Late Onset Nephrogenic Systemic Fibrosis in a Patient with Stage 3 Chronic Kidney Disease: a Case Report.

Nephrogenic systemic fibrosis (NSF) is a progressive systemic fibrosing disease that may occur after gadolinium contrast exposure. It can lead to severe complications and even death. NSF is highly prevalent among patients with advanced chronic kidney disease (CKD). In this report, however, we describe the case of a patient with NSF that occurred during early CKD. A 65-year-old man with stage 3a CKD was transferred to our hospital because of lower extremity edema. The medical history revealed that he was exposed to gadolinium 185 days earlier, and the result of his tibial skin biopsy was consistent with NSF. The patient underwent a combined therapy with ultraviolet-A1 phototherapy and methotrexate and steroid therapy for 6 months. The combined therapy stopped the systemic progression of NSF.

A unique case of nephrogenic systemic fibrosis from gadolinium exposure in a patient with normal eGFR.

A 57-year-old woman presented with swelling and thickening of the skin of the lower extremities. Three months prior to presentation, patient had MRI with gadolinium as part of an evaluation for suspected pancreatic malignancy. Creatinine levels at the time of gadolinium exposure were 0.9-1.2 mg/dL, with a corresponding estimated glomerular filtration rate of 64 mL/min/1.73m2 by modification of diet in renal disease equation. Twenty-four-hour urine creatinine clearance was performed as an outpatient following development of symptoms. This revealed a creatinine clearance of 23 mL/min, suggestive of advanced chronic kidney disease despite an estimated glomerular filtration rate of 64 mL/min/1.73m2 Skin biopsy was positive for sclerosing dermopathy. These findings, in addition to the temporal association with gadolinium exposure, led to the diagnosis of nephrogenic systemic fibrosis.

Erythema nodosum masking nephrogenic systemic fibrosis as initial skin manifestation.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a complication of the gadolinium-based contrast agent used in imaging studies. It is typically characterised by hard, erythematous and indurated skin plaques with surrounding subcutaneous oedema. Distinct papules and subcutaneous nodules can also be seen. Fibrocytes in NSF are immunohistochemically positive for CD34. CASE PRESENTATION: We present a case of NSF occurred after gadolinium exposure in which the initial presentation mimics an erythema nodosum (EN)-like picture. An initial skin biopsy showed EN. Subsequently the patient developed progressive skin and joints contracture. A repeated skin biopsy done three months later confirmed the diagnosis of NSF. As far as we are aware, this is the second reported case of NSF that mimicked the presentation of EN in the early phase of the disease. CONCLUSIONS: The appearance of EN-like disease can be one of the early manifestations of NSF. We hope that early recognition of this unusual presentation can alert the physician or nephrologist to the potential diagnosis of NSF.

[Cutaneous manifestations in renal diseases]. / Hautmanifestationen bei Nierenerkrankungen.

In addition to general skin changes like pallor or dryness and the frequent, often excruciating nephrogenic pruritus, specific diseases in patients with renal failure may occur. Acquired perforating dermatoses are usually also highly pruritic. Calciphylaxis is a severe disease with poor prognosis. Nonhealing wounds with superinfection and progression to sepsis are characteristic. Bullous lesions can be caused by disturbances in porphyrin metabolism. Nephrogenic systemic fibrosis is a disease which was first described in 2000. Its incidence is already on the decline. Furthermore, this article provides an overview of systemic diseases which have both skin symptoms and kidney changes. These include connective tissue diseases, vasculitis or sarcoidosis and amyloidosis. After a kidney transplantation, particular attention must be paid to the development of skin tumors and infections. The last part of this article is dedicated to genodermatoses with skin and renal involvement, where numerous causative mutations have already been characterized. Knowing the correlations of characteristic skin symptoms and specific, potentially life-threatening kidney disease is important in order to initiate further investigations and steps such as referral to nephrologists at an early stage.

Edema, Hyperpigmentation, Induration: 3 Skin Signs Heralding Danger in Patients on Maintenance Hemodialysis.

