Gadolinium Exposure Research Articles

Authors Reply to: Gadolinium Exposure in Organ Donors May Cause Nephrogenic Systemic Fibrosis in Transplant Recipients Never Exposed to Gadolinium

Authors Reply to: Gadolinium Exposure in Organ Donors May Cause Nephrogenic Systemic Fibrosis in Transplant Recipients Never Exposed to Gadolinium

Removal of gadolinium by peritoneal dialysis

An association between gadolinium-containing contrast and the development of nephrogenic systemic fibrosis (NSF) has been increasingly recognized. For patients receiving hemodialysis (HD) who are exposed to gadolinium, the Federal Drug Administration (FDA) recommends HD to remove this contrast agent in order to minimize the risk of NSF. This study examines if gadolinium can be removed by frequent exchanges by peritoneal dialysis (PD). Following administration of 0.1 mmol/kg of gadodiamide to a patient with end-stage renal disease, the serum clearance of this contrast agent by automated PD was examined. 10 and 15 exchanges of PD using an automated cycler were respectively performed during the first and second 24-hour periods after gadolinium exposure. Serum gadolinium levels were measured 1 hour after the gadolinium administration, then at 24 and 48 hours after PD was initiated. 90% of the gadolinium was removed from the circulation in 2 days with a regimen of 10-15 exchanges per day of PD. For patients on chronic maintenance PD who receive gadolinium, our case suggests that a temporary intensive automated PD regimen, aimed at maximizing clearance of this contrast agent immediately after exposure, could be an effective alternative when institution of HD is problematic.

Gadolinium Exposure in Organ Donors May Cause Nephogenic System Fibrosis in Transplant Recipients Never Exposed to Gadolinium

Gadolinium Exposure in Organ Donors May Cause Nephogenic System Fibrosis in Transplant Recipients Never Exposed to Gadolinium

Gadolinium-based contrast agents, erythropoietin and nephrogenic systemic fibrosis in patients with end-stage renal failure.

Sir, Nephrogenic systemic fibrosis (NSF) is a rare and debilitating disorder, which affects patients with kidney failure. An association with gadolinium-based contrast agents for magnetic resonance imaging (MRI) was found [1]. However, not all NSF patients had a prior gadolinium exposure [2]. Recently, an association of NSF and the use of erythropoietin was proposed [3]. Our aim was, thus, to investigate the use of gadolinium-based contrast agents and erythropoietin in haemodialysis patients with and without NSF. Four patients in our dialysis unit developed NSF (between 2002 and 2006). We retrospectively compared those to all other patients requiring chronic haemodialysis (n = 61; data collection in August 2007). Besides demographic characteristics, we investigated haemoglobin levels, iron and erythropoietin supplementation, parameters of inflammation, Kt/V and exposure to gadolinium. Table ​Table11 gives the basic characteristics of patients and controls. There were no differences with regard to age, sex, number of previous kidney transplantations, cumulative time on haemodialysis or primary renal disease. The same was true for Kt/V. The haemoglobin levels were comparable, but NSF patients received higher doses of erythropoietin (331.1 ± 215.1 versus 133.3 ± 99.5 U/week/kg body weight; P 0.05). Table 1 Basic characteristics and laboratory parameters In the NSF group, on average, more contrast enhanced MRIs had been performed [3.0 ± 1.2 per patient (range 2–4) versus 1.8 ± 2.0 per patient (range 0–10); the mean dose contrast agent 12.6 ± 5.4 versus 11.6 ± 4.6 mmol/MRI]. In the control group, the following contrast agents were used: gadopentetate dimeglumine 94 times, gadodiamide 9 times, gadobutrol 4 times and gadobenate dimeglumine once. In the NSF group, gadopentetate dimeglumine and gadodiamide were used six times each. The cumulative dose of contrast agent was higher in the NSF group (0.57 ± 0.14 versus 0.29 ± 0.37 mmol/kg body weight; P < 0.05). In the NSF group, the time from the last administration of a contrast agent to the first symptoms was 2 weeks till 5 months. Comparing those patients with a minimum of two MRIs (as this is the minimum number in the NSF group) patients in the NSF group, again, received higher doses of erythropoietin (331.1 ± 215.1 versus 128.1 ± 215.1 U/week/kg body weight; P < 0.05). There is growing evidence for a pathogenic role of gadolinium ions as causing agents in the development of NSF [1]. However, not all patients with NSF have been exposed to gadolinum-containing contrast agents [2,5,6]. There seems to be a reasonable likelihood of additional (co-)triggers, which may-–alone or in combinations-–play a role in the pathogenesis of NSF. In some studies, an association between erythropoietin and NSF [3,7,8] could be found, while not in others [6,9]. One of the cardinal features of NSF is the presence of CD34+ fibrocytes [10]. These cells resemble bone marrow-derived progenitors. One hypothesis says that erythropoietin could drive the development of NSF by increasing the number of circulating haematopoietic stem cells and endothelial progenitor cells, thereby increasing the pool of CD34+ cells. These cells finally may enter the tissue and enhance the fibrotic process. Alternatively, the higher dosage might also reflect erythropoietin resistance in the presence of chronic inflammation, making higher dosages necessary to achieve equal levels of haemoglobin [3,4,11]. The findings of our study have to be interpreted cautiously. The number of NSF patients is small and whether the association with erythropoietin is causative or reflects erythropoietin resistance cannot be answered. However, even if gadolinium seems to be the major culprit in the development of NSF, there is no final proof and a number of questions remain open. The search for (co-)triggers in the development of NSF is strongly warranted. This is especially true in light of limited treatment options of this disabling disease. Conflict of interest statement. None declared.

