Nephrogenic Systemic Fibrosis Is Mediated by Myeloid C-C Chemokine Receptor 2.

Gadolinium-based contrast agents are implicated in several pathologic abnormalities (long-term retention in vital organs such as the skin and the brain) and are the cause of a sometimes fatal condition in patients, nephrogenic systemic fibrosis. Bone marrow-derived fibrocytes and the monocyte chemoattractant protein-1 inflammatory pathway have been implicated as mediators of the adverse effects induced by gadolinium-based contrast agents. Mechanistic studies are scant; therefore, a mouse model of nephrogenic systemic fibrosis was established. Dermal cellularity was increased in contrast-treated green fluorescent protein (GFP) chimeric mice. GFP in the skin and fibrosis were increased in the contrast-treated chimeric animals. Monocyte chemoattractant protein-1 and C-C chemokine receptor 2 were increased in the tissues from contrast-treated mice. C-C chemokine receptor 2-deficient recipients of GFP-expressing marrow had an abrogation of gadolinium-induced pathology and displayed less GFP-positive cells in the skin. Wild-type animals that received C-C chemokine receptor 2-deficient bone marrow had a complete abrogation of dermal pathology. That GFP levels and expression increase in the skin, in tandem with a fibrocyte marker, supports the blood-borne circulating fibrocyte hypothesis of the disease. As of now, fibrocyte trafficking has yet to be demonstrated. Importantly, our data demonstrate that the monocyte chemoattractant protein-1/C-C chemokine receptor 2 axis plays a critical role in the pathogenesis of nephrogenic systemic fibrosis.

Gadolinium-Induced Nephrogenic Systemic Fibrosis.

The column in this issue is supplied by Anita H. Shah, M.D., and Juan Jose Olivero, M.D. Dr. Shah obtained her medical degree at The University of Texas Medical Branch in Galveston and is currently an internal medicine resident at Houston Methodist Hospital. Dr. Olivero is a nephrologist at Houston Methodist Hospital and a member of the hospital's Nephrology Fellowship Training Program. He obtained his medical degree from the University of San Carlos School of Medicine in Guatemala, Central America, and completed his residency and nephrology fellowship at Baylor College of Medicine in Houston, Texas.

Incidence of Nephrogenic Systemic Fibrosis Using Gadobenate Dimeglumine in 1423 Patients With Renal Insufficiency Compared With Gadodiamide.

OBJECTIVE: The purpose of this study was to assess the incidence of nephrogenic systemic fibrosis (NSF) before and after educational interventions, implementation of a clinical screening process, and change to gadobenate dimeglumine in patients who had an estimated glomerular filtration rate (eGFR) of 30 mL/min per 1.72 m or less. METHODS: This is a Health Insurance Portability and Accountability Act compliant, institutional review board exempt study. Two periods were studied-July 2005 to June 2006, during which gadodiamide was utilized as our magnetic resonance (MR) contrast agent, and November 2006 to August 2014, during which gadobenate dimeglumine was used as our MR contrast agent in patients who had an eGFR 30 mL/min per 1.72 m or less. In addition to a change in the MR contrast agent, education of our staff physician to the risks of NSF with MR contrast agents and the implementation of a clinical screening process occurred. The rate of NSF before and after the interventions was compared using the χ test. RESULTS: There was a statistically significant difference in the incidence of NSF in patients with an eGFR 30 mL/min per 1.72 m or less between the 2 periods: July 2005 to June 2006, 6 of 246 patients were diagnosed with NSF (P < 0.001), versus November 2006 to August 2014, 0 of 1423 patients were diagnosed with NSF. CONCLUSIONS: Our data demonstrates a marked decrease in the incidence of NSF after education of our referring physicians, implementation of clinical screening process, and change to gadobenate dimeglumine from gadodiamide in patients with renal insufficiency. This approach potentially provides an acceptable risk-benefit profile for patients with renal insufficiency that required MR imaging for clinical care.

Dermatologic Manifestations in End-stage Renal Disease.

