Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration.

Gadolinium-based contrast agents (GBCAs) have transformed magnetic resonance imaging (MRI) by facilitating the use of contrast-enhanced MRI to allow vital clinical diagnosis in a plethora of disease that would otherwise remain undetected. Although over 500 million doses have been administered worldwide, scientific research has documented the retention of gadolinium in tissues, long after exposure, and the discovery of a GBCA-associated disease termed nephrogenic systemic fibrosis, found in patients with impaired renal function. An understanding of the pharmacokinetics in humans and animals alike are pivotal to the understanding of the distribution and excretion of gadolinium and GBCAs, and ultimately their potential retention. This has been well studied in humans and more so in animals, and recently there has been a particular focus on potential toxicities associated with multiple GBCA administration. The purpose of this review is to highlight what is currently known in the literature regarding the pharmacokinetics of gadolinium in humans and animals, and any toxicity associated with GBCA use.

Gadolinium Deposition and Nephrogenic Systemic Fibrosis: A Radiologist's Primer.

Gadolinium-based contrast agents (GBCAs) have an excellent safety profile. However, over the last 2 decades, two specific concerns have surfaced. GBCAs are associated with nephrogenic systemic fibrosis (NSF) and tissue retention of gadolinium. NSF is a rare fibrosing disorder with a poor prognosis, which is characterized by skin and subcutaneous thickening as well as systemic manifestations. The disease has been reported exclusively in patients with advanced renal disease, and it is associated with higher doses and specific types of GBCAs. The number of new cases of NSF has fallen over the past decade, presumably because of adherence by health care providers to regulatory guidelines, which continue to evolve. While gadolinium retention has been known to occur in the liver and bones, the relatively recent findings of deposition and retention in the brain have reignited the debate concerning the safety profile of GBCAs. Despite these concerns, there have been no proven health effects related to gadolinium deposition and retention other than NSF. The authors review the different categories of GBCAs available for commercial use, discuss NSF and gadolinium retention in the brain, and provide updates on the latest U.S. and European regulatory guidelines regarding use of these agents. Given the frequency with which GBCAs are used in clinical practice, it is imperative for all radiologists to learn the current guidelines to provide the safest and highest quality of patient care. ©RSNA, 2019.

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.

Nephrogenic systemic fibrosis: A 15-year retrospective study at a single tertiary care center.

BACKGROUND: Despite multiple therapeutic approaches for nephrogenic systemic fibrosis (NSF), no single treatment has convincingly shown consistent benefit. The most successful outcomes have been associated with recovery of renal function, although evidence remains limited and past studies have been inconclusive. OBJECTIVE: We sought to investigate whether improvement of renal function via successful transplantation or via return of renal function after acute kidney injury correlates with improvement of NSF, and to further characterize the clinical features and progression of NSF. METHODS: A retrospective medical chart review led to the identification of patients (n = 8) diagnosed with NSF who presented to a single academic tertiary referral center over a 15-year period. These 8 patients were contacted by phone to obtain information related to treatment and clinical course of their NSF and renal function. Statistical analysis was performed using Fisher's exact test. RESULTS: There is a significant correlation (P = .0286) of improved renal function with improvement of NSF. All 4 patients who had improvement of renal function also had improvement of NSF. Two of these patients had end-stage renal disease and a successful kidney transplant, and two had acute kidney injury that resolved. No improvement in NSF was observed without kidney function resolution. LIMITATIONS: Our study is limited by a small sample size (n = 8) and a retrospective study design, which increased its potential for selection and recall bias. CONCLUSION: Improvement of renal function through either transplantation or resolution of acute kidney injury with medical management is significantly associated with improvement of NSF.

Biological effects of MRI contrast agents: gadolinium retention, potential mechanisms and a role for phosphorus.

No discussion of challenges for chemistry in molecular imaging would be complete without addressing the elephant in the room-which is that the purest of chemical compounds needs to interact with a biological system in a manner that does not perturb normal biology while still providing efficacious feedback to assist in diagnosis of disease. In the past decade, magnetic resonance imaging (MRI) agents long considered inert have produced adverse effects in certain patient populations under certain treatment regimens. More recently, inert blood pool agents have been found to deposit in the brain. Release of free metal is often suspected as the culprit but that hypothesis has yet to be validated. In addition, even innocuous agents can cause painful side effects during injection in some patients. In this brief review, we summarize known biological effects for gadolinium- and iron-based MRI contrast agents, and discuss some of the potential mechanisms for the observed biological effects, including the potential role of phosphorus imbalance, related to kidney disease or cancer, in destabilizing gadolinium-based chelates and precipitating free gadolinium.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

[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.

Skin manifestations of chronic kidney disease.

