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Diagnostic testing in AKI: Let’s move the field forward
In this issue of the Journal of Hospital Medicine, Lusica et al.1 discuss the utility of urine eosinophils (UEs) in evaluating for acute interstitial nephritis (AIN) in patients with acute kidney injury (AKI), an important and oft-confused concern in medicine. I can’t think of a more appropriate topic for the “Things We Do for No Reason” (TWDFNR) series. Numerous tests are ordered in the evaluation of AKI.2 Many, such as batteries of serological tests, are unnecessary and add little diagnostic information. Some, such as UEs and fractional excretion of sodium (FENa), provide misinformation. And others, such as contrast-enhanced computed tomography scans, are potentially harmful.2 In a previous TWDFNR article, the limitations of FENa in the evaluation of AKI were reviewed.3 There are common threads linking the shortcomings of UEs and FENa and even new diagnostic tests. What are the lessons from these studies, and how might clinicians best apply them in their practice?
As reviewed in this issue, UE testing is employed in AKI to evaluate for hospital-acquired AIN. Small initial studies led to widespread use of this test, despite methodological flaws.4 A later, definitive study involving 566 patients who had both UEs and kidney biopsies performed within the same week demonstrated that UEs offered no diagnostic value in AKI.5 The same pattern occurred in the increased use of FENa to distinguish prerenal azotemia from acute tubular necrosis in AKI patients.3 Small studies in highly select patients supported its use for this purpose.6 Subsequently, larger studies in more diverse populations noted that FENa was associated with many false positive and negative results,6 likely due to more widespread use of this test in disease states such as cirrhosis, congestive heart failure, chronic kidney disease, and diabetes, which were not included in initial studies.
It is apparent that clinicians have been led astray by small, flawed positive studies employed in highly selected populations. These initial positive studies based on excessively large effect size estimates were subsequently shown to be negative in larger studies with more plausible effect sizes. Examples of this error are seen in publications involving prophylactic measures to reduce contrast nephrotoxicity.7 Early studies on N-acetylcysteine administration prior to radiocontrast exposure showed positive results. Examination of these studies, however, demonstrates 2 key problems: 1) inclusion of small numbers of patients due to power calculations based on excessively large effect sizes, and 2) use of clinically unimportant endpoints such as serum creatinine changes.7 The same issue complicates studies evaluating isotonic sodium bicarbonate vs. normal saline for contrast prophylaxis.7
The past 10-plus years have seen a proliferation of studies evaluating the utility of novel biomarkers for early diagnosis and prognosis in AKI. Have we fallen down the same rabbit hole in evaluating these new diagnostic tests for AKI? There is reason for concern if we examine published studies of novel biomarkers in other areas of medicine. To this point, many highly cited novel biomarker studies used for various diagnostic purposes (eg, cancer, infection, cardiovascular disease) employed excessively large effect size estimates for postulated associations that resulted in small, underpowered studies with initially positive results.8 Subsequent large studies and meta-analyses reported negative or modestly positive test results when examining these same associations.8 But we may be moving in the right direction. An early urine biomarker publication from a small, single center study9 revealed overly optimistic results (area under the curve [AUC], 0.998; sensitivity, 100%; specificity, 98%) for AKI prediction. Subsequent large, multicenter biomarker studies showed only modest improvement in their discriminative value when compared with traditional clinical models.10 These results precluded U.S. Food and Drug Administration (FDA) approval of most novel biomarkers for clinical practice and they were not adopted. In 2014, the FDA approved the point-of-care urinary biomarker TIMP-2/IGFBP7 (NephroCheck®) for predicting risk of AKI based on fairly rigorous testing using larger numbers of patients, heterogeneous populations, and important clinical endpoints.11 In a 522-patient discovery cohort, this biomarker had an AUC of 0.80 for AKI prediction, which was validated in a 722-patient cohort and subsequently followed by a 420-patient multicenter cohort study revealing similar test characteristics (AUC, 0.82; sensitivity, 92%; specificity, 46%).11 A study involving 382 critically ill AKI patients noted that this biomarker had a hazard ratio of 2.16 (95% confidence interval [CI] 1.32 to 3.53) for predict
In summary, clinicians should be aware of the strengths and limitations of diagnostic tests ordered in AKI patients, as seen with the overly optimistic results in small, flawed UE and FENa studies. While we have taken a step in the right direction with diagnostic and prognostic biomarkers for AKI, we must apply rigorous study design to diagnostic tests under evaluation before adopting them into clinical practice. Only then can we move the field forward and improve patient care.
Disclosure
Nothing to report.
1. Lusica M, Rondon-Berrios H, Feldman L. Urine eosinophils for acute interstitial nephritis. J Hosp Med. 2017;12(5):343-345. PubMed
2. Leaf DE, Srivastava A, Zeng X, et al. Excessive diagnostic testing in acute kidney injury. BMC Nephrol. 2016;17:9. PubMed
3. Pahwa AK, Sperati CJ. Urinary fractional excretion indices in the evaluation of acute kidney injury. J Hosp Med. 2016;11(1):77-80. PubMed
4. Perazella MA, Bomback AS. Urinary eosinophils in AIN: farewell to an old biomarker? Clin J Am Soc Nephrol. 2013;8(11):1841-1843. PubMed
5. Muriithi AK, Nasr SH, Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol. 2013;8(11):1857-1862. PubMed
6. Perazella MA, Coca SG. Traditional urinary biomarkers in the assessment of hospital-acquired AKI. Clin J Am Soc Nephrol. 2012;7(1):167-174. PubMed
7. Weisbord SD, Palevsky PM. Strategies for the prevention of contrast-induced acute kidney injury. Curr Opin Nephrol Hypertens. 2010;19(6):539-549. PubMed
8. Ioannidis JP, Panagiotou OA. Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses. JAMA. 2011;305(21):2200-2210. PubMed
9. Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231-1238. PubMed
10. Schaub JA, Parikh CR. Biomarkers of acute kidney injury and associations with short- and long-term outcomes. F1000Res. 2016;5(F1000 Faculty Rev.):986. PubMed
11. McMahon BA, Koyner JL. Risk stratification for acute kidney injury: Are biomarkers enough? Adv Chronic Kidney Dis. 2016;23(3):167-178. PubMed
In this issue of the Journal of Hospital Medicine, Lusica et al.1 discuss the utility of urine eosinophils (UEs) in evaluating for acute interstitial nephritis (AIN) in patients with acute kidney injury (AKI), an important and oft-confused concern in medicine. I can’t think of a more appropriate topic for the “Things We Do for No Reason” (TWDFNR) series. Numerous tests are ordered in the evaluation of AKI.2 Many, such as batteries of serological tests, are unnecessary and add little diagnostic information. Some, such as UEs and fractional excretion of sodium (FENa), provide misinformation. And others, such as contrast-enhanced computed tomography scans, are potentially harmful.2 In a previous TWDFNR article, the limitations of FENa in the evaluation of AKI were reviewed.3 There are common threads linking the shortcomings of UEs and FENa and even new diagnostic tests. What are the lessons from these studies, and how might clinicians best apply them in their practice?
As reviewed in this issue, UE testing is employed in AKI to evaluate for hospital-acquired AIN. Small initial studies led to widespread use of this test, despite methodological flaws.4 A later, definitive study involving 566 patients who had both UEs and kidney biopsies performed within the same week demonstrated that UEs offered no diagnostic value in AKI.5 The same pattern occurred in the increased use of FENa to distinguish prerenal azotemia from acute tubular necrosis in AKI patients.3 Small studies in highly select patients supported its use for this purpose.6 Subsequently, larger studies in more diverse populations noted that FENa was associated with many false positive and negative results,6 likely due to more widespread use of this test in disease states such as cirrhosis, congestive heart failure, chronic kidney disease, and diabetes, which were not included in initial studies.
It is apparent that clinicians have been led astray by small, flawed positive studies employed in highly selected populations. These initial positive studies based on excessively large effect size estimates were subsequently shown to be negative in larger studies with more plausible effect sizes. Examples of this error are seen in publications involving prophylactic measures to reduce contrast nephrotoxicity.7 Early studies on N-acetylcysteine administration prior to radiocontrast exposure showed positive results. Examination of these studies, however, demonstrates 2 key problems: 1) inclusion of small numbers of patients due to power calculations based on excessively large effect sizes, and 2) use of clinically unimportant endpoints such as serum creatinine changes.7 The same issue complicates studies evaluating isotonic sodium bicarbonate vs. normal saline for contrast prophylaxis.7
The past 10-plus years have seen a proliferation of studies evaluating the utility of novel biomarkers for early diagnosis and prognosis in AKI. Have we fallen down the same rabbit hole in evaluating these new diagnostic tests for AKI? There is reason for concern if we examine published studies of novel biomarkers in other areas of medicine. To this point, many highly cited novel biomarker studies used for various diagnostic purposes (eg, cancer, infection, cardiovascular disease) employed excessively large effect size estimates for postulated associations that resulted in small, underpowered studies with initially positive results.8 Subsequent large studies and meta-analyses reported negative or modestly positive test results when examining these same associations.8 But we may be moving in the right direction. An early urine biomarker publication from a small, single center study9 revealed overly optimistic results (area under the curve [AUC], 0.998; sensitivity, 100%; specificity, 98%) for AKI prediction. Subsequent large, multicenter biomarker studies showed only modest improvement in their discriminative value when compared with traditional clinical models.10 These results precluded U.S. Food and Drug Administration (FDA) approval of most novel biomarkers for clinical practice and they were not adopted. In 2014, the FDA approved the point-of-care urinary biomarker TIMP-2/IGFBP7 (NephroCheck®) for predicting risk of AKI based on fairly rigorous testing using larger numbers of patients, heterogeneous populations, and important clinical endpoints.11 In a 522-patient discovery cohort, this biomarker had an AUC of 0.80 for AKI prediction, which was validated in a 722-patient cohort and subsequently followed by a 420-patient multicenter cohort study revealing similar test characteristics (AUC, 0.82; sensitivity, 92%; specificity, 46%).11 A study involving 382 critically ill AKI patients noted that this biomarker had a hazard ratio of 2.16 (95% confidence interval [CI] 1.32 to 3.53) for predict
In summary, clinicians should be aware of the strengths and limitations of diagnostic tests ordered in AKI patients, as seen with the overly optimistic results in small, flawed UE and FENa studies. While we have taken a step in the right direction with diagnostic and prognostic biomarkers for AKI, we must apply rigorous study design to diagnostic tests under evaluation before adopting them into clinical practice. Only then can we move the field forward and improve patient care.
