Coexistence of nephrogenic systemic fibrosis and calciphylaxis in a gadolinium-naïve, chronic haemodialysis patient.

We present a case of a man in his 40s who was on haemodialysis for over 20 years presenting with rapidly progressive decline in mobility, associated with fixed flexion deformities of joints and peau d'orange appearance of skin together with areas of ulceration that was concerning for calciphylaxis. Skin biopsies were consistent with both nephrogenic systemic fibrosis and calciphylaxis. He has never had exposure to gadolinium-based contrast agent. His treatment included daily dialysis sessions, which were challenging due to vascular access issues and three times weekly sodium thiosulfate. He rapidly declined in hospital and died within 2 weeks of presentation while being treated for a hospital-acquired pneumonia.

NSF evaluation of gadolinium biodistribution in renally impaired rats: Using novel metabolic Gd2O3 nanoparticles coated with ß-cyclodextrin (Gd2O3@PCD) in MR molecular imaging.

The use of conventional gadolinium(Gd)-based contrast agents in magnetic resonance imaging (MRI) poses a significant risk of Nephrogenic Systemic Fibrosis (NSF) syndrome in patients with impaired renal function (grades 4 and 5). To address this issue, a new study has introduced a novel metabolic Gadolinium oxide nanoparticle (Gd2O3 NPs) coated with ß-cyclodextrin (ßCD). The study aims to investigate NSF syndrome by quantifying tissue Gd deposition biodistribution in renal impairment rats using MR molecular imaging. This is the first study of its kind to use this approach. A group of 20 rats were divided into four groups, each containing five rats that underwent 5/6 nephrectomy. The rats received 12 intravenous injections of a novel homemade synthesized gadolinium oxide polycyclodextrin (Gd2O3@PCD) at a dose of 0.1 mmol/kg, conventional contrast agents (CAs) drugs of Omniscan (Gd-DTPA-BMA) and Dotarem (Gd-DOTA), at a dose of 2.5 mmol/kg, and 250 µl saline for two injections per week during six weeks. T1-weighted MR imaging was performed before the injections and once a week for six weeks to quantify Gd deposition in four different organs (skin, liver, heart, and lung) in rats using inductively coupled plasma mass spectrometry (ICP-MS). The relationship between Signal-to-Noise Ratio (SNR) and biodistribution of Gd deposition due to NSF-induced syndrome was also calculated. The results of the study showed that the Gd concentrations in tissues were significantly higher in the Gd2O3@PCD group compared to the other groups, without any significant histopathological changes (P < 0.05). In the Gd2O3@PCD group, Gd was mainly deposited in the skin, followed by the liver, lung, and heart, without any symptoms of thickening or hardening of the skin. The Gd concentrations in the skin, liver, lung, and heart were significantly lower in the Dotarem group than in the Omniscan group (P < 0.05). In the histopathological examinations, the Omniscan group showed increased cellularity in the dermis. A significant hyperintensity was observed in the Gd2O3@PCD-treated rats compared to the Dotarem and Omniscan groups in the liver, heart, and lung. Compared to conventional Gd-based CAs, the novel metabolically Gd2O3@PCD with increased SNR, biosafety, and a considerably lower probability of developing NSF, has potential applicability for diagnosing patients with renal diseases in clinical MR Molecular Imaging (MRMI).

Where does the gadolinium go? A review into the excretion and retention of intravenous gadolinium.

Gadolinium-based contrast agents (GBCAs) are commonly used in medical imaging. Most intravenously (IV) administered gadolinium is excreted via the kidneys, and pathological retention in renal failure leading to nephrogenic systemic fibrosis (NSF) is well described. More recently, retention of gadolinium in the body in the absence of renal disease has been identified, with unknown clinical consequences. Many patients are aware of this, either through the media or via comprehensive consent documentation. Some internet sites, without hard evidence, have suggested a constellation of possible symptoms associated with GBCA retention. Recent experience with patients ascribing symptoms to a contrast-enhanced MRI examination prompted this review of the fate of injected GBCA after MRI study, and of information available to patients online regarding gadolinium retention.

Safety and incremental prognostic value of stress cardiovascular magnetic resonance in patients with known chronic kidney disease.