Skin manifestations associated with chronic kidney disease are very common. Most of these conditions present in the end stages and may affect the patient's quality of life. Knowledge of these entities can contribute to establishing an accurate diagnosis and prognosis. Severe renal pruritus is associated with increased mortality and a poor prognosis. Nail exploration can provide clues about albumin and urea levels. Nephrogenic systemic fibrosis is a preventable disease associated with gadolinium contrast. Comorbidities, such as diabetes mellitus and secondary hyperparathyroidism, can lead to acquired perforating dermatosis and calciphylaxis, respectively. Effective and innovative treatments are available for all of these conditions.

Nephrogenic systemic fibrosis is associated with hypophosphataemia: a case-control study.

OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is an iatrogenic fibrosing disorder that primarily affects individuals with chronic kidney disease (CKD) following exposure to gadolinium-based contrast agents (GBCAs). Derangements of calcium and phosphorus have been reported in patients with NSF. The aim of this study was to investigate potential factors in addition to GBCA exposure that may be involved in the pathogenesis of NSF. We hypothesized that patients with stage 5 CKD and NSF would manifest greater alterations in calcium, phosphorus and fibroblast growth factor 23 (FGF23) levels than those who do not have NSF. METHODS: Levels of phosphorus, calcium, FGF23 and 25-hydroxy-vitamin D were measured in 10 patients with stage 5 CKD and biopsy-proven NSF and in 19 patients with stage 5 CKD without NSF. Statistical analyses were performed using Fisher's exact test for categorical variables and the Kruskal-Wallis test for continuous variables. RESULTS: Patients with NSF had significantly lower phosphorus levels compared with controls (P = 0.01). There were no significant differences between NSF patients and controls in calcium, 25-hydroxy-vitamin D, intact parathyroid hormone or FGF23 levels. CONCLUSION: Differences in phosphorus metabolism may exist between patients with stage 5 CKD and NSF compared with patients with stage 5 CKD without NSF.

Role of endothelin-1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis (NSF) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)-containing contrast agents used for magnetic resonance imaging trigger the development of NSF. However, the causative role of Gd and the mechanism of Gd-induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin-1 (ET-1)/ET receptor (ETR) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET-1/ETR signalling in Gd-induced fibrosis and calcification in NSF. First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue-derived mesenchymal stem cells (hMSC) in vitro. Next, we examined the expression of ET-1 and ETR-A in hMSC using proliferation or calcification assay. ET-1 and ETR-A expression in hMSC treated with Gd were elevated. ET-1/ETR signalling inhibitor, bosentan, inhibited Gd-induced proliferation and calcification of hMSC. In addition, bosentan inhibited Gd-induced phosphorylation of ERK and Akt in hMSC. Plasma ET-1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR-A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET-1/ETR signalling. Our results contribute to understand the pathogenesis of NSF.

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.

Appropriate and safe use of diagnostic imaging.

Risks of diagnostic imaging include cancer from radiation exposure and nephrogenic systemic fibrosis. The increase in volume of imaging between 1980 and 2006 has led to a sixfold increase in annual per capita radiation exposure. It is predicted that 2 percent of future cancers will be caused by radiation from computed tomography (CT) exposure. Gadolinium contrast media should be avoided in patients with stage 4 or 5 chronic kidney disease because of the risk of nephrogenic systemic fibrosis. Appropriate use of imaging based on guidelines for specific clinical conditions can reduce these risks. Although noncontrast CT of the head is needed to rule out bleeding in patients with suspected stroke within the first three hours of symptom onset, diffusion-weighted imaging with magnetic resonance of the head and neck is superior to CT within three to 24 hours of symptom onset. Headache merits neuroimaging in special circumstances only. Sestamibi radioisotope has less radiation than thallium for myocardial perfusion imaging. Use of intravenous contrast media with abdominopelvic CT significantly increases the diagnostic accuracy for appendicitis. Cholescintigraphy has better discrimination to diagnose acute cholecystitis than CT in patients with equivocal ultrasonography results. Limited three-view intravenous urography is recommended in pregnancy to evaluate urolithiasis if initial ultrasonography findings are negative or equivocal. Given that many asymptomatic adults have abnormal findings on lumbar spine magnetic resonance imaging, this modality generally should not be performed for nonspecific chronic low back pain in the absence of red flags. Whole body scanning is not supported by current evidence.

Selected skin diseases with systemic involvement.

The skin is often a window to systemic disease that is available to the trained eye of the dermatologist. Herein, we focus on four dermatoses with associated systemic conditions of interest: scleromyxedema and monoclonal gammopathy, nephrogenic systemic fibrosis in the setting of renal insufficiency, dermatitis herpetiformis and celiac disease, and psoriasis as a risk factor for cardiovascular disease. Dermatologists can play a crucial role in recognizing the cutaneous manifestations linked with these conditions. Identifying the related underlying disorder will contribute to appropriate diagnosis and improved management.

Scleroderma mimics.