Disclosure
Nothing to report.
In this issue of the Journal of Hospital Medicine, Lusica et al.1 discuss the utility of urine eosinophils (UEs) in evaluating for acute interstitial nephritis (AIN) in patients with acute kidney injury (AKI), an important and oft-confused concern in medicine. I can’t think of a more appropriate topic for the “Things We Do for No Reason” (TWDFNR) series. Numerous tests are ordered in the evaluation of AKI.2 Many, such as batteries of serological tests, are unnecessary and add little diagnostic information. Some, such as UEs and fractional excretion of sodium (FENa), provide misinformation. And others, such as contrast-enhanced computed tomography scans, are potentially harmful.2 In a previous TWDFNR article, the limitations of FENa in the evaluation of AKI were reviewed.3 There are common threads linking the shortcomings of UEs and FENa and even new diagnostic tests. What are the lessons from these studies, and how might clinicians best apply them in their practice?
As reviewed in this issue, UE testing is employed in AKI to evaluate for hospital-acquired AIN. Small initial studies led to widespread use of this test, despite methodological flaws.4 A later, definitive study involving 566 patients who had both UEs and kidney biopsies performed within the same week demonstrated that UEs offered no diagnostic value in AKI.5 The same pattern occurred in the increased use of FENa to distinguish prerenal azotemia from acute tubular necrosis in AKI patients.3 Small studies in highly select patients supported its use for this purpose.6 Subsequently, larger studies in more diverse populations noted that FENa was associated with many false positive and negative results,6 likely due to more widespread use of this test in disease states such as cirrhosis, congestive heart failure, chronic kidney disease, and diabetes, which were not included in initial studies.
It is apparent that clinicians have been led astray by small, flawed positive studies employed in highly selected populations. These initial positive studies based on excessively large effect size estimates were subsequently shown to be negative in larger studies with more plausible effect sizes. Examples of this error are seen in publications involving prophylactic measures to reduce contrast nephrotoxicity.7 Early studies on N-acetylcysteine administration prior to radiocontrast exposure showed positive results. Examination of these studies, however, demonstrates 2 key problems: 1) inclusion of small numbers of patients due to power calculations based on excessively large effect sizes, and 2) use of clinically unimportant endpoints such as serum creatinine changes.7 The same issue complicates studies evaluating isotonic sodium bicarbonate vs. normal saline for contrast prophylaxis.7
The past 10-plus years have seen a proliferation of studies evaluating the utility of novel biomarkers for early diagnosis and prognosis in AKI. Have we fallen down the same rabbit hole in evaluating these new diagnostic tests for AKI? There is reason for concern if we examine published studies of novel biomarkers in other areas of medicine. To this point, many highly cited novel biomarker studies used for various diagnostic purposes (eg, cancer, infection, cardiovascular disease) employed excessively large effect size estimates for postulated associations that resulted in small, underpowered studies with initially positive results.8 Subsequent large studies and meta-analyses reported negative or modestly positive test results when examining these same associations.8 But we may be moving in the right direction. An early urine biomarker publication from a small, single center study9 revealed overly optimistic results (area under the curve [AUC], 0.998; sensitivity, 100%; specificity, 98%) for AKI prediction. Subsequent large, multicenter biomarker studies showed only modest improvement in their discriminative value when compared with traditional clinical models.10 These results precluded U.S. Food and Drug Administration (FDA) approval of most novel biomarkers for clinical practice and they were not adopted. In 2014, the FDA approved the point-of-care urinary biomarker TIMP-2/IGFBP7 (NephroCheck®) for predicting risk of AKI based on fairly rigorous testing using larger numbers of patients, heterogeneous populations, and important clinical endpoints.11 In a 522-patient discovery cohort, this biomarker had an AUC of 0.80 for AKI prediction, which was validated in a 722-patient cohort and subsequently followed by a 420-patient multicenter cohort study revealing similar test characteristics (AUC, 0.82; sensitivity, 92%; specificity, 46%).11 A study involving 382 critically ill AKI patients noted that this biomarker had a hazard ratio of 2.16 (95% confidence interval [CI] 1.32 to 3.53) for predict
In summary, clinicians should be aware of the strengths and limitations of diagnostic tests ordered in AKI patients, as seen with the overly optimistic results in small, flawed UE and FENa studies. While we have taken a step in the right direction with diagnostic and prognostic biomarkers for AKI, we must apply rigorous study design to diagnostic tests under evaluation before adopting them into clinical practice. Only then can we move the field forward and improve patient care.
Disclosure
Nothing to report.
1. Lusica M, Rondon-Berrios H, Feldman L. Urine eosinophils for acute interstitial nephritis. J Hosp Med. 2017;12(5):343-345. PubMed
2. Leaf DE, Srivastava A, Zeng X, et al. Excessive diagnostic testing in acute kidney injury. BMC Nephrol. 2016;17:9. PubMed
3. Pahwa AK, Sperati CJ. Urinary fractional excretion indices in the evaluation of acute kidney injury. J Hosp Med. 2016;11(1):77-80. PubMed
4. Perazella MA, Bomback AS. Urinary eosinophils in AIN: farewell to an old biomarker? Clin J Am Soc Nephrol. 2013;8(11):1841-1843. PubMed
5. Muriithi AK, Nasr SH, Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol. 2013;8(11):1857-1862. PubMed
6. Perazella MA, Coca SG. Traditional urinary biomarkers in the assessment of hospital-acquired AKI. Clin J Am Soc Nephrol. 2012;7(1):167-174. PubMed
7. Weisbord SD, Palevsky PM. Strategies for the prevention of contrast-induced acute kidney injury. Curr Opin Nephrol Hypertens. 2010;19(6):539-549. PubMed
8. Ioannidis JP, Panagiotou OA. Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses. JAMA. 2011;305(21):2200-2210. PubMed
9. Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231-1238. PubMed
10. Schaub JA, Parikh CR. Biomarkers of acute kidney injury and associations with short- and long-term outcomes. F1000Res. 2016;5(F1000 Faculty Rev.):986. PubMed
11. McMahon BA, Koyner JL. Risk stratification for acute kidney injury: Are biomarkers enough? Adv Chronic Kidney Dis. 2016;23(3):167-178. PubMed
1. Lusica M, Rondon-Berrios H, Feldman L. Urine eosinophils for acute interstitial nephritis. J Hosp Med. 2017;12(5):343-345. PubMed
2. Leaf DE, Srivastava A, Zeng X, et al. Excessive diagnostic testing in acute kidney injury. BMC Nephrol. 2016;17:9. PubMed
3. Pahwa AK, Sperati CJ. Urinary fractional excretion indices in the evaluation of acute kidney injury. J Hosp Med. 2016;11(1):77-80. PubMed
4. Perazella MA, Bomback AS. Urinary eosinophils in AIN: farewell to an old biomarker? Clin J Am Soc Nephrol. 2013;8(11):1841-1843. PubMed
5. Muriithi AK, Nasr SH, Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis. Clin J Am Soc Nephrol. 2013;8(11):1857-1862. PubMed
6. Perazella MA, Coca SG. Traditional urinary biomarkers in the assessment of hospital-acquired AKI. Clin J Am Soc Nephrol. 2012;7(1):167-174. PubMed
7. Weisbord SD, Palevsky PM. Strategies for the prevention of contrast-induced acute kidney injury. Curr Opin Nephrol Hypertens. 2010;19(6):539-549. PubMed
8. Ioannidis JP, Panagiotou OA. Comparison of effect sizes associated with biomarkers reported in highly cited individual articles and in subsequent meta-analyses. JAMA. 2011;305(21):2200-2210. PubMed
9. Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231-1238. PubMed
10. Schaub JA, Parikh CR. Biomarkers of acute kidney injury and associations with short- and long-term outcomes. F1000Res. 2016;5(F1000 Faculty Rev.):986. PubMed
11. McMahon BA, Koyner JL. Risk stratification for acute kidney injury: Are biomarkers enough? Adv Chronic Kidney Dis. 2016;23(3):167-178. PubMed
© 2017 Society of Hospital Medicine
The Hospitalist and NSF
What Is Nephrogenic Systemic Fibrosis?
Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease that occurs after exposure to gadolinium‐based contrast (GBC) in the presence of severe renal failure of acute or chronic nature.1, 27 As suggested by its former name, nephrogenic fibrosing dermopathy, the cardinal feature of this disorder is skin involvement. Symptoms begin anywhere from 2 to 75 days after exposure to GBC, though usually within 2 months.27 Initial signs and symptoms may include sharp and sometimes excruciating pain, tightening and burning of the skin associated with redness and swelling, symmetrical involvement, distribution with predilection for the extremities more than the trunk, and sparing of the face. The dependent lower extremities are more severely involved than the upper extremities. Dermal induration may occur in the form of plaques, nodules, and papules resulting in a woody texture on palpation. These findings usually progress over weeks to months with extensive dermal fibrosis involving entire limbs. Ultimately the patient may develop severe joint contractures and marked limitations in mobility.8 A fulminant presentation is seen in approximately 5% of patients who develop a rapidly progressive course over as short a time period as 2 weeks.
Systemic organ involvement including fibrosis of the heart, lung, diaphragm, skeletal muscles, and other organs has been described and has been associated with fatal outcomes.79
Though more frequent in those with end‐stage renal disease (ESRD), NSF has been seen in those with stage 4 and 5 chronic kidney disease (CKD) and acute kidney injury (AKI). Incidence rates have been difficult to calculate due to lack of exposure data in most studies, though 1 small case‐control study found 4.3 cases per 1000 patient years among hemodialysis patients with an absolute risk of 3.4% in the exposed patient.4 Interestingly, incident NSF rates published in a Centers for Disease Control case‐control study of 19 NSF sufferers were much higher for peritoneal dialysis (4.6 cases/100 patients) than for hemodialysis (0.61/100 patients).2 This is likely related to the different GBC clearance achieved with these modalities.
