Case-control study of gadodiamide-related nephrogenic systemic fibrosis.

BACKGROUND: Nephrogenic systemic fibrosis may be caused by gadolinium (Gd)-containing magnetic resonance imaging contrast agents. Most reported cases were associated with one particular agent, gadodiamide. Yet, unidentified cofactors might explain why only a minority of renal failure patients exposed to gadodiamide develop nephrogenic systemic fibrosis. METHODS: We conducted a case-control study of 19 histologically verified cases and 19 sex- and age-matched controls. All subjects had chronic renal failure when exposed to gadodiamide. Clinical, biochemical and pharmacological data were retrieved from medical records. RESULTS: Cases had been exposed to a mean gadodiamide dose of 0.29 mmol/kg (range 0.18-0.50) shortly before first signs of nephrogenic systemic fibrosis. Controls had been exposed to 0.28 mmol/kg (0.13-0.49). Cumulative gadodiamide exposure while in chronic kidney disease stage 5 was significantly higher among cases compared with controls (0.41 vs 0.31 mmol/kg, P = 0.05) and among severe cases (n = 9) compared with non-severe cases (0.49 vs 0.33 mmol/kg, P = 0.02). Severe cases developed primarily among patients in regular haemodialysis therapy at exposure. Cases had higher serum concentrations of ionized calcium and phosphate than controls and tended to receive higher doses of epoietin-beta than controls at time of exposure. Severe cases were treated with higher doses of epoietin-beta than non-severe cases at exposure (10.8 vs 4.4 10(3) IU/week, P = 0.02). CONCLUSIONS: Increasing cumulative gadodiamide exposure, high-dose epoietin-beta treatment, and higher serum concentrations of ionized calcium and phosphate increase the risk of gadodiamide-related nephrogenic systemic fibrosis in renal failure patients. Severe cases seem to develop primarily among patients in regular haemodialysis therapy at exposure.     

Recent topics related to nephrogenic systemic fibrosis associated with gadolinium‐based contrast agents

Nephrogenic systemic fibrosis is a progressive, potentially fatal, multiorgan‐system fibrosing disease related to exposure of patients with renal failure to gadolinium‐based contrast agents used in magnetic resonance imaging. Between 1997 and 2007, more than 500 cases of nephrogenic systemic fibrosis in patients with severe renal insufficiency (glomerular filtration rate less than 30 mL/min/1.73 m²) were reported, and no known cases of nephrogenic systemic fibrosis have occurred in patients with a glomerular filtration rate of more than 30 mL/min/1.73 m² without acute kidney injury. Additional major risk factors are use of high‐dose and specific gadolinium‐based contrast agents, a pro‐inflammatory state. Although the mechanism of nephrogenic systemic fibrosis is unclear and there is no consistently‐effective therapy, nephrogenic systemic fibrosis is an entity that can be eliminated by observing recent recommended guidelines for gadolinium‐based contrast agents and nephrogenic systemic fibrosis. This article reviews current knowledge about nephrogenic systemic fibrosis and focuses mainly on how to prevent it.     

Nephrogenic systemic fibrosis, in patients with end-stage kidney disease on dialysis, in the greater Auckland region, from 2000-2006

Aim: Nephrogenic systemic fibrosis (NSF) is a rare and serious disease characterised by thickening and hardening of the skin with fibrosis of the dermis with CD34‐positive fibrocytes. NSF occurs in patients with renal failure and has been linked to exposure of gadolinium contrast agents. The Auckland region has a population of 1.3 million with consultation and dialysis services for patients with end stage kidney disease provided by two separate renal units. The aim of this study was to determine the incidence and frequency of NSF in the Auckland region and determine the risk based on exposure to gadolinium based contrast agents. Methods: A retrospective case notes review of all patients with end stage kidney disease under the care of the renal services between 1^st January 2000 and 31^st December 2006 was undertaken. All cases of proven or suspected NSF were identified. Using a picture archive and communications support system all imaging and exposure to contrast was identified. Results: Three cases of biopsy proven NSF and two further cases of clinical NSF were identified. In all cases there was exposure to Gadolinium. This risk of NSF on exposure to any gadolinium based contrast agents was 0.67%. Gadodiamide was used in one institution where all five cases of NSF were seen, gadodiamide was used in 1% of patients in the other institution with no recognised cases. Conclusion: The incidence of NSF is low with the greatest risk on exposure to linear, non‐ionic chelates, with no ethnic predisposition.     

