom of NSF was 2-75 days (median, 25 days). Of the 13 patients, seven (54%) became severely disabled and one died at 21 months after gadodiamide exposure. Subsequent case-control series found the odds ratio to range from 8.97 to 22.33 for prior exposure to gadodiamide or other GBCA in ESRD and acute kidney injury (AKI) patients.
Prevalence of NSF has ranged between 3.5% to 4% in ESRD patients exposed to GBCA. Yearly incidence was reported as 4.6% for a population of hospitalized patients whose (GFR) was less than 60 mL/min/1.73m2 and had a pro-inflammatory event. Incidence was calculated to be 4.3 cases per 1000 patient-years in a stable outpatient (ESRD) population. Each radiologic study using (GBCA) presented a 2.4% absolute risk for NSF in the same recent series.
NSF cases have been reported in patients with AKI or CKD and in renal or liver transplant recipients with compromised renal function. All patients with documented NSF had renal impairment with either ESRD, AKI, or CKD with an estimated glomerular filtration rate (GFR) below 30 mL/min per 1.73m2. Patients with ESRD appear to be at the highest risk for NSF, and those with CKD Stage 4 also appeared to be at elevated risk. Peritoneal dialysis appears to be associated with a greater risk for NSF compared to hemodialysis.
Risk for NSF appears to increase with repeated administration with an odds ratio of 2.618.10,11 Risk for NSF appears to increase with use of double-dose (0.2 mmol/kg) compared with single-dose (0.1 mmol/kg) gadodiamide administration with an odds ratio of 12.19. Acidosis was initially reported as a risk factor favoring NSF occurrence with mean bicarbonate level of 19.5 ± 1.7 mmol/L versus 22.95 ± 0.58 mmol/L in unaffected cases. Mean bicarbonate level was 22.5 mmol/L, 23.5 ± 1.1 mmol/L and 22.3 ± 2.74 in three subsequent reports with no association found with NSF. Higher rHuEpo doses have been reportedly in cases with NSF but this could be a result of inflammation and resistance to rHuEpo.4,6,12 ACE inhibitors were thought to be protective but this was not consistently observed. Pro-inflammatory state may be a predisposing factor.
Given the significant morbidity and mortality associated with NSF, the FDA has stated that the benefits and risks associated with using a GBCA upon recommending or performing an MRI or MRA should be carefully weighed in light of recent reports of NSF observed following administration of these agents. Alternative imaging methods and/or contrast agents should be used whenever possible. A total of five GBCA (Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance) are currently approved for use in the United States.
There is no consistently successful treatment for NSF. It is not known if hemodialysis post-exposure prevents it. A current recommendation is to initiate hemodialysis within two to three hours of a GBCA administration, followed by a second session within 24 hours. Treatments that have been used with some success and continue to be investigated include oral steroids, plasmapher-esis, extracorporeal photopheresis and sodium thiosulfate. Additional information on NSF is available on the InternationalCenter for Nephrogenic Fibrosing Dermopathy Research Web site (www.icnfdr.org).