NSF has no predilection for gender, race, nationality or age group. Those with liver disease and lower body weight or lower muscle mass appear to be at greater risk, which may be related to overestimation of glomerular filtration rate (GFR) with falsely low creatinines seen in such patients. Risk is likely increased as well by multiple exposures to GBC in close proximity. Related host cofactors have not been identified, though elevated serum calcium and phosphate concentrations, exposure to high dose erythropoietin, and iron overload have been considered.10, 11
The diagnosis of NSF requires compatible clinical findings along with consistent histopathology. Suspicious clinical findings in a patient with underlying kidney disease (AKI, CKD stages 4 and 5) who has been exposed to a GBC agent, should prompt skin biopsy. An incisional or deep punch biopsy to allow examination of dermis, epidermis and subcutaneous fat is required. The primary feature is the presence of collagen bundles with increased dermal spindle cells that stain for CD34 and procollagen I. Importantly, an inflammatory infiltrate is absent.12, 13
The major differential diagnosis includes scleroderma, eosinophilic fasciitis, morphea, scleromyxedema, and calcific uremic arteriolopathy. Scleroderma is distinguished by clinical findings such as facial involvement, Raynaud's phenomenon, and sclerodactyly with histology demonstrating normal or decreased numbers of fibroblasts on skin biopsy. Scleromyxedema is marked clinically by facial involvement, paraproteinemia on laboratory testing, and presence of inflammation sometimes seen on biopsy. Calcific uremic arteriolopathy (called calciphylaxis by some), which also occurs in those with kidney failure, is distinguished clinically by usually focal skin changes with cutaneous necrosis and ulceration and livedo reticularis; skin biopsy often reveals medial calcification of the vasculature with intimal fibrosis and luminal thrombosis.
What Is the Role of GBC in NSF?
The cause of NSF remained elusive for several years. Initially described in 2006 with several case series confirming the association, the role GBC agents in the pathogenesis of NSF gained widespread acceptance.1, 27 It should be noted that there are 5 cases of NSF described in kidney transplant patients where no exposure to Gadolinium was found.14, 15 Therefore, the possibility of other triggers remains.
The currently proposed pathogenesis needs to be understood in the context of gadolinium's pharmacologic properties. Gadolinium in its free ionic form (Gd3+) is highly toxic and therefore is sequestered by a non‐toxic organic molecule called a chelate.16, 17 Dissociation of the Gd3+ from a chelate may occur through a process called transmetallation when the chelate binds with another endogenous metal such as zinc or copper, allowing the release of free Gd3+. It is this free gadolinium that appears to be culpable in development of NSF.18 GBC chelates can be categorized based on their biochemical structure (linear vs. macrocyclic) and their charge (ionic vs. non‐ionic). Macrocyclic chelates bind Gd3+ more tightly than linear chelates and possess lower dissociation rates,19 which may have implications for possible toxicity.
The prolonged half‐life of GBC in the context of renal failure appears to predispose GBC to transmetallation and dissociation of Gd3+ from its chelate. Following intravenous injection, GBC is excreted unchanged by the kidneys via glomerular filtration. As a result, elimination half‐life, which is approximately 1.6 hours in normal individuals, is increased approximately 4‐ to 33‐fold in renal failure, depending on the level of GFR.16, 17, 20, 21 This increases the potential for Gd3+ dissociation through prolonged circulation times.
It has been postulated that once dissociated, deposition of the Gd3+ ion into skin and other organs sets off a cascade of poorly understood events that result in edema and fibrosis.18 Recent findings of gadolinium deposition in the skin of patients with NSF as well as an animal model of NSF following GBC exposure support this hypothesis.2225 It appears that vascular trauma, endothelial dysfunction or transudation (edema) allows the Gd3+ metal to enter the tissues. This may explain the preponderance of initial symptoms in dependent areas of the limbs.
What Can Be Done to Prevent NSF?
Avoid GBC Exposure in at Risk Patients
GBC agents are contraindicated in those with ESRD, CKD with estimated GFR <30 mL/minute/1.73 m2 (stages 4 and 5) and AKI. It has become common practice to use the 4‐variable Modification of Diet in Renal Disease (MDRD) formula in estimating GFR.26 Importantly, no estimating formula can be used in the context of a rising serum creatinine concentration as occurs with AKI. If a patient has AKI, one must assume a GFR <15 mL/minute until proven otherwise.
In those with low muscle mass the MDRD estimated GFR may overestimate the true GFR.27 Therefore, the Cockcroft‐Gault estimated creatinine clearance or a 24 hour urine‐based creatinine clearance may be useful in identifying at risk patients with underlying CKD.
Choose the Lowest Risk GBC Agent
When GBC use is deemed necessary in the high risk individual, an agent with a macrocyclic chelate (gadoteridol in the United States) is recommended.28 No published cases of NSF have been described with singular use of such agents. In addition, a retrospective study demonstrated no cases of NSF in ESRD patients on hemodialysis exposed to gadoteridol over a 7‐year period.29 This is not unexpected given the pharmacologic properties of this GBC agent.
Gadodiamide, a linear, non‐ionic agent, appears to produce the greatest risk of NSF as the largest number of NSF cases has been reported with this agent. By October 2007, 283 of 447 cases reported to the Food and Drug Administration (FDA) were exposed to gadodiamide.28 The significant preponderance with this agent is unlikely related to market share, reporting bias or publication bias. Gadopentetate, a linear, ionic agent, which had the greatest market share during this time, was responsible for approximately a quarter of cases reported to the FDA.28 Based on these data, gadodiamide and gadopentetate (and probably all linear agents) should be avoided in high risk patients.
Use Lower Doses of GBC
The FDA approved dose of all GBC agents, except the macrocyclic agent gadoteridol, is 0.1 mmol/kg.30 It appears that higher off‐label doses of GBC agents (0.3‐0.4 mmol/kg) which have been utilized for vascular studies (magnetic resonance angiography [MRA]), may have contributed to the emergence of NSF several years after these agents became available.
Develop a Protocol With Radiology and Nephrology Departments
Assessment of Renal Function Prior to Contrast Administration Is Required
Radiology departments should identify those with ESRD, CKD with estimated GFR <30 mL/minute/1.73 m2 (stages 4 and 5) and AKI. Using the 4‐variable MDRD formula in estimating GFR with the caveats previously noted, radiology departments will identify most at‐risk patients. Since the MDRD formula will be inaccurate in the setting of ESRD and AKI, these diagnoses should be determined through other means (for example, the patient's medical history) as part of the consent process.
Alternative Radiologic Imaging Modalities to GBC Enhanced Magnetic Resonance Imaging Should Be Utilized When Suitable in Those at High Risk
Newer techniques should be investigated as alternatives to GBC exposure. These include Magnetic Resonance Imaging (MRI) without GBC‐enhancement, where options such as 3D time‐of‐flight MRA, phase‐contrast angiography, and arterial spin labeling‐MR provide excellent information about blood vessels and blood flow.31 MRI with ultra‐small paramagnetic iron oxide particles may offer a future alternative in those that need a contrast‐based scan for diagnosis.32
However, since contrast enhanced MRI/MRA studies remain extremely important imaging modalities, their use may be required in some high risk individuals. In this circumstance, a macrocyclic chelate employed at the lowest dose possible, is recommended. The radiologist and nephrologist should be consulted in these instances.
Hemodialysis
Although hemodialysis efficiently clears GBC, its removal is not complete. Furthermore, it is not clear whether the damage has already occurred by the time a hemodialysis treatment can be instituted.33 It should be recognized that GBC removal after one treatment averages 65% to 73.8%; 3 to 4 sessions are required to remove 99% of the contrast agent.21, 34 Peritoneal dialysis on the other hand is an ineffective method of GBC removal (T1/2 of 52.7 hours).21 Because not all of the circulating Gd3+ is removed with a single hemodialysis treatment, prolonged tissue exposure occurs in these patients. This is reflected by the development of NSF in patients despite undergoing consecutive hemodialysis treatments following GBC exposure.3 Therefore, based on incomplete GBC removal with hemodialysis and the lack of evidence supporting prevention of NSF with this modality, we and others33, 35 strongly recommend avoidance of GBC in all patients with advanced kidney disease (GFR <30), regardless of the availability of hemodialysis. As such, the ability to perform hemodialysis after GBC in and of itself does not justify such exposure. However, if GBC use is deemed essential, then immediate hemodialysis should be strongly considered after exposure with further treatment on consecutive days.
Once NSF Develops, What Treatments Options are Available?
Unfortunately there is lack of a universally effective therapy for NSF. Several interventions have been described mainly in anecdotal case reports and very small case series. They have been recently reviewed (Table 2).360
| GBC Formulation | Year of Approval | Charge | Molecular Structure | Probable Risk of NSF* |
|---|---|---|---|---|
| Gadopentetate (Magnevist) | 1988 | Ionic | Linear | Medium |
| Gadoteridol (Prohance) | 1992 | Non‐ionic | Cyclic | Very low |
| Gadodiamide (Omniscan) | 1993 | Non‐ionic | Linear | High |
| Gadoversetamide (OptiMARK) | 1999 | Non‐ionic | Linear | Medium |
| Gadobenate (MultiHance) | 2004 | Ionic | Linear | Low |
|
| Therapies most likely to benefit |
| Kidney transplant (in ESRD) |
| Physical therapy |
| Pain control |
| Therapies with anecdotal success |
| Extracorporeal photopharesis |
| Sodium thiosulfate |
| Therapies with limited success |
| Drugs: Glucocorticoids, Pentoxifylline, Cyclophosphamide, Thalidomide |
| Immunomodulatory: Plasmapharesis, Intravenous immunoglobulin |
| Local: Intralesional IFN‐alpha, topical calcipotriene, other phototherapy |
Physical therapy is the mainstay of treatment for NSF. Physical therapy (and occupational therapy if needed) is essential to help prevent or slow the progression of joint contractures. Adequate pain relief, often with narcotics, is essential for patient comfort and to allow tolerance of physical therapy. Therapies with anecdotal benefit include extracorporeal photopheresis and infusions of sodium thiosulfate, a substance with chelating properties. Other interventions, such as immunosuppressive agents, topical agents and other phototherapies have shown limited success.
