Patient characteristics and risk factors for nephrogenic systemic fibrosis following gadolinium exposure

Nephrogenic systemic fibrosis (NSF) is a systemic illness, which only affects patients with kidney failure. NSF risk increases with progressively lower levels of kidney function. It is characterized by red skin areas or plaques that develop over several weeks to painful thickened skin with a "woody" texture, resembling "peau d'orange." It may ultimately cause flexion contractures of joints. Skin biopsy reveals thickened collagen bundles, mucin deposition, proliferation of fibroblasts and elastic fibers, without inflammation. Originally described as nephrogenic fibrosing dermopathy (NFD), because of its primarily cutaneous manifestation, it was renamed NSF because of the involvement of various organs like the lungs, myocardium, or striated muscles. The pathogenesis of the disease is not known yet, but recently we suggested a strong association between development of NSF and exposure to gadolinium-based contrast (GBC) agents, thereafter confirmed by other authors. As a consequence of our recent observations, medical authorities imposed restrictions that exclude patients with advanced levels of renal insufficiency from potentially important magnetic resonance imaging studies with gadolinium. Unfortunately, the only alternatives in many situations (examination of brain, lungs, vasculature) are imaging modalities using iodinated radiocontrast agents. Thus, clinicians are faced with weighing the potential risk of NSF from GBC exposure against the risk of acute kidney injury-associated with radiocontrast media. In this dilemma, clinicians must identify patients at high-risk to develop NSF. Known risk factors critical for the development of NSF after exposure to GBC agents (certain chelates and higher doses) are end-stage renal disease requiring dialysis, especially those with little or no residual renal function, and advanced kidney disease not on dialysis. Other potential risk factors include metabolic acidosis, iron overload/intravenous iron, divalent ion disturbances, endothelial/vascular injury, and high erythropoietin doses. Further studies are required.     

Imaging patients with kidney disease in the era of NSF: can it be done safely?

Nephrogenic systemic fibrosis (NSF) was first recognized as a complication of gadolinium-based contrast (GBC) exposure in 2006 and confirmed subsequently by numerous investigators. Early information on the toxicity of free gadolinium (Gd3+) and the pharmacokinetics of this agent in patients with underlying kidney disease were likely unrecognized subtle clues to its potential for adverse effects in humans. Since the recognition of NSF as a complication of GBC exposure, our approach to imaging in patients with kidney disease has been altered. As these patients require various forms of imaging to diagnose associated conditions, we must utilize an evidence-based approach to imaging options. It is our responsibility to identify patients at high risk to suffer this complication and choose between non-GBC imaging modalities, radiocontrast-based imaging modalities, and GBC imaging modalities based on risk:benefit assessment. The benefits of rapid, accurate diagnosis must be weighed against risks associated with CT scan with radiocontrast (radiation exposure, allergic contrast reactions, acute kidney injury), GBC imaging (development of NSF), and missed diagnoses due to use of suboptimal imaging modalities in an effort to avoid radiocontrast and GBC agent exposure.     

Gadolinium and nephrogenic systemic fibrosis: an update

Nephrogenic systemic fibrosis (NSF) is a multisystem disease seen exclusively in patients with renal impairment. It can be severely debilitating and sometimes fatal. There is a strong association with gadolinium-based contrast agents used in magnetic resonance imaging (MRI). Risk factors include renal impairment and proinflammatory conditions, e.g. major surgery and vascular events. Although there is no single effective treatment for NSF, the most successful outcomes are seen following restoration of renal function, either following recovery from acute kidney injury or following renal transplantation. There have been ten biopsy-proved pediatric cases of NSF, with no convincing evidence that children have a significantly altered risk compared with the adult population. After implementation of guidelines restricting the use of gadolinium-based contrast agents in at-risk patients, there has been a sharp reduction in new cases and no new reports in children. Continued vigilance is recommended: screening for renal impairment, use of more stable gadolinium chelates, consideration of non-contrast-enhanced MRI or alternative imaging modalities where appropriate.     

