Prospective Cohort Study of Nephrogenic Systemic Fibrosis in Patients With Stage 3–5 Chronic Kidney Disease Undergoing MRI With Injected Gadobenate Dimeglumine or Gadoteridol
Abstract
OBJECTIVE. The purpose of this study was to determine the incidence of nephrogenic systemic fibrosis (NSF) in patients with chronic kidney disease (CKD) and moderate-to-severe impairment of kidney function who had not previously been exposed to gadolinium-based contrast agents (GBCAs) or referred to undergo contrast-enhanced MRI with gadobenate dimeglumine or gadoteridol.
SUBJECTS AND METHODS. Two multicenter prospective cohort studies evaluated the incidence of unconfounded NSF in patients with stage 3 CKD (estimated glomerular filtration rate [eGFR] in cohort 1, 30–59 mL/min/1.73 m2) or stage 4 or 5 CKD (eGFR in cohort 2, < 30 mL/min/1.73 m2) after injection of gadobenate dimeglumine (study A) or gadoteridol (study B). A third study (study C) determined the incidence of NSF in patients with stage 4 or 5 CKD who had not received a GBCA in the 10 years before enrollment. Monitoring for signs and symptoms suggestive of NSF was performed via telephone at 1, 3, 6, and 18 months, with clinic visits occurring at 1 and 2 years.
RESULTS. For studies A and B, the populations evaluated for NSF comprised 363 and 171 patients, respectively, with 318 and 159 patients in cohort 1 of each study, respectively, and with 45 and 12 patients in cohort 2, respectively. No signs or symptoms of NSF were reported or detected during the 2 years of patient monitoring. Likewise, no cases of NSF were reported for any of the 405 subjects enrolled in study C.
CONCLUSION. To our knowledge, and consistent with reports in the literature, no association of gadobenate dimeglumine or gadoteridol with unconfounded cases of NSF has yet been established. Study data confirm that both gadoteridol and gadobenate dimeglumine properly belong to the class of GBCAs considered to be associated with the lowest risk of NSF.
Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy [1], is a rare systemic fibrosing disorder reminiscent of, but distinct from, scleroderma or scleromyxedema. It is characterized by thickening and induration of the skin, flexion contractures and impaired mobility of the nearby joints, and fibrosing changes in the connective tissues of internal organs [2]. The clinical course of NSF is progressive and may cause mild-to-severe disability or even death.
Although the first cases of NSF were identified in 1997 and the first published report of 14 cases appeared in 2000 [3], it was not until 2006 that a possible association between NSF and exposure to gadolinium-based contrast agents (GBCAs) became apparent [4]. Since that time, approximately 1600 cases have been reported to the U.S. Food and Drug Administration (FDA) and other regulatory authorities, although many spontaneous reports are duplicates or lack fundamental information with which to confirm a diagnosis of NSF [5]. By December 2012, a total of 815 distinct cases of NSF had been reported in 200 articles in the peer-reviewed literature, the vast majority (595/815 [73.0%]) of which were observed in the United States [5]. Of the 815 published cases, 806 occurred in patients with acute renal failure or severe chronic kidney disease (CKD) (defined as stage 4 or 5 CKD, in accordance with the CKD classification of the U.S. National Kidney Foundation [6], and an estimated glomerular filtration rate [eGFR] of < 30 mL/min/1.73 m2) [5]. Of the cases of NSF reported in the peer-reviewed literature and for which administration of a specific GBCA was noted, approximately 78% of unconfounded single-agent cases have been associated with gadodiamide (Omniscan, GE Healthcare), 20% with gadopentetate dimeglumine (Magnevist, Bayer HealthCare), and 1.3% with gadoversetamide (OptiMARK, Mallinckrodt Imaging). Very few single-agent cases (0.7%) have been associated with gadobutrol (Gadovist, Bayer HealthCare), and no unconfounded cases have ever been reported for gadobenate dimeglumine (MultiHance, Bracco Diagnostics), gadoxetate disodium (Eovist, Bayer HealthCare), gadofosveset trisodium (Ablavar, Lantheus Medical Imaging), gadoterate meglumine (Dotarem, Guerbet), or gadoteridol (ProHance, Bracco Diagnostics) [5]. The greater association of NSF with gadodiamide, gadoversetamide, and gadopentetate dimeglumine has led to contraindication of these contrast agents in patients with severe CKD (stage 4 or 5) or acute kidney injury [7].
In response to the postulated association of NSF with GBCA administration, the FDA mandated in 2007 that the manufacturers of the five GBCAs that were approved at that time in the United States perform prospective cohort studies of patients with moderate, severe, and end-stage renal disease who had been referred for routine MRI examinations, to ascertain the incidence of NSF after exposure to each of these agents. Although this could not be accomplished for gadodiamide, gadoversetamide, and gadopentetate dimeglumine after contraindication of these agents, studies of gadobenate dimeglumine and gadoteridol proceeded.
We present the findings of these two prospective cohort studies of patients with moderate, severe, and end-stage renal disease who were referred for routine MRI examinations with either gadobenate dimeglumine or gadoteridol administration. We also present findings from a control study of patients with severe CKD or end-stage renal disease who had no history of exposure to GBCAs in the 10 years before enrollment.
Subjects and Methods
These multicenter postmarketing cohort studies were designed to prospectively observe and compare the incidence rates of NSF in patients with moderate CKD (defined as stage 3 CKD with an eGFR of 30–59 mL/min/1.73 m2) and in patients with severe CKD or end-stage renal disease (defined as stage 4 or 5 CKD with an eGFR < 30 mL/min/1.73 m2) after gadobenate dimeglumine or gadoteridol was injected during MRI as part of clinical management. The two studies were sponsored by Bracco Diagnostics and were registered at ClincalTrials.gov (identifiers NCT00600951, for the study involving gadobenate dimeglumine [study A, which began in January 2008], and NCT00600834, for the study involving gadoteridol [study B, which began in February 2008]). A control study (identifier NCT00773409 [study C, which began in October 2008]) was performed to evaluate patients with severe CKD or end-stage renal disease who had not been exposed to a GBCA in the 10 years before enrollment. Institutional review board and regulatory approval were granted from each participating center, and all patients provided written informed consent. The lead author had complete access to all study results, and all authors had full control of the data and statistical results included in this report, including data that might have represented a potential conflict of interest for Bracco Diagnostics and its employees.