233: Clinical Improvement in Nephrogenic Systemic Fibrosis (NSF) Following Renal Transplantation: Should ‘NSF Points’ be Considered in Allocation?

CLINICAL IMPROVEMENT IN NEPHROGENIC SYSTEMIC FIBROSIS (NSF) FOLLOWING RENAL TRANSPLANTATION: SHOULD ‘NSF POINTS’ BE CONSIDERED IN ALLOCATION? Sharad Sathyan , Swetha Nataraj, M. Atiq Dada, K. Vinay Ranga Medicine / Transplantation, Hartford hospital/UCHC, Farmington, CT NSF is a fibrosing disease with serious consequences including limb contractures, multi organ involvement and high mortality. Gadolinium exposure is implicated. Treatment has been largely disappointing. A 62 year old female on peritoneal dialysis for 18 months due to ESRD secondary to hypertension and chronic NSAID use underwent an MRI with contrast for work up of a complex renal cyst. Four weeks later, the skin over her lower extremities became sensitive to touch with burning sensation and periodic sharp shooting pains, with progressive tightening of her skin with time. On exam, the skin appeared tight and hyperpigmented with linear bands extending up to the lower thigh. Biopsy showed thickened and haphazardly arranged reticular dermal collagen bundles with prominent clefts, consistent with NSF. The skin tightness progressed to involve both her lower extremities entirely. She received a cadaveric renal transplant in July 2007. In the several weeks post transplant, the patient has reported improvement in the swelling of her lower extremities, and that she can actually pinch the skin over her thighs, and this was also confirmed clinically using a pinching score. A repeat skin biopsy is planned. NSF is characterized by thickening and hardening of the skin and can also involve other organs. Skin lesions are variable, and can lead to joint contractures. Apart from renal failure, Gadolinium exposure during MRI/MRA in patients is the most consistent risk factor. Free Gadolinium is liberated from its chelates upon administration to patients with CKD, and is highly toxic. It is thought to undergo transmetallation in vivo, with other metals such as Copper, Zinc and Calcium, and once phagocytosed by macrophages, is associated with an increase in profibrotic cytokines or growth factors leading to dermal or systemic fibrosis. There is no proven effective cure for NSF with only a return of renal function documented to be effective. Since this condition is relentlessly progressive, thought may be given for these patients to receive extra points in the renal allocation schema to receive timely transplantation.

Gadolinium and nephrogenic systemic fibrosis: Association or causation (Review Article)

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 m(2)).

What Causes Nephrogenic Systemic Fibrosis?

What Causes Nephrogenic Systemic Fibrosis?

