Nephrogenic systemic fibrosis: an emerging entity

Nephrogenic systemic fibrosis (NSF) is a progressive disorder which has been seen only in patients with chronic kidney disease. It is associated with fibrosis of the skin and connective tissue throughout the body. The skin thickens and becomes hard, rigid, and coarse, which severely restricts movement of the joints. It can also lead to widespread fibrosis of internal organs involving lungs, heart, diaphragm, esophagus, and skeletal muscle, and in some cases may lead to death. Based on case series reports and skin biopsy showing gadolinium (Gd) ions, NSF has been directly linked to Gd contrast exposure given during MRI/MRA. There are over 250 reported cases of NSF worldwide with hundreds still not reported or remaining undiagnosed. Symptoms of NSF appear within 2-75 days, with a mean of 25 days after exposure to Gd contrast. This disorder is not well understood, and more research is needed to obtain information about how Gd causes this condition. Currently there is no effective treatment, so prevention is the only way to avoid this serious illness.     

Nephrogenic systemic fibrosis and gadolinium-based contrast agents

The strong association between nephrogenic systemic fibrosis (NSF) and exposure to gadolinium-based contrast agents (GBCAs) has greatly affected the care of patients with kidney disease. NSF has been reported in patients with ESRD, CKD, and acute kidney injury (AKI). The majority of cases have occurred in patients with ESRD, but about 20% have been reported in patients with AKI or CKD stages 4 and 5. There is also a risk difference among GBCAs, with the Food and Drug Administration contraindicating 3 linear agents in patients at risk. Given the significant morbidity and mortality of NSF, it is imperative to identify individuals at risk. Although there are no data to support a role for hemodialysis (HD) in reducing the risk for NSF after administration of GBCAs, immediate HD is still recommended within 2 hours. Patients maintained on peritoneal dialysis seem to be at high risk and immediate HD is also recommended. However, this is not the current recommendation for CKD stages 4 and 5, especially with suspected lower risk of noncontraindicated agents. Individualized assessment is important and especially in those patients close to dialysis initiation. Instituting policies is important to address the imaging needs of patients with CKD and AKI while ensuring a balance between benefits and risks.     

Prognostic value of urinary kidney injury molecule 1, interleukin 18 and cystatin C as biomarkers for gadolinium-based contrast-induced nephropathy in the elderly patients

Objective To assess the prognostic values of urinary kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18) and cystatin C (Cys C) for gadolinium-based contrast-induced nephropathy (Gd-CIN) in the elderly patients. Methods A total of sixty elderly patients who underwent enhanced magnetic resonance imaging (MRI) using gadolinium-based contrast media (GBC) from December 2010 to December 2011 were enrolled. Serum and urine samples were collected before and after the procedure. The levels of urinary KIM-1, IL-18 and Cys C were measured by ELISA respectively. Serum and urine creatinine levels were measured by automatic biochemical analyzer. Results Among 60 patients, Gd-CIN was diagnosed in 8 (13.3%) patients. At 24 h after MRI in the Gd-CIN group, the levels of urinary KIM-1, IL-18 and Cys C were significantly increased compared with the baseline values. Compared with non-Gd-CIN group, the levels of urinary KIM-1, IL-18 and Cys C at 24 h and urinary IL-18 at 48 h after GBC administration were significantly increased (P＜0.05). There were no significant differences in levels of urinary KIM-1, Cys C at 48 h after GBC administration between Gd-CIN and non-Gd-CIN group (P＞0.05). Logistic regression analysis showed that the levels of urinary KIM-1 and IL-18 at 24 h after GBC injection were independent predictive biomarkers of Gd-CIN (OR＝1.612, 1.009, all P＜0.05). The predictable time of acute kidney injury onset determined by urinary KIM-1, IL-18 and Cys C levels was 24 h earlier than that by serum creatinine. Conclusion Urinary KIM-1, IL-18 and Cys C may be early predictive biomarkers of elderly Gd-CIN, which shows a good performance in early diagnosis of Gd-CIN as compared with serum creatinine.     

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.     

Good MRI images: to Gad or not to Gad?

Gadolinium-based magnetic resonance imaging (MRI) contrast agents (Gad-CA) were formerly considered as alternatives to X-ray-employed iodinated media. Although originally thought to be nonnephrotoxic and proven to be nonhazardous in a healthy population, the Gad-CA safety issue is progressively more controversial in the high-risk group of end-stage renal disease (ESRD) patients. Recently, Gad-CAs have not only been blamed for harmless side effects such as dizziness or nausea but also for much more severe complications such as acute renal failure, pancreatitis, or even the development of so-called “nephrogenic systemic fibrosis” in patients with renal failure, culminating in the prohibition of gadodiamide (Omniscan) administration in ESRD patients and, due to renal-organ immaturity, in newborns and infants up to 1 year old. This editorial is written to give insights into the molecular structure of Gad-CAs as well as into the potential biochemical pathomechanisms underlying the aforementioned severe clinical manifestations. Furthermore, a review about the latest literature on Gad-CA nephrotoxicity is provided. Potential risk factors are mentioned and strategies to avoid deterioration of renal function are presented. Cases with Gad-CA-associated adverse events should be adequately documented and reported appropriately. MRI professionals should collaborate closely with their colleagues from other medical specialties to identify patients with adverse events.     

