G e n i t o u r i n a r y I m a g i n g • C l i n i c a l Pe r s p e c t i ve Davenport et al. The Challenges of Assessing CIN
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Genitourinary Imaging Clinical Perspective
The Challenges in Assessing Contrast-Induced Nephropathy: Where Are We Now? Matthew S. Davenport 1 Richard H. Cohan1 Shokoufeh Khalatbari2 James H. Ellis1 Davenport MS, Cohan RH, Khalatbari S, Ellis JH
OBJECTIVE. The objective of our study was to exposit the shifting perspectives on contrast-induced nephropathy (CIN) for IV low-osmolar iodinated contrast media. CONCLUSION. The historically inflated risk of CIN reflects logistic and intellectual pitfalls that continue to confound the study of this disease. Recent advances have clarified that the incidence of CIN is much lower than previously thought, but there are lingering questions. We suggest that CIN is likely real but is rare and offer directions for future study.
S
Keywords: complications, contrast-induced nephropathy (CIN), contrast media, low-osmolar contrast medium (LOCM), safety DOI:10.2214/AJR.13.11369 Received June 13, 2013; accepted after revision August 3, 2013. Financial support for this work was provided by a grant from the Society of Uroradiology. R. H. Cohan is a consultant to a law firm representing GE Healthcare regarding ongoing NSF litigation. J. H. Ellis has provided consulting work to GE Healthcare for contrast media–related matters. M. S. Davenport and S. Khalatbari had control of all information that might represent a conflict of interest for the other authors. 1 Department of Radiology, University of Michigan Health System, 1500 E Medical Center Dr, B2-A209P, Ann Arbor, MI 48109-5030. Address correspondence to M. S. Davenport ([email protected]). 2 Michigan Institute for Clinical & Health Research, Ann Arbor, MI.
AJR 2014; 202:784–789 0361–803X/14/2024–784 © American Roentgen Ray Society
784
ince the 1960s, the results of experimental and clinical studies have suggested an association between iodinated contrast material exposure and acute kidney injury [1– 6]. A causal relationship between the two has been supported or presumed by often-cited studies [5], which has led many to consider any acute kidney injury after intravascular iodinated contrast material exposure as contrast-induced nephropathy (CIN) [7]. For decades, CIN has been perceived as an important risk in patients who receive contrast medium [5, 8, 9]. However, the waters are muddied by several important considerations. First, early work on CIN evaluated high-osmolar contrast medium (HOCM) [4, 10] that is no longer used for routine intravascular studies; low-osmolar contrast medium (LOCM) is used now instead. The relative risk of acute kidney injury from exposure to HOCM compared with LOCM is uncertain [3, 11]. Second, most clinical studies of CIN included patients undergoing cardiac arteriography [7]—examinations that expose the kidneys to atheroemboli and a concentrated contrast material bolus that may not be generalizable to typical IV injections (e.g., contrast-enhanced CT) [12]. Atheroemboli and hemodynamic instability during cardiac angiography confound the diagnosis of CIN by obfuscating the cause of acute kidney injury. Third, there has been a common presumption that any acute kidney injury temporally related to contrast material exposure must have been caused by contrast material (i.e.,
CIN) and not by one or more other nephrotoxic risk factors [13]. However, without a matched control group to assess the baseline risk of acute kidney injury, it is impossible to determine a causal effect of contrast material in the clinical setting. Fourth, unfortunately, very few clinical studies of CIN include a control group of patients not exposed to contrast material [7]. This limitation is problematic because of the large fraction of patients who experience acute kidney injury unrelated to contrast material—patients in whom CIN might be diagnosed erroneously if they happened to receive it [13]. Fifth, the few studies of CIN that do include a control group are often confounded by a control population with a paradoxically higher rate of post-CT acute kidney injury [14], which may be a direct result of retrospective selection bias. The control groups are typically composed of nonrandomized nonselected populations who underwent unenhanced CT—populations enriched with patients at risk for acute kidney injury because of the clinical reluctance to administer IV LOCM to patients at perceived increased risk of CIN [14, 15]. The control populations with this bias who undergo unenhanced CT in retrospective and prospective observational studies might mask the nephrotoxic effect of contrast material. Sixth, CIN studies usually rely on serum creatinine as a biomarker of renal injury to indicate that CIN has occurred, but serum creatinine is a poor, indirect, nonspecific, lagging reflection of renal function that re-
