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A small proportion of nephropathy patients administered gadolinium contrast agents for nuclear magnetic resonance have been reported to develop nephrogenic systemic fibrosis (NSF). This paper introduces the mechanism of the transformation and deposition of NSF, aiming to reveal the chemical nature of the gadolinium phosphate bioparticles in nephrogenic system fibrosis. This research will provide an important theoretical basis for future studies on the occurrence, development, and formation of nephrogenic system fibrosis and the removal of sediment residues. Moreover, a new idea for introducing a biocompatible second chelating agent into the gadolinium contrast agent system has been proposed, which aims to improve the safe use of gadolinium contrast agent. [ABSTRACT FROM AUTHOR]

Keloidal scleroderma is a variant of scleroderma that presents as firm keloidal nodules or plaques. Due to the similarity in morphology and pathology, it is often distinguished from a hypertrophic scar or keloid. We report a case of keloidal scleroderma with rare nodular and diffuse spindle cell infiltration in histopathology. Recognition of this unusual histopathological feature may help clinicians improve their knowledge and avoid misdiagnosis.

Background: The risk of gadolinium (Gd)-based contrast agent (GBCA)-induced nephrogenic systemic fibrosis (NSF) in patients with end-stage renal disease (ESRD) and the efficacy of prophylactic hemodialysis (HD) for protection against NSF are not well understood or summarized in the literature. Purpose: To determine the risk for NSF related to frequency and time per dialysis session after Gd-magnetic resonance imaging (MRI) by emphasizing the safety of Gd-MRI in patients with ESRD. Material and Methods: This retrospective observational study identified all GBCA injections for MRI examinations performed at two tertiary referral hospitals between 2005 and 2020. All clinical data, including dialysis records and medical history, were investigated for each patient through 2021. The end of follow-up coincided with the last hospital visit. Results: Overall, 1129 patients with ESRD underwent 1461 Gd-MRI scans (41.5% gadoterate, 39.4% gadobutrol, and 7.7% gadoxetate); a total of 958 patients with 1229 (84.1%) examinations underwent HD on the day of the MRI study, within 2.1 ± 2.0 h (range = 0.2–15.7 h) immediately after Gd exposure. In 53.4% of scans, frequent HD had been performed urgently and then twice more on consecutive days to prophylactically avoid NSF. No cases of NSF were identified during the follow-up period (mean = 81.7 ± 50.5 months) regardless of dose of HD. Conclusion: No cases of NSF were reported in 1461 Gd-MRI examinations of 1129 inpatients with ESRD on HD. Our findings support the lack of benefit of frequent prophylactic HD being performed urgently within 4 h of the receipt of GBCA. [ABSTRACT FROM AUTHOR]

Intravenous administration of gadolinium-based contrast agents (GBCA) in patients with impaired renal function has been of concern to primary care physicians due to the potential worsening of renal dysfunction and nephrogenic systemic fibrosis (NSF). Our objective was to compare the potential change in estimated glomerular filtration rate (eGFR) in patients with known severe renal dysfunction (eGFR <30 ml/min), following Gadoterate meglumine (GM) administration with patients who do not receive contrast. An IRB-approved retrospective analysis of all patients who underwent MRI examination at our institution, for any indication, between January 2016 and September 2020. Inclusion criteria: pre-MRI eGFR <30 ml/min within 24 h of MRI, follow-up eGFR between 48 and 96 h post-MRI, and absence of peritoneal or hemodialysis. The individuals who received GM (492 scans) were identified as cases, and those who did not receive contrast (1101 scans) were identified as controls for our study. Delta-eGFR response was calculated and covariate-adjusted, and propensity score analysis was performed. No significant eGFR decrease was observed in patients who received GM compared to those who did not receive GM in our study. Also, no relationship between comorbidity, severity and contrast selection was observed. The use of Gadolinium contrast in MRI is often of critical importance for determining accurate anatomic relationships, differentiation of benign from malignant lesions, or determination of resolving vs. worsening disease. Though the risk of contrast administration can never be entirely ignored, especially in patients with low eGFR, our study indicates that safe administration of GM can be performed even in patients with severe kidney disease. • The use of Gadolinium contrast in an MRI exam is often of critical importance for determining accurate anatomic relationships, differentiation of benign from malignant lesions, or determination of resolving vs. worsening disease. • Though the risk of contrast administration can never be entirely ignored, especially in patients with low eGFR, safe administration of Gadoterate meglumine can be performed even in patients with severe kidney disease. • No significant eGFR decrease was observed in patients who received Gadoterate meglumine compared to those who did not receive Gadoterate contrast material. There is no relationship between comorbidity, severity, and contrast selection. • The benefits are clear and of significant impact in numerous clinical situations where safe contrast-MRI protocols in this severe kidney disease population can be established especially in situations where contrast administration is crucial in patient diagnosis and management. [ABSTRACT FROM AUTHOR]