AKI resolution has been observed to result in regression of lesions.1, 3740 Presumably, resolution of the AKI allows for clearance of gadolinium and other profibrotic mediators, though definitive evidence of this is not available. Based on the observed response to AKI recovery, it is not surprising that improvement after kidney transplantation has also been described.1, 41 However, responses have not been consistent.39, 42
Consensus Guidelines and Recommendations
Nephrology societies have not yet developed consensus guidelines. Only the European Society of Urogenital Radiology has issued guidelines to date.43 These guidelines are consistent with expert opinions published elsewhere and are reflected in our approach regarding prevention of NSF (Table 3).
|
| 1. GBC agents are contraindicated in patients on dialysis regardless of availability of rapid treatment after exposure |
| 2. Avoid MRI with GBC in those with GFR <30 ml/min (estimated by MDRD formula) |
| MDRD formula may overestimate GFR in those of low weightconsider Cockcroft‐Gault calculation or 24 hour urine collection for creatinine clearance |
| MDRD is invalid in patient with a rising serum creatinine concentration. Assume GFR <30 in those with acutely rising serum creatinine concentration |
| 3. Consider alternative imaging studies or MRI studies without Gadolinium consult radiologist |
| 4. If GBC study is a necessity, then as low a dose as possible of a macrocyclic chelate would be recommended |
| 5. If an exposure to gadolinium occurs in ESRD, hemodialysis should be performed as soon as possible and repeated on consecutive days |
| 6. If an exposure to gadolinium occurs in CKD 4 or 5 or AKI patient (not on dialysis), an individualized approach should be undertaken when considering temporary catheter placement and initiation of hemodialysis |
The FDA has sent out several alerts since June 2006, the most recent in May 2007.30, 4446 In its Information for Healthcare Professionals alert, the FDA outlines recommendations. These are included in our final recommendations shown in Table 3.30 Those with a recent liver transplant, or those with chronic liver disease, who have associated kidney insufficiency of any severity, have also been identified by the FDA as an at risk group. This is based on reports of NSF occurring more commonly in patients with AKI who have these underlying conditions.47
Conclusions
With the high and increasing rates of AKI, CKD and ESRD seen among hospitalized patients,48 the need for vigilance when obtaining imaging with GBC agents becomes particularly important in the inpatient setting. As a preventable disease, it is incumbent upon us to fully understand the risk factors and potential pitfalls that may result in a patient exposed to these agents. The hospitalist has the unique role of acting as a firewall between the patient and the imaging study that may put him or her at risk for this devastating disorder.
Identification of GBC as a major culprit in the development of NSF and hence avoidance of this agent in those at the highest risk is expected to reduce the incidence of NSF. It is likely that the future will bring further understanding of the underlying mechanisms of gadolinium‐induced NSF and with this understanding, even safer strategies for GBC usage. However, until safer contrast agents become available, avoidance of GBC exposure in those with advanced acute or CKD remains our most important defense.
- .Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?Nephrol Dial Transplant.2006;21(4):1104–1108.
- Nephrogenic fibrosing dermopathy associated with exposure to gadolinium‐containing contrast agents–St. Louis, Missouri, 2002–2006.MMWR Morb Mortal Wkly Rep.2007;56(7):137–141.
- ,,,,,.Gadodiamide‐associated nephrogenic systemic fibrosis: why radiologists should be concerned.AJR Am J Roentgenol.2007;188(2):586–592.
- ,,.Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure.Clin J Am Soc Nephrol.2007;2(2):264–267.
- ,,,,.Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan).Invest Radiol.2007;42(2):139–145.
- ,,, et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast‐enhanced magnetic resonance imaging.J Am Soc Nephrol.2006;17(9):2359–2362.
- ,,, et al.Nephrogenic systemic fibrosis: risk factors and incidence estimation.Radiology.2007;243(1):148–157.
- ,,.Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy).Curr Opin Rheumatol.2006;18(6):614–617.
- . Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001–2007. Available at http://www.icnfdr.org. Accessed December 2009.
- ,,,,.Case‐control study of gadodiamide‐related nephrogenic systemic fibrosis.Nephrol Dial Transplant.2007;22(11):3174–3178.
- ,,, et al.Nephrogenic fibrosing dermopathy and high‐dose erythropoietin therapy.Ann Intern Med.2006;145(3):234–235.
- ,.Nephrogenic systemic fibrosis: an update.Curr Rheumatol Rep.2006;8(2):151–157.
- ,.Nephrogenic systemic fibrosis: early recognition and treatment.Semin Dial.2008;21(2):123–128.
- ,,.Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature.Am J Transplant.2007;7(10):2425–2432.
- .Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting.Eur J Radiol.2008;66(2):230–234.
- .MR contrast agents, the old and the new.Eur J Radiol.2006;60(3):314–323.
- ,,,,,.Magnetic resonance contrast agents: from the bench to the patient.Curr Pharm Des.2005;11(31):4079–4098.
- .Tissue deposition of gadolinium and development of NSF: a convergence of factors.Semin Dial.232008.
- .Safety of magnetic resonance contrast media.Top Magn Reson Imaging.2001;12(4):309–314.
- ,,, et al.Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment.Invest Radiol.1999;34(7):443–448.
- ,,.Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis.Acad Radiol.1998;5(7):491–502.
- ,,.Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol.2007;56(1):27–30.
- ,,,,.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol.2007;56(1):21–26.
- ,,.Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol.2007;56(4):710–712.
- ,,,,,.A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium‐based contrast media.Invest Radiol.2008;43(1):65–75.
- ,,,.A simplified equation to predict GFR from S‐creatinine [abstract].J Am Soc Nephrol.2000;11:155A.
- ,,,.Assessing kidney function–measured and estimated glomerular filtration rate.N Engl J Med.2006;354(23):2473–2483.
- ,.Nephrogenic systemic fibrosis risk: is there a difference between gadolinium‐based contrast agents?Semin Dial.2008;21(2):129–134.
- .Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long‐term hemodialysis.Clin J Am Soc Nephrol.2008;3(3):747–751.
- US Food and Drug Administration: Information for Healthcare Professionals: Gadolinium‐Containing Contrast Agents for Magnetic Resonance Imaging (MRI) ProHance, and MultiHance). Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705HCP.pdf. Accessed December 2009.
- ,.Nephrogenic systemic fibrosis: non‐gadolinium options for the imaging of CKD/ESRD patients.Semin Dial.2008;21(2):160–165.
- ,,, et al.Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?Kidney Int.2008;75(5):465–474.
- .Dialytic therapies to prevent NSF following gadolinium exposure in high‐risk patients.Semin Dial.2008;21(2):145–149.
- ,,,,.Dialyzability of gadodiamide in hemodialysis patients.Radiat Med.2006;24(6):445–451.
- ,,,,,.Nephrogenic systemic fibrosis and its association with gadolinium exposure during MRI.Cleve Clin J Med.2008;75(2):95–97, 103–104, 106 passim.
- ,,.Treatment of nephrogenic systemic fibrosis: limited options but hope for the future.Semin Dial.2008;21(2):155–159.
- ,,,,.Nephrogenic fibrosing dermopathy.Am J Dermatopathol.2001;23(5):383–393.
- ,,,,.Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure.Am J Med.2003;114(7):563–572.
- ,,,.Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis.Arch Dermatol.2007;143(8):1025–1030.
- ,,,.A case of nephrogenic fibrosing dermopathy.Ann Acad Med Singapore.2004;33(4):527–529.
- ,,,,,.Nephrogenic fibrosing dermopathy: two pediatric cases.J Pediatr.2003;143(5):678–681.
- ,,.Nephrogenic fibrosing dermopathy in children.Pediatr Nephrol.2006;21(9):1307–1311.
- .ESUR guideline: gadolinium‐based contrast media and nephrogenic systemic fibrosis.Eur Radiol.2007;17(10):2692–2696.
- US Food and Drug Administration: FDA News: FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01638.html. Accessed December 2009.
- US Food and Drug Administration: Public Health Advisory: Gadolinium‐containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed December 2009.
- US Food and Drug Administration: Public Health Advisory: Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm. Accessed December 2009.
- ,,, et al.Nephrogenic systemic fibrosis among liver transplant recipients: a single institution experience and topic update.Am J Transplant.2006;6(9):2212–2217.
- Hospitalization discharge diagnoses for kidney disease–United States, 1980–2005.MMWR Morb Mortal Wkly Rep. 282008;57(12):309–312.
- ,,,.Response to the FDA's May 23, 2007, nephrogenic systemic fibrosis update.Radiology.2008;246(1):11–14.
- .How should nephrologists approach gadolinium‐based contrast imaging in patients with kidney disease?Clin J Am Soc Nephrol.2008;3(3):649–651.
What Is Nephrogenic Systemic Fibrosis?
Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease that occurs after exposure to gadolinium‐based contrast (GBC) in the presence of severe renal failure of acute or chronic nature.1, 27 As suggested by its former name, nephrogenic fibrosing dermopathy, the cardinal feature of this disorder is skin involvement. Symptoms begin anywhere from 2 to 75 days after exposure to GBC, though usually within 2 months.27 Initial signs and symptoms may include sharp and sometimes excruciating pain, tightening and burning of the skin associated with redness and swelling, symmetrical involvement, distribution with predilection for the extremities more than the trunk, and sparing of the face. The dependent lower extremities are more severely involved than the upper extremities. Dermal induration may occur in the form of plaques, nodules, and papules resulting in a woody texture on palpation. These findings usually progress over weeks to months with extensive dermal fibrosis involving entire limbs. Ultimately the patient may develop severe joint contractures and marked limitations in mobility.8 A fulminant presentation is seen in approximately 5% of patients who develop a rapidly progressive course over as short a time period as 2 weeks.