BACKGROUND: Cardiovascular disease (CVD) is the main cause of mortality in patients with chronic kidney disease (CKD). Although several studies have demonstrated the consistently high prognostic value of stress cardiovascular magnetic resonance (CMR), its prognostic value in patients with CKD is not well established. We aimed to assess the safety and the incremental prognostic value of vasodilator stress perfusion CMR in consecutive symptomatic patients with known CKD. METHODS: Between 2008 and 2021, we conducted a retrospective dual center study with all consecutive symptomatic patients with known stage 3 CKD, defined by estimated glomerular filtration rate (eGFR) between 30 and 60 ml/min/1.73 m2, referred for vasodilator stress CMR. All patients with eGFR < 30 ml/min/1.73 m2 (n = 62) were excluded due the risk of nephrogenic systemic fibrosis. All patients were followed for the occurrence of major adverse cardiovascular events (MACE) defined as cardiac death or recurrent nonfatal myocardial infarction (MI). Cox regression analysis was used to determine the prognostic value of stress CMR parameters. RESULTS: Of 825 patients with known CKD (71.4 ± 8.8 years, 70% men), 769 (93%) completed the CMR protocol. Follow-up was available in 702 (91%) (median follow-up 6.4 (4.0-8.2) years). Stress CMR was well tolerated without occurrence of death or severe adverse event related to the injection of gadolinium or cases of nephrogenic systemic fibrosis. The presence of inducible ischemia was associated with the occurrence of MACE (hazard ratio [HR] 12.50; 95% confidence interval [CI] 7.50-20.8; p < 0.001). In multivariable analysis, ischemia and late gadolinium enhancement were independent predictors of MACE (HR 15.5; 95% CI 7.72 to 30.9; and HR 4.67 [95% CI 2.83-7.68]; respectively, both p < 0.001). After adjustment, stress CMR findings showed the best improvement in model discrimination and reclassification above traditional risk factors (C-statistic improvement: 0.13; NRI = 0.477; IDI = 0.049). CONCLUSIONS: In patients with known stage 3 CKD, stress CMR is safe and its findings have an incremental prognostic value to predict MACE over traditional risk factors.

The need for prophylactic hemodialysis to protect against nephrogenic systemic fibrosis in patients with end-stage renal disease receiving gadolinium-based contrast agents.

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.

What you need to know about: imaging in patients with renal failure.

Contrast-enhanced medical imaging is commonly requested in clinical practice. Contrast media provide better differentiation of tissue enhancement, improves the soft tissue contrast resolution, and enhances the ability to study the physiology and function of the organs and/or systems. However, contrast media may cause complications, especially in patients with renal failure. This article discusses the use of contrast media in common imaging modalities and the relationship between contrast media and renal function. Administration of iodinated contrast media in computed tomography may cause contrast-associated acute kidney injury; the risk factors and preventive strategies for this are elaborated in this article. Administration of gadolinium-based contrast media in magnetic resonance imaging may lead to nephrogenic systemic fibrosis. Therefore, precautions should be taken when planning for medical imaging for patients with pre-existing acute kidney injury or end-stage chronic kidney disease, for whom contrast media administration in computed tomography or magnetic resonance imaging may be relatively contraindicated. Alternatively, ultrasound contrast agents can be safely used in patients with acute kidney injury or chronic kidney disease. Clinical teams should discuss these patients with radiologists, taking into account the risk-benefits of contrast media, to determine the optimal imaging protocol or modality to answer the clinical query.

Adverse Events Associated with Intra-Arterial Administration of Gadolinium-Based Contrast Agents: A Systematic Review and Meta-Analysis.

PURPOSE: To determine the risk of immediate hypersensitivity reactions (HRs), contrast-associated acute kidney injury (CA-AKI), nephrogenic systemic fibrosis (NSF), and gadolinium retention associated with use of intra-arterial gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched from 1988 (GBCAs approved for clinical use) to March 2021 for studies reporting adverse events associated with intra-arterial administration of GBCAs. The number of adverse events and GBCA administrations were used to calculate incidence in individual studies, and results across studies were pooled using random-effects meta-analysis. RESULTS: There were 72 studies (patients = 1,221) that reported on HR, 59 studies (patients = 1,142) that reported on CA-AKI, and 6 studies (patients = 291) that reported on NSF. No studies reported gadolinium retention as an outcome. Based on 5 events and 1,451 GBCA administrations, the incidence of HR per 100 administrations was 0.95 (95% CI, 0.52-1.51). Based on 90 events and 1,318 GBCA administrations, the incidence of CA-AKI per 100 administrations was 5.94 (95% CI, 3.92-8.34). Based on 7 events and 361 GBCA administrations, the incidence of NSF per 100 Group I GBCA administrations was 4.72 (95% CI, 0.35-13.70). There were no unconfounded NSF events after Group II GBCA administration. CONCLUSIONS: HRs to intra-arterial administration of GBCAs are rare, with no serious reactions. Limited data demonstrate a higher-than-expected rate of CA-AKI; however, multiple confounding factors were noted. Thus, any causative link of CA-AKI to GBCA remains controversial. Also, severe physiologic reactions (including life-threatening arrhythmias) during coronary angiography have been reported.

