What nephrologists need to know about gadolinium

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What nephrologists need to know about gadolinium

  1. 1. review www.nature.com/clinicalpractice/neph What nephrologists need to know about gadolinium Jeffrey G Penfield* and Robert F Reilly Jr Continuing Medical Education online S U M M A rY Medscape, LLC is pleased to provide online continuing Gadolinium chelates are commonly used to improve tissue contrast in MRI. medical education (CME) for this journal article, Until recently the use of gadolinium was thought to be risk-free compared allowing clinicians the opportunity to earn CME credit. with alternative contrast agents. Recent studies, however, have raised serious Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to concerns regarding the safety of gadolinium chelates. Although safe provide CME for physicians. Medscape, LLC designates in patients with normal kidney function, administration of these agents in this educational activity for a maximum of 1.0 AMA PRA people with renal dysfunction can result in up to three clinical problems that Category 1 CreditsTM. Physicians should only claim credit the nephrologist should be familiar with. The first is nephrogenic systemic commensurate with the extent of their participation in the activity. All other clinicians completing this activity will fibrosis (NSF), which was initially observed in 1997. Although manifesting be issued a certificate of participation. To receive credit, primarily in skin, NSF can also cause systemic fibrosis, leading to disabling please go to http://www.medscape.com/cme/ncp contractures and even death. Gadodiamide is the agent that has been most and complete the post-test. frequently associated with NSF, but other chelates might also pose a risk. The Learning objectives second clinical problem is that gadolinium chelates cause acute kidney injury, Upon completion of this activity, participants should be especially at high doses required for angiography. The third problem is that able to: several laboratory artifacts are associated with gadolinium administration, 1 Describe the metabolism and properties of gadolinium. 2 Identify the connection between gadolinium and with pseudohypocalcemia being the most important. The risk of a patient renal disease and its mechanism. experiencing all three of these complications increases as renal function 3 Specify laboratory abnormalities associated with declines. In light of these problems, nephrologists need to re-evaluate the the use of gadolinium. risks and benefits of gadolinium administration in patients with chronic 4 Describe the clinical presentation and treatment of nephrogenic systemic fibrosis. kidney disease stage 3 or greater, as well as in those with acute kidney injury. 5 List recommendations for the use of gadolinium. keywords contrast-induced nephropathy, gadolinium, nephrogenic fibrosing dermopathy, nephrogenic systemic fibrosis, pseudohypocalcemia IntroduCtIon rEvIEw CrItErIA We searched a variety of medical literature sources, including PubMed, MRI has become an essential part of current MEDLINE, and nephrology and basic science journals, for information on medical practice on the basis of the high quality gadolinium, mechanisms of gadolinium toxicity, nephrogenic fibrosing of the images the method is able to produce. dermopathy, nephrogenic systemic fibrosis, and pseudohypocalcemia and other Vascular enhancement with a gadolinium-based laboratory artifacts. Three hundred and eleven references published between 1962 and June 2007 were selectively reviewed. contrast agent further improves the results of MRI. Clinical trials and extensive clinical experi- ence have proven that gadolinium-based contrast agents are safe in patients with normal kidney function. As renal function deteriorates, however, JG Penfield is Staff Physician in the Section of Nephrology at Veterans Affairs the safety of these agents diminishes. Nephrogenic North Texas Health Care System and Assistant Professor of Medicine in the Department of Medicine, The University of Texas Southwestern Medical systemic fibrosis (NSF) is associated with gado- Center. RF Reilly Jr is Acting Chairman of the Department of Medicine and linium chelates and occurs exclusively in patients Chief of the Section of Nephrology, at Veterans Affairs North Texas Health with decreased renal function. The nephrotoxicity Care System, as well as Fredric L Coe Professor of Nephrolithiasis Research in of these agents also becomes more pronounced as Mineral Metabolism at the Department of Medicine, The University of Texas renal function declines. Derangement of labora- Southwestern Medical Center, Dallas, TX, USA. tory measurements as a result of administration of gadolinium chelates is observed in patients with Correspondence *Veterans Affairs North Texas Health Care System, 4500 S Lancaster Road, Dallas, TX 75216, USA normal renal function, but the effect is greater and jeffrey.penfield@va.gov its duration longer in patients with renal insuf- ficiency. This Review discusses the adverse effects received 10 May 2007 Accepted 17 August 2007 www.nature.com/clinicalpractice of gadolinium-based contrast agents in patients doi:10.1038/ncpneph0660 with decreased renal function. 654 nAtUre clinicAl prActice NEPHROLOGY dEcEmbER 2007 vOL 3 NO 12 © 2007 Nature Publishing Group
  2. 2. review www.nature.com/clinicalpractice/neph table 1 Gadolinium chelates approved for use during MRI. Chelate Trade name Approving Chemical Charge dissociation Molecular Half-life Proportion NsF cases (abbreviation) (manufacturer) body structure half-life weight (h ±sd) excreted reported (year of (da) within 24 h to FdA May approval) (% ±sd) 2007 Gadopentetate Magnevist® FDA and Linear Ionic 10 min 939.0 1.60 ± 0.13 91 ± 13 21 dimeglumine (Bayer HealthCare EMEA (Gd-DTPA) Pharmaceuticals; (1988) Montville, NJ) Gadoteridol ProHance® (Bracco FDA and Cyclic Nonionic 3 h 558.7 1.57 ± 0.08 94.4 ± 4.8 1 (patient (Gd-HP-DO3A) Diagnostics; EMEA also received Princeton, NJ) (1992) Omniscan®) Gadodiamide Omniscan® FDA and Linear Nonionic 30 s 573.6 1.30 ± 0.27 95.4 ± 5.5 85 (Gd-DTPA-BMA) (GE Healthcare, EMEA Chalfont St Giles, (1993) Buckinghamshire, UK) Gadobenate MultiHance® FDA and Linear Ionic NA 1,058.2 1.17 ± 0.26 NA 1 (patient dimeglumine (Bracco Diagnostics) EMEA 2.02 ± 0.60 also received (Gd-BOPTA) (2004) Omniscan®) Gadoversetamide OptiMARK® FDAa Linear Nonionic NA 661.8 1.73 ± 0.32 95.5 ± 17.4 6 (Gd-DTPA-BMEA) (Mallinckrodt; (1999) Hazelwood, MO) Gadobutrol Gadovist® (Bayer EMEA Cyclic Nonionic NA 604.0 1.50 NA None (Gd-BT-DO3A) Schering Pharma; (2001) Berlin, Germany) Gadoterate Dotarem® (Guerbet; EMEA Cyclic Ionic NA 559.0 1.50 90 None meglumine Paris, France) (1989) (Gd-DOTA) Gadoxetic acid Primovist® (Bayer EMEA Linear Ionic NA 682.0 0.95 >99b None disodium salt Schering Pharma) (2004) (Gd-EOB-DTPA) Gadofosveset Vasovist® (Bayer EMEA Linear Ionic NA 958.0 2.0–3.0 NA None trisodium Schering Pharma) (2005) aBeing reviewed by the EMEA. bExcreted in both urine and feces. Abbreviations: EMEA, European Agency for the Evaluation of Medical Products; NA, not available; NSF, nephrogenic systemic fibrosis. GAdoLInIuM and reduces the toxicity of the agent. The LD50 Gadolinium is a rare earth element from the in rodents increases 100-fold with chelation.3 lanthanide series that is used as a contrast agent Five different gadolinium chelates are approved in MRI because of its powerful paramagnetic in the US by the FDA for use as MRI agents properties. Its seven unpaired electrons perturb (shown in Table 1). In the US, approximately proton relaxation in water, resulting in a short- 26.9 million MRI scans were performed in