Skin changes are common in patients on dialysis. This study focused on putative associations of specific skin findings with comorbidities and mortality.We performed a retrospective analysis of data from 508 patients on maintenance hemodialysis therapy in 7 centers in the German State of North Rhine Westphalia. Data had been collected by interview, from patient files, and from targeted physical examination in an earlier prospective study screening hemodialysis patients for the presence of nephrogenic systemic fibrosis. While on dialysis, patients' extremities had been examined for any of the following: edematous skin at the lower extremities, hyperpigmentation, induration, and xerosis cutis. Our present data analyses focused on associated mortality and comorbidities.Five hundred eight patients (median age 71 years, range 20.0-95.9; n = 292 men) had agreed to participate in the initial study: 48% (n = 243) were diabetics and 46% (n = 232) had been diagnosed with coronary heart disease. On examination, 86% of patients (n = 439) presented with at least 1 of the prespecified skin changes. Skin edema (n = 89; 18%), hyperpigmentation (n = 74; 15%), and induration (n = 9; 2%) were independently associated with increased mortality over 24 months (P < 0.002, P < 0.030, and P < 0.020, respectively).In our study, prespecified skin changes indicated an increased mortality risk in patients on chronic hemodialysis. Routinely assessing the skin of dialysis patients represents a simple, reliable, and cost effective means of identifying those at greatest risk.

Do ASARM peptides play a role in nephrogenic systemic fibrosis?

Nephrogenic systemic fibrosis (NSF) is a devastating condition associated with gadolinium (Gd3+)-based contrast agents (GBCAs) in patients with kidney disease. The release of toxic Gd3+ from GBCAs likely plays a major role in NSF pathophysiology. The cause and etiology of Gd3+ release from GBCAs is unknown. Increased Acidic Serine Aspartate Rich MEPE-associated peptides (ASARM peptides) induce bone mineralization abnormalities and contribute to renal phosphate-handling defects in inherited hypophosphatemic rickets and tumor-induced osteomalacia. The proteolytic cleavage of related bone matrix proteins with ASARM motifs results in release of ASARM peptide into bone and circulation. ASARM peptides are acidic, reactive, phosphorylated inhibitors of mineralization that bind Ca2+ and hydroxyapatite. Since the ionic radius of Gd3+ is close to that of Ca2+, we hypothesized that ASARM peptides increase the risk of NSF by inducing release of Gd3+ from GBCAs. Here, we show 1) ASARM peptides bind and induce release of Gd3+ from GBCAs in vitro and in vivo; 2) A bioengineered peptide (SPR4) stabilizes the Gd3+-GBCA complex by specifically binding to ASARM peptide in vitro and in vivo; and 3) SPR4 peptide infusion prevents GBCA-induced NSF-like pathology in a murine model with increased ASARM peptide (Hyp mouse). We conclude ASARM peptides may play a role in NSF and SPR4 peptide is a candidate adjuvant for preventing or reducing risk of disease.

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.

Nephrogenic Systemic Fibrosis Manifesting a Decade After Exposure to Gadolinium.

IMPORTANCE: Nephrogenic systemic fibrosis (NSF) is a fibrosing skin disorder that develops in patients with kidney failure and has been linked to exposure to gadolinium-containing contrast agents. The time between exposure to gadolinium and the initial presentation of NSF is typically weeks to months but has been documented to be as long as 3½ years. We report a case of NSF developing 10 years after exposure to gadolinium. OBSERVATIONS: A long-term hemodialysis patient was exposed to gadolinium several times between 1998 and 2004 during magnetic resonance angiography of his abdominal vessels and arteriovenous fistula. In 2014, he was seen at our clinic with new dermal papules and plaques. Biopsy of affected skin showed thickening of collagen, CD34+ spindle cells, and increased mucin in the dermis, supporting the diagnosis of NSF. CONCLUSIONS AND RELEVANCE: The clinical history and histopathological features of this case support the diagnosis of NSF 10 years after exposure to gadolinium. Although the use of gadolinium contrast agents in patients with kidney failure has markedly decreased, patients with exposure to gadolinium years to decades previously may manifest the disease.

Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis.

The combined use of elemental bioimaging and speciation analysis is presented as a novel means for the diagnosis of nephrogenic systemic fibrosis (NSF), a rare disease occurring after administration of gadolinium-based contrast agents (GBCA) for magnetic resonance imaging (MRI), in skin samples of patients suffering from renal insufficiency. As the pathogenesis of NSF is still largely unknown particularly with regard to the distribution and potential retention of gadolinium in the human organism, a skin biopsy sample from a suspected NSF patient was investigated. The combination of inductively coupled plasma mass spectrometry (ICP-MS), laser ablation (LA) ICP-MS for quantitative elemental bioimaging, and hydrophilic interaction liquid chromatography (HILIC) ICP-MS for speciation analysis allowed one to unambiguously diagnose the patient as a case of NSF. By means of ICP-MS, a total gadolinium concentration from 3.02 to 4.58 mg/kg was determined in the biopsy sample, indicating a considerable deposition of gadolinium in the patient's skin. LA-ICP-MS revealed a distinctly inhomogeneous distribution of gadolinium as well as concentrations of up to 400 mg/kg in individual sections of the skin biopsy. Furthermore, the correlation between the distributions of phosphorus and gadolinium suggests the presence of GdPO4 deposits in the tissue section. Speciation analysis by means of HILIC-ICP-MS showed the presence of the intact GBCA Gd-HP-DO3A eight years after the administration to the patient. The concentration of the contrast agent in the aqueous extract of the skin biopsy was found to be 1.76 nmol/L. Moreover, evidence for the presence of further highly polar gadolinium species in low concentrations was found.

Fibrosis sistémica nefrogénica: la pandemia que no fue / Causal relationship between the use of gadolinium based contrast media and nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is a severe iatrogenic disease that affect patients with impaired renal function exposed to gadolinium-based contrast agents. Clinically, symptoms develop within days or weeks after the exposure and mimic a scleromyxedema. The causal relationship between use of gadolinium-based contrast agents and NSF led to develop clinical guidelines aiming to limit the use of this contrast medium in high risk patients. These guidelines decreased the incidence of NSF in the last years. Unfortunately there is no specific treatment for NSF yet. Thus, strict adherence to current guidelines is key to prevent new cases. Renal dysfunction is increasingly common in our population. Therefore, practicing physicians should be aware of this potential complication of the use of gadolinium based contrast media.

The differential diagnosis of systemic sclerosis.

PURPOSE OF REVIEW: The new American College of Rheumatology/European League Against Rheumatism classification criteria will enable earlier diagnosis and, therefore, the use of newer treatment modalities for systemic sclerosis (SSc). It is therefore critical to exclude non-SSc causes for diffuse skin thickening as early as possible. RECENT FINDINGS: The recently described gadolinium-induced nephrogenic systemic fibrosis may mimic SSc as may other conditions which require a different treatment strategy. Recently, treatment with immunoablation and autologous stem cell transplantation has been shown to significantly benefit some patients with conditions such as scleromyxoedema and SSc. The more accurate measurement of SSc-specific autoantibodies such as topoisomerase 1, centromere and RNA polymerase has recently allowed a more precise subclassification of SSc with implications for treatment and prognosis. SUMMARY: Skin thickening is a nonspecific manifestation of many different processes including (rarely) early scleroderma, which is mostly symmetrical and associated with Raynaud's phenomenon, nailfold capillaroscopic changes and antinuclear antibodies. If the latter three factors are absent, then other conditions must be excluded, the commonest being eosinophilic fasciitis. Skin biopsy (looking for eosinophil infiltration, increased mucin or amyloid deposition), SSc-specific autoantibodies or paraproteins in blood and a careful medical history and system screening will exclude nonscleroderma conditions.

Nephrogenic systemic fibrosis in the podiatric patient.