Gadolinium-enhanced cardiac magnetic resonance has revolutionized cardiac imaging in the last two decades and has emerged as an essential and powerful tool for the characterization and treatment guidance of a wide range of cardiovascular diseases. However, due to the high prevalence of chronic renal dysfunction in patients with cardiovascular conditions, the risk of nephrogenic systemic fibrosis (NSF) after gadolinium exposure has been a permanent concern. Even though the newer macrocyclic agents have proven to be much safer in patients with chronic kidney disease and end-stage renal failure, clinicians must fully understand the clinical characteristics and risk factors of this devastating pathology and maintain a high degree of suspicion to prevent and recognize it. This review aimed to summarize the existing evidence regarding the physiopathology, clinical manifestations, diagnosis, and prevention of NSF related to the use of gadolinium-based contrast agents. [ABSTRACT FROM AUTHOR]

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'.

Since its introduction more than 35 years ago, gadolinium-enhanced MRI has fundamentally changed medical practice. Although extraordinarily safe, gadolinium-based contrast agents (GBCAs) may have side effects. Four distinct safety considerations include acute allergiclike reactions, nephrogenic systemic fibrosis (NSF), gadolinium deposition, and symptoms associated with gadolinium exposure. Acute reactions after GBCA administration are uncommon-far less than with iodinated contrast agents-and, although rare, serious reactions can occur. NSF is a rare but serious sclerodermalike condition occurring in patients with kidney failure after exposure to American College of Radiology (ACR) group I GBCAs. Group II and III GBCAs are considered lower risk, and, through their use, NSF has largely been eliminated. Unrelated to NSF, retention of trace amounts of gadolinium in the brain and other organs has been recognized for over a decade. Deposition occurs with all agents, although linear agents appear to deposit more than macrocyclic agents. Importantly, to date, no data show any adverse biologic or clinical effects from gadolinium deposition, even with normal kidney function. This article summarizes the latest safety evidence of commercially available GBCAs with a focus on new agents, discusses updates to the ACR NSF GBCA safety classifications, and describes approaches for strengthening the evidence needed for regulatory decisions.

Gadolinium (Gd) is one of the rare-earth elements. The properties of its trivalent cation (Gd3+) make it suitable to serve as the central ion in chelates administered intravenously to patients as a contrast agent in magnetic resonance imaging. Such Gd-chelates have been used for more than thirty years. During the past decades, knowledge has increased about potential harmful effects of Gd-chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially disabling and lethal disease, nephrogenic systemic fibrosis. Restricting the use of Gd-chelates in persons with severely impaired renal function has decreased the occurrence of this toxic effect in the last decade. There has also been an increasing awareness of Gd-retention in the body, even in patients without renal dysfunction. The cumulative number of doses given, and the chemical structure of the chelate given, are factors of importance for retention in tissues. This review describes the chemical properties of Gd and its medically used chelates, as well as its toxicity and potential side effects related to injection of Gd-chelates. [ABSTRACT FROM AUTHOR]

Revealing the anatomical structures, functions, and distribution of vasculature via contrast agent (CA) enhanced magnetic resonance imaging (MRI) is crucial for precise medical diagnosis and therapy. The clinically used MRI CAs strongly rely on Gd‐chelates, which exhibit low T1 relaxivities and high risks of nephrogenic systemic fibrosis (NSF) for patients with renal dysfunction. It is extremely important to develop high‐performance and safe CAs for MRI. Herein, it is reported that ultra‐small NaGdF4 nanoparticles (UGNs) can serve as an excellent safe MRI CA via surface engineering with rationally designed novel hydrophilic block co‐polymer (BPn). By optimizing the polymer molecular weights, the polymer‐functionalized UGNs (i.e., UGNs‐BP14) are obtained to exhibit remarkably higher relaxivity (11.8 mm–1 s–1 at 3.0 T) than Gd‐DTPA (3.6 mm–1 s–1) due to their ultracompact and abundant hydrophilic surface coating. The high performance of UGNs‐BP14 enables us to sensitively visualize microvasculature with a small diameter of ≈0.17 mm for up to 2 h, which is the thinnest blood vessel and the longest time window for low field (1.0 T) MR angiography ever reported, and cannot be achieved by using the clinically used Gd‐DTPA under the same conditions. More importantly, renal clearable UGNs‐BP14 show lower risks of inducing NSF in comparison with Gd‐DTPA due to their negligible release of Gd3+ ions after modification with the novel hydrophilic block copolymer. The study presents a novel avenue for boosting imaging‐performance and systemic biosafety of UGNs as a robust MRI CA with great potential in precise diagnosis of vasculature‐related diseases. [ABSTRACT FROM AUTHOR]