Nephrogene systemische Fibrose (NSF) nach Applikation gadoliniumhaltiger Kontrastmittel bei Shuntpatienten

Nephrogenic systemic fibrosis (NSF) is a rare, etiologically unclear disorder in patients with end-stage renal disease (ESRD) and is possibly caused by gadolinium-based contrast agents. NSF usually develops 2–3 months after application of such agents. Herein we present a case with an extraordinarily long time course, underscoring the requirement of certain cofactors such as chronic inflammation and accelerated atherosclerosis – a common feature in ESRD patients – for NSF development. A 52-year-old woman with ESRD for 25 years developed NSF more than 4 years after the administration of gadolinium-based contrast media. Remarkable in her past medical history was an advanced vascular sclerosis due to a chronic inflammatory state and a secondary hyperparathyroidism. This case shows that NSF can occur any time after exposure to gadolinium-based contrast agents, which seem to be a necessary, but not the sole, cause of NSF. A review of the current literature and up-to-date recommendations are also given.     

Gadolinium and nephrogenic systemic fibrosis: association or causation

SUMMARY:   With widespread availability of magnetic resonance imaging (MRI), it has become standard practice for patients with severe renal impairment or previous severe reactions to iodine-containing contrast media to receive gadolinium-based MRI contrast agents instead of traditional radiographic contrast agents, particularly for magnetic resonance angiography. However, there is growing concern about the use of gadolinium contrast agents in the presence of severe renal insufficiency, because of increasing reports of nephrogenic fibrosing dermopathy (NFD)/nephrogenic systemic fibrosis (NSF), associated with the exposure to certain gadolinium-containing contrast agents. In this review we explore the causal link between gadolinium exposure and NSF, using an established system of epidemiological criteria proposed by Bradford Hill. Though the current evidence makes gadolinium a strong suspect as an aetiologic agent for NSF in the presence of severe renal failure, the die is not cast yet. At this stage there needs to be cautious approach to the use of gadolinium-containing contrast agents in the presence of severe renal failure (glomerular filtration rate <30 mL/min per 1.73 m²).     

Contrast associated nephropathy after intravenous administration: what is the magnitude of the problem?

Intravenous contrast media (CM) is often used in clinical practice to enhance CT scan imaging. For many years, contrast-induced nephropathy (CIN) was thought to be a common occurrence and to result in dire consequences. When treating patients with abnormal renal function, it is not unusual that clinicians postpone, cancel, or replace contrast-enhanced imaging with other, perhaps less informative tests. New studies however have challenged this paradigm and the true risk attributable to intravenous CM for the occurrence of CIN has become debatable. In this article, we review the latest relevant medical literature and aim to provide an evidence-based answer to questions surrounding the risk, outcomes, and potential mitigation strategies of CIN after intravenous CM administration.     

Iodinated contrast media and the role of renal replacement therapy

Iodinated contrast media are among the most commonly used pharmacologic agents in medicine. Although generally highly safe, iodinated contrast media are associated with several adverse effects, most significantly the risk of acute kidney injury, particularly in patients with underlying renal dysfunction. By virtue of their pharmacokinetic characteristics, these contrast agents are efficiently cleared by hemodialysis and to a lesser extent, hemofiltration. This has led to research into the capacity for renal replacement therapies to prevent certain adverse effects of iodinated contrast. This review examines the molecular and pharmacokinetic characteristics of iodinated contrast media and critically analyzes data from past studies on the role of renal replacement therapy to prevent adverse effects of these diagnostic agents.     

NSF: WHAT WE KNOW AND WHAT WE NEED TO KNOW: Nephrogenic Systemic Fibrosis: A Sufficient Reason to Avoid Gadolinium‐Based Contrast in All Patients with Renal Impairment?

Nephrogenic systemic fibrosis (NSF) was recently linked to gadolinium-based contrast (GBC) exposure in patients with renal failure. As result, the U.S. Food and Drug Administration (FDA), the UK Commission on Human Medicines (CHM) and the European Pharmacovigilance Working Party Committee for Medicinal Products for Human Use (CHMP) recommended that GBC should be avoided in patients with advanced renal failure (GFR < 30 ml/minute/1.73 m2). Ones initial reaction is to advise avoidance of GBC exposure in patients with any level of kidney disease to prevent this awful complication. However, this approach is not based on data nor is it practical for patients who would benefit from this diagnostic modality. Thus, while complete avoidance cannot currently be advocated, GBC-enhanced MRI in renal impairment should be reserved for neurological and vascular cases where the quality of information gained is sufficient to justify the risk of potential devastating adverse effects of NSF.     

Good MRI images: to Gad or not to Gad?