Patients
Patients enrolled in studies A and B were divided into two cohorts according to the degree of their risk for the development of NSF. Cohort 1 in each study comprised patients with moderate CKD for whom the risk of developing NSF was still unknown. Cohort 2 comprised patients with severe to end-stage CKD for whom the risk of developing NSF was estimated to be as high as 2.4% per GBCA-enhanced MRI examination [8]. Patients exposed to these agents were enrolled in the two cohorts on the basis of their renal function only (as measured by the eGFR), regardless of age, sex, race, indication for MRI, GBCA dose received, or body areas imaged. All patients were administered gadobenate dimeglumine or gadoteridol as part of clinical management.
The eGFR was calculated (as specified below) using a serum creatinine value obtained in the 24 hours before contrast agent injection. Patients were ineligible for inclusion if they had received any GBCA in the 12 months before enrollment in the study; if they had any medical condition or other circumstances that would significantly decrease the chances of obtaining reliable data; if they had ever been suspected of having NSF or had been given a diagnosis of NSF before the study-specific MRI was performed; or if they were unable or unwilling to return for necessary office visits, to be examined by dermatologists, or to undergo deep-skin biopsy and laboratory or other diagnostic evaluations should development of NSF be suspected.
Requirements for enrollment in study C were that patients had not received a GBCA in the 10 years before enrollment and that they had severe CKD or end-stage kidney failure (including patients receiving dialysis), as defined by eGFR determinations calculated from serum creatinine values obtained within 24 hours before informed consent was signed. Patients enrolled in study C were not required to undergo a contrast-enhanced MRI examination, and inclusion in the study was independent of age, sex, or race. Criteria for exclusion from study C were similar to those for exclusion from studies A and B, with the additional criterion that patients must not have been listed on a kidney transplant registry (to ensure that full follow-up data were available).
Studies A and B were performed at 16 and eight investigational centers, respectively, in the United States, Canada, and Europe. Study C was performed at 12 centers in the United States and Canada.
Patient Screening
A qualifying serum creatinine value was obtained for all patients during the 24 hours before the study-specific MRI examination was performed (in studies A and B) or during the 24 hours before patients provided informed consent (in study C). The Modification of Diet in Renal Disease Study equation [9] was then used to calculate the eGFR for all adult (≥ 18 years) patients, whereas the Schwartz formula [10–12] was to be used for all enrolled patients younger than 18 years.
A complete medical history of each patient (including detailed renal history, including cause and date of diagnosis) was obtained within 24 hours of the study-specific MRI examination (in studies A and B) or in the 24 hours before informed consent was signed (in study C). Any proinflammatory conditions (including thromboembolic events or coagulation abnormalities), systemic infection, tissue trauma (e.g., that resulting from surgery, including liver or kidney transplantation), and interventional vascular procedures (e.g., arteriovenous fistula reconstruction or repair), were recorded, as were details regarding administration of erythropoietin, if given.
Patient Monitoring
Patients enrolled in studies A and B each underwent contrast-enhanced MRI examination with gadobenate dimeglumine or gadoteridol administration, respectively. In each case, the date of examination, the reason for the examination, the specific indication, and the volume of contrast agent administered was recorded. Monitoring for signs and symptoms of NSF was thereafter performed for 2 years, with each patient required to make clinic visits at 1 and 2 years and with contact by telephone required at 1, 3, 6, and 18 months after the injection of either gadobenate dimeglumine or gadoteridol. In the event that signs or symptoms consistent with NSF were exhibited, plans were in place for the patient to undergo a detailed examination by a dermatologist, who could then refer the patient for deep skin biopsy, laboratory evaluations, and other diagnostic tests, as necessary. Patients enrolled in study C underwent an identical monitoring schedule for 2 years, beginning immediately after signed informed consent was provided.
Any significant changes in medical history, including major events (thromboembolic events, surgeries, and hospital admissions), that any patient experienced in any of the three studies during the 2-year follow-up were recorded. In addition, if any patient in any study underwent an MRI examination or any other radiologic examination involving administration of a GBCA after the initial (i.e., baseline) visit, full details of the examination (date, reason, indication, type of GBCA used, and volume of GBCA administered) were recorded, along with the serum creatinine and eGFR values obtained before examination, if available.
Diagnosis of Nephrogenic Systemic Fibrosis
In the event that a patient reported signs or symptoms suggestive of NSF, or if such signs or symptoms were detected during scheduled clinic visits, an experienced dermatologist was to examine the patient. The dermatologist would then assign a clinical NSF score based on past and present renal history and the findings of the physical examination (with attention to specific major and minor criteria as described by Girardi et al. [2]), laboratory evaluations, and, in some cases, other diagnostic evaluations to rule in or out other disease processes that mimic NSF. The clinical NSF score was based on a 5-point scale from 0 to 4, where 0 was diagnostic of another entity (e.g., scleromyxedema), 1 was inconsistent with NSF (no or one minor criteria), 2 was suggestive of NSF (more than one minor criterion), 3 was consistent with NSF (one major criterion), and 4 was highly consistent with NSF (more than one major criterion). Any skin involvement was to be documented with photographs of the affected areas.
If NSF could not be ruled out immediately (i.e., if the assigned clinical NSF score was > 0), histopathologic assessments of samples obtained from deep full-thickness biopsy specimens of the involved skin were to be made. Thereafter, a histologic NSF score was to be made on the basis of histopathologic criteria described by Girardi et al. [2]. The histologic NSF score was based on a 5-point scale similar to that of the clinical NSF score, where 0 was diagnostic of another entity (i.e., one of the other exclusionary criteria was satisfied or another disorder was diagnosed), 1 was inconsistent with NSF (one criterion), 2 was suggestive of NSF (two criteria), 3 was consistent with NSF (three criteria), and 4 was highly consistent with NSF (four or five criteria).