Nephrogenic systemic fibrosis (NSF) is a severely debilitating disease that was first described in the literature by Cowper and colleagues in 2000. It is pertinent to the field of podiatry because patients with NSF first manifest cutaneous symptoms in the lower extremity in the form of fibrosing lesions. To date, these lesions have been documented only in people with moderate to severe kidney failure. There is speculation that gadolinium, used as a contrast agent for imaging, might be the inciting factor that triggers a cascade of events that results in the inappropriate fibrosis both in the dermis and in deeper tissues. Nephrogenic systemic fibrosis has been shown to cause these lesions in the lungs, pleura, diaphragm, myocardium, pericardium, and dura mater, the presence of which are typically indicative of severe progression of NSF. In cases where the lesions are manifest in the periarticular tissue, joint contractures and restricted range of motion can often result. We provide a quick synopsis of NSF, and a short case study that describes the authors' experience with one of their patients who requested a surgical consult as a result of being wheelchair-bound due to NSF's sequelae.

Nephrogenic systemic fibrosis: concepts and perspectives / Fibrose nefrogênica sistêmica: conceitos e perspectivas

Nephrogenic systemic fibrosis is a chronic, progressive condition that develops in some patients with renal impairment after exposure to gadolinium-based contrast agents used in magnetic resonance imaging. Thickening of the skin is typical, usually affecting the extremities. Visceral organs can also be affected. The diagnosis of the disease requires careful clinicopathological correlation. Treatment aims at restoring renal function, which is associated with delayed progression and, eventually, remission of skin changes. Reduction and prevention of nephrogenic systemic fibrosis cases are based on limiting the use of gadolinium-based contrast agents in patients with kidney disorders (especially in patients with advanced renal failure at stages 4 and 5), and restricting their use to situations in which they are essential to diagnosis/follow-up. Other than limiting exposure to gadolinium based contrast agents, no effective preventive methods have been reported. Due to increased awareness about the disease among radiologists and nephrologists, the incidence of nephrogenic systemic fibrosis is declining.

Fibrose nefrogênica sistêmica é condição crônica, progressiva, desenvolvida caracteristicamente em pacientes nefropatas após exposição a contrastes radiológicos que contenham gadolínio. O espessamento cutâneo é aspecto típico, envolvendo predominantemente as extremidades. Envolvimento visceral pode ocorrer. O diagnóstico da doença requer cuidadosa correlação clínico-patológica. O tratamento visa à restauração da função renal, que se associa ao retardo da progressão e, eventualmente, remissão das alterações cutâneas. A prevenção da ocorrência e redução da incidência baseiam-se na limitação do uso de contrastes à base de gadolínio em nefropatas (especialmente na insuficiência renal avançada em estágios 4 e 5), restringindo-os às condições nas quais seja imprescindível ao diagnóstico/acompanhamento. À exceção da restrição de exposição aos agentes de contraste a base de gadolínio, não há métodos preventivos efetivos relatados. Devido à ampla divulgação da doença entre radiologistas e nefrologistas, a incidência da fibrose nefrogênica sistêmica está em declínio.

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.

Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines.

PURPOSE: To retrospectively determine the incidence of nephrogenic systemic fibrosis (NSF) in a large academic medical center after the adoption of restrictive gadolinium-based contrast agent (GBCA) administration guidelines. MATERIALS AND METHODS: For this retrospective HIPAA-compliant study, institutional review board approval was obtained and the requirement for informed consent was waived. Restrictive GBCA guidelines were adopted in May 2007. The guidelines (a) require a recent serum creatinine level measurement in any patient who is aged 60 years or older and/or at risk for renal disease, (b) limit the maximal weight-based GBCA dose administered to any patient with an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/m(2) to 20 mL, and (c) prohibit the administration of any GBCA in patients who have an eGFR lower than 30 mL/min/m(2) and/or are undergoing chronic dialysis treatment (except in emergency situations). The electronic medical records were searched for all contrast material-enhanced magnetic resonance (MR) imaging examinations performed during the post-guidelines adoption period between January 2008 and March 2010 and the pre-guidelines adoption and transitional period between January 2002 and December 2007. Separate pathology records were searched for biopsy-confirmed cases of NSF during the same study periods. The incidences of NSF during the pre-guidelines adoption and transitional period and post-guidelines adoption period were compared by using the paired Z test. RESULTS: A total of 52,954 contrast-enhanced MR examinations were performed during the post-guidelines adoption period. Of these 52,954 examinations, 46,464 (88%) were performed in adult patients with an eGFR of 60 mL/min/m(2) or higher or presumed normal renal function and 6454 (12%) were performed in patients with an eGFR of 30-59 mL/min/m(2). Thirty-six patients with an eGFR lower than 30 mL/min/m(2) underwent contrast-enhanced MR imaging for emergent indications. Review of the pathology records for January 2008 to September 2010 revealed no new cases of NSF resulting from GBCA exposure. CONCLUSION: After restrictive guidelines regarding GBCA administration were instituted, no new cases of NSF were identified among 52,954 contrast-enhanced MR examinations, including those performed in patients with an eGFR lower than 60 mL/min/m(2).