Gadolinium-based magnetic resonance imaging (MRI) contrast agents (Gad-CA) were formerly considered as alternatives to X-ray-employed iodinated media. Although originally thought to be nonnephrotoxic and proven to be nonhazardous in a healthy population, the Gad-CA safety issue is progressively more controversial in the high-risk group of end-stage renal disease (ESRD) patients. Recently, Gad-CAs have not only been blamed for harmless side effects such as dizziness or nausea but also for much more severe complications such as acute renal failure, pancreatitis, or even the development of so-called “nephrogenic systemic fibrosis” in patients with renal failure, culminating in the prohibition of gadodiamide (Omniscan) administration in ESRD patients and, due to renal-organ immaturity, in newborns and infants up to 1 year old. This editorial is written to give insights into the molecular structure of Gad-CAs as well as into the potential biochemical pathomechanisms underlying the aforementioned severe clinical manifestations. Furthermore, a review about the latest literature on Gad-CA nephrotoxicity is provided. Potential risk factors are mentioned and strategies to avoid deterioration of renal function are presented. Cases with Gad-CA-associated adverse events should be adequately documented and reported appropriately. MRI professionals should collaborate closely with their colleagues from other medical specialties to identify patients with adverse events.     

Nephrogenic systemic fibrosis and the use of gadolinium-based contrast agents

Nephrogenic systemic fibrosis (NSF) is a disease seen exclusively in patients with decreased renal function. The use of gadolinium-based contrast agents (GBCAs) has a strong association with NSF. Linear non-ionic GBCAs that are more prone to release free gadolinium are the more likely to cause NSF. The number of reported cases has increased recently, and there are currently nine pediatric cases, the patients ranging in age from 8 years to 19 years, and the oldest adult patient is 87 years of age. The most successful treatment is improvement of renal function with renal transplantation or with recovery of acute kidney injury. NSF can be severely debilitating and even fatal. Avoidance of a GBCA in patients at risk, or limitation of the dose in the patients who need gadolinium enhancement, is recommended.     

Contrast-induced nephropathy--prevention and risk reduction.

Contrast-induced nephropathy (CIN) is a serious, but potentially preventable adverse event associated with the use of iodinated contrast media (CM). Studies suggest that the occurrence of CIN is directly related to the number of pre-existing patient risk factors such as pre-existing renal insufficiency (RI) with or without diabetes, advanced age, congestive heart failure and dehydration. Because the risk factors for CIN are common and the consequences serious or even life-threatening, it is important for physicians to implement preventive strategies. Although the optimal strategy for preventing CIN has not been fully established, it is important to first identify patients at risk. The commonly used methods for identifying patients at risk include use of patient questionnaires, review of medical history and measurement of serum creatinine levels prior to the administration of CM. Estimation of the glomerular filtration rate (GFR) before CM administration should be encouraged. To prevent the development of CIN, patients should be well-hydrated and nephrotoxic medications should be withdrawn at least 24 h prior to CM. Use of the minimal necessary CM dose is recommended, as the nephrotoxic effect of CM is dose-dependent. Furthermore, appropriate selection of CM is important. The incidence of CIN has been shown to be lower when an iso-osmolar CM rather than a low-osmolar CM (iohexol) is used in patients with RI and diabetes. Pharmacological intervention with calcium channel blockers, dopamine and N-acetylcysteine have not consistently been shown to reduce the incidence of CIN. This article will review the risk factors for the development of CIN and discuss practical strategies for its prevention in at-risk patients.     

Gadolinium and Nephrogenic Systemic Fibrosis: Have We Overreacted?

Imaging is an increasingly important part of clinical medicine and contrast enhancement adds valuable diagnostic information. Prior to 2006 gadolinium based contrast agents (GBCA) were used in patients with kidney disease in an attempt to avoid the adverse consequences of iodinated contrast agents. The amount administered often exceeded the United States Food and Drug Administration (FDA)-recommended dosing. After the association between GBCA and nephrogenic systemic fibrosis (NSF) was reported, usage of GBCA was markedly reduced in patients with kidney disease. As a result, iodinated contrast was often used in place of GBCA. Recently, several studies showed that the risk of NSF using GBCA with increased thermodynamic and kinetic stability or increased relaxivity along with a restricted use policy has dramatically reduced NSF risk in patients with chronic kidney disease (CKD). We discuss the risks of GBCA and iodinated contrast use in different stages of CKD and suggest that in some situations GBCA use may pose less overall risk to the patient with advanced kidney disease.     