Objectives: Gadoxetic acid (GA) is a half-biliary excreted gadolinium-based contrast agent (GBCA) administered at lower dose than gadobenic acid with similar ionic structure. Gadobenic acid is considered low-risk for nephrogenic systemic fibrosis (NSF) in patients with impaired renal function; however, safety of GA is unclear. The objective of this study was to determine the incidence of NSF in oncology patients undergoing GA-enhanced MRI and to update the risk estimate of NSF in patients receiving GA with severe renal impairment. Materials and methods: We retrospectively identified GA-enhanced MRI performed for treatment planning in confirmed cancer patients between March 2011 and December 2020. Serum creatinine values within 180 days of GA administration were retrieved and estimated glomerular filtration rate (eGFR) calculated. The eGFR value nearest to each MRI examination was used. The search result was linked to a prospectively maintained registry of reported cases of NSF. An updated literature review was conducted to identify published cases of NSF related to GA administration in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2 or on dialysis) and the incidence of NSF with 95% confidence intervals (CI) was determined combining published data with our results. Results: 192 oncology patients underwent GA-enhanced MRI, mean age was 65.6 ± 11.8 years with 73 women. The mean eGFR was 89.6 ± 33.0 mL/min/1.73 m2. There were 33 patients with moderate (eGFR 30–60 mL/min/1.73 m2) and 1 patient with severe (eGFR < 30 mL/min/1.73 m2) renal impairment. There were no reported cases of NSF. Updated literature review including our results identified 340 patients with severe renal impairment or on dialysis with zero cases of NSF (0/340; 95% confidence intervals 0% and 0.9%). Conclusion: No cases of NSF were documented in this study related to gadoxetic acid use in oncology patients, including those with moderate and severe renal impairment. Recent data indicate use of gadoxetic acid in patients with renal impairment can be considered low-risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The purpose of this study was to systematically search for long-term complications, including Nephrogenic Systemic Fibrosis (NSF), in patients who were previously administered the gadolinium-based contrast agent Gadofosveset at our institute. All patients who were administered Gadofosveset at our institute between 2006 and 2009 were identified in our Radiological Information System (RIS). Clinical data such as cause of death during follow-up, and dermatological or nephrological diseases were systematically searched for in electronic patient records (EPR). During 2006–2009, Gadofosveset was administered a total of 67 times to 62 patients. One patient was unavailable for follow-up. The remaining 61 patients were followed up for up to 14 (median 12) years based on RIS and EPR data. There were 13 deaths among the 61 patients, all assessed as unrelated to Gadofosveset administration. No dermatological or renal disease suggestive of NSF, or potentially related to Gadofosveset administration, was found. At the time of examination, six patients were diagnosed with various stages of renal insufficiency, three of whom were on hemodialysis. Another three patients were diagnosed with renal insufficiency during the follow-up period, but none of these diagnoses were suspected to be related to the administration of Gadofosveset. Based on the results of this retrospective safety analysis of up to 14 years following 1–2 exposures, we conclude that Gadofosveset in clinical practice is safe in the long-term. [ABSTRACT FROM AUTHOR]

Gadolinium retention in the brain and other organs has recently been identified by imaging and confirmed histologically. No direct clinical effects of gadolinium retention, which occurs after gadolinium-based contrast agent (GBCA) administration for MRI, have been scientifically accepted at this time. However, there is understandable concern among medical professionals and the public about the potential effects of gadolinium retention, particularly in the brain. Part of this concern might stem from the identification of nephrogenic systemic fibrosis caused by GBCAs in people with severe renal failure in 2006. This article briefly describes the characteristics of GBCAs; reviews and differentiates gadolinium retention, nephrogenic systemic fibrosis, and "gadolinium deposition disease" or "gadolinium toxicity"; and discusses societal guidelines and current usage in children. With the belief that GBCAs should not be withheld for appropriate indications in the absence of evidence of its potential risks, we offer a framework for determining when GBCA use is appropriate and suggestions for discussing its risks and benefits with children and their families. [ABSTRACT FROM AUTHOR]