AJR:202, April 2014
Downloaded from www.ajronline.org by East Carolina University on 06/09/14 from IP address 150.216.68.200. Copyright ARRS. For personal use only; all rights reserved
The Challenges of Assessing CIN lies on the serum accumulation of creatinine after a nephrotoxic event [16]. Serum creatinine values are modified by diet and muscle mass and exhibit daily physiologic variations. In general, serum creatinine level is not well suited for assessing acute nephrotoxic exposures with a small effect size. Seventh, the study of CIN is further confounded by the numerous definitions of CIN [15]. Absolute (e.g., 0.3, 0.5 mg/dL) and percentage (e.g., 25%, 50%, 100%) increases in serum creatinine values have been variably used in isolation or combination, resulting in a wide range of reported CIN incidences depending on the degree of baseline renal impairment, use of a control group, and chosen definition. Last, most controlled CIN studies are dominated by patients with normal or only mildly impaired renal function; these populations may not be at particular risk of CIN [4], and serum creatinine may be a particularly insensitive marker of acute renal impairment in these patients (i.e., patients with a large functional reserve) [16]. Because of the historic reluctance to administer contrast material to at-risk patients, patients who may be at highest risk are rarely incorporated into studies of CIN incidence. These confounding issues have made it very difficult to determine the nephrotoxic potential of intravascular iodinated contrast material. Without this information, one cannot hope to perform an appropriate risk-benefit analysis with regard to administering IV LOCM or implementing CIN risk-mitigation strategies in any particular patient. Experimental Evidence Supporting the Existence of Contrast-Induced Nephropathy Because of the difficulties establishing a causative relationship between IV LOCM and CIN in a clinical population, some investigators have explored the question of whether CIN from IV LOCM is indeed a real phenomenon [17] or, assuming that it is real, whether CIN from IV LOCM is clinically relevant [18]. These studies are at odds with other work suggesting that CIN is not only genuine, but also associated with greater morbidity and mortality in at-risk patients [8]. Resolving these differences in the clinical arena is challenging because of the ethical considerations involved. Specifically, it is difficult to ethically justify experimentally withholding contrast material when it otherwise would be given or experimentally administering contrast material when it otherwise would be withheld. An-
imal and other laboratory-based models have been used as alternatives to help answer these important questions, and they have produced interesting results. There are numerous nonclinical data supporting the nephrotoxic potential of all iodinated radiographic contrast media regardless of osmolality. Contrast material exposure has been associated in a range of experimental settings with numerous potentially nephrotoxic events, including altered renal hemodynamics [19, 20], tubular epithelial vacuolization and necrosis [19, 21], renal tubular sodium transport modulation [22], inhibition of renal active sodium transport [23], glomerular damage [3], transient reductions in filtration fraction and glomerular filtration rate (GFR) [10, 24], reductions in afferent arteriolar diameter [25], impaired nitric oxide bioavailability [25, 26], caliber reductions in the medullary descending vasa recta [26], potentiation of angiotensin II effects [25, 26], direct renal tubular cytotoxic effects [27], and increased urinary markers of renal injury [21], among others. This multitude of data supporting the theory that iodinated contrast medium has both a direct and indirect role on the development of acute kidney injury provides evidence against arguments that CIN is a spurious phenomenon. However, the results of most of these studies are complicated by the extrapolation of biochemical or physiologic alterations