ened T1 relaxation time and increased magnetic 2006 and in 45% of these cases a gadolinium resonance signal intensity. Gadolinium in its chelate was administered.4 To date, more than unbound state is highly toxic. It is a potent inhib- 200 million patients worldwide have been itor of calcium channels and has considerable exposed to gadolinium chelates.5 cardiovascular and neurologic toxicity. In mice, The only FDA-approved indication for gado- the median lethal dose (LD50; i.e. the amount linium chelates is use as a contrast agent in MRI required to kill 50% of the population) of at a dose of 0.1 mmol/kg.6 These agents are GdCl3 is just 100–200 mg/kg.1 Free gadolinium also used for magnetic resonance angiography is deposited in liver, bone and lymph nodes and, (MRA) and as contrast agents in arteriography once there, is slowly released from the body at a and venography, but these are not FDA-approved rate of less than 1% per day.2 indications. Dosages for these procedures are Gadolinium must be chelated for use in not standardized, but in a 1999 survey the humans. Chelation improves the water solubility nephrotoxicity of doses as high as 0.9 mmol/kg dEcEmbER 2007 vOL 3 NO 12 PENFIELd ANd REILLY nAtUre clinicAl prActice NEPHROLOGY 655 © 2007 Nature Publishing Group
  3. 3. review www.nature.com/clinicalpractice/neph was not considered to be important by the dimeglumine. These two agents are the gado- majority of practitioners.7 linium preparations most frequently used in The pharmacokinetic properties of most gado- the US, which could account for a proportion linium chelates are similar. The compounds are of the increased incidence of NSF associated water soluble, excreted unchanged by glomerular with these chelates. Market share alone does filtration, do not undergo biotransformation, not, however, explain the disparity in the and are distributed in extracellular fluid. Notable number of cases reported to be caused by these exceptions to these rules include gadoxetic acid two agents. (Primovist®; Bayer Schering Pharma, Berlin, The propensity of gadolinium chelates to Germany), gadofosveset trisodium (Vasovist®; undergo transmetalation might influence their Bayer Schering Pharma) and gadobenate dimeg- toxicity. Transmetalation refers to the capacity lumine (MultiHance®; Bracco Diagnostics, of other cations in the body (e.g. zinc, copper Princeton, NJ). Gadoxetic acid is taken up by and calcium) to displace gadolinium from hepatocytes; up to 50% of the agent is excreted its chelate.12 Copper has high affinity for the in feces and 50% in urine. The chelate is used chelates, but is not present in the body at suffi- for enhanced imaging of the liver.8 Between cient concentrations to displace large amounts 80–96% of circulating gadofosveset trisodium of gadolinium. The concentration of calcium is bound to plasma proteins, and the compound in serum is high, but the affinity of calcium for has been used as a blood pool agent.9 Only a chelates is low. Zinc has moderate affinity and a small proportion of circulating gadobenate sufficiently high serum concentration to displace dimeglumine is protein bound; it is taken up gadolinium.11 In humans and experimental by hepatocytes and has a fecal excretion rate of models, the extent of transmetalation can be 4%.10 Other gadolinium chelates are not bound evaluated in vivo as urinary zinc excretion. by proteins or eliminated in feces. Molecular If gadolinium is displaced from its chelate by weights of the compounds range from 558 zinc, zinc binds the chelate and is subsequently to 1,058 daltons. The half-life of gadolinium excreted in urine. There are marked differences chelates in patients with normal renal function among the gadolinium chelates in the rates is approximately 1.5 hours, and more than 90% of short-term (within 3 hours) urinary zinc of a dose is excreted in 24 hours (Table 1). excretion after administration of 0.1 mmol/kg The differences in the effects of various of chelate. Interestingly, these differences corre- gadolinium preparations are attributable spond to the kinetic stability of these agents. to gadolinium’s capacity to dissociate from In a study in humans, urinary zinc excretion chelates. The LD50s in rodents for various was highest with gadodiamide (27.4 μmol) and gadolinium chelates were found to vary intermediate with gadopentetate dimeglumine up to 50-fold, but all were lethally toxic (5.9 μmol), both of which are linear chelates.13 when the same amount of gadolinium was By contrast, in the same study, urinary zinc released from the chelate.11 Gadodiamide excretion was lowest with the cyclic chelate (Omniscan®; GE Healthcare, Chalfont St Giles, gadoteridol (1.2 μmol). Buckinghamshire, UK) has the shortest dissocia- Similarly, in vitro studies have shown that tion constant—30 seconds compared with linear chelates (i.e. gadodiamide, gadopentetate 10 minutes and with 3 hours for gadopentetate dimeglumine and gadobenate dimeglumine) are dimeglumine (Magnevist®; Bayer HealthCare susceptible to transmetalation, but cyclic chelates Pharmaceuticals, Montville, NJ) and gado- (i.e. gadoteridol, gadobutrol [Gadovist®; Bayer teridol (ProHance®, Bracco Diagnostics), Schering Pharma] and gadoterate meglumine respectively. The longer dissociation constant [Dotarem®; Guerbet, Paris, France]) are resistant of gadoteridol is probably a function of its to this process.14 cyclic structure; most other gadolinium chelates have a linear structure. Release of gadolinium nEphrotoxICIty of GAdoLInIuM from a cyclic chelate requires all four cova- ChELAtEs lent bonds to be broken simultaneously. The MRI and/or MRA with gadolinium enhance- more flexible structure of linear chelates more ment is often used instead of iodinated-contrast readily facilitates gadolinium release. This fact radiographic methods. MRI provides superior might account for the higher incidence of NSF image quality to iodinated contrast methods, associated with gadodiamide and gadopentetate and methods that use iodinated contrast are 656 nAtUre clinicAl prActice NEPHROLOGY PENFIELd ANd REILLY dEcEmbER 2007 vOL 3 NO 12 © 2007 Nature Publishing Group
  4. 4. review www.nature.com/clinicalpractice/neph associated with a risk of acute kidney injury nEphroGEnIC systEMIC fIbrosIs (AKI); for many years, gadolinium chelates were NSF was first observed in 1997 and the initial thought to be risk-free. Gadolinium is used in case series published in 2000.31 The condition X-ray angiography in place of iodinated contrast, was originally known as ‘nephrogenic fibrosing particularly in patients with chronic kidney dermopathy’ because it manifested primarily in disease (CKD). Early investigations reported skin. Later cases revealed more-diffuse involve- that gadolinium chelates were not associated ment including subcutaneous tissue, striated with AKI in patients with CKD (Table 2).15–24 muscle, the diaphragm and pleurae, the peri- The limitations of these reports include small cardium, and the myocardium. The name of the sample size, lack of control groups, poor disorder was changed to NSF in 2005.32 uniformity of pretreatment regimens, variable Potential etiological agents for NSF remained gadolinium doses and routes of administration, elusive for many years, but the condition was and different definitions of contrast-induced known to occur exclusively in patients with nephropathy (CIN). Higher than recommended decreased renal function.33 The association doses of gadolinium chelates (>0.2 mmol/kg) with gadolinium chelates was first described in were used in several of the studies. In response January 2006 in an Austrian study by Grobner.34 to these early reports and the desire to avoid Five of nine patients who