Purpose: To assess the risk of nephrogenic systemic fibrosis (NSF) in patients with renal impairment undergoing gadoxetic acid-enhanced magnetic resonance imaging. Methods: This retrospective study included patients who had an estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m2 or had undergone dialysis around the time of gadoxetic acid exposure from January 2010 to November 2019. All patients received at least one intravenous injection of gadoxetic acid at a fixed dose of 2.5 mmol. The primary endpoint was the development of NSF after exposure to gadoxetic acid based on Girardi's clinicopathological scoring system. Results: A total of 204 patients with renal impairment received 424 injections of gadoxetic acid, of which 131 and 54 had an eGFR of 30–59 and < 30 mL/min per 1.73 m2, respectively, and 19 had undergone hemodialysis. Eighty-two patients received multiple injections, with 23 receiving five or more injections. The dose of each exposure ranged from 0.02 to 0.07 mmol/kg and the cumulative doses ranged from 0.02 to 0.45 mmol/kg. Thirty-three patients had concomitant Child–Pugh class B or C cirrhosis. No NSF was detected during follow-up (median 20 months; range 6 days to 111 months). The upper bound of the 95% confidence interval for NSF risk was 2.2% and 1.1% per patient and examination, respectively. Conclusion: No NSF was detected in this study. However, it is premature to ascertain the risk of NSF using gadoxetic acid in patients with renal impairment and further studies are warranted. [ABSTRACT FROM AUTHOR]

PurposeTo determine the risk of nephrogenic systemic fibrosis (NSF) in a cohort of patients with chronic liver disease.Materials and methodsThis retrospective, Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study was performed at a single tertiary liver center. The study cohort comprised 1167 patients with chronic liver disease followed in a liver clinic and exposed to gadolinium-based contrast agents (GBCAs) between February 2004 and October 2007. A retrospective review of medical records was performed. For each patient, data were collected on demographics, history of GBCA exposure, presence of purported risk factors for NSF, and histopathological evidence of NSF.ResultsOf the 1167 patients with chronic liver disease, 58% (n = 678) had cirrhosis. The patients had a total of 2421 separate GBCA exposures. Fifty-five percent (n = 646) had a single exposure, 19% (n = 218) had two exposures, and 26% (n = 303) had three or more exposures. Seventy-two percent (n = 843) of patients had renal insufficiency, 25 patients (2.1%) had hepatorenal syndrome, 80 patients (6.8%) were in the perioperative liver transplant period, and 49 patients (4.2%) had one or more additional risk factors for NSF. None of the 1167 patients developed NSF.ConclusionChronic liver disease does not appear to be a significant risk factor for NSF.

Gadolinium-enhanced cardiac magnetic resonance has revolutionized cardiac imaging in the last two decades and has emerged as an essential and powerful tool for the characterization and treatment guidance of a wide range of cardiovascular diseases. However, due to the high prevalence of chronic renal dysfunction in patients with cardiovascular conditions, the risk of nephrogenic systemic fibrosis (NSF) after gadolinium exposure has been a permanent concern. Even though the newer macrocyclic agents have proven to be much safer in patients with chronic kidney disease and end-stage renal failure, clinicians must fully understand the clinical characteristics and risk factors of this devastating pathology and maintain a high degree of suspicion to prevent and recognize it. This review aimed to summarize the existing evidence regarding the physiopathology, clinical manifestations, diagnosis, and prevention of NSF related to the use of gadolinium-based contrast agents.