Was There Something Rotten in Denmark: Nephrogenic System Fibrosis Cases Occurring in Copenhagen.

More than half of all serious adverse drug reactions are identified seven years after FDA approval. One recent and unusual example involves a syndrome initially termed nephrogenic dermatopathic fibrosis, and then called nephrogenic systemic fibrosis (NSF).

Gadolinium-Based Contrast Agents: Updates and Answers to Typical Questions Regarding Gadolinium Use.

Gadolinium-based contrast agents have expanded the diagnostic usefulness and capability of magnetic resonance imaging. Despite their highly favorable safety profile, these agents have been associated with nephrogenic systemic fibrosis in a small number of patients who have advanced kidney disease. Recently, trace amounts of gadolinium deposition in the brain and other organs have been reported after contrast exposure, even in patients with normal renal function. In this review, we provide a brief overview of recent updates and discuss typical clinical situations related to the use of gadolinium-based contrast agents.

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.

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.

Risk of nephrogenic systemic fibrosis (NSF) in oncology patients receiving gadoxetic acid and updated risk of estimate of NSF in patients receiving gadoxetic acid with moderate and severe renal impairment.

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.

Long-term safety of Gadofosveset in clinical practice.

PURPOSE: 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. MATERIALS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Gadolinium retention: should pediatric radiologists be concerned, and how to frame conversations with families.

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.

Neutrophil elastase in the development of nephrogenic systemic fibrosis (NSF)-like skin lesion in renal failure mouse model.

Although neutrophil elastase (NE) may play a role in lung fibrosis and liver fibrosis, NE involvement in the development of nephrogenic systemic fibrosis has been unclear. We investigated the involvement of NE in the development of nephrogenic systemic fibrosis-like skin lesions post-injections of linear gadolinium-based contrast agents in renal failure mouse models. Renal failure mouse models were randomly divided into three groups: control group (saline), gadodiamide group, and gadopentetate group. Each solution was intravenously administered three times per week for three weeks. The mice were observed daily for skin lesions. Quantification of skin lesions, infiltrating inflammatory cells, and profibrotic cytokines in the affected skin was performed by immunostaining and reverse-transcription polymerase chain reaction (RT-PCR). Blood samples were collected from the facial vein to quantify NE enzymatic activity. The 158Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry (ICP-MS). In the gadodiamide group, the mRNA expression of fibrotic markers was increased in the skin lesions compared to the control group. In the gadopentetate group, only collagen 1α and TGF-ß mRNA expression were higher than in the control group. The expression of CD3+, CD68+, NE cells and the NE activity in the blood serum were significantly higher in the gadodiamide and gadopentetate groups compared to the control group. Gadolinium concentration in the skin of the gadodiamide group was significantly higher than the gadopentetate group, while almost no traces of gadolinium were found in the control group. Although gadopentetate and gadodiamide affected the fibrotic markers in the skin differently, NE may be involved in the development of fibrosis linked to the GBCAs injections in renal failure mouse models.

Use of Intravenous Gadolinium-based Contrast Media in Patients with Kidney Disease and the Risk of Nephrogenic Systemic Fibrosis: Radiology In Training.

A 66-year-old male patient with end-stage chronic kidney disease undergoing maintenance dialysis and with a history of group I intravenous gadolinium-based contrast media (GBCM) administration presented with clinical and pathologic findings consistent with nephrogenic systemic fibrosis. A summary of the evidence and recommendations for use of intravenous GBCM in patients with kidney disease is presented. © RSNA, 2021.