in a laboratory setting to the clinical entity of CIN. Extrapolation may be unfounded and therefore requires clinical validation. In addition, only a subset of the cited studies [3, 21, 24–27] investigated LOCM or isosmolar contrast medium (IOCM). The remainder explicitly or implicitly [10, 19, 20, 22, 23] studied HOCMs that are no longer used for modern intravascular studies. Simple Retrospective Controls and a Changing Paradigm Despite experimental evidence to the contrary, it has been difficult to show CIN in the clinical arena. This has been especially true since Rao and Newhouse [7] pointed out that the literature was in dire need of controlled studies. After that landmark work [7], multiple studies utilizing nonrandomized nonselected retrospective control subjects have appeared in the literature, and most have failed to show a nephrotoxic effect of IV LOCM [28–38]; this implies that CIN from IV LOCM is either nonexistent or clinically insignificant. These studies and others were re-
cently summarized in a meta-analysis by McDonald et al. [14]; they also concluded that no nephrotoxic effect of IV LOCM has been shown. However, in their analysis, McDonald et al. [14] also importantly noted that the contrast material–receiving groups in these studies had a somewhat lower relative risk of acute kidney injury, a lower incidence of mortality, and a lesser need for subsequent dialysis. These results are unexpected. One would expect that in properly controlled studies, the patients not receiving IV LOCM should have no more than an equivalent likelihood of developing acute kidney injury compared with patients receiving IV LOCM. If these results are to be believed, one would be forced to conclude not only that IV LOCM is not nephrotoxic, but also that it actually improves renal function! It is much more likely that these consistently counterintuitive observations indicate that the unadjusted retrospective unenhanced CT population is fundamentally biased by intentional clinical avoidance of IV LOCM in patients with other nephrotoxic risk factors. This proof of bias in these nonrandomized studies is important because nephrotoxic contaminants in the control populations undergoing unenhanced CT could obscure any nephrotoxic effect of IV LOCM in the experimental populations and might in part explain the lack of CIN detected in these studies. Addressing this bias is critical if conclusive statements are to be made about the causal relationship between IV LOCM and clinical CIN. To do so requires a new paradigm in studies of CIN. Advanced Retrospective Controls: Addressing Selection Bias Propensity score matching is an advanced statistical technique that can be used to reduce retrospective treatment selection bias in CIN studies [39]. It improves substantially on simple retrospective controls by assigning each patient in the cohort a propensity score derived from pre-CT nephrotoxic risk factors that might predict whether someone would be administered iodinated contrast material. Propensity scoring in this context therefore indicates the statistical likelihood that a patient would receive iodinated contrast material based on the pre-CT nephrotoxic risk factors for that patient. Patients with similar propensity scores (predicted probability of receiving contrast material) who did not receive iodinated contrast material are matched 1:1 to those who did, mimicking a prospective randomized study. If the
AJR:202, April 2014 785
Downloaded from www.ajronline.org by East Carolina University on 06/09/14 from IP address 150.216.68.200. Copyright ARRS. For personal use only; all rights reserved
Davenport et al. assessed risk factors and subsequent match are sufficiently close, the final matched-pair samples would indicate that both patients had an equivalent likelihood of being administered IV LOCM and the same background risk of acute kidney injury, just as if they had been randomly assigned to receive contrast material or not. Three large retrospective studies [40–42; references 40 and 42 are partially derived from the same patient population] have recently used this propensity score–matching technique to assess the incidence of CIN while addressing the nephrotoxic contaminants in their unenhanced CT populations. In each of these studies, a range of pre-CT patient data that might modulate post-CT acute kidney injury risk were used to determine the likelihood that a patient would receive IV LOCM or IOCM (on the basis of those risk factors). Each