Scleroderma is a rare systemic autoimmune disease with multiple organ manifestations, including skin fibrosis. The groups of disorders classified as scleroderma mimics share the common thread of skin thickening but are otherwise quite incongruous in terms of underlying disease process and other organ involvement. This article reviews the clinical presentation, etiology, and treatment options available for scleroderma mimics, including morphea, scleredema, diabetic cheiroarthropathy, scleromyxedema, nephrogenic systemic fibrosis, and eosinophilic fasciitis. Through greater understanding of these diseases and the associated extradermal implications, we hope to facilitate recognition of scleroderma and its mimics.

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 m(2)) 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 m(2) 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 with Osseous Metaplasia in a Kidney-Pancreas Transplant Patient.

A French (Caucasian) woman with a history of nonobstructive hypertrophic cardiopathy, type 1 diabetes mellitus, cataract, and ante-hypophysary insufficiency had undergone multiple magnetic resonance imaging (MRI) studies. She had developed end-stage renal disease (ESRD) and had undergone hemodialysis for 10 years before receiving a kidney-pancreas allotransplantation at the age of 48 years. She received antithymocyte globulins as induction immunosuppression and steroids (5 mg/d), mycophenolate mofetil (2 g/d), and tacrolimus (5 mg/d) as maintenance immunosuppression. Following transplantation, she underwent a cerebral MRI with injection of a gadolinium-based contrast agent (GBCA) in the work-up for Schwartz-Bartter syndrome. Shortly thereafter, she progressively developed cutaneous infiltration, sclerosis, and hyperpigmentation on her extremities and back (Figure 1), firm nodules on the thighs and the right hand, and confluent papules on the back, all of which were asymptomatic. She had no facial involvement, sclerodactyly, periungual telangiectasias, Raynaud syndrome, or arthralgias. Histologic examination showed mild epidermal hyperplasia and a thickened dermis containing several fibroblasts and some histiocytes (Figure 2a). The alcian blue stain revealed increased dermal mucin deposits (Figure 3b). Remarkably, several round-to-ovoid, well-limited yellowish collagenous structures containing basophilic (elastic) fibers were seen in the dermis (Figures 2b, 2c, 3a, and 4a). These "elasto-collagenous balls" stained blue with Masson's trichrome stain (Figure 4c); the orcein stain confirmed the presence of elastic fibers within them (Figure 4b). Some orange-yellow elasto-collagenous balls contained osteocytes, indicative of osseous metaplasia (Figure 5); these were von Kossa stain-positive, highlighting calcium deposition (Figure 4d). Immunohistochemically, the dermal fibroblasts were variably CD34-positive. Factor XIIIa+ dermal dendrocytes and histiocytic, occasionally multinucleated, CD68+ cells were also seen. (SKINmed. 2022;20:145-148).

An Unusual Case of Deep Localized Scleroderma in a Patient with Chronic Kidney Disease.

Localized scleroderma (LS) is a rare fibrosing disorder of skin and underlying tissues. Although it can affect all races, it has a higher prevalence in whites. Deep LS is the least common among seven LS variants, representing less than 5% of cases, and typically affects areas of pressure such as the hips and waist. We report a unique clinical case of bilateral lower extremity deep LS in a 51-year-old Puerto Rican woman with chronic kidney disease (CKD). In patients with CKD, it is important to distinguish LS from nephrogenic systemic fibrosis (NSF). Both can present with skin fibrosis and contractures over joints yet have significantly differing treatment approaches and prognosis. Our case report is unique due to the patient's Puerto Rican ethnicity, CKD history, and isolated anterior lower extremity involvement. In this report, we highlight key clinical and histopathological findings of LS, and how they differ from that of NSF.

Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations.

BACKGROUND: The condition that came to be known as nephrogenic systemic fibrosis (NSF) was first reported in 2000 and, in 2001, was termed "nephrogenic fibrosing dermopathy." Since then, NSF has been the subject of a wide-ranging multidisciplinary medical investigation that has proven an indisputable link to renal disease and a compelling association with the increasing use of gadolinium-containing magnetic resonance imaging contrast agents in the renally impaired. OBJECTIVE: Although precise causation and risk factors continue to be elucidated, the need for reproducible prospective epidemiologic data demands clear and objective criteria for the diagnosis of NSF. METHODS: Experts in NSF diagnosis used their experience and the resources of the Yale International NSF Registry to develop a clinicopathological diagnostic system for NSF. RESULTS: A consensus scoring system incorporating a clinical and histopathological atlas was devised to guide and standardize the evaluation and diagnosis of NSF. LIMITATIONS: There is no laboratory test that can be used as a gold standard to diagnose NSF. To overcome this, we relied on classic clinicopathological presentations, published sources, and consensus clinical expertise to ensure the integrity of the study population. CONCLUSION: The clinicopathological definition of NSF provides guidance to physicians for the evaluation and diagnosis of NSF. Clinical, laboratory, and histopathological features comprise a schema that excludes conditions mimicking NSF while facilitating its reproducible and accurate diagnosis, even among physicians with little prior clinical experience with this entity. This definition can serve as a working diagnostic standard for future research and as the basis for adjudicating borderline cases.

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.