received gadodiamide CIN, gadolinium chelates were frequently used developed NSF within 2–4 weeks of exposure. for standard venography and arteriography, and These patients had metabolic acidosis whereas higher doses than those approved by the FDA the four patients without NSF did not, but this were administered. association was not confirmed in later reports. Subsequent reports (Table 3) detected an In May 2006, the Danish Medicines Agency increased risk of AKI associated with gado- reported 25 cases of NSF that had occurred after linium chelates in patients with CKD.25–28 gadodiamide exposure.35 Five of these cases had These studies included more patients, one study been reported previously by Grobner, and twenty was prospective, and the doses used were, on were newly reported cases from Denmark. The average, higher than those used in earlier series. FDA issued a black box warning in June 2006 There is at least one biopsy-documented case that was updated in December 2006 and again in report of gadolinium-induced AKI; histological May 2007. The warning reiterated the association examination of the sample showed acute tubular of gadolinium chelates with NSF. necrosis, similar to that associated with CIN Although there is good evidence that only three caused by iodinated contrast.29 One case report of the five FDA-approved gadolinium chelates describes a patient with CKD who received are associated with NSF, the FDA warned that all iodinated contrast for coronary angiography gadolinium chelates had the potential to cause but suffered no nephrotoxic effects.5 Three NSF. The FDA recommended that gadolinium years later he developed AKI after receiving chelates be used in patients with advanced kidney just 0.14 mmol/kg of gadodiamide for an MRA, failure (i.e. those on dialysis or with an estimated indicating that gadolinium could be more glomerular filtration rate [GFR] <15 ml/min nephrotoxic than iodinated contrast even at per 1.73 m2) only if absolutely necessary, and doses less than 0.2 mmol/kg. that it might be prudent to initiate hemodialysis It is not known whether the cause of nephro- promptly after gadolinium administration toxicity associated with gadolinium chelates is in these patients. This recommendation was the chelate itself or free gadolinium. As both formulated on the basis of studies by Okada and gadolinium chelates and iodinated contrast colleagues36 that showed gadolinium excretion cause acute tubular necrosis, it is reasonable to rates of 78.2%, 95.6%, 98.7% and 99.5% in the recommend avoiding high doses of gadolinium first, second, third and fourth post-gadolinium and maintaining adequate hydration in patients dialysis sessions, respectively. with CKD. In a 2000 position paper, the Contrast Media Safety Committee of the European Society LInk bEtwEEn GAdoLInIuM of Urogenital Radiology recommended, on the And nEphroGEnIC systEMIC fIbrosIs basis of nephrotoxicity data, that gadolinium Several groups have examined the potential link chelates should not be used in place of iodinated between gadolinium administration and NSF. contrast media for radiographic examinations in Deo et al.37 studied a group of patients treated in a patients with CKD.30 dialysis practice in Bridgeport, CT. Three cases of dEcEmbER 2007 vOL 3 NO 12 PENFIELd ANd REILLY nAtUre clinicAl prActice NEPHROLOGY 657 © 2007 Nature Publishing Group
  5. 5. review www.nature.com/clinicalpractice/neph table 2 Summary of the results of studies that showed that gadolinium did not cause acute kidney injury. study design sample Agent(s) dose used renal status renal outcome Preventive size used (mmol/kg) treatment (mean age) used Rofsky et al. Workup of renal 5 (69 years) Magnevist® 0.1 Creatinine No increase in creatinine NA (1991)20 mass >2.0 mg/dl (range concentration 2.2–6.0 mg/dl) Bellin et al. Prospective 20 Dotarem® 0.1 GFR No >25% increase in creatinine None (1992)15 study of (Cockroft–Gault) concentration; creatinine consecutive <60 ml/min concentration increased >10% patients; (mean in 5 controls and 3 gadolinium- intravenous 21.1 ± 3.2 ml/min) exposed patients gadolinium (n = 10) vs no contrast (n = 10) Prince et al. Retrospective 64 Magnevist® 0.2–0.4 Creatinine CIN (defined as ≥0.5 mg/dl NA (1996)18 study of (n = 21), >1.5 mg/dl increase in creatinine iodinated Omniscan® concentration) occurred in contrast vs (n = 37) or 29% (9 of 31 patients) exposed gadolinium ProHance® to iodinated contrast and 0% (n = 6) exposed to gadolinium Kaufman Digital 14 Omniscan® ≤0.4 Creatinine CIN (defined as ≥0.5 mg/dl increase NA et al. subtraction (66.7 years) or ≥1.5 mg/dl (mean in creatinine concentration at (1999)17 vena cavogram Magnevist® 2.8 ± 1.1 mg/dl) 48 h) did not occur; creatinine concentration of 3 patients increased as a result of causes other than gadolinium exposure Spinosa Renal 25 Omniscan® <0.3 Creatinine CIN (defined as >0.5 mg/dl increase Hydration et al. arteriogram (59 years) >1.5 mg/dl in creatinine concentration at (1999)23 (mean 3.1 mg/dl) 48 h) did not occur; creatinine concentration of 2 patients increased as a result of causes other than gadolinium exposure Hammer Arterial digital 34 Magnevist® 0.4 Creatinine CIN (defined as >0.5 mg/dl NA et al. subtraction (53.1 years) >1.5 mg/dl increase in creatinine (1999)16 angiography concentration) occurred in 3% (1 of 34 patients) Spinosa Retrospective 42 Omniscan® ≤ 0.4 Creatinine CIN (defined as ≥0.5 mg/dl 300–500 ml et al. study of >1.5 mg/dl (mean increase in creatinine normal (2000)22 iodinated 2.2 mg/dl, range concentration) occurred in 40% saline contrast and 1.6–3.6 mg/dl) (6 of 15 patients) exposed to before CO2 (n = 15), iodinated contrast and 5% (1 of procedure gadolinium and 20 patients) exposed to gadolinium CO2 (n = 20) and CO2 alone (n = 7) Townsend Prospective 32 Omniscan® 0.2 Creatinine CIN (defined as >0.5 mg/dl Normal et al. study of clearance increase in creatinine saline after (2000)24 gadolinium vs 20–29 ml/min concentration) did not occur bolus normal saline (n = 9), infusion only 30–60 ml/min (no imaging (n = 11) performed) Sancak Upper 16 Omniscan® 0.3 Mean creatinine Largest increase in creatinine NA et al. extremity (53 years) 1.5 mg/dl (range concentration was 0.2 mg/dl (2002)21 or superior 1.2–1.8 mg/dl) vena cava venography Rieger et al. Prospective 32 Magnevist® 0.34 ± 0.06 Creatinine CIN (defined as >0.5 mg/dl increase Normal (2002)19 procedures >1.5 mg/dl (mean in creatinine concentration at saline (arterial and 3.6 ± 1.4 mg/dl) 72 h) did not occur; creatinine intravenous ) concentration of 1 patient increased as a result of cholesterol emboli To convert mg/dl to μmol/l, multiply by 88.4. Abbreviations: CIN, contrast-induced nephropathy; GFR, glomerular filtration rate; NA, not available. 658 nAtUre clinicAl prActice NEPHROLOGY PENFIELd ANd REILLY dEcEmbER 2007 vOL 3 NO 12 © 2007 Nature Publishing Group