End-stage renal disease (ESRD) is a rapidly growing global health problem within the past decades due to increased life expectancy, diabetes mellitus, hypertension, and vascular diseases. Since ESRD is not curable definitively, patients suffering from ESRD have a very low quality of life; therefore, symptomatic management is the cornerstone of medical treatment. Uremia affects almost all body organs, such as skin, through different mechanisms including biochemical, vascular, neurologic, immunologic, hematologic, endocrine, and electrolyte and volume balance disturbances. Some of these conditions are associated with significant morbidity, and patients with ESRD commonly present with a spectrum of dermatologic disorders. Each one has its own unique presentation and treatment approaches. In this review article, we discuss the clinical presentation, pathophysiology, and treatment of the most common skin disorders associated with ESRD.

Superior vena cava obstruction associated with nephrogenic systemic fibrosis.

A 56-year-old woman with hypertension-induced end stage renal disease presented with skin thickening and mottled discoloration. Cutaneous biopsy showed increased dermal fibroblasts embedded in fibromyxoid stroma with scattered perivascular and interstitial mononuclear cells. Immunohistochemistry revealed prominent CD34+ dendritic cells in septal spaces, consistent with Nephrogenic Systemic Fibrosis (NSF). Seven years and two years prior she had received a gadolinium-based contrast agent (GBCA). She died due to NSF. Gross autopsy revealed a thickened and stenotic superior vena cava (SVC). Extensive fibrosis of the SVC, dermis, and subcutaneous tissue was noted, together with hyalinized collagen fibers within the muscular wall of the intestines and dura mater. These findings support the importance of skin changes in the recognition of life threatening extracutaneous tissue involvement in NSF.

Localized cutaneous fibrosing disorders.

This article acquaints the reader with disorders of the skin that might mimic systemic sclerosis but whose pathology is localized to the skin and/or has extracutaneous manifestations that are different than systemic sclerosis. These disorders include localized scleroderma (morphea), eosinophilic fasciitis, scleredema, scleromyxedema, nephrogenic systemic fibrosis, and chronic graft-versus-host disease. Particular emphasis is placed on clinical and histopathologic features that help the clinician differentiate between these disorders. Treatment options are briefly reviewed.

Gadolinium in pediatric cardiovascular magnetic resonance: what we know and how we practice.

BACKGROUND: The association of gadolinium-based contrast agents (GBCAs) with nephrogenic systemic fibrosis (NSF) has led to a heightened awareness towards patients' renal function. Whereas detailed guidelines exist for the use of GBCAs in adult patients, best practice is less well defined in children, especially in the very young. We aimed at identifying current practice with regards to the use of GBCAs in children who undergo cardiovascular magnetic resonance. METHODS: We conducted a worldwide survey among cardiac imagers with pediatric expertise. The questionnaire contained 21 questions covering the imagers' work environments, GBCAs used, monitoring of renal function, and a special emphasis was placed on the practice in neonates. RESULTS: The survey yielded 70 replies. The single most commonly used GBCA was gadopentetate dimeglumine 34/70 (49%). Among the respondents, the choice of GBCA was more importantly based on availability 26/70 (37%) and approval by a pharmaceutical licensing body that most closely reflects the indication 16/70 (23%) than image quality 7/70 (10%) and side effect profile 8/70 (11%). 55/70 (79%) of respondents performed scans in neonates <1 week of age and 52/55 (95%) of them used GBCA in neonates. 65/70 (93%) respondents at least assess some of their patients' renal functions. Formula-based estimate of glomerular filtration rate is the most popular assessment method 35/65 (54%). In patients with a glomerular filtration rate < 30 ml/min/1.73 m(2) 62/70 (89%) of respondents do not administer gadolinium at all. The single most common side effect of gadolinium was noted to be nausea/emesis 34/57 (60%) followed by discomfort at injection site 17/57 (30%). CONCLUSIONS: Cardiac imagers are aware of the immature renal function and physiological differences of their pediatric patients that place them at risk for NSF. Epidemiological data is needed for pediatric cardiovascular licensure of gadolinium compounds and for the creation of practice guidelines which will replace current-day practice based on individual clinical judgment.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Gadolinio y fibrosis sistémica nefrogénica / Gadolinium and nephrogenic systemic fibrosis

Inicialmente llamada dermopatía fibrosante nefrogénica, la fibrosis sistémica nefrogénica (FSN) está fuertemente ligada a la inyección endovenosa de medios de contraste -basados en gadolinio- en pacientes con insuficiencia renal. En esta revisión corta se analiza la fisiopatología y la clínica, la responsabilidad del radiólogo en la prevención a través de la puesta en práctica de las reglamentaciones vigentes y, por último, se mencionan algunos conceptos sobre el tratamiento de los pacientes con insuficiencia renal crónica que deben exponerse a la inyección de gadolinio...