Risk for Nephrogenic Systemic Fibrosis with Gadoteridol (ProHance) in Patients Who Are on Long-Term Hemodialysis

Recent studies strongly link nephrogenic systemic fibrosis to gadolinium administration for magnetic resonance imaging. In a recent advisory, the Food and Drug Administration stated that all gadolinium-containing chelates are potentially associated with nephrogenic systemic fibrosis; however, most reported cases are linked to gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). Given the severe consequences of nephrogenic systemic fibrosis, it is critical to define the risks associated with each gadolinium-containing chelate. The purpose of this study was to examine nephrogenic systemic fibrosis risk in a hemodialysis population exposed to gadoteridol (ProHance). Appointment logs were used to generate a database of all long-term hemodialysis patients at the Dallas Veterans Affairs hospital since August 2001. These patients were then examined in the Veterans Affair's electronic medical record system for gadolinium exposure during magnetic resonance imaging from 2000 through 2007, a period during which gadoteridol was the sole contrast agent used. A total of 141 patients were identified with 198 gadoteridol exposures. No cases of nephrogenic systemic fibrosis were identified. The observed frequency of nephrogenic systemic fibrosis was compared with the expected frequency (2.4%) using one-way chi(2) and binomial analysis, yielding a P < 0.05, indicating that the result was not explained by chance alone. It is concluded that the risk for nephrogenic systemic fibrosis with gadoteridol in patients who are on long-term hemodialysis may be lower than with gadodiamide and gadopentetate dimeglumine.

Nephrogenic systemic fibrosis and its association with gadolinium exposure during MRI

Nephrogenic systemic fibrosis (NSF) is a newly recognized systemic disorder characterized by widespread tissue fibrosis in patients with impaired renal function. Recent reports suggest that NSF is associated with exposure to gadolinium-based contrast agents used in magnetic resonance imaging. NSF can be very debilitating and can lead to serious complications and death. Health care providers should exercise caution when considering the use of gadolinium-based imaging studies in patients with renal dysfunction.

NSF: WHAT WE KNOW AND WHAT WE NEED TO KNOW: Dialytic Therapies to Prevent NSF Following Gadolinium Exposure in High‐Risk Patients

AbstractProlonged exposure to gadolinium‐based contrast (GBC) appears to be the core pathophysiologic factor in the development of nephrogenic systemic fibrosis (NSF). As the GBC is renally excreted, this condition is predominantly seen only following exposure in patients with severe reductions in renal function. Fortunately, GBC is easily hemodialyzed with 95% of an administered dose removed after two hemodialysis sessions. Peritoneal dialysis, on the other hand, is not an efficient means of GBC removal. This has led to recommendations to hemodialyze a high‐risk patient immediately following GBC administration and to repeat the treatment the following day. Although this approach seems logical and is more aggressive than the usual thrice‐weekly hemodialysis schedule that most patients were receiving when they developed this devastating condition, there are no data to support the supposition that this approach will reduce the risk of NSF. Therefore, although an aggressive hemodialysis strategy postexposure is not unreasonable, it is probably best at this point to try to avoid GBC administration altogether in these high‐risk patients.

NSF: WHAT WE KNOW AND WHAT WE NEED TO KNOW: Patient Characteristics and Risk Factors for Nephrogenic Systemic Fibrosis Following Gadolinium Exposure

AbstractNephrogenic 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.

Gadolinium-Contrast Toxicity in Patients with Kidney Disease: Nephrotoxicity and Nephrogenic Systemic Fibrosis