The intersection of these two values within the diagnosis and reporting grid defined by Girardi et al. [2] then had to result in one of six diagnostic possibilities: NSF, consistent with NSF, suggestive of NSF, inconsistent with NSF, NSF excluded (no alternative diagnosis provided), or alternative diagnosis made.
Additional Safety Assessments
Patients enrolled in studies A and B were monitored for adverse events (AEs) for 2 hours after the administration of gadobenate dimeglumine or gadoteridol. AEs were classified as serious (e.g., death, a life-threatening event, or an event requiring or prolonging hospitalization) or nonserious (e.g., mild [no disability or incapacity; self-resolving], moderate [no disability or incapacity; requiring treatment], or severe [temporary or mild disability or incapacity; requiring treatment]). Assessment of event severity and evaluation of its relationship (probable, possible, unrelated, or unknown) to the study agent were made by the investigating radiologist.
Statistical Methods
The primary objective of each study was to estimate the incidence of NSF (i.e., the percentage of cases with an overall combined clinicohistologic NSF score of 1 or 2) at both the 1- and 2-year follow-up visits. For studies A and B, this was to be done for both patient cohorts. The incidence (plus 95% CI) was defined as the number of cases of NSF observed during each period divided by the total number of eligible patients. Secondary objectives, if cases of NSF occurred, were to compare the incidence of NSF in patients with stage 4 CKD (eGFR, 15–29 mL/min/1.73 m2) with the incidence in patients with stage 5 CKD (eGFR, < 15 mL/min/1.73 m2). For patients in studies A and B, the relative risk (the incidence in cohort 2 divided by the incidence in cohort 1) and its 95% CI were also to be determined. Patients who underwent another GBCA-enhanced MRI examination during the follow-up period were to be excluded from the analysis for the calculation of NSF incidence.
Initially, at the request of the FDA, 600 patients with moderate CKD and 400 patients with severe CKD or kidney failure were to be enrolled in each of studies A and B, whereas a minimum of 400 patients were to be enrolled in study C. However, postmarketing surveillance reports suggesting that the overall incidence of NSF was lower than the original literature-based estimate subsequently led the FDA in June 2011 to lift its postmarketing requirement to conduct these studies, after which time enrollment was stopped. However, all patients enrolled to that point were monitored until the completion of the 2-year follow-up.
Results
A summary of the patients enrolled in each study and the numbers of patients available for evaluation at each follow-up point are presented in Table 1. Of the 366 patients enrolled in study A, one received a GBCA other than gadobenate dimeglumine, one was too large for the scanner, and one had an eGFR of 63.6 mL/min/1.73 m2 at the time of the examination. These three patients were therefore excluded from study A. Similarly, of the 176 patients enrolled in study B, two underwent an unenhanced MRI examination, two were claustrophobic, and one had an eGFR of 64.2 mL/min/1.73 m2 at the time of the examination. These five patients were similarly excluded from study B. The NSF analysis populations available for studies A and B therefore comprised 363 and 171 patients, respectively (318 and 159 in cohort 1 of each study, respectively, and 45 and 12 patients in cohort 2 of each study, respectively). Although the studies were designed to permit the enrollment of all subjects regardless of age, only adult subjects were enrolled at each center. The demographic characteristics of the patients enrolled in each of the three studies are provided in Table 2, whereas a summary of the underlying renal history of each patient population is given in Table 3.
| Patient Population Characteristics | Study A | Study B | Study C (N = 405) | ||||
|---|---|---|---|---|---|---|---|
| Total (N = 366) | Cohort 1a (n = 321) | Cohort 2b (n = 45) | Total (N = 176) | Cohort 1a (n = 163) | Cohort 2b (n = 13) | ||
| Initial safety populationb (no.) | 363 | 318 | 45 | 171 | 159 | 12 | 405 |
| Patients who discontinued the study during the first yeard | 68 (18.7) | 63 (19.8) | 5 (11.1) | 35 (20.5) | 33 (20.8) | 2 (16.7) | 31 (7.7) |
| Patients who died during the first year | 41 (11.3) | 26 (8.2) | 15 (33.3) | 13 (7.6) | 11(6.9) | 2 (16.7) | 46 (11.4) |
| Population at 1-year follow-up for NSF analysise | 295 (81.3) | 255 (80.2) | 40 (88.9) | 136 (79.5) | 126 (79.2) | 10 (83.3) | 374 (92.3) |
| Patients not in 1-year follow-up who returned for 2-year follow-up | 14 (3.9) | 13 (4.1) | 1(2.2) | 5(2.9) | 5 (3.1) | 0 | 7(1.7) |
| Patients who discontinued the study during the second yeard | 29 (8.0) | 28 (8.8) | 1(2.2) | 20 (11.7) | 20 (12.6) | 0 | 7(1.7) |
| Patients who died during the second year | 13 (3.6) | 10 (3.1) | 3(6.7) | 6(3.5) | 5 (3.1) | 1 (8.3) | 45 (11.1) |
| Population at 2-year follow-up for NSF analysise | 280 (77.1) | 240 (75.5) | 40 (88.9) | 121 (70.8) | 111 (69.8) | 10 (83.3) | 374(92.3) |
Note—Data are no. (%) of patients in the safety population. Patients who died within follow-up period are included. NSF = nephrogenic systemic fibrosis.
a
Patients with an estimated glomerular filtration rate (eGFR) of 30–59 mL/min/1.73 m2.
b
Patients with an eGFR < 30 mL/min/1.73 m2.
c
All patients enrolled in study C and patients enrolled in studies A and B who received contrast agent.
d
Includes patients lost to follow-up, patients who withdrew consent, patients who were excluded for protocol violations (e.g., received a second gadolinium-based contrast agent), and patients who discontinued the study for other reasons.