Safety of gadolinium contrast angiography in patients with chronic renal insufficiency

OBJECTIVE: To prevent iodinated contrast medium-induced nephrotoxicity, gadolinium has been used increasingly for magnetic resonance angiography (MRA) or conventional digital subtraction angiography (DSA) to visualize arterial anatomy in patients undergoing vascular surgery who are considered at high risk because of chronic renal insufficiency. We assessed the safety of gadolinium-based contrast medium as a substitute for iodinated contrast medium-enhanced examinations. We determined the incidence of gadolinium-induced nephrotoxicity in a clinical setting and searched for contributing risk factors.Patients and methods In a single-center retrospective study from December 1999 to January 2001, 218 inpatients underwent MRA and 42 inpatients underwent DSA, with gadolinium as the sole contrast agent. Patient comorbid conditions, indications for vascular imaging, contrast dose, urine output, baseline and post-procedure serum creatinine concentration (SCr), and outcome were recorded for all patients in whom gadolinium-induced renal failure developed. RESULTS: Of 260 patients who received gadolinium-based contrast agents, at a dose of 0.25 mmol/kg or more, 195 patients (75%) had pre-test baseline chronic renal insufficiency. In 7 of 195 patients (3.5%) acute renal failure developed after gadolinium-based contrast medium administration, for MRA (n = 153) in 3 patients (1.9%) and DSA (n = 42) in 4 patients (9.5%). Average baseline SCr in the 195 patients with chronic renal insufficiency was 38.2 +/- 1.6 mL/min/1.73 m(2), and in the 7 patients in whom acute renal failure developed, baseline SCr was 32.5 +/- 7.8 mL/min/1.73 m(2) (P =.33). Respective intravenous and intra-arterial gadolinium doses in these 7 patients ranged from 0.31 to 0.41 mmol/kg for MRA and 0.27 to 0.42 mmol/kg for DSA. Acute renal failure did not develop in any of 65 patients with normal baseline SCr. CONCLUSION: Despite reports of negligible nephrotoxicity, rarely gadolinium-based contrast agents can cause acute renal failure in patients with underlying chronic renal insufficiency. Estimation of creatinine clearance alone does not enable prediction of which patients are likely to have acute renal failure. Patients at high-risk should be identified, and prophylactic measures should be taken to reduce the risk for nephrotoxicity.     

Nephrogenic systemic fibrosis: epidemiology update

PURPOSE OF REVIEW: The aim of this article is to outline the history of nephrogenic systemic fibrosis, a new and serious disease of patients with renal failure, and to give an update on its aetiology and prevalence. RECENT FINDINGS: Epidemiological and histochemical studies demonstrated that gadolinium-containing contrast agents used for magnetic resonance imaging have an essential causative role in most, if not all, cases of nephrogenic systemic fibrosis. One particular agent, gadodiamide, caused the majority of cases, but gadopentetate dimeglumine has also been implicated in several cases. Increasingly poor renal function, aberrations in calcium-phosphate metabolism and erythropoietin treatment seem to increase the risk of the disease and its severity. Up to 25-30% of patients with renal failure exposed to gadolinium-based contrast agents may develop nephrogenic systemic disease. The figure varies with type of gadolinium-based contrast agent and patient characteristics. There is no established curative treatment of the disease, but rapid recovery of renal function or hastened kidney transplantation may be beneficial. SUMMARY: It is mandatory to avoid exposing patients with renal failure to gadodiamide and gadopentetate dimeglumine. Other linear gadolinium-based contrast agents should be used with great caution. It is premature to conclude whether cyclic gadolinium-based contrast agents are totally safe in renal failure.     

Contrast-induced nephropathy: definition, epidemiology, and patients at risk

Radiological procedures utilizing intravascular iodinated contrast media injections are being widely applied for both diagnostic and therapeutic purposes. This has resulted in an increasing incidence of procedure-related contrast-induced nephropathy (CIN). The definition of CIN includes absolute (> or = 0.5 mg/dl) or relative increase (> or = 25%) in serum creatinine at 48-72 h after exposure to a contrast agent compared to baseline serum creatinine values, when alternative explanations for renal impairment have been excluded. Although the risk of renal function impairment associated with radiological procedures is low (0.6-2.3%) in the general population, it may be very high in selected patient subsets (up to 20%), especially in patients with underlying cardiovascular disease. This review provides information on the known risk factors for the development of CIN, and completes with describing user-friendly CIN risk score based on the readily available information.     