Contrast-induced nephropathy and nephrogenic systemic fibrosis: minimizing the risk.

INTRODUCTION: Contrast-enhanced cross-sectional imaging is essential to the urologist's practice. Traditionally, patients with impaired renal function could not be imaged with a computed tomography (CT) scan with contrast due to the risk of contrast-induced nephropathy (CIN). These patients could alternatively be imaged by magnetic resonance imaging (MRI) with gadolinium. However, the recent identification of the association between nephrogenic systemic fibrosis (NSF) and gadolinium administration has created significant challenges for urologists and radiologists when faced with the need for evaluation with contrast-enhanced cross-sectional imaging. In this review, we summarize the most comprehensive articles discussing both NSF and CIN and present a straightforward, evidence-based algorithm to determine the appropriate approach to cross-sectional imaging for all patients, as well as future directions regarding cross-sectional imaging. MATERIALS AND METHODS: A MEDLINE literature search for review articles from 1966 to August 2009 was performed. Selected additional articles for specific topics were also reviewed. This search yielded a total of 25 articles for NSF and 28 for CIN that were reviewed. RESULTS: The pathophysiology and risk factors of NSF and CIN are discussed, as well as potential interventions to decrease either morbidity or incidence. A multidisciplinary (urologist, nephrologist, radiologist) evidence-based algorithm is introduced for managing patients in need of cross-sectional imaging. CONCLUSIONS: The associated risks of contrast-enhanced, cross-sectional imaging has created significant challenges for urologic evaluation. We propose an evidence-based approach to guide patient therapy, which can minimize patient risk and physician anxiety, while simplifying the decision-making process.

Nephrogenic systemic fibrosis: review of 370 biopsy-confirmed cases.

Discovery of an association between gadolinium-based contrast agents (GBCAs) and nephrogenic systemic fibrosis (NSF) has led to less use of GBCA-enhanced magnetic resonance imaging in dialysis patients and patients with severe renal failure at risk of NSF, and the virtual elimination of new cases of NSF. But shifting patients with renal failure to alternative imaging methods may subject patients to other risks (e.g., ionizing radiation or iodinated contrast). This review paper examines 370 NSF cases reported in 98 articles to analyze NSF risk factors. Eliminating multiple risk factors by limiting GBCA dose to a maximum of 0.1 mmol/kg, dialyzing patients undergoing dialysis quickly following GBCA administration, delaying GBCA in acute renal failure until after renal function returns or dialysis is initiated, and avoiding nonionic linear GBCA in patients with renal failure especially when there are proinflammatory conditions may substantially reduce the risk of NSF.

Pathomechanisms of nephrogenic systemic fibrosis: new insights.

Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is a generalized fibrotic disorder occurring in people with renal failure, following exposure to gadolinium-based contrast agents used to enhance MRI. The cellular elements involved in pathology of NSF include bone-marrow-derived collagen-producing fibrocytes, myofibroblasts and activated macrophages. Mechanisms that have been hypothesized to play a role in the pathogenesis of NSF include upregulation of osteopontin, imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinase 1, and presence of transforming growth factor-ß, nuclear factor κB, decorin and metallothioneins. Gadolinium (both free and chelated) is thought to be a bioactive trigger for NSF. Elucidation of these potential pathomechanisms would be useful for development of targeted therapies for NSF.

Update on nephrogenic systemic fibrosis: are we making progress?

Nephrogenic systemic fibrosis is a rare fibrosing disorder associated with the use of gadolinium-based contrast agents in patients with renal dysfunction. However, only a small proportion of at-risk patients develops the disorder, and the exact determinants of disease are still not completely clear. Here, we present an update on emerging evidence for the role of gadolinium-based contrast agents, renal dysfunction, and background inflammation in disease expression, with a focus on current experimental models. Based on these findings, significant progress has been made in our understanding of the pathophysiology of this disorder over the last few years. This review provides a summary of these developments with discussion of the implications for clinical practice and directions for additional study.