patient who received IV LOCM or IOCM was then matched with another patient who did not receive IV LOCM or IOCM but who had a similar propensity score. Of course, the efficiency of a propensity score–matched study is only as good as the factors chosen for inclusion in the model. If factors with weak predictive ability are included and, more important, if factors with strong predictive ability are excluded, the model will suffer and yield results that resemble those of an unmatched study. However, when optimal propensity score modeling is performed, much of the retrospective selection bias that drives patients with nephrotoxic risks away from IV LOCM or IOCM can be removed and the nephrotoxic potential of IV LOCM or IOCM can be analyzed. Propensity Score–Matched Results: Differences Despite the many common conclusions offered by the three recent propensity score– matched studies [40–42], there is one fairly substantial difference: two studies by Davenport et al. [40, 42] found IV LOCM and/or IOCM to be an independent nephrotoxic risk factor in patients with severe chronic renal impairment (with progressively increased risk as renal function declined), whereas the third study by McDonald et al. [41] did not. How could three studies using fairly similar methods, similar contrast media policies (use of IOCM in patients with severe renal impairment), and large sample sizes (> 10,000 patients in each) come to two different conclusions? We consider two plausible explanations: first, that IV LOCM and IOCM does not cause
786
CIN, and the propensity score–matched studies showing it does [40, 42] had systematic bias favoring contrast medium administration in patients with greater inherent risk of acute kidney injury; or, second, that IV LOCM and IOCM does cause CIN, but the methods used to eliminate retrospective selection bias in the propensity score–matched study showing it does not [41] were less efficient. For the first of these possible explanations to be true, the populations in the studies by Davenport et al. [40, 42] who underwent contrast-enhanced CT would need to be enriched with patients at significantly greater risk of acute kidney injury by factors not addressed in their propensity score–matched analyses—a phenomenon heretofore not encountered among any CIN study using retrospective control subjects [14, 28–38, 41]. Given the large sample size of each of the studies by Davenport et al. [40, 42], the only likely way this possible explanation could be true is if there is a striking and statistically significant local difference at the authors’ institution that predisposes patients at greatest risk of acute kidney injury (estimated GFR
Downloaded from www.ajronline.org by East Carolina University on 06/09/14 from IP address 150.216.68.200. Copyright ARRS. For personal use only; all rights reserved
Genitourinary Imaging Clinical Perspective
The Challenges in Assessing Contrast-Induced Nephropathy: Where Are We Now? Matthew S. Davenport 1 Richard H. Cohan1 Shokoufeh Khalatbari2 James H. Ellis1 Davenport MS, Cohan RH, Khalatbari S, Ellis JH
OBJECTIVE. The objective of our study was to exposit the shifting perspectives on contrast-induced nephropathy (CIN) for IV low-osmolar iodinated contrast media. CONCLUSION. The historically inflated risk of CIN reflects logistic and intellectual pitfalls that continue to confound the study of this disease. Recent advances have clarified that the incidence of CIN is much lower than previously thought, but there are lingering questions. We suggest that CIN is likely real but is rare and offer directions for future study.
S
Keywords: complications, contrast-induced nephropathy (CIN), contrast media, low-osmolar contrast medium (LOCM), safety DOI:10.2214/AJR.13.11369 Received June 13, 2013; accepted after revision August 3, 2013. Financial support for this work was provided by a grant from the Society of Uroradiology. R. H. Cohan is a consultant to a law firm representing GE Healthcare regarding ongoing NSF litigation. J. H. Ellis has provided consulting work to GE Healthcare for contrast media–related matters. M. S. Davenport and S. Khalatbari had control of all information that might represent a conflict of interest for the other authors. 1 Department of Radiology, University of Michigan Health System, 1500 E Medical Center Dr, B2-A209P, Ann Arbor, MI 48109-5030. Address correspondence to M. S. Davenport ([email protected]). 2 Michigan Institute for Clinical & Health Research, Ann Arbor, MI.