Gadolinium-induced nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis is a new disease whose incidence has peaked and receded over the past decade. It occurs in the presence of significant renal impairment, either acute or chronic (MDRD creatinine clearance of <30 mL/min/1.73 m(2)), and is associated with the administration of gadolinium-based contrast (GBC). Since 2006, the incidence of this disease has decreased markedly in patients with renal impairment, mainly owing to protocols that have not administered GBC to patients with creatinine clearances of less than 30 mL/min/1.73 m(2), and in some cases with the use of less toxic and lower doses of GBC. The purpose of this article is to review the current status of GBC use for imaging in patients with kidney disease.     

Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure.

BACKGROUND: Nephrogenic systemic fibrosis is a debilitating disease occurring exclusively in patients with renal failure. The aetiology of nephrogenic systemic fibrosis is unclear, but recent reports suggest that exposure to gadolinium for enhancement of magnetic resonance imaging may play a role. In the present study, we assessed the association of exposure to gadolinium with the development of nephrogenic systemic fibrosis in patients with various stages of chronic kidney disease. METHODS: We analysed the exposure to gadolinium and development of nephrogenic systemic fibrosis in 849 patients on renal replacement therapy over 5 years. We also performed inquiry of development of the nephrogenic systemic fibrosis in 592 patients exposed to gadolinium and estimated to be in stages 3 and 4 of chronic kidney disease. RESULTS: In 849 patients undergoing chronic dialysis from 2001 through 2006 time period, four of the 261 who had received gadolinium (1.5%) and none of the 588 not exposed to gadolinium developed clinically apparent disease. The odds ratio for developing nephrogenic systemic fibrosis was 6.671 [95% confidence interval (CI) 1.537-53.97] in patients with a single gadolinium exposure compared to patients without gadolinium exposure. This ratio increased to 44.5 (95% CI 2.362-2913) in patients with multiple gadolinium exposures compared to patients not receiving gadolinium. None of the 592 patients estimated to be in stage 3 or 4 of chronic kidney disease developed nephrogenic systemic fibrosis after exposure to gadolinium. CONCLUSION: Gadolinium exposure is associated with nephrogenic systemic fibrosis in patients on chronic renal replacement therapy at a low rate. This association appears to increase with repeated exposure to gadolinium. Since nephrogenic systemic fibrosis may be clinically occult, its prevalence may be higher than reported. Despite this association, it is unclear if gadolinium is the sole or most important factor in the pathogenesis of the disease.     

Clinical improvement of nephrogenic systemic fibrosis after kidney transplantation

Nephrogenic systemic fibrosis (NSF) has been observed with increased frequency in recent years. Progressive hardening of the skin advancing to severe woody induration and the development of thickened hyperpigmented plaques on the extremities and the trunk are the main clinical features. Further progression of the disease results in flexion contractures of the upper and lower extremities, resulting in immobilization and severe morbidity. In this study, we reviewed our experience with seven end-stage renal disease patients who were referred to our center between January 2004 and June 2005 for kidney transplant evaluation or for diagnosis and treatment of their deteriorating condition. Diagnosis in all patients was confirmed by skin and muscle biopsy. Three of these patients underwent renal transplantations, and softening of the skin and improved mobility of the joints was noted after kidney transplantation. Three of the four patients who remained on dialysis showed further deterioration of their NSF despite a trial of immunosuppressive therapy. Improvement after transplantation could be secondary to immunosuppression, increased renal clearance and/or more effective fluid management.     

Gadolinium and nephrogenic systemic fibrosis: an update

Nephrogenic systemic fibrosis (NSF) is a multisystem disease seen exclusively in patients with renal impairment. It can be severely debilitating and sometimes fatal. There is a strong association with gadolinium-based contrast agents used in magnetic resonance imaging (MRI). Risk factors include renal impairment and proinflammatory conditions, e.g. major surgery and vascular events. Although there is no single effective treatment for NSF, the most successful outcomes are seen following restoration of renal function, either following recovery from acute kidney injury or following renal transplantation. There have been ten biopsy-proved pediatric cases of NSF, with no convincing evidence that children have a significantly altered risk compared with the adult population. After implementation of guidelines restricting the use of gadolinium-based contrast agents in at-risk patients, there has been a sharp reduction in new cases and no new reports in children. Continued vigilance is recommended: screening for renal impairment, use of more stable gadolinium chelates, consideration of non-contrast-enhanced MRI or alternative imaging modalities where appropriate.     

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.     