[Nephrogenic systemic fibrosis]. / Fibrose systémique néphrogénique.

Nephrogenic systemic fibrosis is a recently described entity that occurs in patients with advanced renal failure. Its cause is probably toxic. The patients develop skin thickening, which is usually symmetrical on the limbs and sometimes extend to the trunk. Joint contractures and muscle sclerosis confine the patients to wheelchair. Systemic involvement may occur and includes cardiomyopathy, pulmonary fibrosis and diaphragmatic paralysis. The diagnosis is confirmed by the association of skin fibrosis and a cellular infiltration composed of CD34+ fibrocytes. Prognosis is severe with many deaths, rarely directly related to the disease. An improvement of lesions is possible, especially in case of resolution of the renal insufficiency. Several treatments have been evaluated, but none has shown consistent benefit. The toxic culprit is likely to be the gadolinium ions (Gd(+++)), released from some contrast agents used in nuclear magnetic resonance imaging. Evidence of the responsibility of Gd(+++) is based on epidemiologic, biochemical and experimental data. Recommendations have been published for patients with renal insufficiency requiring a nuclear magnetic resonance imaging. If they are followed and efficient, it is likely that nephrogenic systemic sclerosis will disappear.

Immunohistochemical aspects of the fibrogenic pathway in nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis (NSF) is a rare gadolinium-dependent disorder of the skin and viscera. The aim of this study was to revisit some immunopathologic clues of NSF, including the characterization of glycosaminoglycans, cell tensegrity, and cell proliferation in the dermis. Immunohistochemistry was done using antibodies directed to vimentin, CD34, Factor XIIIa, calprotectin, α-smooth muscle actin, Ulex europaeus agglutinin-1 (UEA-1), and MIB1/Ki67 and to glycosaminoglycans, including CD44 var3, versican, and perlecan. The vimentin+ cell density was markedly increased. The vast majority of them corresponded to CD34+ or Factor XIIIa+ dermal dendrocytes (DD) showing distinct cell tensegrity. CD34+DD were slender, elongated, and usually scattered in the dermis but focally clustered in nodular collections. By contrast, Factor XIIIa+ was plump with squat dendrites showing no evidence for being under mechanical stress. Cells in the vicinity of the microvasculature were rounded and exhibited calprotectin immunoreactivity typical for monocyte/macrophages. The microvasculature highlighted by UEA-1 and α-smooth muscle actin looked unremarkable. The cell proliferation highlighted by the MIB/Ki67 immunoreactivity was unusually high (>20%) in the interstitial stromal cells. Stromal cells enriched in versican were plump, abundant, and seemed interconnected each other by a dense network of dendrites. By contrast, the immunolabeling for perlecan and CD44 var 3 was unremarkable. In conclusion, the cell population involved in NSF seemed phenotypically heterogeneous, and its growth fraction was clearly boosted in the skin. The intracellular load in versican was prominent. The aspect of cell tensegrity did not suggest the influence of mechanical stress putting stromal cells under tension in the dermis.

Nephrogenic systemic fibrosis. A debilitating disease causing fibrosis of the skin and inner organs in patients with kidney failure.

Nephrogenic systemic fibrosis (NSF) is a rare and debilitating disease which affects patients with kidney failure. The most obvious manifestation is fibrosis of the skin, but it also frequently involves the locomotor system and the inner organs. An association has been found with the administration of gadolinium-containing contrast agents, which are given to provide enhanced contrast during magnetic resonance imaging. It is thought that unstable chelate complexes release toxic gadolinium. Other triggers or co-triggers may also be relevant. No effective treatment currently exists for NSF, so prevention of the disease is of the utmost importance. If gadolinium-containing contrast agents need to be administered to patients who have kidney failure, a cyclic agent should be used, and the dosage should be as low as possible. Although no proof is yet available that hemodialysis prevents NSF, it is effective in the clearance of gadolinium and should therefore be considered as a treatment immediately after the imaging.