  6. 6. review www.nature.com/clinicalpractice/neph table 3 Summary of the results of studies that showed that gadolinium is nephrotoxic. study design sample Agent(s) used dose used renal status renal outcome Preventive size (mmol/kg) treatment used Sam Retrospective, 195 Magnevist® 0.28 Creatinine CIN (defined as >1.0 mg/dl NA et al. uncontrolled study (n = 195) clearance increase in creatinine (2003)28 of patients with CKD <80 ml/min concentration at 48 h plus (January 1999 to (Cockroft– oligoanuria) occurred in January 2001) Gault); mean 3.5% (7 of 195 patients); 38.2 ± 16 ml/min 1.9% (3 of 153) of magnetic resonance angiography group and 9.5% (4 of 42) of digital subtraction angiography group were affected Erley Prospective, 21 Gadovist® (n = 10) 0.57 ± 0.17 Creatinine CIN (defined as >50% Intravenous et al. randomized study or iohexol (n = 11) >1.5 mg/dl or decrease in GFR) occurred hydration (2004)27 GFR <50 ml/min in 50% (5 of 10 patients) exposed to gadolinium and 45% (5 of 11) exposed to iohexol Briguori Retrospective study of 25 Omniscan® (n = 8) 0.6 ± 0.3 Creatinine CIN (defined as ≥0.5 mg/dl Normal (2006)25 consecutive patients or Gadovist® (range >2 mg/dl or increase in creatinine saline plus N- who had undergone (n = 17); three 0.28–1.23) creatinine concentration within 48 h acetylcysteine coronary procedures, parts agent clearance or need for dialysis within compared with historical mixed with one <40 ml/min 5 days) occurred in 28% controls part iodinated (7 of 25 patients) exposed contrast vs to gadolinium plus iodinated iodinated contrast and contrast alone 6.5% (2 of 32) exposed to iodinated contrast only Ergun Retrospective, 91 Magnevist®, 0.2 Stage 3 and CIN (defined as ≥0.5 mg/dl NA et al. uncontrolled study Omniscan® 4 CKD; mean increase in creatinine (2006)26 (February 1999 to or Dotarem® estimated GFR concentration within 72 h) March 2005); creatinine 33 ml/min (range occurred in 12% (11 of concentration measured 15–58 ml/min) 91 patients) before, and 1, 3, 7 and approximately 30 days after, exposure to gadolinium To convert mg/dl to μmol/l, multiply by 88.4. Abbreviations: CIN, contrast-induced nephropathy; CKD, chronic kidney disease; GFR, glomerular filtration rate; NA, not available. NSF were identified during an 18 month period significant risk factor for NSF was gadolinium that ended 1 July 2006; two of these patients had exposure within 12 months of diagnosis (odds received gadodiamide and one had received gado- ratio 8.97). The attack rate for peritoneal dialysis pentetate dimeglumine. The incidence of NSF patients was 4.6 per 100 patients and was 0.61 per among all hemodialysis patients in this study was 100 for hemodialysis patients. The number of 4.3 cases per 1,000 patient years. The risk of devel- peritoneal dialysis patients in this study was small, oping NSF was 2.4% per gadolinium exposure.37 but evidence from a study by Joffe et al. of poor In another study, 33 cases of NSF were reported in clearance of gadolinium chelates during peritoneal the St Louis, MO, area. Nineteen confirmed cases dialysis supports this finding.39 were evaluated in more detail in a case-controlled Khurana and co-workers40 reviewed the study.38 Four patients had been exposed to gado- case records of six patients who had developed linium more than 1 year before diagnosis of NSF NSF between 19 days and 2 months after gado- and one individual had no known exposure. diamide exposure. One patient had AKI, one The remainder had received gadolinium within patient had AKI superimposed on advanced a year of diagnosis. Two patients had AKI and CKD, another was on hemodialysis, and three the remainder were chronic dialysis patients. had stage 5 CKD but were not yet on dialysis. In multivariate analysis, the only statistically This report emphasizes that NSF occurs in dEcEmbER 2007 vOL 3 NO 12 PENFIELd ANd REILLY nAtUre clinicAl prActice NEPHROLOGY 659 © 2007 Nature Publishing Group
  7. 7. review www.nature.com/clinicalpractice/neph patients with reduced renal function and is not included two individuals with CKD stage 3 plus confined to the dialysis population. In a study AKI. One was a liver transplant recipient, the other in Denmark, 13 people developed NSF between a renal transplant recipient. The authors empha- 2 and 75 days after exposure to gadodiamide.41 sized that AKI in the setting of a proinflammatory The odds ratio for exposure was 32.5 in these event could have contributed to the development patients compared with patients with end- of NSF in these two patients. stage renal disease (ESRD) who had not been Marckmann et al.45 reviewed 19 cases of exposed. No association of NSF with acidosis gadodiamide-induced NSF to identify potential was detected. The same authors reported no cofactors. The primary risk factor for NSF was an new cases of NSF at their institution since the increasing cumulative dose of gadodiamide. The use of gadodiamide was discontinued in March investigators also observed a statistically signifi- 2006.42 The total number of NSF cases related cant correlation between NSF and elevated serum to gadodiamide that they have observed has now calcium and phosphorus concentrations, and increased to 24. The extra cases are the result between NSF and higher doses of epoetin beta. of delayed diagnosis of NSF that was caused There was no correlation of NSF with acidosis, by exposure to gadodiamide before its use was use of angiotensin-converting-enzyme (ACE) discontinued at their institution (P Marckmann, inhibitors, or serum parathyroid levels. personal communication). At least 96 reported cases of NSF have been Broome et al.43 reported 12 patients who associated with gadolinium-containing contrast developed NSF after gadodiamide exposure. media. The type of gadolinium chelate used A total of 559 MRI exams were performed on was reported for 63 cases; all but one patient 168 dialysis patients. The 12 patients who devel- received gadodiamide (this individual received oped NSF (301 gadodiamide exposures) were gadopentetate dimeglumine) and one patient compared with those who were not exposed received both gadodiamide and gadobenate to gadodiamide (258 MRI exams). Four of the dimeglumine. There are no published case twelve patients were liver transplant recipients reports linking gadoversetamide (OptiMARK®; with AKI secondary to hepatorenal syndrome. Mallinckrodt, Hazelwood, MO) with NSF, The odds ratio for exposure to gadodiamide was although six cases have been reported to again high, at 22.3, and the prevalence of NSF MedWatch, the FDA safety information and among gadodiamide-exposed dialysis patients adverse event reporting program. MedWatch was 4%. Patients receiving gadodiamide doses reports are generated by volunteer clinicians of 0.1 mmol/kg and those receiving doses of and are not peer-reviewed. As of 17 January 0.2 mmol/kg were compared. The odds ratio 2007, 85 cases of NSF associated with gado- for developing NSF for those on the higher dose diamide, 21 cases associated with gadopentetate was 12.1, indicating that the risk of developing dimeglumine, and 6 cases associated with gado- the condition is dose dependent. Daily dialysis, versetamide, had been reported to the FDA. starting on the day of gadolinium administration, NSF has also been reported to develop after for 3 days did not prevent NSF in three patients. sequential administration of gadodiamide In another series, thirteen patients devel- and gadobenate dimeglumine, as well as after oped NSF after being exposed to gadolinium; sequential administration of gadodiamide and all received gadodiamide, and one was exposed gadoteridol.6 Only two patients who devel- to both gadobenate dimeglumine and gado- oped NSF without any known exposure to diamide.44 These patients were compared with gadolinium are reported in the literature.38,46 a group of 4,236 individuals who received gado- linium but did not develop NSF. Affected patients tIssuE dEposItIon of GAdoLInIuM had higher serum creatinine concentrations Gadolinium can be deposited in the bone tissue and had undergone a greater number of contrast- of normal individuals. Deposition in bone enhanced magnetic resonance exams than those was examined in patients with normal kidney who did not develop NSF. Those with NSF were function undergoing hip replacement after also affected by more proinflammatory events gadolinium-enhanced MRI.47 Gadolinium was (defined as surgery, thromboembolic vascular administered 3–8 days before surgery and levels events, or systemic infections), emphasizing in operative bone fragments were measured. the potential contribution of inflammation to the The concentration of gadolinium was four development of NSF. This series of patients also times higher (1.77 ppm) in patients who received 660 nAtUre clinicAl prActice NEPHROLOGY PENFIELd ANd REILLY dEcEmbER 2007 vOL 3 NO 12 © 2007 Nature Publishing Group