e
All patients who had an eGFR < 60 mL/min/1.73 m2 at baseline who received the prescribed study agent (gadobenate dimeglumine or gadoteridol) in each study, who had data at follow-up evaluations, and who received no other GBCA during the entire follow-up period.
| Characteristic | Study A | Study B | Study C (N = 405) | ||||
|---|---|---|---|---|---|---|---|
| Total (N = 363) | Cohort 1 (n = 318) | Cohort 2 (n = 45) | Total (N = 171) | Cohort 1 (n = 159) | Cohort 2 (n = 12) | ||
| Sexa | |||||||
| Male | 201 (55.4) | 177 (55.7) | 24 (53.3) | 70 (40.9) | 62 (39.0) | 8 (66.7) | 238 (58.8) |
| Female | 162 (44.6) | 141 (44.3) | 21 (46.7) | 101 (59.1) | 97(61.0) | 4(33.3) | 167(41.2) |
| Age (y)b | 67.5 ± 11.6 [20, 92] | 68.1 ± 11.3 [20, 92] | 63.6 ± 13.4 [28, 85] | 68.1 ± 10.4 [30, 93] | 68.4 ± 9.9 [40, 93] | 64.8 ± 15.9 [30, 85] | 63.0 ± 14.1 [19, 95] |
| Age group (y)a | |||||||
| 18-65 | 136 (37.5) | 116 (36.5) | 20 (44.4) | 67 (39.2) | 60 (37.7) | 7(58.3) | 225 (55.6) |
| > 65 | 227 (62.5) | 202 (63.5) | 25 (55.6) | 104 (60.8) | 99 (62.3) | 5(41.7) | 180 (44.4) |
| Weight (kg)b | 82.4 ± 18.1 [40.5, 155.0] | 82.5 ± 17.6 [40.5, 136.3] | 81.9 ± 21.8 [41.8, 155.0] | 79.4 ± 20.5 [43.6, 134.5] | 79.1 ± 20.0 [43.6, 131.5] | 83.1 ± 26.4 [49.0, 134.5] | 86.4 ± 25.4 [39.7, 227.0] |
| Height (cm)b | 168.5 ± 10.6 [132, 195] | 168.7 ± 10.4 [133, 195] | 167.4 ± 11.9 [132, 187] | 165.6 ± 11.6 [132, 205] | 165.2 ± 11.6 [132, 205] | 170.9 ± 9.7 [155, 183] | 169.3 ± 11.3 [125, 200] |
| Racea | |||||||
| White | 312 (86.0) | 276 (86.8) | 36 (80.0) | 152 (88.9) | 143 (89.9) | 9 (75.0) | 254 (62.7) |
| Black | 36 (9.9) | 29 (9.1) | 7(15.6) | 16(9.4) | 14(8.8) | 2 (16.7) | 107 (26.4) |
| Asian | 6 (1.7) | 6(1.9) | 0 | 1 (0.6) | 1 (0.6) | 0 | 3(0.7) |
| Other | 9(2.5) | 7(2.2) | 2 (4.4) | 2 (1.2) | 1 (0.6) | 1 (8.3) | 41 (10.1) |
| Serum creatinine (mg/mL)b | 1.77 ± 1.33 [1.0, 16.7] | 1.49 ± 0.33 [1.0, 2.6] | 3.98 ± 3.07 [1.8, 16.7] | 1.52 ± 0.74 [1.0, 7.4] | 1.38 ± 0.27 [1.0, 2.4] | 3.38 ± 1.83 [1.8, 7.4] | 3.23 ± 1.36 [1.5, 8.1] |
| Estimated glomerular filtration rate (mL/min/1.73 m2) b | 43.3±11.4 [4.0, 62.7] | 46.3 ± 7.73 [30.1, 62.7] | 22.01 ± 7.89 [4.0, 29.9] | 46.2 ± 9.81 [6.8, 71.7] | 48.0 ± 7.31 [30.5, 71.7] | 22.49 ± 7.69 [6.8, 29.4] | 21.13 ± 5.96 [6.8, 38.0] |
a
Data are no. (%) of patients in the safety population.
b
Data are mean ± SD [minimum value, maximum value].
| Underlying Medical History | Study A | Study B | Study C (N = 405) | ||||
|---|---|---|---|---|---|---|---|
| Total (N = 363) | Cohort 1 (n = 318) | Cohort 2 (n = 45) | Total (N = 171) | Cohort 1 (n = 159) | Cohort 2 (n = 12) | ||
| Nephrotoxic drug therapy | 6(1.7) | 4 (1.3) | 2(4.4) | 4(2.3) | 4 (2.5) | 0 | 7(1.7) |
| Diabetic nephropathy | 86 (23.7) | 66 (20.8) | 20 (44.4) | 49 (28.7) | 46 (28.9) | 3 (25.0) | 180 (44.4) |
| Renal artery stenosis | 6(1.7) | 6 (1.9) | 0 | 3(1.8) | 3(1.9) | 0 | 8(2.0) |
| Polycystic kidney disease | 4(1.1) | 4(1.3) | 0 | 8(4.7) | 7 (4.4) | 1 (8.3) | 13(3.2) |
| Systemic lupus erythematosus | 1 (0.3) | 1 (0.3) | 0 | 0 | 0 | 0 | 7 (1.7) |