Systemic organ involvement including fibrosis of the heart, lung, diaphragm, skeletal muscles, and other organs has been described and has been associated with fatal outcomes.79
Though more frequent in those with end‐stage renal disease (ESRD), NSF has been seen in those with stage 4 and 5 chronic kidney disease (CKD) and acute kidney injury (AKI). Incidence rates have been difficult to calculate due to lack of exposure data in most studies, though 1 small case‐control study found 4.3 cases per 1000 patient years among hemodialysis patients with an absolute risk of 3.4% in the exposed patient.4 Interestingly, incident NSF rates published in a Centers for Disease Control case‐control study of 19 NSF sufferers were much higher for peritoneal dialysis (4.6 cases/100 patients) than for hemodialysis (0.61/100 patients).2 This is likely related to the different GBC clearance achieved with these modalities.
NSF has no predilection for gender, race, nationality or age group. Those with liver disease and lower body weight or lower muscle mass appear to be at greater risk, which may be related to overestimation of glomerular filtration rate (GFR) with falsely low creatinines seen in such patients. Risk is likely increased as well by multiple exposures to GBC in close proximity. Related host cofactors have not been identified, though elevated serum calcium and phosphate concentrations, exposure to high dose erythropoietin, and iron overload have been considered.10, 11
The diagnosis of NSF requires compatible clinical findings along with consistent histopathology. Suspicious clinical findings in a patient with underlying kidney disease (AKI, CKD stages 4 and 5) who has been exposed to a GBC agent, should prompt skin biopsy. An incisional or deep punch biopsy to allow examination of dermis, epidermis and subcutaneous fat is required. The primary feature is the presence of collagen bundles with increased dermal spindle cells that stain for CD34 and procollagen I. Importantly, an inflammatory infiltrate is absent.12, 13
The major differential diagnosis includes scleroderma, eosinophilic fasciitis, morphea, scleromyxedema, and calcific uremic arteriolopathy. Scleroderma is distinguished by clinical findings such as facial involvement, Raynaud's phenomenon, and sclerodactyly with histology demonstrating normal or decreased numbers of fibroblasts on skin biopsy. Scleromyxedema is marked clinically by facial involvement, paraproteinemia on laboratory testing, and presence of inflammation sometimes seen on biopsy. Calcific uremic arteriolopathy (called calciphylaxis by some), which also occurs in those with kidney failure, is distinguished clinically by usually focal skin changes with cutaneous necrosis and ulceration and livedo reticularis; skin biopsy often reveals medial calcification of the vasculature with intimal fibrosis and luminal thrombosis.
What Is the Role of GBC in NSF?
The cause of NSF remained elusive for several years. Initially described in 2006 with several case series confirming the association, the role GBC agents in the pathogenesis of NSF gained widespread acceptance.1, 27 It should be noted that there are 5 cases of NSF described in kidney transplant patients where no exposure to Gadolinium was found.14, 15 Therefore, the possibility of other triggers remains.
The currently proposed pathogenesis needs to be understood in the context of gadolinium's pharmacologic properties. Gadolinium in its free ionic form (Gd3+) is highly toxic and therefore is sequestered by a non‐toxic organic molecule called a chelate.16, 17 Dissociation of the Gd3+ from a chelate may occur through a process called transmetallation when the chelate binds with another endogenous metal such as zinc or copper, allowing the release of free Gd3+. It is this free gadolinium that appears to be culpable in development of NSF.18 GBC chelates can be categorized based on their biochemical structure (linear vs. macrocyclic) and their charge (ionic vs. non‐ionic). Macrocyclic chelates bind Gd3+ more tightly than linear chelates and possess lower dissociation rates,19 which may have implications for possible toxicity.
The prolonged half‐life of GBC in the context of renal failure appears to predispose GBC to transmetallation and dissociation of Gd3+ from its chelate. Following intravenous injection, GBC is excreted unchanged by the kidneys via glomerular filtration. As a result, elimination half‐life, which is approximately 1.6 hours in normal individuals, is increased approximately 4‐ to 33‐fold in renal failure, depending on the level of GFR.16, 17, 20, 21 This increases the potential for Gd3+ dissociation through prolonged circulation times.
It has been postulated that once dissociated, deposition of the Gd3+ ion into skin and other organs sets off a cascade of poorly understood events that result in edema and fibrosis.18 Recent findings of gadolinium deposition in the skin of patients with NSF as well as an animal model of NSF following GBC exposure support this hypothesis.2225 It appears that vascular trauma, endothelial dysfunction or transudation (edema) allows the Gd3+ metal to enter the tissues. This may explain the preponderance of initial symptoms in dependent areas of the limbs.
What Can Be Done to Prevent NSF?
Avoid GBC Exposure in at Risk Patients
GBC agents are contraindicated in those with ESRD, CKD with estimated GFR <30 mL/minute/1.73 m2 (stages 4 and 5) and AKI. It has become common practice to use the 4‐variable Modification of Diet in Renal Disease (MDRD) formula in estimating GFR.26 Importantly, no estimating formula can be used in the context of a rising serum creatinine concentration as occurs with AKI. If a patient has AKI, one must assume a GFR <15 mL/minute until proven otherwise.
In those with low muscle mass the MDRD estimated GFR may overestimate the true GFR.27 Therefore, the Cockcroft‐Gault estimated creatinine clearance or a 24 hour urine‐based creatinine clearance may be useful in identifying at risk patients with underlying CKD.
Choose the Lowest Risk GBC Agent
When GBC use is deemed necessary in the high risk individual, an agent with a macrocyclic chelate (gadoteridol in the United States) is recommended.28 No published cases of NSF have been described with singular use of such agents. In addition, a retrospective study demonstrated no cases of NSF in ESRD patients on hemodialysis exposed to gadoteridol over a 7‐year period.29 This is not unexpected given the pharmacologic properties of this GBC agent.
Gadodiamide, a linear, non‐ionic agent, appears to produce the greatest risk of NSF as the largest number of NSF cases has been reported with this agent. By October 2007, 283 of 447 cases reported to the Food and Drug Administration (FDA) were exposed to gadodiamide.28 The significant preponderance with this agent is unlikely related to market share, reporting bias or publication bias. Gadopentetate, a linear, ionic agent, which had the greatest market share during this time, was responsible for approximately a quarter of cases reported to the FDA.28 Based on these data, gadodiamide and gadopentetate (and probably all linear agents) should be avoided in high risk patients.
Use Lower Doses of GBC
The FDA approved dose of all GBC agents, except the macrocyclic agent gadoteridol, is 0.1 mmol/kg.30 It appears that higher off‐label doses of GBC agents (0.3‐0.4 mmol/kg) which have been utilized for vascular studies (magnetic resonance angiography [MRA]), may have contributed to the emergence of NSF several years after these agents became available.
Develop a Protocol With Radiology and Nephrology Departments
Assessment of Renal Function Prior to Contrast Administration Is Required
Radiology departments should identify those with ESRD, CKD with estimated GFR <30 mL/minute/1.73 m2 (stages 4 and 5) and AKI. Using the 4‐variable MDRD formula in estimating GFR with the caveats previously noted, radiology departments will identify most at‐risk patients. Since the MDRD formula will be inaccurate in the setting of ESRD and AKI, these diagnoses should be determined through other means (for example, the patient's medical history) as part of the consent process.
Alternative Radiologic Imaging Modalities to GBC Enhanced Magnetic Resonance Imaging Should Be Utilized When Suitable in Those at High Risk
Newer techniques should be investigated as alternatives to GBC exposure. These include Magnetic Resonance Imaging (MRI) without GBC‐enhancement, where options such as 3D time‐of‐flight MRA, phase‐contrast angiography, and arterial spin labeling‐MR provide excellent information about blood vessels and blood flow.31 MRI with ultra‐small paramagnetic iron oxide particles may offer a future alternative in those that need a contrast‐based scan for diagnosis.32
However, since contrast enhanced MRI/MRA studies remain extremely important imaging modalities, their use may be required in some high risk individuals. In this circumstance, a macrocyclic chelate employed at the lowest dose possible, is recommended. The radiologist and nephrologist should be consulted in these instances.
Hemodialysis
Although hemodialysis efficiently clears GBC, its removal is not complete. Furthermore, it is not clear whether the damage has already occurred by the time a hemodialysis treatment can be instituted.33 It should be recognized that GBC removal after one treatment averages 65% to 73.8%; 3 to 4 sessions are required to remove 99% of the contrast agent.21, 34 Peritoneal dialysis on the other hand is an ineffective method of GBC removal (T1/2 of 52.7 hours).21 Because not all of the circulating Gd3+ is removed with a single hemodialysis treatment, prolonged tissue exposure occurs in these patients. This is reflected by the development of NSF in patients despite undergoing consecutive hemodialysis treatments following GBC exposure.3 Therefore, based on incomplete GBC removal with hemodialysis and the lack of evidence supporting prevention of NSF with this modality, we and others33, 35 strongly recommend avoidance of GBC in all patients with advanced kidney disease (GFR <30), regardless of the availability of hemodialysis. As such, the ability to perform hemodialysis after GBC in and of itself does not justify such exposure. However, if GBC use is deemed essential, then immediate hemodialysis should be strongly considered after exposure with further treatment on consecutive days.
Once NSF Develops, What Treatments Options are Available?
Unfortunately there is lack of a universally effective therapy for NSF. Several interventions have been described mainly in anecdotal case reports and very small case series. They have been recently reviewed (Table 2).360
| GBC Formulation | Year of Approval | Charge | Molecular Structure | Probable Risk of NSF* |
|---|---|---|---|---|
| Gadopentetate (Magnevist) | 1988 | Ionic | Linear | Medium |
| Gadoteridol (Prohance) | 1992 | Non‐ionic | Cyclic | Very low |
| Gadodiamide (Omniscan) | 1993 | Non‐ionic | Linear | High |
| Gadoversetamide (OptiMARK) | 1999 | Non‐ionic | Linear | Medium |
| Gadobenate (MultiHance) | 2004 | Ionic | Linear | Low |
|
| Therapies most likely to benefit |
| Kidney transplant (in ESRD) |
| Physical therapy |
| Pain control |
| Therapies with anecdotal success |
| Extracorporeal photopharesis |
| Sodium thiosulfate |
| Therapies with limited success |
| Drugs: Glucocorticoids, Pentoxifylline, Cyclophosphamide, Thalidomide |
| Immunomodulatory: Plasmapharesis, Intravenous immunoglobulin |
| Local: Intralesional IFN‐alpha, topical calcipotriene, other phototherapy |
Physical therapy is the mainstay of treatment for NSF. Physical therapy (and occupational therapy if needed) is essential to help prevent or slow the progression of joint contractures. Adequate pain relief, often with narcotics, is essential for patient comfort and to allow tolerance of physical therapy. Therapies with anecdotal benefit include extracorporeal photopheresis and infusions of sodium thiosulfate, a substance with chelating properties. Other interventions, such as immunosuppressive agents, topical agents and other phototherapies have shown limited success.