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 fibrosing dermopathy in children

Nephrogenic fibrosing dermopathy (NFD) is an entity of unknown etiology that has only been reported in patients with impaired kidney function. It has characteristic diagnostic findings by skin biopsy and due to its systemic involvement in some reported cases, the term “nephrogenic systemic fibrosis” has been recently suggested as more appropriate for the nomenclature of this entity. There is no curative treatment currently available and very few cases have been reported in children. We hereby report two cases so as to alert pediatric health care providers about the existence of this disorder.     

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.     

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.     

Gadolinium and nephrogenic systemic fibrosis: association or causation

SUMMARY:   With widespread availability of magnetic resonance imaging (MRI), it has become standard practice for patients with severe renal impairment or previous severe reactions to iodine-containing contrast media to receive gadolinium-based MRI contrast agents instead of traditional radiographic contrast agents, particularly for magnetic resonance angiography. However, there is growing concern about the use of gadolinium contrast agents in the presence of severe renal insufficiency, because of increasing reports of nephrogenic fibrosing dermopathy (NFD)/nephrogenic systemic fibrosis (NSF), associated with the exposure to certain gadolinium-containing contrast agents. In this review we explore the causal link between gadolinium exposure and NSF, using an established system of epidemiological criteria proposed by Bradford Hill. Though the current evidence makes gadolinium a strong suspect as an aetiologic agent for NSF in the presence of severe renal failure, the die is not cast yet. At this stage there needs to be cautious approach to the use of gadolinium-containing contrast agents in the presence of severe renal failure (glomerular filtration rate <30 mL/min per 1.73 m²).     

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.     

载超顺磁性氧化铁高分子液态氟碳纳米粒的制备及体外显像

目的制备一种能同时用于超声造影及MR成像的多模态造影剂,观察其体外成像效果。方法采用双乳化法合成载超顺磁性氧化铁（SPIO）纳米颗粒及全氟己烷（PFH）的高分子微球（s-PFH／PLGA）,检测其一般特性及光声信号。对不同浓度的s—PFH／PLGA水囊模型进行超声显影,以JC200聚焦超声肿瘤治疗系统辐照后观察回声强度变化;对不同铁含量的s—PFH／PLGA进行MR成像。结果透射电镜下s—PFH／PLGA呈球形,SPIO颗粒均匀分布在外壳上,平均粒径（738．9±158．4）nm,平均电位（-15．9士6．9）mV,并检测到明显光声信号。体外超声显像中s—PFH／PLGA呈点状高回声,HIFU辐照后回声强度增强。s-PFH／PLGA在T2wI中呈负增强显像;随着铁含量增高,MRI信号呈降低趋势。结论成功制备的载SPIO及PFH多模态造影剂具有体外超声、MR显影功能。     

评价对比剂肾病患者继发终末期肾脏病的风险模型及应用性研究

目的搜集与对比剂肾病(CIN)相关的临床指标,构建评判该患者继发终末期肾脏病(ESRD)的风险性模型,并验证其应用性。方法连续性纳入CIN患者为研究队列,分析研究对象初始入院时的各项临床资料及实验室检查结果,并对其进行为期18个月的随访以确认预后,依据随访结果,进行远期风险性预测和相关危重度评判分析。结果本次研究纳入215例CIN患者,14例失访,19例随访期内进展至ESRD。Cox回归分析显示,近期重复接受造影、高MRS量表评分、高尿肾损伤分子-1(uKIM-1)含量、高尿微量蛋白(umAlb)含量、高尿中性粒细胞明胶酶相关脂质运载蛋白(uNGAL)含量为CIN患者发病18个月内继发ESRD的独立危险因素。以umAlb=36.80ng/ml、uNGAL=128.21ng/ml、uKIM-1=137.56pg/ml为临界值预测CIN患者进展至ESRD的ROC曲线下面积分别为0.746、0.756、0.768。结论本研究建立CIN患者继发ESRD的风险预测模型,并对相关危险因素进行了量化,进一步完善了CIN的诊疗体系。     

神经精神狼疮磁共振成像研究现状及进展

神经精神狼疮是系统性红斑狼疮的严重并发症之一,MRI可在一定程度上揭示其所导致的神经精神症状与脑部异常改变之间的联系。本文就MRI对于NPSLE的研究现状及进展进行综述。     

核磁共振成像在肝纤维化和肝硬化诊断应用中的研究现状

肝纤维化和肝硬化是一个慢性进展性的病理过程,评估肝纤维化程度对于临床治疗有重要意义.目前临床常用于评估肝纤维化程度的方式分为有创性和无创性两种方式.核磁共振成像作为一种无创性的评估方式有一定的应用前景.本文就核磁共振成像评估肝纤维化和肝硬化程度的临床应用现状作一综述.