| Multiple myeloma | 1 (0.3) | 1 (0.3) | 0 | 0 | 0 | 0 | 1 (0.2) |
| Hypertensive nephropathy | 193 (53.2) | 176 (55.3) | 17 (37.8) | 121 (70.8) | 111 (69.8) | 10 (83.3) | 161 (39.8) |
| Renal cell carcinoma | 24 (6.6) | 22 (6.9) | 2(4.4) | 11(6.4) | 9(5.7) | 2 (16.7) | 2(0.5) |
| Glomerulonephritis | 7(1.9) | 5 (1.6) | 2(4.4) | 3(1.7) | 3(1.9) | 0 | 20 (4.9) |
| Acute kidney injury | 10 (2.8) | 9(2.8) | 1 (2.2) | 2(1.2) | 2(1.3) | 0 | 2(0.5) |
| Renal atrophy | 4(1.1) | 2(0.6) | 2(4.4) | 1 (0.6) | 1 (0.6) | 0 | 0 |
| Hepatorenal syndrome | 3(0.8) | 3(0.9) | 0 | 0 | 0 | 0 | 1 (0.2) |
| IgA nephropathy | 3(0.8) | 1 (0.3) | 2(4.4) | 0 | 0 | 0 | 4(1.0) |
| Nephroangiosclerosis | 1 (0.3) | 1 (0.3) | 0 | 2 (1.2) | 1 (0.6) | 1 (8.3) | 10(2.5) |
| Pyelonephritis | 3(0.8) | 2(0.6) | 1 (2.2) | 1 (0.6) | 1 (0.6) | 0 | 0 |
| Urinary tract cancer (bladder) | 6(1.7) | 6(1.9) | 0 | 3(1.7) | 3(1.9) | 0 | 0 |
| Calcineurin inhibitor-induced nephropathy | 1 (0.3) | 1 (0.3) | 0 | 0 | 0 | 0 | 1 (0.2) |
| Buerger disease | 0 | 0 | 0 | 2(1.2) | 2(1.3) | 0 | 1 (0.2) |
| Focal hyalinosis | 1 (0.3) | 1 (0.3) | 0 | 1 (0.6) | 1 (0.6) | 0 | 0 |
| Oncocytoma | 1 (0.3) | 1 (0.3) | 0 | 1 (0.6) | 1 (0.6) | 0 | 0 |
| Schonlein-Henoch purpura | 1 (0.3) | 0 | 1 (2.2) | 0 | 0 | 0 | 0 |
| Chronic allograft nephropathy | 1 (0.3) | 0 | 1 (2.2) | 0 | 0 | 0 | 0 |
| Contrast agent-induced nephropathy | 1 (0.3) | 1 (0.3) | 0 | 0 | 0 | 0 | 1 (0.2) |
| Oxalate nephropathy | 1 (0.3) | 0 | 1(2.2) | 0 | 0 | 0 | 0 |
| Medullary sponge kidney | 0 | 0 | 0 | 1 (0.6) | 0 | 1 (8.3) | 0 |
| Sarcoidosis | 3(0.8) | 3(0.9) | 0 | 0 | 0 | 0 | 0 |
| Wegener granulomatosis | 0 | 0 | 0 | 0 | 0 | 0 | 2(0.5) |
| Atheroembolic disease | 0 | 0 | 0 | 0 | 0 | 0 | 2(0.5) |
| Other | 9(2.5) | 9(2.8) | 0 | 3(1.7) | 3(1.9) | 0 | 17(4.2) |
| Unknown | 43 (11.8) | 43 (13.5) | 0 | 19 (11.1) | 19 (11.9) | 0 | 3(0.7) |
| History of dialysis | 44 (12.1) | 24 (7.5) | 20 (44.4) | 6(3.5) | 5 (3.1) | 1 (8.3) | 280 (69.1) |
| Hemodialysis | 43 (11.8) | 23 (7.2) | 20 (44.4) | 6(3.5) | 5 (3.1) | 1 (8.3) | 258 (63.7) |
| Peritoneal dialysis | 7(1.9) | 1 (0.3) | 6 (13.3) | 0 | 0 | 0 | 41 (10.1) |
| History of renal transplant | 31 (8.5) | 22 (6.9) | 9 (20.0) | 5(2.9) | 5 (3.1) | 0 | 27 (6.7) |
| Nonrenal organ transplant (liver, pancreas, lung, or heart) | 10 (2.8) | 10 (3.1) | 0 | 2 (1.2) | 2(1.3) | 0 | 1 (0.2) |
| Received erythropoietin | 34 (9.4) | 12(3.8) | 22 (48.9) | 6(3.5) | 3(1.9) | 3 (25.0) | 278 (68.6) |
Note—Data are no. (%) of patients in the safety population. Patients may have findings in more than one anatomic system.
Details of the investigational procedures used at baseline are presented in Table 4. The mean (± SD) dose of gadobenate dimeglumine administered in study A was 0.11 ± 0.04 mmol/kg, although this was skewed upward primarily because the dose used for MRA procedures (0.14 ± 0.05 mmol/kg) was slightly higher than the approved dose. The mean dose of gadoteridol administered in study B was 0.1 ± 0.05 mmol/kg, although higher doses were administered to four patients who underwent MRI of the chest and 13 patients who underwent MRA.