AKI resolution has been observed to result in regression of lesions.1, 3740 Presumably, resolution of the AKI allows for clearance of gadolinium and other profibrotic mediators, though definitive evidence of this is not available. Based on the observed response to AKI recovery, it is not surprising that improvement after kidney transplantation has also been described.1, 41 However, responses have not been consistent.39, 42
Consensus Guidelines and Recommendations
Nephrology societies have not yet developed consensus guidelines. Only the European Society of Urogenital Radiology has issued guidelines to date.43 These guidelines are consistent with expert opinions published elsewhere and are reflected in our approach regarding prevention of NSF (Table 3).
|
| 1. GBC agents are contraindicated in patients on dialysis regardless of availability of rapid treatment after exposure |
| 2. Avoid MRI with GBC in those with GFR <30 ml/min (estimated by MDRD formula) |
| MDRD formula may overestimate GFR in those of low weightconsider Cockcroft‐Gault calculation or 24 hour urine collection for creatinine clearance |
| MDRD is invalid in patient with a rising serum creatinine concentration. Assume GFR <30 in those with acutely rising serum creatinine concentration |
| 3. Consider alternative imaging studies or MRI studies without Gadolinium consult radiologist |
| 4. If GBC study is a necessity, then as low a dose as possible of a macrocyclic chelate would be recommended |
| 5. If an exposure to gadolinium occurs in ESRD, hemodialysis should be performed as soon as possible and repeated on consecutive days |
| 6. If an exposure to gadolinium occurs in CKD 4 or 5 or AKI patient (not on dialysis), an individualized approach should be undertaken when considering temporary catheter placement and initiation of hemodialysis |
The FDA has sent out several alerts since June 2006, the most recent in May 2007.30, 4446 In its Information for Healthcare Professionals alert, the FDA outlines recommendations. These are included in our final recommendations shown in Table 3.30 Those with a recent liver transplant, or those with chronic liver disease, who have associated kidney insufficiency of any severity, have also been identified by the FDA as an at risk group. This is based on reports of NSF occurring more commonly in patients with AKI who have these underlying conditions.47
Conclusions
With the high and increasing rates of AKI, CKD and ESRD seen among hospitalized patients,48 the need for vigilance when obtaining imaging with GBC agents becomes particularly important in the inpatient setting. As a preventable disease, it is incumbent upon us to fully understand the risk factors and potential pitfalls that may result in a patient exposed to these agents. The hospitalist has the unique role of acting as a firewall between the patient and the imaging study that may put him or her at risk for this devastating disorder.
Identification of GBC as a major culprit in the development of NSF and hence avoidance of this agent in those at the highest risk is expected to reduce the incidence of NSF. It is likely that the future will bring further understanding of the underlying mechanisms of gadolinium‐induced NSF and with this understanding, even safer strategies for GBC usage. However, until safer contrast agents become available, avoidance of GBC exposure in those with advanced acute or CKD remains our most important defense.
What Is Nephrogenic Systemic Fibrosis?
Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease that occurs after exposure to gadolinium‐based contrast (GBC) in the presence of severe renal failure of acute or chronic nature.1, 27 As suggested by its former name, nephrogenic fibrosing dermopathy, the cardinal feature of this disorder is skin involvement. Symptoms begin anywhere from 2 to 75 days after exposure to GBC, though usually within 2 months.27 Initial signs and symptoms may include sharp and sometimes excruciating pain, tightening and burning of the skin associated with redness and swelling, symmetrical involvement, distribution with predilection for the extremities more than the trunk, and sparing of the face. The dependent lower extremities are more severely involved than the upper extremities. Dermal induration may occur in the form of plaques, nodules, and papules resulting in a woody texture on palpation. These findings usually progress over weeks to months with extensive dermal fibrosis involving entire limbs. Ultimately the patient may develop severe joint contractures and marked limitations in mobility.8 A fulminant presentation is seen in approximately 5% of patients who develop a rapidly progressive course over as short a time period as 2 weeks.
Systemic organ involvement including fibrosis of the heart, lung, diaphragm, skeletal muscles, and other organs has been described and has been associated with fatal outcomes.79
Though more frequent in those with end‐stage renal disease (ESRD), NSF has been seen in those with stage 4 and 5 chronic kidney disease (CKD) and acute kidney injury (AKI). Incidence rates have been difficult to calculate due to lack of exposure data in most studies, though 1 small case‐control study found 4.3 cases per 1000 patient years among hemodialysis patients with an absolute risk of 3.4% in the exposed patient.4 Interestingly, incident NSF rates published in a Centers for Disease Control case‐control study of 19 NSF sufferers were much higher for peritoneal dialysis (4.6 cases/100 patients) than for hemodialysis (0.61/100 patients).2 This is likely related to the different GBC clearance achieved with these modalities.
NSF has no predilection for gender, race, nationality or age group. Those with liver disease and lower body weight or lower muscle mass appear to be at greater risk, which may be related to overestimation of glomerular filtration rate (GFR) with falsely low creatinines seen in such patients. Risk is likely increased as well by multiple exposures to GBC in close proximity. Related host cofactors have not been identified, though elevated serum calcium and phosphate concentrations, exposure to high dose erythropoietin, and iron overload have been considered.10, 11
The diagnosis of NSF requires compatible clinical findings along with consistent histopathology. Suspicious clinical findings in a patient with underlying kidney disease (AKI, CKD stages 4 and 5) who has been exposed to a GBC agent, should prompt skin biopsy. An incisional or deep punch biopsy to allow examination of dermis, epidermis and subcutaneous fat is required. The primary feature is the presence of collagen bundles with increased dermal spindle cells that stain for CD34 and procollagen I. Importantly, an inflammatory infiltrate is absent.12, 13
The major differential diagnosis includes scleroderma, eosinophilic fasciitis, morphea, scleromyxedema, and calcific uremic arteriolopathy. Scleroderma is distinguished by clinical findings such as facial involvement, Raynaud's phenomenon, and sclerodactyly with histology demonstrating normal or decreased numbers of fibroblasts on skin biopsy. Scleromyxedema is marked clinically by facial involvement, paraproteinemia on laboratory testing, and presence of inflammation sometimes seen on biopsy. Calcific uremic arteriolopathy (called calciphylaxis by some), which also occurs in those with kidney failure, is distinguished clinically by usually focal skin changes with cutaneous necrosis and ulceration and livedo reticularis; skin biopsy often reveals medial calcification of the vasculature with intimal fibrosis and luminal thrombosis.
What Is the Role of GBC in NSF?
The cause of NSF remained elusive for several years. Initially described in 2006 with several case series confirming the association, the role GBC agents in the pathogenesis of NSF gained widespread acceptance.1, 27 It should be noted that there are 5 cases of NSF described in kidney transplant patients where no exposure to Gadolinium was found.14, 15 Therefore, the possibility of other triggers remains.
The currently proposed pathogenesis needs to be understood in the context of gadolinium's pharmacologic properties. Gadolinium in its free ionic form (Gd3+) is highly toxic and therefore is sequestered by a non‐toxic organic molecule called a chelate.16, 17 Dissociation of the Gd3+ from a chelate may occur through a process called transmetallation when the chelate binds with another endogenous metal such as zinc or copper, allowing the release of free Gd3+. It is this free gadolinium that appears to be culpable in development of NSF.18 GBC chelates can be categorized based on their biochemical structure (linear vs. macrocyclic) and their charge (ionic vs. non‐ionic). Macrocyclic chelates bind Gd3+ more tightly than linear chelates and possess lower dissociation rates,19 which may have implications for possible toxicity.
The prolonged half‐life of GBC in the context of renal failure appears to predispose GBC to transmetallation and dissociation of Gd3+ from its chelate. Following intravenous injection, GBC is excreted unchanged by the kidneys via glomerular filtration. As a result, elimination half‐life, which is approximately 1.6 hours in normal individuals, is increased approximately 4‐ to 33‐fold in renal failure, depending on the level of GFR.16, 17, 20, 21 This increases the potential for Gd3+ dissociation through prolonged circulation times.
It has been postulated that once dissociated, deposition of the Gd3+ ion into skin and other organs sets off a cascade of poorly understood events that result in edema and fibrosis.18 Recent findings of gadolinium deposition in the skin of patients with NSF as well as an animal model of NSF following GBC exposure support this hypothesis.2225 It appears that vascular trauma, endothelial dysfunction or transudation (edema) allows the Gd3+ metal to enter the tissues. This may explain the preponderance of initial symptoms in dependent areas of the limbs.
What Can Be Done to Prevent NSF?
Avoid GBC Exposure in at Risk Patients
GBC agents are contraindicated in those with ESRD, CKD with estimated GFR <30 mL/minute/1.73 m2 (stages 4 and 5) and AKI. It has become common practice to use the 4‐variable Modification of Diet in Renal Disease (MDRD) formula in estimating GFR.26 Importantly, no estimating formula can be used in the context of a rising serum creatinine concentration as occurs with AKI. If a patient has AKI, one must assume a GFR <15 mL/minute until proven otherwise.
In those with low muscle mass the MDRD estimated GFR may overestimate the true GFR.27 Therefore, the Cockcroft‐Gault estimated creatinine clearance or a 24 hour urine‐based creatinine clearance may be useful in identifying at risk patients with underlying CKD.