AJR 2014; 202:784–789 0361–803X/14/2024–784 © American Roentgen Ray Society
784
ince the 1960s, the results of experimental and clinical studies have suggested an association between iodinated contrast material exposure and acute kidney injury [1– 6]. A causal relationship between the two has been supported or presumed by often-cited studies [5], which has led many to consider any acute kidney injury after intravascular iodinated contrast material exposure as contrast-induced nephropathy (CIN) [7]. For decades, CIN has been perceived as an important risk in patients who receive contrast medium [5, 8, 9]. However, the waters are muddied by several important considerations. First, early work on CIN evaluated high-osmolar contrast medium (HOCM) [4, 10] that is no longer used for routine intravascular studies; low-osmolar contrast medium (LOCM) is used now instead. The relative risk of acute kidney injury from exposure to HOCM compared with LOCM is uncertain [3, 11]. Second, most clinical studies of CIN included patients undergoing cardiac arteriography [7]—examinations that expose the kidneys to atheroemboli and a concentrated contrast material bolus that may not be generalizable to typical IV injections (e.g., contrast-enhanced CT) [12]. Atheroemboli and hemodynamic instability during cardiac angiography confound the diagnosis of CIN by obfuscating the cause of acute kidney injury. Third, there has been a common presumption that any acute kidney injury temporally related to contrast material exposure must have been caused by contrast material (i.e.,
CIN) and not by one or more other nephrotoxic risk factors [13]. However, without a matched control group to assess the baseline risk of acute kidney injury, it is impossible to determine a causal effect of contrast material in the clinical setting. Fourth, unfortunately, very few clinical studies of CIN include a control group of patients not exposed to contrast material [7]. This limitation is problematic because of the large fraction of patients who experience acute kidney injury unrelated to contrast material—patients in whom CIN might be diagnosed erroneously if they happened to receive it [13]. Fifth, the few studies of CIN that do include a control group are often confounded by a control population with a paradoxically higher rate of post-CT acute kidney injury [14], which may be a direct result of retrospective selection bias. The control groups are typically composed of nonrandomized nonselected populations who underwent unenhanced CT—populations enriched with patients at risk for acute kidney injury because of the clinical reluctance to administer IV LOCM to patients at perceived increased risk of CIN [14, 15]. The control populations with this bias who undergo unenhanced CT in retrospective and prospective observational studies might mask the nephrotoxic effect of contrast material. Sixth, CIN studies usually rely on serum creatinine as a biomarker of renal injury to indicate that CIN has occurred, but serum creatinine is a poor, indirect, nonspecific, lagging reflection of renal function that re-
AJR:202, April 2014
Downloaded from www.ajronline.org by East Carolina University on 06/09/14 from IP address 150.216.68.200. Copyright ARRS. For personal use only; all rights reserved
The Challenges of Assessing CIN lies on the serum accumulation of creatinine after a nephrotoxic event [16]. Serum creatinine values are modified by diet and muscle mass and exhibit daily physiologic variations. In general, serum creatinine level is not well suited for assessing acute nephrotoxic exposures with a small effect size. Seventh, the study of CIN is further confounded by the numerous definitions of CIN [15]. Absolute (e.g., 0.3, 0.5 mg/dL) and percentage (e.g., 25%, 50%, 100%) increases in serum creatinine values have been variably used in isolation or combination, resulting in a wide range of reported CIN incidences depending on the degree of baseline renal impairment, use of a control group, and chosen definition. Last, most controlled CIN studies are dominated by patients with normal or only mildly impaired renal function; these populations may not be at particular risk of CIN [4], and serum creatinine may be a particularly insensitive marker of acute renal impairment in these patients (i.e., patients with a large functional reserve) [16]. Because of the historic reluctance to administer contrast material to at-risk patients, patients who may be at highest risk are rarely incorporated into studies of CIN incidence. These confounding issues have made it very difficult to determine the nephrotoxic potential of intravascular iodinated contrast material. Without this information, one cannot hope to perform an appropriate risk-benefit analysis with regard to