| Examination, Exposure | Study A | Study B | ||||
|---|---|---|---|---|---|---|
| Total (N = 363) | Cohort 1 (n = 318) | Cohort 2 (n = 45) | Total (N = 171) | Cohort 1 (n = 159) | Cohort 2 (n = 12) | |
| All | ||||||
| Patients with product exposure (no.) | 361a,b | 317a | 44b | 171 | 159 | 12 |
| Contrast agent received (mmol/kg), mean ± SD | 0.11 ± 0.04 | 0.1 ± 0.04 | 0.11 ± 0.05 | 0.1 ± 0.05 | 0.1 ± 0.05 | 0.12 ± 0.04 |
| CNS (brain, spine) | ||||||
| Patients with product exposure (no.) | 106 | 97 | 9 | 39 | 39 | 0 |
| Contrast agent received (mmol/kg), mean ± SD | 0.09 ± 0.02 | 0.09 ± 0.02 | 0.08 ± 0.04 | 0.07 ± 0.03 | 0.07 ± 0.03 | |
| Chest (heart, lung) | ||||||
| Patients with product exposure (no.) | 11 | 11 | 0 | 4 | 4 | 0 |
| Contrast agent received (mmol/kg), mean ± SD | 0.11 ± 0.05 | 0.11 ± 0.05 | 0.15 ± 0.06 | 0.15 ± 0.06 | ||
| Upper abdomen (liver, kidney, pancreas) | ||||||
| Patients with product exposure (no.) | 106 | 96 | 10 | 62 | 55 | 7 |
| Contrast agent received (mmol/kg), mean ± SD | 0.09 ± 0.03 | 0.09 ± 0.03 | 0.08 ± 0.03 | 0.1 ± 0.05 | 0.1 ± 0.05 | 0.1 ± 0.01 |
| Lower abdomen (uterus, ovaries, prostate) | ||||||
| Patients with product exposure (no.) | 16 | 11 | 5 | 20 | 20 | 0 |
| Contrast agent received (mmol/kg), mean ± SD | 0.09 ± 0.03 | 0.1 ± 0.03 | 0.07 ± 0.03 | 0.1 ± 0.01 | 0.1 ± 0.01 | |
| MR angiography | ||||||
| Patients with product exposure (no.) | 95 [96]b | 77 | 18 [19]b | 13 | 10 | 3 |
| Contrast agent received (mmol/kg), mean ± SD | 0.14 ± 0.05 | 0.14 ± 0.05 | 0.16 ± 0.03 | 0.2 ± 0.06 | 0.2 ± 0.07 | 0.17 ± 0.02 |
| Other | ||||||
| Patients with product exposure (no.) | 27 [28]a | 25 [26]a | 2 | 33 | 31 | 2 |
| Contrast agent received (mmol/kg), mean ± SD | 0.1 ± 0.04 | 0.1 ± 0.04 | 0.08 ± 0.05 | 0.1 ± 0.04 | 0.1 ± 0.04 | 0.1 ± 0.01 |
a
Data were available for 25 of 26 patients undergoing MRI for another application (CNS + MR angiography). Dose was impossible to calculate for one patient in cohort 1 who was administered 65 mL of gadobenate dimeglumine, because the weight of the patient was not recorded.
b
Data were available for 18 of 19 patients undergoing MR angiography; dose was impossible to calculate for one patient in cohort 2 who was undergoing abdominal MR angiography, because the volume of gadobenate dimeglumine administered was not recorded.
Overall, 96 patients in study A (89 patients in cohort 1 and seven in cohort 2) and 36 patients in study B (32 patients in cohort 1 and four in cohort 2) underwent one or more follow-up GBCA-enhanced MRI examinations subsequent to the initial baseline procedure and within the 2-year monitoring period. Of these patients, 34 in study A and 11 in study B received a GBCA other than gadobenate dimeglumine or gadoteridol, respectively, and were excluded (because of protocol violations) from all analyses subsequent to the follow-up MRI examination in question. The remaining patients (62 patients in study A [57 in cohort 1 and five in cohort 2] and 25 patients in study B [21 in cohort 1 and four in cohort 2]) each underwent follow-up MRI examination with gadobenate dimeglumine (study A) or gadoteridol (study B) and were included in subsequent analyses. Care was taken to ensure that all follow-up examinations, including any that were performed at institutions other than the principal investigating center that initially enrolled the patient, were fully reported and recorded. Details of the follow-up examinations performed with gadobenate dimeglumine or gadoteridol are given in Table 5.
| No. of Follow-Up Examinations, Cohort | Study Aa | Study Bb | ||
|---|---|---|---|---|
| No. of Patients | Volume Administered Per Procedureb (mL) | No. of Patients | Volume Administered Per Procedureb (mL) | |
| One examination | ||||
| Cohort 1d | 41 | 6-45 | 15 | 7-20 |
| Cohort 2e | 5 | 11-40 | 3 | 15 |
| Two examinations | ||||
| Cohort 1 | 12 | 7-50 | 4 | 6-34 |
| Cohort 2 | — | — | — | — |
| Three examinations | ||||
| Cohort 1 | 2 | 3 × 8 mL; 8 mL + 2 × 15 mL | 1 | 3 × a |
| Cohort 2 | — | — | 1 | 8, 11, and 12 |
| Four examinations | ||||
| Cohort 1 | 1 | 3 × 17 mL + 8 mL | 1 | 4 × 18 |
| Cohort 2 | — | — | — | — |
| Five examinations | ||||
| Cohort 1 | 1 | 6 × 5 | — | — |
| Cohort 2 | — | — | — | — |
Note—Dash (—) indicates no follow-up MRI examinations performed.
a
Patients received gadobenate dimeglumine.
b
Patients received gadoteridol.
c
Presented as range (min, max) for multiple patients undergoing one or two follow-up examinations and as specific volumes for individual patients undergoing three, four or five follow-up examinations.
d
Patients with an eGFR of 30–59 mL/min/1.73 m2.
e
Patients with an eGFR less than 30 mL/min/1.73 m2.
Incidence of Nephrogenic Systemic Fibrosis
No cases of NSF occurred in patients in any of the three studies at any time during the 2-year monitoring period, and no reports of NSF have been received for any patient subsequent to the 2-year monitoring period. A total of 11 patients (six patients in study A, three in study B, and two in study C) were referred to a dermatologic specialist for examination. Four additional patients in study C had symptoms suggestive of NSF but were not referred to a dermatologist by their treating physicians because their conditions were considered stable and because there was prior knowledge of the skin lesions that were observed: one patient had skin induration resulting from repeated episodes of dermatitis, one had thickening of the skin in spots, one had swollen lower extremities with seeping and chronic stasis, and one had silver-dollarsized dark-colored induration located lateral to the left antecubital region. Of the six patients in study A who were referred to an experienced dermatologist, three had a clinical NSF score of 0 and did not proceed to biopsy and histopathologic examination. The remaining three patients in study A who underwent a deep skin tissue biopsy had a clinical NSF score of 1 and a histologic NSF score of 0, with final diagnoses of morphea, venous insufficiency, and nummular eczema. All three patients in study B had a clinical NSF score of 0 and did not proceed to skin biopsy. No other patients in studies A or B had symptoms suggestive of NSF.