Choose the Lowest Risk GBC Agent
When GBC use is deemed necessary in the high risk individual, an agent with a macrocyclic chelate (gadoteridol in the United States) is recommended.28 No published cases of NSF have been described with singular use of such agents. In addition, a retrospective study demonstrated no cases of NSF in ESRD patients on hemodialysis exposed to gadoteridol over a 7‐year period.29 This is not unexpected given the pharmacologic properties of this GBC agent.
Gadodiamide, a linear, non‐ionic agent, appears to produce the greatest risk of NSF as the largest number of NSF cases has been reported with this agent. By October 2007, 283 of 447 cases reported to the Food and Drug Administration (FDA) were exposed to gadodiamide.28 The significant preponderance with this agent is unlikely related to market share, reporting bias or publication bias. Gadopentetate, a linear, ionic agent, which had the greatest market share during this time, was responsible for approximately a quarter of cases reported to the FDA.28 Based on these data, gadodiamide and gadopentetate (and probably all linear agents) should be avoided in high risk patients.
Use Lower Doses of GBC
The FDA approved dose of all GBC agents, except the macrocyclic agent gadoteridol, is 0.1 mmol/kg.30 It appears that higher off‐label doses of GBC agents (0.3‐0.4 mmol/kg) which have been utilized for vascular studies (magnetic resonance angiography [MRA]), may have contributed to the emergence of NSF several years after these agents became available.
Develop a Protocol With Radiology and Nephrology Departments
Assessment of Renal Function Prior to Contrast Administration Is Required
Radiology departments should identify those with ESRD, CKD with estimated GFR <30 mL/minute/1.73 m2 (stages 4 and 5) and AKI. Using the 4‐variable MDRD formula in estimating GFR with the caveats previously noted, radiology departments will identify most at‐risk patients. Since the MDRD formula will be inaccurate in the setting of ESRD and AKI, these diagnoses should be determined through other means (for example, the patient's medical history) as part of the consent process.
Alternative Radiologic Imaging Modalities to GBC Enhanced Magnetic Resonance Imaging Should Be Utilized When Suitable in Those at High Risk
Newer techniques should be investigated as alternatives to GBC exposure. These include Magnetic Resonance Imaging (MRI) without GBC‐enhancement, where options such as 3D time‐of‐flight MRA, phase‐contrast angiography, and arterial spin labeling‐MR provide excellent information about blood vessels and blood flow.31 MRI with ultra‐small paramagnetic iron oxide particles may offer a future alternative in those that need a contrast‐based scan for diagnosis.32
However, since contrast enhanced MRI/MRA studies remain extremely important imaging modalities, their use may be required in some high risk individuals. In this circumstance, a macrocyclic chelate employed at the lowest dose possible, is recommended. The radiologist and nephrologist should be consulted in these instances.
Hemodialysis
Although hemodialysis efficiently clears GBC, its removal is not complete. Furthermore, it is not clear whether the damage has already occurred by the time a hemodialysis treatment can be instituted.33 It should be recognized that GBC removal after one treatment averages 65% to 73.8%; 3 to 4 sessions are required to remove 99% of the contrast agent.21, 34 Peritoneal dialysis on the other hand is an ineffective method of GBC removal (T1/2 of 52.7 hours).21 Because not all of the circulating Gd3+ is removed with a single hemodialysis treatment, prolonged tissue exposure occurs in these patients. This is reflected by the development of NSF in patients despite undergoing consecutive hemodialysis treatments following GBC exposure.3 Therefore, based on incomplete GBC removal with hemodialysis and the lack of evidence supporting prevention of NSF with this modality, we and others33, 35 strongly recommend avoidance of GBC in all patients with advanced kidney disease (GFR <30), regardless of the availability of hemodialysis. As such, the ability to perform hemodialysis after GBC in and of itself does not justify such exposure. However, if GBC use is deemed essential, then immediate hemodialysis should be strongly considered after exposure with further treatment on consecutive days.
Once NSF Develops, What Treatments Options are Available?
Unfortunately there is lack of a universally effective therapy for NSF. Several interventions have been described mainly in anecdotal case reports and very small case series. They have been recently reviewed (Table 2).360
| GBC Formulation | Year of Approval | Charge | Molecular Structure | Probable Risk of NSF* |
|---|---|---|---|---|
| Gadopentetate (Magnevist) | 1988 | Ionic | Linear | Medium |
| Gadoteridol (Prohance) | 1992 | Non‐ionic | Cyclic | Very low |
| Gadodiamide (Omniscan) | 1993 | Non‐ionic | Linear | High |
| Gadoversetamide (OptiMARK) | 1999 | Non‐ionic | Linear | Medium |
| Gadobenate (MultiHance) | 2004 | Ionic | Linear | Low |
|
| Therapies most likely to benefit |
| Kidney transplant (in ESRD) |
| Physical therapy |
| Pain control |
| Therapies with anecdotal success |
| Extracorporeal photopharesis |
| Sodium thiosulfate |
| Therapies with limited success |
| Drugs: Glucocorticoids, Pentoxifylline, Cyclophosphamide, Thalidomide |
| Immunomodulatory: Plasmapharesis, Intravenous immunoglobulin |
| Local: Intralesional IFN‐alpha, topical calcipotriene, other phototherapy |
Physical therapy is the mainstay of treatment for NSF. Physical therapy (and occupational therapy if needed) is essential to help prevent or slow the progression of joint contractures. Adequate pain relief, often with narcotics, is essential for patient comfort and to allow tolerance of physical therapy. Therapies with anecdotal benefit include extracorporeal photopheresis and infusions of sodium thiosulfate, a substance with chelating properties. Other interventions, such as immunosuppressive agents, topical agents and other phototherapies have shown limited success.
AKI resolution has been observed to result in regression of lesions.1, 3740 Presumably, resolution of the AKI allows for clearance of gadolinium and other profibrotic mediators, though definitive evidence of this is not available. Based on the observed response to AKI recovery, it is not surprising that improvement after kidney transplantation has also been described.1, 41 However, responses have not been consistent.39, 42
Consensus Guidelines and Recommendations
Nephrology societies have not yet developed consensus guidelines. Only the European Society of Urogenital Radiology has issued guidelines to date.43 These guidelines are consistent with expert opinions published elsewhere and are reflected in our approach regarding prevention of NSF (Table 3).
|
| 1. GBC agents are contraindicated in patients on dialysis regardless of availability of rapid treatment after exposure |
| 2. Avoid MRI with GBC in those with GFR <30 ml/min (estimated by MDRD formula) |
| MDRD formula may overestimate GFR in those of low weightconsider Cockcroft‐Gault calculation or 24 hour urine collection for creatinine clearance |
| MDRD is invalid in patient with a rising serum creatinine concentration. Assume GFR <30 in those with acutely rising serum creatinine concentration |
| 3. Consider alternative imaging studies or MRI studies without Gadolinium consult radiologist |
| 4. If GBC study is a necessity, then as low a dose as possible of a macrocyclic chelate would be recommended |
| 5. If an exposure to gadolinium occurs in ESRD, hemodialysis should be performed as soon as possible and repeated on consecutive days |
| 6. If an exposure to gadolinium occurs in CKD 4 or 5 or AKI patient (not on dialysis), an individualized approach should be undertaken when considering temporary catheter placement and initiation of hemodialysis |
The FDA has sent out several alerts since June 2006, the most recent in May 2007.30, 4446 In its Information for Healthcare Professionals alert, the FDA outlines recommendations. These are included in our final recommendations shown in Table 3.30 Those with a recent liver transplant, or those with chronic liver disease, who have associated kidney insufficiency of any severity, have also been identified by the FDA as an at risk group. This is based on reports of NSF occurring more commonly in patients with AKI who have these underlying conditions.47
Conclusions
With the high and increasing rates of AKI, CKD and ESRD seen among hospitalized patients,48 the need for vigilance when obtaining imaging with GBC agents becomes particularly important in the inpatient setting. As a preventable disease, it is incumbent upon us to fully understand the risk factors and potential pitfalls that may result in a patient exposed to these agents. The hospitalist has the unique role of acting as a firewall between the patient and the imaging study that may put him or her at risk for this devastating disorder.
Identification of GBC as a major culprit in the development of NSF and hence avoidance of this agent in those at the highest risk is expected to reduce the incidence of NSF. It is likely that the future will bring further understanding of the underlying mechanisms of gadolinium‐induced NSF and with this understanding, even safer strategies for GBC usage. However, until safer contrast agents become available, avoidance of GBC exposure in those with advanced acute or CKD remains our most important defense.
- .Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?Nephrol Dial Transplant.2006;21(4):1104–1108.
- Nephrogenic fibrosing dermopathy associated with exposure to gadolinium‐containing contrast agents–St. Louis, Missouri, 2002–2006.MMWR Morb Mortal Wkly Rep.2007;56(7):137–141.
- ,,,,,.Gadodiamide‐associated nephrogenic systemic fibrosis: why radiologists should be concerned.AJR Am J Roentgenol.2007;188(2):586–592.
- ,,.Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure.Clin J Am Soc Nephrol.2007;2(2):264–267.
- ,,,,.Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan).Invest Radiol.2007;42(2):139–145.
- ,,, et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast‐enhanced magnetic resonance imaging.J Am Soc Nephrol.2006;17(9):2359–2362.
- ,,, et al.Nephrogenic systemic fibrosis: risk factors and incidence estimation.Radiology.2007;243(1):148–157.
- ,,.Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy).Curr Opin Rheumatol.2006;18(6):614–617.
- . Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001–2007. Available at http://www.icnfdr.org. Accessed December 2009.
- ,,,,.Case‐control study of gadodiamide‐related nephrogenic systemic fibrosis.Nephrol Dial Transplant.2007;22(11):3174–3178.
- ,,, et al.Nephrogenic fibrosing dermopathy and high‐dose erythropoietin therapy.Ann Intern Med.2006;145(3):234–235.
- ,.Nephrogenic systemic fibrosis: an update.Curr Rheumatol Rep.2006;8(2):151–157.
- ,.Nephrogenic systemic fibrosis: early recognition and treatment.Semin Dial.2008;21(2):123–128.
- ,,.Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature.Am J Transplant.2007;7(10):2425–2432.