Nephrogenic metaplasia: long-term haemodialysis and anuria as potential risk factors and reversibility with renal transplantation

AIM.: To determine the incidence of nephrogenic metaplasia in patientswith defunctionalized bladders due to long-term end-stage renalfailure on haemodialysis. METHODS.: From the dialysis registry of the Princess Alexandra Hospital13 anuric patients who had been on haemodialysis for 10 or moreyears were identified. Of these, seven were currently awaitingrenal transplantation and six had successful transplants. Endoscopicassessment of their lower urinary tracts was performed. RESULTS.: Three cases of nephrogenic metaplasia were identified. In onecase this led to significant haematuria following transplantation.However, the changes of nephrogenic metaplasia disappeared overthe subsequent 18 months without specific treatment. CONCLUSIONS.: It appears that a chronically defunctionalized bladder in thepresence of end-stage renal failure is associated with an increasedrisk of nephrogenic metaplasia. These changes may spontaneouslyregress following transplantation and restoration of bladderfunction.     

Gadolinium Is Not the Only Trigger for Nephrogenic Systemic Fibrosis: Insights From Two Cases and Review of the Recent Literature

Nephrogenic systemic fibrosis (NSF) is an emerging fibrosing disease with serious consequences in patients with acute and chronic kidney disease including solid organ and renal transplant recipients. It has recently been linked to gadolinium exposure. Almost all recently reported cases of NSF were found to be preceded by gadolinium administration, which led the FDA to issue a warning against the use of gadolinium in patients with moderate-to-severe reduction in the glomerular filtration rate. We report two organ transplant recipients who developed NSF and in whom extensive record review failed to document any prior gadolinium exposure. We then critically review the recently published literature linking NSF and gadolinium and we propose other possible triggers. We conclude that gadolinium is not the only trigger for NSF, and that the search for other triggers should be sought. We believe that this information is an important addition to the NSF literature, such that the definitive etiology and pathogenesis of NSF can be researched.     

Nephrogenic Systemic Fibrosis Among Liver Transplant Recipients: A Single Institution Experience and Topic Update

Nephrogenic systemic fibrosis (NSF) is a recently characterized systemic fibrosing disorder developing in the setting of renal insufficiency. NSF's rapidly progressive nature resulting in disability within weeks of onset makes early diagnosis important. Two reports of NSF after liver transplantation are known of. We present three cases of NSF developing within a few months after liver transplantation and review the current literature. Loss of regulatory control of the circulating fibrocyte, its aberrant recruitment, in a milieu of renal failure and a recent vascular procedure appear important in its development. Known current therapies lack consistent efficacy. Only an improvement in renal function has the greatest likelihood of NSF's resolution. Delayed recognition may pose a significant barrier to functional recovery in the ubiquitously deconditioned liver transplant patient. Early recognition and implementation of aggressive physical therapy appear to have the greatest impact on halting its progression.     

Chronic inflammation and accelerated atherosclerosis as important cofactors in nephrogenic systemic fibrosis following intravenous gadolinium exposure

Nephrogenic systemic fibrosis (NSF) is a rare disorder in patients with chronic kidney disease characterized by an increased tissue deposition of collagen. Its pathogenesis remains unclear. Prior studies indirectly suggested a possible impact of chronic inflammation and accelerated atherosclerosis—a common feature in kidney diseased patients—whereas recent data focused almost exclusively on gadolinium (Gd)-based MR contrast agents. Usually NSF develops a maximum of 2–3 months after Gd. Longer intervals have not yet been described. Therefore, we present the first case with an extraordinary long time course in terms of chronic inflammation. A 52-year-old Caucasian woman with end-stage renal disease was admitted to our hospital with progressive muscle weakness and skin induration resulting in growing immobility. Her past medical history revealed a secondary HPT, multiple vascular complications, a seronegative rheumatoid arthritis, and a pituitary gland adenoma. The latter conditions led to multiple MR examinations with Gd-based contrast agents, the last one more than 4 years ago. Numerous laboratory tests were performed including ESR, CRP, intact parathyroid hormone (iPTH), serum ferritin, cyclic-citrullinated peptide antibodies (CCP), ANA, ANCA, immunoelectrophoresis, and serology for hepatitis as well as human immunodeficiency virus. Eventually a skin biopsy of her left thigh was obtained. The laboratory investigation showed persistently elevated levels of CRP, ESR, serum ferritin, and iPTH, whereas all other parameters were inconspicuous. The hisology displayed typical signs of nephrogenic systemic fibrosis. NSF can occur at any time after Gd exposure in the long term. Gd is a necessary, but not the sole cause of NSF. Certain other cofactors such as chronic inflammation and accelerated atherosclerosis seem to be involved.     

功能磁共振成像诊断肝纤维化研究进展

肝纤维化（HF）是肝硬化发展的必经阶段,早期诊断与干预对于阻止其向肝硬化发展具有重要临床意义。近年来,功能磁共振成像（fMRI）的发展,使得MRI在观察HF形态学改变的同时,能够更全面地了解功能变化,利于早期诊断。本文对fMRI诊断HF的应用进展进行综述。