Other Safety Assessments
A total of 12 AEs were noted among eight of 363 patients (2.2%) who had gadobenate dimeglumine administered. All eight patients were enrolled in cohort 1, and all AEs were considered to be mild in intensity. Seven of the 12 AEs reported occurred in three of the 363 patients (0.8%) and were considered to be possibly related to the administration of gadobenate dimeglumine. These seven AEs included four that were considered to have a probable relationship (one patient had urticaria [one hive], and one patient each had nausea, vomiting, or sneezing) and three for which the relationship was considered to be unknown, with injection site pain, injection site swelling, and agitation occurring in one patient each. All AEs resolved spontaneously without treatment.
Similar safety findings were noted among the patients who were administered gadoteridol. Four of 171 patients (2.3%) experienced a total of seven AEs. Again, all four patients were enrolled in cohort 1, and all AEs were considered to be mild in intensity. Of the seven AEs reported, four occurred in three of the 171 patients (1.8%) and were considered to have a probable relationship with administration of gadoteridol. These AEs included nausea in one patient, a hot and burning sensation in one patient, and hypersensitivity (one pimple) in one patient. All events resolved spontaneously without treatment.
Discussion
On the basis of published clinical data, the onset of NSF symptoms occurs within the first 12 months after the last exposure to GBCAs in approximately 85% cases and within 2 years after the last exposure to GBCAs in approximately 98% of cases [5]. Given these time frames, the 2 years of follow-up in the three studies reported herein were considered sufficient to identify and confirm cases of NSF should they have occurred.
No cases of NSF were identified in either study A or study B, despite stringent monitoring of all patients by means of regular telephone interviews and hospital visits. This was true even for patients exposed to additional, sometimes large-volume (in one case, up to 50-mL), injections of gadobenate dimeglumine or gadoteridol during one or more (up to five) routine follow-up examinations performed to assess disease evolution or evaluate treatment response during the 2-year monitoring period. The results obtained for large numbers of patients (318 and 159 patients in studies A and B, respectively) who had an eGFR value of 31–59 mL/min/1.73 m2 allow us to reasonably exclude the risk of NSF development in patients with a moderate degree of chronic renal impairment who were exposed to gadobenate dimeglumine or gadoteridol. A similar conclusion has been drawn elsewhere for patients with moderate renal impairment who were exposed to gadobenate dimeglumine [13].
The population most at risk for development of NSF (i.e., patients who had an eGFR < 30 mL/min/1.73 m2) was more limited, with 45 of those patients exposed to gadobenate dimeglumine and 12 exposed to gadoteridol; however, the fact that no case that was even suggestive of NSF was detected during the 2 years of follow-up is consistent with reports in the literature on the incidence of NSF among patients who have been exposed to these agents. To our knowledge, no confirmed unequivocal unconfounded cases of NSF have been reported to date since the time of the sole administration of either of these agents [5, 7, 14–18]. This finding holds true for a group of 141 patients who were receiving hemodialysis who collectively had a total of 198 exposures to gadoteridol [14] and a group of 403 patients (301 of whom were undergoing dialysis and a further 102 who had a mean eGFR of 17 mL/min/1.73 m2) who had one or more exposures to gadobenate dimeglumine (mean volume administered at the time of the index examination, 24 mL) [18].
When unconfounded cases have been reported, they have been reported in error because of either missing information or misinformation [19] that has since been rectified, or they have been unconfirmed and erroneous volunteer case reports that were not medically confirmed and were inappropriately obtained from searches of uncontrolled databases, such as the FDA Adverse Event Reporting System (MedWatch) database [20].
The reasons for the absence of unconfounded cases of NSF occurring in association with the administration of these agents, despite their use in more than 38 million contrast-enhanced MRI examinations (Bracco, unpublished data), remain unclear because the pathogenesis of NSF remains unclear [21]. One of the more widely held hypotheses involves the release of gadolinium from GBCAs, its binding to phosphates, and its subsequent retention in the skin and other tissues for several weeks or months [22, 23]. In the skin, the insoluble gadolinium phosphate deposits, possibly forming a precipitate engulfed in macrophages, may attract or activate normal circulating fibrocytes (i.e., cells derived from bone marrow that participate in normal wound healing and fibrosis, leading to the aberrant fibrosis seen in NSF) [24, 25]. Four factors may favor the deposition of gadolinium ion in the body: higher and longer-lasting circulating levels of GBCAs, the volume of the GBCA dose administered to patients at risk for developing NSF, repeated exposures, and the stability of the various GBCAs (i.e., their ability to bind to and sequester the gadolinium ion) [26]. In patients with severe impairment of kidney function, elimination of GBCAs is markedly decreased [27–29], leading to more prolonged and elevated plasma concentrations of GBCA, especially after injection of high doses, and to increased availability of the source of gadolinium ions in the circulation.
The absence of unconfounded cases of NSF after exposure to gadoteridol may be ascribed to the contrast agent's macrocyclic structure, high kinetic stability, and lowest propensity to release free gadolinium ions [30], whereas the lack of cases of NSF after the sole administration of gadobenate dimeglumine might derive in part from the benzyloxymethyl group on the gadobenate molecule. Of note, an aromatic substituent is not present on the molecules of gadopentetate, gadodiamide, or gadoversetamide (i.e., the agents most frequently associated with unconfounded cases of NSF), although similar aromatic groups are present on other GBCAs (i.e., gadoxetate and gadofosveset) that, like gadobenate dimeglumine, are not yet associated with unconfounded cases of NSF [31].