  8. 8. review www.nature.com/clinicalpractice/neph gadodiamide than in those who received gado- Skin involvement in NSF is symmetrical, teridol (0.477 ppm). This difference was attributed with extensive waxy thickening and hardening to the increased stability of cyclic gadoteridol of the extremities and torso. Skin can become compared with linear gadodiamide.47,48 hyperpigmented and take on a ‘woody’ texture There are two published reports of gadolinium with plaques and subcutaneous nodules. Unlike deposition being detected in skin affected by scleromyxedema, NSF tends to spare the skin of NSF. High et al. analyzed thirteen affected skin the head and neck, and is not associated with samples from seven patients.49 Gadolinium paraproteinemia.31 A review of published cases had been deposited in four of thirteen samples by Mendoza et al. showed that skin of the lower (four of the seven patients with NSF) at an extremities was affected in 97% of cases, and the average concentration of 70 ppm. A sample of distribution was from ankle to mid thigh.55 uninvolved skin (with actinic keratosis) from The upper extremities were involved in 77% of a patient with NSF had a gadolinium concen- cases, most commonly from the wrist to mid tration of only 5 ppm. In patients with detectable upper arm. Truncal involvement was reported levels of gadolinium, a tissue residence time in 30% of cases,55 and there have been reports of of 4–11 months was postulated on the basis of yellow scleral plaques in the eye.56 Joint contrac- exposure history.49,50 There has been one report tures are a common result of progressive skin, of a patient with NSF whose affected skin was as well as muscle and fascia, fibrosis, and lead examined using scanning electron microscopy to severe immobility.57,58 Progression is rapid and energy-dispersive X-ray spectroscopy.51 in a subset of patients, who can become bed or Interestingly, gadolinium was detected only wheelchair bound as a result of contractures. in areas at which calcium phosphate had been There is an increased risk of thrombosis deposited in blood vessels. manifesting as deep venous thrombosis, a On the basis of the above findings, the pulmonary embolus, thrombosed arterio- proposed etiology for NSF is the deposition venous access, or an atrial thrombus, in patients of free gadolinium in tissue, secondary to with NSF. Elevated levels of antiphospholipid prolonged gadolinium clearance time in patients and anticardiolipin antibodies, deficiencies with decreased renal function. Once deposited in of protein C, protein S and antithrombin III, tissue, free gadolinium is not readily cleared by and presence of factor V Leiden, have all been the kidney because of the poor water solubility observed in such patients.52,59–62 Patients of the agent. The most consistent improvement in with liver disease and those who have under- NSF occurs in patients whose renal dysfunction gone liver transplantation seem to be at reverses. Taken together, these findings indi- increased risk of developing NSF. Originally cate that gadolinium deposition alone cannot thought to be confined to skin, it is now known be the sole cause of NSF. The pathophysiologic that the fibrosis can be systemic and involve interaction between gadolinium deposition and fascia, subcutaneous tissue, and other organs, reduced GFR remains to be determined. including lungs, heart, muscle, kidneys, dura mater, and testes.63–66 In one case of NSF, CLInICAL fEAturEs of nEphroGEnIC progressive fibrosis of the diaphragm eventually systEMIC fIbrosIs led to death from respiratory failure.65 NSF has been reported to affect people across a Examination of skin biopsy samples from broad range of ages (8–86 years). The condition patients with NSF reveals haphazardly-arranged has no gender predilection. In a study by Jain and thickened dermal collagen bundles interspersed co-workers, all patients affected with NSF had a with increased numbers of plump fibroblasts decreased GFR; 90% were on dialysis as a result and mucin deposition.31,67 The skin of some of ESRD or AKI.52 Seven patients were reported patients harbors osteoclast-like giant cells with to have CKD stage 3 or 4, and a disproportionate focal areas of calcification68 and ossification.69 number of these individuals were renal or liver The histology resembles that of a healing wound. transplant recipients. The GFR of these patients Fibrocytes positive for CD34 and procollagen-1 was estimated using serum creatinine measure- are found in affected tissue. These fibrocytes ments. The true GFR of both liver and renal originate in bone marrow and are drawn to transplant recipients is usually lower than the esti- the dermis by an unknown stimulus (possibly mated GFR,53,54 so it is possible that these patients gadolinium deposition). After migrating to the had more severe CKD than was reported. dermis, the fibrocytes differentiate into cells dEcEmbER 2007 vOL 3 NO 12 PENFIELd ANd REILLY nAtUre clinicAl prActice NEPHROLOGY 661 © 2007 Nature Publishing Group
  9. 9. review www.nature.com/clinicalpractice/neph that resemble normal fibroblasts and could be There have been several studies of gadolinium responsible for the excessive fibrosis.64,70,71 pharmacokinetics in hemodialysis patients; data from peritoneal dialysis patients are limited. trEAtMEnt of nEphroGEnIC Published reports have several limitations. For systEMIC fIbrosIs example, conclusions are often drawn on the basis Treatment of NSF is often unsuccessful. Most of decay curves of serum gadolinium concen- therapies have only been tested informally and the tration. During formulation of these curves, it results published as case reports. NSF can improve is assumed that gadolinium is removed from with recovery of renal function after, for example, serum solely by dialysis. This might not be the successful kidney transplantation or resolution of case; sequestration of gadolinium in interstitial AKI. Published reports of treatments are often or intracellular compartments would be errone- of limited value as they do not comment on the ously interpreted as dialytic removal. Joffe et al.39 course of renal dysfunction. Disease regression noted that the half-life of gadolinium (gado- must be interpreted in light of GFR; improve- diamide; 0.1 mmol/kg) during hemodialysis was ment of NSF in the setting of a rising GFR might 2.6 ± 0.4 hours when a low-flux biocompatible result from reversal of the renal lesion and not dialyzer was used for 4 hours three times per week. from therapy for NSF per se. Ultraviolet A1 treat- The authors reported that one hemodialysis session ment was reported to be successful in one patient, removed 65% of gadolinium; however, gadolinium but reversal of AKI might have been the true cause levels in dialysate were not measured. Saitoh and of improvement.72 Plasmapheresis was reportedly colleagues78 reported a gadolinium half-life of effective in another patient, but, again, improve- 1.93 hours during hemodialysis in 13 patients ment of renal function could have been the dialyzed with a 1.5 m2 synthetic-polymer actual cause of recovery.67 Extracorporeal photo- dialyzer at low dialysate flow rates (200 ml/min). pheresis was beneficial in three patients whose Gadodiamide was the administered chelate kidney function did not improve.57 Sodium thio- (0.1 mmol/kg), and dialysis was carried out on sulfate was reported to