Gadolinium is widely employed as a contrast agent for magnetic resonance imaging (MRI) and has generally been considered to be safe. As with iodinated radiocontrast, concern for contrast-induced nephropathy existed with gadolinium-contrast as it possessed many similar qualities (hyperosmolar, renal excretion via glomerular filtration). Early studies in low risk patients suggested a benign renal profile, however, recent studies raise the possibility of nephrotoxicity. In addition, reports of a previously rare condition entitled nephrogenic systemic fibrosis (NSF) have recently emerged in patients with advanced kidney disease and have been linked to exposure to gadolinium-contrast. Nephrogenic systemic fibrosis is a debilitating disorder in which progressive and severe fibrosis of the skin and other systemic organs that leads to significant disability and is associated with increased mortality. Initially reported most commonly in end stage renal disease (ESRD) patients receiving dialysis, it is also described in patients with severe acute kidney injury (AKI) and advanced chronic kidney disease (stages 4 and 5) not requiring dialysis. In addition to underlying kidney disease, the risk of developing NSF is increased with larger doses of gadolinium (or multiple exposures), exposure to specific gadolinium chelates (non-ionic, linear), underlying pro-inflammatory states (in particular vascular endothelial dysfunction), and perhaps some currently unrecognized cofactors. No clearly effective therapies exist for NSF, although recovery from AKI and establishment of normal kidney function with renal transplantation appear to reverse or stabilize the disease in some cases. Avoidance of gadolinium exposure appears to be the best approach for patients who maintain risk factors. When gadolinium exposure occurs, aggressive hemodialysis following exposure may be useful as gadolinium is efficiently removed by this extracorporeal technique. Peritoneal dialysis clearance of gadolinium is poor, but aggressive peritoneal dialysis prescriptions have not been studied for gadolinium removal.

Cutaneous Changes of Nephrogenic Systemic Fibrosis: Predictor of Early Mortality and Association With Gadolinium Exposure

Cutaneous Changes of Nephrogenic Systemic Fibrosis: Predictor of Early Mortality and Association With Gadolinium Exposure

Abstract 2123: Gadolinium-DTPA-Exposure-Induced Systemic Inflammatory Response (GEISIR) in Patients with Chronic Renal Insufficiency

Background Cardiovascular morbidity is extraordinarily high in patients with chronic kidney disease (CKD) and accurate cardiovascular assessment is necessary. Due to the renal toxicity of certain contrast agents, this assessment has often been avoided. MRI contrast agents, such as gadolinium-DTPA, were originally thought to be a non-nephrotoxic alternative to iodinated contrast agents. The purpose of this study was to evaluate the safety of gadolinium-DTPA and to assess side effects in CKD patients who received gadolinium-DTPA during cardiovascular MRI. Methods Between August 2004 and December 2006, we longitudinally investigated 76 end-stage renal disease (ESRD) patients (70 haemodialysis=HD, 6 peritoneal dialysis=PD) who received gadolinium-DTPA during cardiovascular MRI. Results We report for the first time that 8% of ESRD patients experienced a gadolinium-DTPA-exposure-induced systemic inflammatory response (GEISIR). Furthermore, two of them previously not dialyzed CKD patients - rapidly progressed to end-stage renal failure. Conclusion Exposure to gadolinium-DTPA is not as harmless as was initially assumed. In ESRD patients, gadolinium-DTPA may induce severe adverse events, such as GEISIR. Therefore, short-term re-administration of gadolinium should be avoided in ESRD patients. Due to the extremely long half-life of gadolinium-DPTA, especially in PD patients, careful consideration should be given as to whether or not gadolinium-exposed patients require hemodialysis. Further data are imperative to determine optimal measures after gadolinium exposure in CKD patients

Cutaneous changes of nephrogenic systemic fibrosis: Predictor of early mortality and association with gadolinium exposure

Nephrogenic systemic fibrosis (NSF) is a rapidly progressive, debilitating condition that causes cutaneous and visceral fibrosis in patients with renal failure. Little is known about its prevalence or etiology. The aim of this study was to establish the prevalence of NSF and associated risk factors Two cohorts of patients were recruited from 6 outpatient hemodialysis centers and examined for cutaneous changes of NSF, which were defined using a scoring system based on hyperpigmentation, hardening, and tethering of skin on the extremities. Demographic data were gathered, mortality was followed up prospectively for 24 months, and gadolinium exposure was ascertained for a subgroup of patients in the second cohort. Examination reproducibility was 97% in cohort 1. In cohort 2, 25 (13%) of 186 patients demonstrated cutaneous changes of NSF. Twenty-four-month mortality following examination was 48% and 20% in patients with and those without cutaneous changes of NSF, respectively (adjusted hazard ratio 2.9, 95% confidence interval [95% CI] 1.4-5.9). Cutaneous changes of NSF were observed in 16 (30%) of 54 patients with prior exposure to gadopentetate dimeglumine contrast during imaging studies. Exposure to gadolinium-containing contrast was associated with an increased risk of developing cutaneous changes of NSF (odds ratio 14.7, 95% CI 1.9-117.0) compared with nonexposed patients. In patients receiving hemodialysis, NSF is an underrecognized disorder that is associated with increased mortality. Exposure to gadolinium-containing contrast material appears to be a significant risk factor for the development of NSF.