There are at least three reasons why the presence of an aromatic group on the gadobenate molecule is potentially beneficial in patients who have an increased risk of developing NSF. First, it is responsible for the gadobenate molecule interacting weakly and transiently with serum albumin [32, 33]. This causes a slowing of the molecular tumbling rate of the molecule in blood, leading to a longer rotational correlation time with inner shell water protons and, hence, an increase in the T1 relaxation rate (and, thus, r1 relaxivity) of gadobenate dimeglumine relative to other agents that do not interact with serum proteins [34]. The increased r1 relaxivity has been shown to result in greater signal intensity enhancement, improved image quality, and better diagnostic performance for gadobenate dimeglumine, compared with other GBCAs administered at equivalent approved doses of 0.1 mmol/kg [35–37]. A potential benefit for patients at increased risk of NSF is that the dose administered can possibly be reduced without sacrificing diagnostic performance relative to that achievable with other GBCAs administered at a standard dose [38–41]. The possibility of lowering the dose administered to patients at risk for developing NSF is consistent with recommendations and institutional guidelines on the use of GBCAs in this patient population [42, 43]. Second, the aromatic group on the gadobenate molecule potentially increases the stability of the molecule by improving its kinetic inertia. This possibly is the result of an increased steric effect conferred by the bulk of the benzyloxymethyl substituent that hinders unwrapping of the ligand around the gadolinium [31]. Improved kinetic inertia due to the presence of an aromatic moiety has previously been demonstrated for gadofosveset [44]. Third, because of the presence of the aromatic group, a fraction of the injected dose (typically 2–4% of the dose in subjects with normal renal functions) of gadobenate dimeglumine is taken up by functioning hepatocytes and excreted in the bile [45]. Thus, the injected gadolinium has an additional means of escape from the body even in patients with end-stage renal disease who are receiving long-term hemodialysis. As recently reported by Heverhagen et al. [7], a hepatobiliary elimination rate of 5%, converted, corresponds to an eGFR of approximately 6 mL/min/1.73 m2 via the kidney. Although this level of elimination is not much for a healthy patient, it may be significant in patients who are at risk of developing NSF, particularly given that a residual kidney function of approximately 10% (≃ 15 mL/min/1.73 m2) may be sufficient to protect the vast majority of at-risk patients against NSF [46, 47]. To note also is that the level of hepatobiliary elimination might actually increase in a compensatory manner in patients with renal insufficiency, as shown by Swan et al. [27], who noted increased hepatobiliary excretion corresponding to 8% of the injected dose in subjects with severe renal impairment. Increased compensatory hepatobiliary elimination of gadobenate has recently been shown in an animal model of acute renal insufficiency [48]. Of importance, liver disease does not appear to be an additional risk factor for NSF; recent studies of patients with severe chronic liver disease have reported no cases of NSF after the administration of gadobenate dimeglumine [49–51].
None of the 405 patients enrolled in study C (all of whom had an eGFR < 30 mL/min/1.73 m2) had been exposed to any GBCA in the 10 years before the study, and none were administered a GBCA during the 2-year follow-up. Of these 405 patients, 280 (69.1%) had a history of receiving dialysis. Although several factors reported to be associated with NSF (e.g., coagulation abnormalities or thrombotic events, hyperphosphatemia, metabolic acidosis, and the use of high doses of recombinant erythropoietin [52]) were all present in this patient population, no case of NSF was detected. This finding supports the theory that, although factors and conditions other than exposure to GBCAs may possibly facilitate the development of NSF, they do not in themselves trigger the development of NSF.
The incidence of immediate AEs was low (0.8% for gadobenate dimeglumine and 1.8% for gadoteridol), and all AEs were mild in intensity and rapidly self-resolving. Overall, both agents exhibited a satisfactory safety profile in this special population of patients with moderate-to-severe renal impairment.
The strength of these studies lies in the fact that they were prospectively designed and thus not subject to the shortcomings of retrospective assessments, such as selection bias and incomplete data collection. Moreover, the MRI examinations were performed according to the routine practice in place at each institution, with no modification of contrast dose or examination protocol solely for the purposes of the study. Furthermore the studies addressed patients who had differing degrees of renal impairment over an extended 2-year time frame. A possible limitation of the study was the relatively low numbers of patients enrolled (in particular, the group of patients with severe renal impairment) in the context of a disorder as rare as NSF. On the other hand, this study complied with the requirements posed by the FDA.
In conclusion, no cases of NSF occurred after the routine administration of gadobenate dimeglumine or gadoteridol to patients with an increased risk for NSF. Likewise, patients with severe CKD or end-stage renal disease who were not exposed to GBCAs did not develop NSF.
Acknowledgments
We thank the following investigators for recruiting patients into study A or study B: W. Gerald Klingler (Klingler Dermatology, Springfield, IL), Doug Rodriguez ( Tampa General Hospital, Tampa, FL), Stephen Seliger (University of Maryland, Baltimore, MD), Jeffrey Penfield (VA North Texas Health Care System, Dallas, TX), A. Sami Nassif (St. Louis University Hospital, St. Louis, MO), Harvey Schwartz (Sunrise Clinical Research, Hollywood, FL), John Wasenko (SUNY Upstate Medical University, Syracuse, NY; present address: Northern Radiologic Imaging, Watertown, NY), Kirk A. Craig (SUNY Upstate Medical University, Syracuse, NY), Sarah Bastawrous (Puget Sound VAHCS, Seattle, Washington), and Priscilla Winchester (Weill Cornell Medical College, New York, NY; present address: New York University Langone Medical Center, New York, NY).
We also thank the following investigators for recruiting patients into study C: Ihab Wahba (Samaritan Kidney Specialists, Corvallis, OR), Adit Mahale (Sanford Research–USD, Fargo, ND), David Roer (Nephrology and Hypertension Associates, PC, Macon GA), Melvin Laski (Texas Tech University Health Sciences Center, Lubbock, TX), Carlos Martinez (Renal Physicians of GA, PC, Macon, GA), Robert Reilly (VA North Texas Health Care System, Dallas, TX), Todd Minga (Nephrology Associates Research Center, Panama City, FL), Robert Cohen (Southwest Kidney Institute, Tempe, AZ), Daniel Rakowski (Tidewater Kidney Specialists, Inc., Chesapeake, VA), Ronald P Miller (Penn State Hershey Medical Center, Hershey, PA), and Eddie R. Fuller III (UNC Kidney Center, Chapel Hill, NC).
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Submitted: December 29, 2014
Accepted: February 16, 2015
First published: August 21, 2015
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