improve symptoms in a days 1, 3, and 5 after exposure to gadolinium. The patient with ESRD on chronic hemodialysis.73 estimated proportion of gadolinium removed after The mobility of one peritoneal dialysis patient each of these three dialysis sessions was 73.8%, partially improved after the first, but not subse- 92.4%, and 98.9%, respectively; however, dialysate quent, courses of intravenous immunoglobulin.74 was only collected during the first hemodialysis Physical therapy is recommended to prevent and session. Okada and co-workers36 studied 70 hemo- treat joint contractures. dialysis patients who received a 0.1 mmol/kg dose of gadopentetate dimeglumine, and estimated the GAdoLInIuM CLEArAnCE proportions of gadolinium removed after four And rEnAL dIsEAsE 4-hour dialysis sessions to be 72.8%, 95.6%, 98.7%, The half-life and clearance of gadolinium chelates and 99.5%. Dialysate samples were not collected— have been examined in patients with CKD or percentage gadolinium removal was estimated on ESRD who are on hemodialysis or peritoneal the basis of serum concentration decay curves. The dialysis.36,39,75–82 Swan et al.81 measured concen- first dialysis session occurred at variable intervals trations of gadolinium in serum, urine and stool after gadolinium administration (same day in after a single dose of gadobenate dimeglumine 16 patients, next day in 34 patients, 2 days later (0.2 mmol/kg) in patients with varying degrees of in 14 patients, and 3 days later in 6 patients). The type renal function. In people with a normal GFR, the of dialyzer used in the study was not reported. half-life of gadolinium was 1.96 hours. It increased Data from the largest series of peritoneal to 6.11 ± 2.95 hours in those with a GFR of dialysis patients who had received a gadolinium 31–60 ml/min per 1.73 m2 and to 9.48 ± 3.08 hours chelate were reported by Joffe et al.39 Nine in those with a GFR of 10–30 ml/min per 1.73 m2. patients underwent continuous ambulatory Other studies of the half-life of gadobenate dimeg- peritoneal dialysis with four exchanges per day. lumine and gadoversetamide in patients with CKD Dialysate was collected and gadolinium half- yielded similar results.79,80 In nine patients with life was estimated to be 52.7 ± 6.2 hours. Only stage 5 CKD (GFR 2–10 ml/min per 1.73 m2) who 69% of gadolinium had been removed after received a single dose of gadodiamide (0.1 mmol/kg), 22 days of peritoneal dialysis. In a case report Joffe and co-workers found that the half-life of of another peritoneal dialysis patient, who gadolinium was prolonged to 34.3 ± 22.9 hours.39 had received gadoversetamide (0.1 mmol/kg), 662 nAtUre clinicAl prActice NEPHROLOGY PENFIELd ANd REILLY dEcEmbER 2007 vOL 3 NO 12 © 2007 Nature Publishing Group
  10. 10. review www.nature.com/clinicalpractice/neph the gadolinium half-life was reported to be table 4 Recommended minimum waiting 9 hours.76 The patient, however, was producing time from administration of contrast medium 3 liters of residual urine per day. The rate of to collection of plasma sample for the removal of gadolinium by peritoneal clearance measurement of calcium. was low in both studies, at 3.8 ± 0.6 ml/min estimated glomerular filtration waiting time (h) and 5.13 ml/min, respectively. rate (ml/min per 1.73m2) We will not review in vitro studies in detail 20 50 in this article, but some useful insights can be 30 18 gained from them. First-order kinetic modeling 40 11 showed that 12.2–14.7 hours of dialysis were required to remove 97% of an injected gado- 50 8 linium dose.75 Gadolinium clearance during 60 6 dialysis is more efficient when membranes 75 5 with a large pore size are used,83 and nonionic 90 4 gadolinium chelates are more easily removed 130 3 via positively-charged dialysis membranes than Permission obtained from the American Association for ionic gadolinium chelates (see Table 1 for charge Clinical Chemistry © Kang HP et al. (2004) Clin Chem 50: status of gadolinium chelates).77 741–746. LAborAtory AbnorMALItIEs AssoCIAtEd wIth GAdoLInIuM Gadolinium chelates interfere with a wide variety (2 mg/dl) in 42 patients, and in 25 patients was less of assays. The most widely reported laboratory than 1.5 mmol/l (6 mg/dl). Oral or intravenous artifact associated with gadolinium is pseudo- calcium was administered to 18 patients for what hypocalcemia.84–89 Gadolinium can also reduce was mistakenly interpreted as ‘true’ hypocalcemia, ACE levels, alter serum iron concentration even though the patients had no clinical symp- (reduce or elevate, depending on the assay), toms of the disorder. The pseudohypocalcemic increase total iron-binding capacity, and lower effect persisted for up to 4.5 days in patients with serum zinc levels.89 CKD, and was more pronounced at high doses Pseudohypocalcemia was first reported to be of gadodiamide. In patients with a normal GFR associated with gadolinium in 1995.90 It is most who had received low-dose gadodiamide, pseudo- common for gadolinium to affect colorimetric hypocalcemia lasted 4–6 hours. In those whose assays that employ orthocresolphthalein (OCP), GFR was reduced, the artifact persisted for more the agent most frequently used to measure than 24 hours. Recommended minimum waiting calcium concentration. Pseudohypocalcemia times from administration of contrast medium to does not occur when assays that employ atomic collection of plasma sample have been established emission spectroscopy or ion-selective elec- for the Roche OCP assay (Hitachi 747 analyzer; trodes are used. Artifactual reduction of calcium Roche Diagnostics, Indianapolis, IN) on the basis concentration is thought to result either from of GFR (Table 4).91 binding of gadolinium to OCP, which prevents Kang et al.91 also examined the effect of OCP from binding calcium, or from binding of several different gadolinium chelates on in vitro calcium to the excess chelate that is included in calcium concentrations. Gadodiamide and gado- some (but not all) gadolinium chelate prepara- versetamide both reduced calcium levels, whereas tions. Gadodiamide has 0.025 mmol/ml of gadoteridol and gadopentetate dimeglumine did excess chelate and gadopentetate dimeglumine not. Interestingly, both the gadolinium chelates that 0.001 mmol/ml; gadoterate meglumine contains cause pseudohypocalcemia in vitro are packaged no excess chelate. The purpose of including with higher concentrations of excess chelate— excess chelate in gadolinium preparations is to 331 mg/ml for gadoversetamide and 12 mg/ml for maintain gadolinium binding during storage. gadodiamide versus 0.2 mg/ml for gadoteridol and In a study by Prince et al. of 896 patients 0.4 mg/ml for gadopentetate dimeglumine. This whose serum calcium level was measured within fact indicates that pseudohypocalcemia might 24 hours of gadodiamide administration, 165 be the result of calcium binding to excess infused developed pseudohypocalcemia.88 Calcium chelate, rather than of dissociation of gadolinium concentration declined by more than 0.5 mmol/l from chelate in vivo.40 dEcEmbER 2007 vOL 3 NO 12 PENFIELd ANd REILLY nAtUre clinicAl prActice NEPHROLOGY 663 © 2007 Nature Publishing Group