- .Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting.Eur J Radiol.2008;66(2):230–234.
- .MR contrast agents, the old and the new.Eur J Radiol.2006;60(3):314–323.
- ,,,,,.Magnetic resonance contrast agents: from the bench to the patient.Curr Pharm Des.2005;11(31):4079–4098.
- .Tissue deposition of gadolinium and development of NSF: a convergence of factors.Semin Dial.232008.
- .Safety of magnetic resonance contrast media.Top Magn Reson Imaging.2001;12(4):309–314.
- ,,, et al.Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment.Invest Radiol.1999;34(7):443–448.
- ,,.Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis.Acad Radiol.1998;5(7):491–502.
- ,,.Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol.2007;56(1):27–30.
- ,,,,.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol.2007;56(1):21–26.
- ,,.Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol.2007;56(4):710–712.
- ,,,,,.A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium‐based contrast media.Invest Radiol.2008;43(1):65–75.
- ,,,.A simplified equation to predict GFR from S‐creatinine [abstract].J Am Soc Nephrol.2000;11:155A.
- ,,,.Assessing kidney function–measured and estimated glomerular filtration rate.N Engl J Med.2006;354(23):2473–2483.
- ,.Nephrogenic systemic fibrosis risk: is there a difference between gadolinium‐based contrast agents?Semin Dial.2008;21(2):129–134.
- .Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long‐term hemodialysis.Clin J Am Soc Nephrol.2008;3(3):747–751.
- US Food and Drug Administration: Information for Healthcare Professionals: Gadolinium‐Containing Contrast Agents for Magnetic Resonance Imaging (MRI) ProHance, and MultiHance). Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705HCP.pdf. Accessed December 2009.
- ,.Nephrogenic systemic fibrosis: non‐gadolinium options for the imaging of CKD/ESRD patients.Semin Dial.2008;21(2):160–165.
- ,,, et al.Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?Kidney Int.2008;75(5):465–474.
- .Dialytic therapies to prevent NSF following gadolinium exposure in high‐risk patients.Semin Dial.2008;21(2):145–149.
- ,,,,.Dialyzability of gadodiamide in hemodialysis patients.Radiat Med.2006;24(6):445–451.
- ,,,,,.Nephrogenic systemic fibrosis and its association with gadolinium exposure during MRI.Cleve Clin J Med.2008;75(2):95–97, 103–104, 106 passim.
- ,,.Treatment of nephrogenic systemic fibrosis: limited options but hope for the future.Semin Dial.2008;21(2):155–159.
- ,,,,.Nephrogenic fibrosing dermopathy.Am J Dermatopathol.2001;23(5):383–393.
- ,,,,.Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure.Am J Med.2003;114(7):563–572.
- ,,,.Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis.Arch Dermatol.2007;143(8):1025–1030.
- ,,,.A case of nephrogenic fibrosing dermopathy.Ann Acad Med Singapore.2004;33(4):527–529.
- ,,,,,.Nephrogenic fibrosing dermopathy: two pediatric cases.J Pediatr.2003;143(5):678–681.
- ,,.Nephrogenic fibrosing dermopathy in children.Pediatr Nephrol.2006;21(9):1307–1311.
- .ESUR guideline: gadolinium‐based contrast media and nephrogenic systemic fibrosis.Eur Radiol.2007;17(10):2692–2696.
- US Food and Drug Administration: FDA News: FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01638.html. Accessed December 2009.
- US Food and Drug Administration: Public Health Advisory: Gadolinium‐containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed December 2009.
- US Food and Drug Administration: Public Health Advisory: Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm. Accessed December 2009.
- ,,, et al.Nephrogenic systemic fibrosis among liver transplant recipients: a single institution experience and topic update.Am J Transplant.2006;6(9):2212–2217.
- Hospitalization discharge diagnoses for kidney disease–United States, 1980–2005.MMWR Morb Mortal Wkly Rep. 282008;57(12):309–312.
- ,,,.Response to the FDA's May 23, 2007, nephrogenic systemic fibrosis update.Radiology.2008;246(1):11–14.
- .How should nephrologists approach gadolinium‐based contrast imaging in patients with kidney disease?Clin J Am Soc Nephrol.2008;3(3):649–651.
- .Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?Nephrol Dial Transplant.2006;21(4):1104–1108.
- Nephrogenic fibrosing dermopathy associated with exposure to gadolinium‐containing contrast agents–St. Louis, Missouri, 2002–2006.MMWR Morb Mortal Wkly Rep.2007;56(7):137–141.
- ,,,,,.Gadodiamide‐associated nephrogenic systemic fibrosis: why radiologists should be concerned.AJR Am J Roentgenol.2007;188(2):586–592.
- ,,.Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure.Clin J Am Soc Nephrol.2007;2(2):264–267.
- ,,,,.Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan).Invest Radiol.2007;42(2):139–145.
- ,,, et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast‐enhanced magnetic resonance imaging.J Am Soc Nephrol.2006;17(9):2359–2362.
- ,,, et al.Nephrogenic systemic fibrosis: risk factors and incidence estimation.Radiology.2007;243(1):148–157.
- ,,.Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy).Curr Opin Rheumatol.2006;18(6):614–617.
- . Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001–2007. Available at http://www.icnfdr.org. Accessed December 2009.
- ,,,,.Case‐control study of gadodiamide‐related nephrogenic systemic fibrosis.Nephrol Dial Transplant.2007;22(11):3174–3178.
- ,,, et al.Nephrogenic fibrosing dermopathy and high‐dose erythropoietin therapy.Ann Intern Med.2006;145(3):234–235.
- ,.Nephrogenic systemic fibrosis: an update.Curr Rheumatol Rep.2006;8(2):151–157.
- ,.Nephrogenic systemic fibrosis: early recognition and treatment.Semin Dial.2008;21(2):123–128.
- ,,.Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature.Am J Transplant.2007;7(10):2425–2432.
- .Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting.Eur J Radiol.2008;66(2):230–234.
- .MR contrast agents, the old and the new.Eur J Radiol.2006;60(3):314–323.
- ,,,,,.Magnetic resonance contrast agents: from the bench to the patient.Curr Pharm Des.2005;11(31):4079–4098.
- .Tissue deposition of gadolinium and development of NSF: a convergence of factors.Semin Dial.232008.
- .Safety of magnetic resonance contrast media.Top Magn Reson Imaging.2001;12(4):309–314.
- ,,, et al.Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment.Invest Radiol.1999;34(7):443–448.
- ,,.Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis.Acad Radiol.1998;5(7):491–502.
- ,,.Gadolinium deposition in nephrogenic fibrosing dermopathy.J Am Acad Dermatol.2007;56(1):27–30.
- ,,,,.Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol.2007;56(1):21–26.
- ,,.Gadolinium is quantifiable within the tissue of patients with nephrogenic systemic fibrosis.J Am Acad Dermatol.2007;56(4):710–712.
- ,,,,,.A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium‐based contrast media.Invest Radiol.2008;43(1):65–75.
- ,,,.A simplified equation to predict GFR from S‐creatinine [abstract].J Am Soc Nephrol.2000;11:155A.
- ,,,.Assessing kidney function–measured and estimated glomerular filtration rate.N Engl J Med.2006;354(23):2473–2483.
- ,.Nephrogenic systemic fibrosis risk: is there a difference between gadolinium‐based contrast agents?Semin Dial.2008;21(2):129–134.
- .Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long‐term hemodialysis.Clin J Am Soc Nephrol.2008;3(3):747–751.
- US Food and Drug Administration: Information for Healthcare Professionals: Gadolinium‐Containing Contrast Agents for Magnetic Resonance Imaging (MRI) ProHance, and MultiHance). Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705HCP.pdf. Accessed December 2009.
- ,.Nephrogenic systemic fibrosis: non‐gadolinium options for the imaging of CKD/ESRD patients.Semin Dial.2008;21(2):160–165.
- ,,, et al.Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?Kidney Int.2008;75(5):465–474.
- .Dialytic therapies to prevent NSF following gadolinium exposure in high‐risk patients.Semin Dial.2008;21(2):145–149.
- ,,,,.Dialyzability of gadodiamide in hemodialysis patients.Radiat Med.2006;24(6):445–451.
- ,,,,,.Nephrogenic systemic fibrosis and its association with gadolinium exposure during MRI.Cleve Clin J Med.2008;75(2):95–97, 103–104, 106 passim.
- ,,.Treatment of nephrogenic systemic fibrosis: limited options but hope for the future.Semin Dial.2008;21(2):155–159.
- ,,,,.Nephrogenic fibrosing dermopathy.Am J Dermatopathol.2001;23(5):383–393.
- ,,,,.Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure.Am J Med.2003;114(7):563–572.
- ,,,.Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis.Arch Dermatol.2007;143(8):1025–1030.
- ,,,.A case of nephrogenic fibrosing dermopathy.Ann Acad Med Singapore.2004;33(4):527–529.
- ,,,,,.Nephrogenic fibrosing dermopathy: two pediatric cases.J Pediatr.2003;143(5):678–681.
- ,,.Nephrogenic fibrosing dermopathy in children.Pediatr Nephrol.2006;21(9):1307–1311.
- .ESUR guideline: gadolinium‐based contrast media and nephrogenic systemic fibrosis.Eur Radiol.2007;17(10):2692–2696.
- US Food and Drug Administration: FDA News: FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01638.html. Accessed December 2009.
- US Food and Drug Administration: Public Health Advisory: Gadolinium‐containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed December 2009.
- US Food and Drug Administration: Public Health Advisory: Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm. Accessed December 2009.
- ,,, et al.Nephrogenic systemic fibrosis among liver transplant recipients: a single institution experience and topic update.Am J Transplant.2006;6(9):2212–2217.
- Hospitalization discharge diagnoses for kidney disease–United States, 1980–2005.MMWR Morb Mortal Wkly Rep. 282008;57(12):309–312.
- ,,,.Response to the FDA's May 23, 2007, nephrogenic systemic fibrosis update.Radiology.2008;246(1):11–14.
- .How should nephrologists approach gadolinium‐based contrast imaging in patients with kidney disease?Clin J Am Soc Nephrol.2008;3(3):649–651.