[Kidney and iodinated and gadolinium-based contrast agents]. / Rein et produits de contraste iodés et gadolinés.

UNLABELLED: In patients with renal failure, iodinated contrast agents may cause acute deterioration of the renal function and gadolinium-based contrast agents (GBCAs) may cause nephrogenic systemic fibrosis (NSF). The administration of a contrast agent must thus be reviewed for each patient and evaluation of renal function is paramount even though its estimation using formulas derived from the creatinine level may fluctuate. For iodinated contrast agents, contrast induced nephropathy is reduced by hydratation, preferably intravenous, when the GFR is less than 60 ml/min. The risk for intravenous injections is less than the risk for arterial injections, and the GFR threshold may be reduced to 45 ml/min. For gadolinium-based contrast agents, patients at risk for NSF are those with end-stage renal disease and patients undergoing dialysis. In such cases, the injection of a gadolinium-based contrast agent is only considered after a risk-benefit analysis has been completed, an alternate linear or macrocyclic agent issued and the dose limited to 0,1 mmol Gd/kg. Recently, recommendations from US and European agencies have converged. LEARNING OBJECTIVES: to be familiar with the risk factors of CIN with iodinated contrast agents; to be familiar with hydration procedures for patients at risk of CIN; to be familiar with the diagnostic criteria of NSF; to be familiar with the classification of GBCA with regards to the risk of NSF; to be familiar with the contraindications of the different groups of GBCA.

[Imaging and renal failure: from inflammation to fibrosis]. / Imagerie et insuffisance rénale: de l'inflammation à la fibrose.

Multiple chronic renal diseases evolve to end-stage kidney disease due to progressive renal tissue fibrosis at the level of the interstitium or glomeruli. Fibrosis often results from transformation of the extracellular matrix by cytokines and chemokines released by activated cells in the setting of recurrent episodes of acute inflammation. Newer techniques to image intrarenal inflammation and fibrosis are mandatory for the non-invasive evaluation of these processes to improve follow-up and monitoring of drug therapy. These techniques are based on methods of cellular and molecular imaging, and methods of functional, such as diffusion weighted imaging, and structural, such as elastography.

Detection of iron deposition in dermal fibrocytes is a useful tool for histologic diagnosis of nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis (NSF) is a fibrotic disease that presents with a history of renal dysfunction. The differential diagnosis generally includes scleromyxedema, systemic sclerosis, and morphea. Especially, scleromyxedema can be extremely difficult to distinguish microscopically. Although the fibrocytes in NSF are often positive for CD34 and procollagen-I, this is not specific for NSF. We identified positive iron staining in the skin of a patient with NSF and investigated whether this was a specific feature among 9 patients with NSF reported in Japan. We found that 6 of 9 patients showed positive iron staining in the dermal fibrocytes. The amount of iron deposition seemed to have no correlation with the degree of fibrosis or duration of the skin lesions but correlated with apparent history of the use of gadolinium-based contrast agents. As controls, skin biopsies from patients with scleromyxedema, morphea, and systemic sclerosis were evaluated by iron staining. None of these control patients showed iron deposition, indicating that positive iron staining may be specific to NSF and can be a useful tool for NSF diagnosis.