  11. 11. review www.nature.com/clinicalpractice/neph The reduction in ACE levels observed after gadoversetamide and gadopentetate dimeglumine gadolinium administration is thought to result as being associated with an increased risk of NSF, from binding of zinc by the chelate; measurement but do not specifically recommend that these of ACE is zinc dependent. Iron concentration is agents be avoided. As gadodiamide is the agent increased by gadolinium when the Vitros® 950 most often associated with NSF in reported cases, (Ortho-Clinical Diagnostics, Raritan, NJ) and we agree with the ACR and Kuo et al.95 that use of Synchron LX® 20 (Beckman Coulter, Brea, CA) this preparation be avoided in patients with any assays are used.89 Likewise total iron-binding degree of renal dysfunction. It is also prudent to capacity is increased by gadolinium when avoid using gadoversetamide and gadopentetate either the Modular P or Dimension RxL (Roche dimeglumine until more data regarding their risk Diagnostics, Indianapolis, IN, and Dade Behring, become available. These agents are reported to Deerfield, IL, respectively) methods are used cause NSF and, like gadodiamide, have a linear to quantify this parameter. The formazan dye structure and short dissociation half-lives. employed in the zinc assay probably binds gado- The MHRA report states that serum creatinine linium, resulting in a falsely low concentration concentration should be measured before gado- of zinc being detected. linium administration.92 By contrast, the ACR recommends relying on information regarding rECoMMEndAtIons for usE kidney disease provided by the referring physi- of GAdoLInIuM cian or by the patient via a questionnaire.93 Given The FDA,6 Danish Medicines Agency (DMA),35 that even patients with advanced CKD are often United Kingdom Medicines and Healthcare unaware of their disease, we agree with the MHRA products Regulatory Agency (MHRA),92 and that a serum creatinine concentration should be American College of Radiology (ACR),93 among obtained by the referring physician if a gadolinium other organizations, have published recom- chelate is to be administered. If a patient has any mendations regarding gadolinium use. Selected history of kidney disease, determination of serum recommendations by these agencies have been creatinine level should be required by the radiology chosen to frame our discussion of some of the department within 30 days before the imaging more-controversial issues. The MHRA has procedure, or sooner if there is a clinical concern submitted a public assessment report to the about recent deterioration in GFR (e.g. a preceding European Medicines Agency, but this statement iodinated contrast study). We recognize that NSF is does not represent the view of all member states. a rare occurrence in patients with stage 3 or 4 CKD, The DMA report is an independent Danish but we feel that this recommendation is justified publication. The ACR recommendations were given the serious consequences of the disorder. derived from a ‘blue ribbon’ panel and repre- The need for a gadolinium-based contrast sent consensus of ACR members; they have not, study should be carefully considered in a patient however, been adopted as policy by the ACR.94 with CKD stage 3 or greater and alternative The FDA is the only agency to suggest that all imaging modalities should be considered. The gadolinium chelates are potentially linked to lowest possible dose of gadolinium should be NSF.6 The other three organizations mentioned used because development of NSF might be dose above specifically implicate gadodiamide as related.43 The use of gadolinium in angiographic being associated with the highest risk for NSF. studies as an alternative to iodinated contrast This assertion is based on the fact that most should be carefully evaluated because the dose cases of NSF are associated with this gado- required is often high and recent studies indicate linium preparation. The DMA and MHRA that gadolinium is nephrotoxic (see Table 3). view gadodiamide as being contraindicated Other recommendations that are consistent in patients with a GFR of less than 30 ml/min with those in published literature and prudent to per 1.73 m2,35,92 whereas the ACR recommends adopt are that standard gadolinium doses should avoiding gadodiamide in patients with any degree not be exceeded and repeat doses should not be of renal dysfunction.93 Although the FDA does given in less than 1 week, that gadodiamide should not state that any specific preparation is contra- be avoided in patients with renal dysfunction who indicated, it does recommend that physicians have had or are about to undergo liver transplanta- carefully consider the need for any gadolinium tion, and that postponing the imaging study until chelate in patients with moderate kidney renal function has recovered in patients with AKI dysfunction to ESRD. The ACR and MHRA regard should be considered.92 664 nAtUre clinicAl prActice NEPHROLOGY PENFIELd ANd REILLY dEcEmbER 2007 vOL 3 NO 12 © 2007 Nature Publishing Group
  12. 12. review www.nature.com/clinicalpractice/neph Perhaps the most controversial issue is the need gadolinium several times. One patient had under- for post-gadolinium hemodialysis; there is a marked gone renal transplantation, two had undergone difference of opinion on this topic among recom- liver transplantation, and two had advanced mending bodies. The FDA originally stated that it stage 4 CKD (estimated GFR 17–18 ml/min might be prudent to promptly initiate hemodialysis per 1.73 m2). after administration of gadolinium chelates to Taken together, these findings indicate that patients with advanced kidney dysfunction (stage 5 subgroups of patients with CKD stage 3 or 4 might CKD or ESRD). The most recent FDA update be at increased risk of developing NSF after gado- (23 May 2007) recommended consideration linium administration. These subgroups include of prompt post-gadolinium dialysis only in those exposed to gadolinium more than once, patients who were already on hemodialysis liver graft recipients, and patients for whom the (the term “prompt” is not defined in the recom- Modification of Diet in Renal Disease equation mendation).6 The FDA also stated that it is not might overestimate true GFR (e.g. organ trans- known whether hemodialysis prevents NSF. The plant recipients and those with AKI superimposed ACR advocates hemodialysis within 2 hours of on CKD). The risk of developing NSF increases gadolinium administration in patients already as GFR declines through CKD stages 3, 4 and 5 on hemodialysis.93 There is, as yet, no evidence to to ESRD, with a very low risk in CKD stage 3 and support this recommendation. The MHRA does a 2.5% risk per exposure for patients with ESRD. not consider hemodialysis to be indicated in such We agree with the MHRA that the evidence to date instances, due to a lack of evidence regarding its effi- does not justify the risks that are associated with cacy.92 The risks associated with post-gadolinium acute access placement and hemodialysis after hemodialysis are minimal for stable ESRD patients gadolinium exposure. Every effort should be made with functioning accesses; as such, the FDA recom- to postpone any gadolinium-enhanced imaging mendation is reasonable. The MHRA correctly procedures in patients with AKI. At our institution, asserts, however, that there is no evidence that gadoteridol was in use before the association hemodialysis will prevent NSF. Data reported by between NSF and gadolinium chelates was recog- Broome and co-workers for three patients who nized. We will continue to use gadoteridol in developed NSF despite three consecutive daily preference to other FDA-approved gadolinium hemodialysis sessions clearly show that NSF can still chelates because patients receiving gadoteridol develop despite aggressive dialysis.43 Assumptions have the lowest reported incidence of NSF. about gadolinium removal from the body that are Decisions regarding the benefit of hemodialysis made on the basis of plasma concentration decay for gadolinium clearance are also difficult when curves might lead to overestimation of the efficiency managing peritoneal dialysis patients. Peritoneal of gadolinium clearance by hemodialysis. dialysis seems to be an inefficient means