administering IV LOCM or implementing CIN risk-mitigation strategies in any particular patient. Experimental Evidence Supporting the Existence of Contrast-Induced Nephropathy Because of the difficulties establishing a causative relationship between IV LOCM and CIN in a clinical population, some investigators have explored the question of whether CIN from IV LOCM is indeed a real phenomenon [17] or, assuming that it is real, whether CIN from IV LOCM is clinically relevant [18]. These studies are at odds with other work suggesting that CIN is not only genuine, but also associated with greater morbidity and mortality in at-risk patients [8]. Resolving these differences in the clinical arena is challenging because of the ethical considerations involved. Specifically, it is difficult to ethically justify experimentally withholding contrast material when it otherwise would be given or experimentally administering contrast material when it otherwise would be withheld. An-
imal and other laboratory-based models have been used as alternatives to help answer these important questions, and they have produced interesting results. There are numerous nonclinical data supporting the nephrotoxic potential of all iodinated radiographic contrast media regardless of osmolality. Contrast material exposure has been associated in a range of experimental settings with numerous potentially nephrotoxic events, including altered renal hemodynamics [19, 20], tubular epithelial vacuolization and necrosis [19, 21], renal tubular sodium transport modulation [22], inhibition of renal active sodium transport [23], glomerular damage [3], transient reductions in filtration fraction and glomerular filtration rate (GFR) [10, 24], reductions in afferent arteriolar diameter [25], impaired nitric oxide bioavailability [25, 26], caliber reductions in the medullary descending vasa recta [26], potentiation of angiotensin II effects [25, 26], direct renal tubular cytotoxic effects [27], and increased urinary markers of renal injury [21], among others. This multitude of data supporting the theory that iodinated contrast medium has both a direct and indirect role on the development of acute kidney injury provides evidence against arguments that CIN is a spurious phenomenon. However, the results of most of these studies are complicated by the extrapolation of biochemical or physiologic alterations in a laboratory setting to the clinical entity of CIN. Extrapolation may be unfounded and therefore requires clinical validation. In addition, only a subset of the cited studies [3, 21, 24–27] investigated LOCM or isosmolar contrast medium (IOCM). The remainder explicitly or implicitly [10, 19, 20, 22, 23] studied HOCMs that are no longer used for modern intravascular studies. Simple Retrospective Controls and a Changing Paradigm Despite experimental evidence to the contrary, it has been difficult to show CIN in the clinical arena. This has been especially true since Rao and Newhouse [7] pointed out that the literature was in dire need of controlled studies. After that landmark work [7], multiple studies utilizing nonrandomized nonselected retrospective control subjects have appeared in the literature, and most have failed to show a nephrotoxic effect of IV LOCM [28–38]; this implies that CIN from IV LOCM is either nonexistent or clinically insignificant. These studies and others were re-
cently summarized in a meta-analysis by McDonald et al. [14]; they also concluded that no nephrotoxic effect of IV LOCM has been shown. However, in their analysis, McDonald et al. [14] also importantly noted that the contrast material–receiving groups in these studies had a somewhat lower relative risk of acute kidney injury, a lower incidence of mortality, and a lesser need for subsequent dialysis. These results are unexpected. One would expect that in properly controlled studies, the patients not receiving IV LOCM should have no more than an equivalent likelihood of developing acute kidney injury compared with patients receiving IV LOCM. If these results are to be believed, one would be forced to conclude not only that IV LOCM is not nephrotoxic, but also that it actually improves renal function! It is much more likely that these consistently counterintuitive observations indicate that the unadjusted retrospective unenhanced CT population is fundamentally biased by intentional clinical avoidance of IV LOCM in patients with other nephrotoxic risk factors. This proof of bias in these nonrandomized studies is important because nephrotoxic contaminants in the control populations undergoing unenhanced CT could obscure any nephrotoxic effect of IV LOCM in the experimental populations and might in part explain the lack of CIN detected in these studies. Addressing this bias is