Purpose: Low molecular weight iron(III) complex‐based contrast agents (IBCA) including iron(III) trans‐cyclohexane diamine tetraacetic acid [Fe(tCDTA)]− could serve as alternatives to gadolinium‐based contrast agents in MRI. In search for IBCA with enhanced properties, we synthesized derivatives of [Fe(tCDTA)]− and compared their contrast effects. Methods: Trans‐cyclohexane diamine tetraacetic acid (tCDTA) was chemically modified in 2 steps: first the monoanhydride of Trans‐cyclohexane diamine tetraacetic acid was generated, and then it was coupled to amines in the second step. After purification, the chelators were analyzed by high‐performance liquid chromatography, mass spectrometry, and NMR spectrometry. The chelators were complexed with iron(III), and the relaxivities of the complexes were measured at 0.94, 1.5, 3, and 7 Tesla. Kinetic stabilities of the complexes were analyzed spectrophotometrically and the redox properties by cyclic voltammetry. Results: Using ethylenediamine (en) and trans‐1,4‐diaminocyclohexane, we generated monomers and dimers of tCDTA: en‐tCDTA, en‐tCDTA‐dimer, trans‐1,4‐diaminocyclohexane‐tCDTA, and trans‐1,4‐diaminocyclohexane‐tCDTA‐dimer. The iron(III) complexes of these derivatives had similarly high stabilities as [Fe(tCDTA)]−. The iron(III) complexes of the trans‐1,4‐diaminocyclohexane derivatives had higher T1 relaxivities than [Fe(tCDTA)]− that increased with increasing magnetic field strengths and were highest at 6.8 L·mmol−1·s−1 per molecule for the dimer. Remarkably, the relaxivity of [Fe(en‐tCDTA)]+ had a threefold increase from neutral pH toward pH6. Conclusion: Four iron(III) complexes with similar stability in comparison to [Fe(tCDTA)]− were synthesized. The relaxivities of trans‐1,4‐diaminocyclohexane‐tCDTA and trans‐1,4‐diaminocyclohexane‐tCDTA‐dimer complexes were in the same range as gadolinium‐based contrast agents at 3 Tesla. The [Fe(en‐tCDTA)]+ complex is a pH sensor at weakly acidic pH levels, which are typical for various cancer types. [ABSTRACT FROM AUTHOR]

Gadolinium-based contrast agents (GBCAs) have been used to improve image quality of MRI examinations for decades and have an excellent overall safety record. However, there are well-documented risks associated with GBCAs and our understanding and management of these risks continue to evolve. The purpose of this review is to discuss the safety of GBCAs used in MRI in adult and pediatric populations. We focus particular attention on acute adverse reactions, nephrogenic systemic fibrosis and gadolinium deposition. We also discuss the non-GBCA MRI contrast agent ferumoxytol, which is increasing in use and has its own risk profile. Finally, we identify special populations at higher risk of harm from GBCA administration. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a systemic autoimmune condition of unknown cause. Yes-Associated Protein/Tafazzin (YAP/TAZ) are transcriptional coactivators previously demonstrated to be involved in cellular stretch biology, and form the principal effector molecules of the Hippo signalling pathway. The association between YAP/TAZ and stretch is contingent upon their cytoplasmic localisation (with nuclear translocation, the cell adopts a relaxed state). The author weighs the evidence for a central role for YAP/TAZ signalling in scleroderma spanning the major clinical features of the condition. Several of the features unique to SSc are mediated by cytoplasmic localisation of YAP/TAZ, including the stretch phenotype (through binding to NF-2), arterial lumenal obliteration (through their binding to angiomotin), the promotion of hypergammaglobulinaemia (via feedback to the upstream Hippo signalling molecule Mammalian Ste20-like Kinase 1), and the induction of B-Lymphocyte-Induced Maturation Protein-1 leading to the adoption of Th2 lineage, prominent in SSc. One observes that the induction of the fibrotic phenotype of scleroderma is mediated through GLI1/GLI2 (the effector molecules of the Hedgehog pathway). GLI1/GLI2 are induced to reciprocally enter the nucleus when YAP/TAZ is intracytoplasmic. The latter explains the characteristically increased connective tissue growth factor 2 and endothelin-1 expression. In this article, the author references some examples of the role of YAP/TAZ in the biophysically similar condition nephrogenic systemic fibrosis and suggests a role of YAP/TAZ cytoplasmic sequestration in programmed cell death protein 1-ligand antagonist-induced scleroderma.

Gadolinium (Gd) is one of the rare-earth elements. The properties of its trivalent cation (Gd3+) make it suitable to serve as the central ion in chelates administered intravenously to patients as a contrast agent in magnetic resonance imaging. Such Gd-chelates have been used for more than thirty years. During the past decades, knowledge has increased about potential harmful effects of Gd-chelates in patients with severe renal dysfunction. In such patients, there is a risk for a potentially disabling and lethal disease, nephrogenic systemic fibrosis. Restricting the use of Gd-chelates in persons with severely impaired renal function has decreased the occurrence of this toxic effect in the last decade. There has also been an increasing awareness of Gd-retention in the body, even in patients without renal dysfunction. The cumulative number of doses given, and the chemical structure of the chelate given, are factors of importance for retention in tissues. This review describes the chemical properties of Gd and its medically used chelates, as well as its toxicity and potential side effects related to injection of Gd-chelates.