of The risk of developing NSF after gadolinium removing gadolinium. It should be pointed out, exposure in patients with stage 3–5 CKD is however, that this opinion is based on data derived unknown, but seems to be less than the 2.5–4.0% from patients maintained on older chronic ambu- postulated for the ESRD population.37,43 NSF has latory peritoneal dialysis regimens. Improved developed in two patients with stage 3 CKD;44 one clearance might be possible with more-aggressive patient was a renal allograft recipient, the other a cycler-based regimens, and this possibility liver transplant recipient, and GFR was declining warrants further study. That said, data from the in both at the time of multiple exposures to gado- Morbidity and Mortality Weekly Report indicating linium. It is probable that the true GFR of both that the incidence of NSF in gadolinium-exposed patients was lower than that estimated using the peritoneal dialysis patients is 7.5 times higher Modification of Diet in Renal Disease equation.96 than that in hemodialysis patients is alarming.38 The FDA’s original warning in June 2006 and It seems prudent to avoid exposing peritoneal subsequent update in December of that year stated dialysis patients to gadolinium if possible, until that patients with a GFR of less than 60 ml/min the risk is further clarified. If gadolinium must be per 1.73 m2 were at risk of developing NSF after used, gadoteridol should be considered as the first exposure to gadolinium. In the most recent update choice of chelate. Initiating post-exposure hemo- (23 May 2007), the GFR cutoff had been changed to dialysis should be considered, especially if the less than 30 ml/min per 1.73 m2.6 Five patients with patient has a functioning access. Alternatively, stage 4 CKD have developed NSF after gadolinium the peritoneal dialysis prescription could be administration.43,44 All had been exposed to increased. It should be emphasized, however, that dEcEmbER 2007 vOL 3 NO 12 PENFIELd ANd REILLY nAtUre clinicAl prActice NEPHROLOGY 665 © 2007 Nature Publishing Group
  13. 13. review www.nature.com/clinicalpractice/neph these approaches might not prevent NSF and there references 1 Caille JM et al. (1983) Gadolinium as a contrast agent are no data to support them. for NMR. AJNR Am J Neuroradiol 4: 1041–1042 2 Tweedle MF (1992) Physicochemical properties ConCLusIons of gadoteridol and other magnetic resonance contrast agents. Invest Radiol 27 (suppl 1): S2–S6 Over time, the number of indications for, and doses 3 Bousquet JC et al. (1988) Gd-DOTA: characterization of, gadolinium chelates have increased beyond of a new paramagnetic complex. Radiology 166: those originally approved by the FDA. Although 693–698 4 AuntMinnie.com (online 21 February 2007) IMV Report: these increases have probably not compromised MRI market growing. [http://www.auntminnie.com/ the safety of patients with normal renal function, index.asp?Sec=sup&Sub=bai&Pag=dis&ItemId=74472] (accessed 19 June 2007) for those with a reduced GFR the risk of devel- 5 Thomsen HS (2004) Gadolinium-based contrast media oping NSF is now a concern. A strong association may be nephrotoxic even at approved doses. Eur between NSF and gadolinium-based agents has Radiol 14: 1654–1656 6 US Food and Drug Administration (online 23 May emerged from retrospective analyses. Gadolinium 2007) Healthcare professional sheet: gadolinium- has been detected in affected tissue, but there is containing contrast agents for magnetic resonance as yet no definitive proof that gadolinium is the imaging (MRI) (marketed as Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance). [http://www. cause of NSF. Treating an animal model such fda.gov/cder/drug/InfoSheets/HCP/gccaHCP.htm] as a 5/6 nephrectomized rat with gadolinium (accessed 19 June 2007) chelates might provide some insight into causal 7 Morcos SK et al. (1999) Contrast-media-induced nephrotoxicity: a consensus report. Contrast Media relationships. Until more data become available, Safety Committee, European Society of Urogenital it is advisable to avoid using gadolinium chelates Radiology (ESUR). Eur Radiol 9: 1602–1613 (particularly gadodiamide) whenever possible in 8 Hamm B et al. (1995) Phase I clinical evaluation of Gd-EOB-DTPA as a hepatobiliary MR contrast agent: people with severe kidney disease to ESRD. As safety, pharmacokinetics, and MR imaging. Radiology gadolinium chelates can be nephrotoxic, their use 195: 785–792 should no longer be considered ‘safe’ in terms of 9 Lauffer RB et al. (1998) MS-325: albumin-targeted contrast agent for MR angiography. Radiology 207: CIN. If a gadolinium chelate is administered, the 529–538 physician should be familiar with associated labora- 10 Kirchin MA et al. (1998) Gadobenate dimeglumine (Gd-BOPTA): an overview. Invest Radiol 33: 798–809 tory artifacts so that unnecessary treatment is not 11 Cacheris WP et al. (1990) The relationship between initiated on the basis of erroneous values. thermodynamics and the toxicity of gadolinium complexes. Magn Reson Imaging 8: 467–481 kEy poInts 12 Idee JM et al. (2006) Clinical and biological ■ Originally thought to be safe contrast agents, consequences of transmetallation induced by contrast gadolinium chelates have recently been shown agents for magnetic resonance imaging: a review. to be associated with the development of Fundam Clin Pharmacol 20: 563–576 nephrogenic systemic fibrosis (NSF) in patients 13 Puttagunta NR et al. (1996) Human in vivo comparative study of zinc and copper with impaired renal function transmetallation after administration of magnetic resonance imaging contrast agents. Invest Radiol 31: ■ NSF, previously known as nephrogenic 739–742 fibrosing dermopathy, occurs only in patients 14 Laurent S et al. (2006) Comparative study of the with kidney dysfunction, is characterized by physicochemical properties of six clinical low waxy thickening of the skin of the extremities molecular weight gadolinium contrast agents. Contrast and torso, and commonly leads to joint Media Mol Imaging 1: 128–137 15 Bellin MF et al. (1992) Gd-DOTA: evaluation of its renal contractures and immobility tolerance in patients with chronic renal failure. Magn Reson Imaging 10: 115–118 ■ The proposed, but not yet proven, etiology of 16 Hammer FD et al. (1999) Gadolinium dimeglumine: NSF is tissue deposition of free gadolinium an alternative contrast agent for digital subtraction that is liberated from chelates, secondary to angiography. Eur Radiol 9: 128–136 prolonged gadolinium clearance time due 17 Kaufman JA et al. (1999) Gadolinium-based contrast to impaired renal function agents as an alternative at vena cavography in patients with renal insufficiency—early experience. Radiology ■ Treatments for NSF have only been tested 212: 280–284 informally; the condition has been shown to 18 Prince MR et al. (1996) Nephrotoxicity of high-dose gadolinium compared with iodinated contrast. J Magn improve in response to recovery of kidney Reson Imaging 6: 162–166 function 19 Rieger J et al. (2002) Gadolinium as an alternative contrast agent for diagnostic and interventional ■ Several authorities have issued angiographic procedures in patients with impaired recommendations for use of gadolinium renal function. Nephrol Dial Transplant 17: 824–828 chelates; most advise caution when 20 Rofsky NM et al. (1991) Renal lesion characterization considering use of these agents in patients with gadolinium-enhanced MR imaging: efficacy and safety in patients with renal insufficiency. Radiology with renal dysfunction 180: 85–89 666 nAtUre clinicAl prActice NEPHROLOGY PENFIELd ANd REILLY dEcEmbER 2007 vOL 3 NO 12 © 2007 Nature Publishing Group

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