critical if conclusive statements are to be made about the causal relationship between IV LOCM and clinical CIN. To do so requires a new paradigm in studies of CIN. Advanced Retrospective Controls: Addressing Selection Bias Propensity score matching is an advanced statistical technique that can be used to reduce retrospective treatment selection bias in CIN studies [39]. It improves substantially on simple retrospective controls by assigning each patient in the cohort a propensity score derived from pre-CT nephrotoxic risk factors that might predict whether someone would be administered iodinated contrast material. Propensity scoring in this context therefore indicates the statistical likelihood that a patient would receive iodinated contrast material based on the pre-CT nephrotoxic risk factors for that patient. Patients with similar propensity scores (predicted probability of receiving contrast material) who did not receive iodinated contrast material are matched 1:1 to those who did, mimicking a prospective randomized study. If the
AJR:202, April 2014 785
Downloaded from www.ajronline.org by East Carolina University on 06/09/14 from IP address 150.216.68.200. Copyright ARRS. For personal use only; all rights reserved
Davenport et al. assessed risk factors and subsequent match are sufficiently close, the final matched-pair samples would indicate that both patients had an equivalent likelihood of being administered IV LOCM and the same background risk of acute kidney injury, just as if they had been randomly assigned to receive contrast material or not. Three large retrospective studies [40–42; references 40 and 42 are partially derived from the same patient population] have recently used this propensity score–matching technique to assess the incidence of CIN while addressing the nephrotoxic contaminants in their unenhanced CT populations. In each of these studies, a range of pre-CT patient data that might modulate post-CT acute kidney injury risk were used to determine the likelihood that a patient would receive IV LOCM or IOCM (on the basis of those risk factors). Each patient who received IV LOCM or IOCM was then matched with another patient who did not receive IV LOCM or IOCM but who had a similar propensity score. Of course, the efficiency of a propensity score–matched study is only as good as the factors chosen for inclusion in the model. If factors with weak predictive ability are included and, more important, if factors with strong predictive ability are excluded, the model will suffer and yield results that resemble those of an unmatched study. However, when optimal propensity score modeling is performed, much of the retrospective selection bias that drives patients with nephrotoxic risks away from IV LOCM or IOCM can be removed and the nephrotoxic potential of IV LOCM or IOCM can be analyzed. Propensity Score–Matched Results: Differences Despite the many common conclusions offered by the three recent propensity score– matched studies [40–42], there is one fairly substantial difference: two studies by Davenport et al. [40, 42] found IV LOCM and/or IOCM to be an independent nephrotoxic risk factor in patients with severe chronic renal impairment (with progressively increased risk as renal function declined), whereas the third study by McDonald et al. [41] did not. How could three studies using fairly similar methods, similar contrast media policies (use of IOCM in patients with severe renal impairment), and large sample sizes (> 10,000 patients in each) come to two different conclusions? We consider two plausible explanations: first, that IV LOCM and IOCM does not cause
786
CIN, and the propensity score–matched studies showing it does [40, 42] had systematic bias favoring contrast medium administration in patients with greater inherent risk of acute kidney injury; or, second, that IV LOCM and IOCM does cause CIN, but the methods used to eliminate retrospective selection bias in the propensity score–matched study showing it does not [41] were less efficient. For the first of these possible explanations to be true, the populations in the studies by Davenport et al. [40, 42] who underwent contrast-enhanced CT would need to be enriched with patients at significantly greater risk of acute kidney injury by factors not addressed in their propensity score–matched analyses—a phenomenon heretofore not encountered among any CIN study using retrospective control subjects [14, 28–38, 41]. Given the large sample size of each of the studies by Davenport et al. [40, 42], the only likely way this possible explanation could be true is if there is a striking and statistically significant local difference at the authors’ institution that predisposes patients at greatest risk of acute kidney injury (estimated GFR