Nephrogenic systemic fibrosis and gadolinium exposure: Association and lessons for idiopathic fibrosing disorders

Nephrogenic systemic fibrosis and gadolinium exposure: Association and lessons for idiopathic fibrosing disorders

La fibrose systémique néphrogénique : nouveau coup dur pour les insuffisants rénaux

To date, more than 200 cases of nephrogenic systemic fibrosis have been documented worldwide. All patients have had renal failure, most of them requiring dialysis. We herein describe the course of a hemodialyzed patient who developed nephrogenic systemic fibrosis in the months following magnetic resonance angiography of the lower extremities. The disease is characterized by skin thickening and tendon fibrosis leading to joint contractures that can quickly confine the patient to a wheelchair. Systemic involvement may occur, leading to cardiomyopathy, pulmonary fibrosis, pulmonary hypertension or even death. No consistently effective therapy has been reported. An association between gadolinium exposure and the development of the disease has been found, although no causal link has yet been proven. In a patient with renal failure, magnetic resonance imaging with gadolinium enhancement should be done only after having seriously considered the risk/benefit ratio. Implications concerning the choice of imaging methods when searching for ischemic nephropathy or aorto-iliac disease before renal transplantation are discussed.

Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure

Nephrogenic systemic fibrosis is a debilitating disease occurring exclusively in patients with renal failure. The aetiology of nephrogenic systemic fibrosis is unclear, but recent reports suggest that exposure to gadolinium for enhancement of magnetic resonance imaging may play a role. In the present study, we assessed the association of exposure to gadolinium with the development of nephrogenic systemic fibrosis in patients with various stages of chronic kidney disease. We analysed the exposure to gadolinium and development of nephrogenic systemic fibrosis in 849 patients on renal replacement therapy over 5 years. We also performed inquiry of development of the nephrogenic systemic fibrosis in 592 patients exposed to gadolinium and estimated to be in stages 3 and 4 of chronic kidney disease. In 849 patients undergoing chronic dialysis from 2001 through 2006 time period, four of the 261 who had received gadolinium (1.5%) and none of the 588 not exposed to gadolinium developed clinically apparent disease. The odds ratio for developing nephrogenic systemic fibrosis was 6.671 [95% confidence interval (CI) 1.537-53.97] in patients with a single gadolinium exposure compared to patients without gadolinium exposure. This ratio increased to 44.5 (95% CI 2.362-2913) in patients with multiple gadolinium exposures compared to patients not receiving gadolinium. None of the 592 patients estimated to be in stage 3 or 4 of chronic kidney disease developed nephrogenic systemic fibrosis after exposure to gadolinium. Gadolinium exposure is associated with nephrogenic systemic fibrosis in patients on chronic renal replacement therapy at a low rate. This association appears to increase with repeated exposure to gadolinium. Since nephrogenic systemic fibrosis may be clinically occult, its prevalence may be higher than reported. Despite this association, it is unclear if gadolinium is the sole or most important factor in the pathogenesis of the disease.

Nephrogenic Systemic Fibrosis

Nephrogenic systemic fibrosis (NSF) is a devastating complication of severe renal failure. Recent reports suggest that exposure to gadolinium-containing contrast agents (GCCA) is associated with the occurrence of NSF. The population of patients with ESRD in and around Bridgeport, CT, was studied during an 18-mo period. The incidence of NSF was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for NSF. The association between gadolinium exposure and NSF was highly significant (P < or = 0.001). It is concluded that GCCA exposure is a major risk factor for NSF in the ESRD population. Because of the significant morbidity and mortality with NSF, it is believed that gadolinium exposure should be avoided in patients with ESRD. In the event that exposure cannot be avoided, careful consideration of the potential consequences, including a thorough discussion of the risks and benefits of GCCA, is advised.