Advanced Renal Mass Imaging: Diffusion and Perfusion MRI

Computed tomography (CT) is considered the imaging modality of choice in evaluation of renal lesions. The advantages of magnetic resonance imaging (MRI) compared to CT include superior soft tissue contrast, avoidance of ionizing radiation and iodinated contrast media, and the possibility of performing functional and advanced imaging techniques such as diffusion-weighted (DWI) and perfusion–weighted imaging (PWI). Although the traditional role of MRI in the evaluation of renal mass is primarily that of a problem-solving tool, DWI and PWI are expanding the role of MRI in management of renal cell cancers. DWI and PWI have shown considerable promise not only in renal lesion detection and characterization as benign or malignant, but also in assessment of renal cell cancer subtype and nuclear grade. Furthermore, these techniques have the potential to assist with tailoring patient- and disease-specific management by providing surgical planning in patients with localized renal cell cancer and assessing treatment response in patients with advanced renal cell cancer undergoing targeted chemotherapy.     

Nephrogenic systemic fibrosis and gadolinium-based contrast agents

The strong association between nephrogenic systemic fibrosis (NSF) and exposure to gadolinium-based contrast agents (GBCAs) has greatly affected the care of patients with kidney disease. NSF has been reported in patients with ESRD, CKD, and acute kidney injury (AKI). The majority of cases have occurred in patients with ESRD, but about 20% have been reported in patients with AKI or CKD stages 4 and 5. There is also a risk difference among GBCAs, with the Food and Drug Administration contraindicating 3 linear agents in patients at risk. Given the significant morbidity and mortality of NSF, it is imperative to identify individuals at risk. Although there are no data to support a role for hemodialysis (HD) in reducing the risk for NSF after administration of GBCAs, immediate HD is still recommended within 2 hours. Patients maintained on peritoneal dialysis seem to be at high risk and immediate HD is also recommended. However, this is not the current recommendation for CKD stages 4 and 5, especially with suspected lower risk of noncontraindicated agents. Individualized assessment is important and especially in those patients close to dialysis initiation. Instituting policies is important to address the imaging needs of patients with CKD and AKI while ensuring a balance between benefits and risks.     

Contrast-induced nephropathy

Contrast-induced nephropathy (CIN) has been extensively studied since the 1950s due, in part, to its devastating adverse events. The intellectual push for additional investigation into pathogenesis and prevention has heightened in recent years due to increased utilization of contrast enhanced imaging studies. Lack of a universal CIN definition and varied glomerular filtration rate markers have resulted in a varied reported incidence. Risk assessment and risk reduction strategies have evolved over the past several years. Current evidence supports volume supplementation before the administration of intravascular contrast to reduce the hazard of CIN. Other strategies to reduce the risk of CIN, including low osmolar contrast media, N-acetylcysteine, and intrarenal fenoldopam therapy, have variable levels of evidence, and further randomized trials are necessary.     

Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists' awareness

Nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) is a recently described disease, occurring only in patients with variable degrees of renal failure (RF) previously exposed to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. Public advisories are consistent on some key points including that no cases of NSF/NFD have been reported in patients with normal renal function, and GBCAs may be toxic in patients with RF due to the prolongation of the half-time allowing dissociation and extravasation of highly toxic gadolinium-free ions, potentially linked to the scleroderma-like NSF/NFD, a systemic disabling disease with a mortality rate of up to 30%. The most intriguing feature remains which cofactor might be at play to explain why the disease occurs only in a minority of exposed patients. Therefore, renal dysfunction (substrate) and gadolinium chelates (trigger agent) are necessary but not sufficient. The challenge for nephrologists includes (a) evidence of transmetallation, such as gadolinium deposits in bone, increased urinary zinc excretion, iron-transferrin dissociation or "spurious hypocalcemia" in exposed people; (b) research for uremic cofactors such as increased serum calcium/phosphate, acidosis, use of phosphate-chelating agents able to act as efficient competitor ligands or other drugs; and (c) identification of at-risk patients (with moderate to severe renal dysfunction) and definition of the role of dialysis in removing gadolinium chelates, if any. Nephrologists are called to action to collect and organize information to identify cofactors for NSF/NFD, and therefore they must be aware of this new pathology, as the eye sees only what the mind knows.