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*Department of Anaesthesia, University of Toronto;
Division of Cardiac Surgery, Toronto General Hospital, University Health Network;
Department of Anaesthesia, University Health Network, University of Toronto; and
Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
Address correspondence and reprint requests to Vivek Rao, MD, PhD, FRCSC, Division of Cardiac Surgery, Department of Surgery, University of Toronto, EN 14-222, Toronto General Hospital, University Health Network, 200 Elizabeth St., Toronto, Ontario, M5G 2C4, Canada. Address e-mail to vivek.rao{at}uhn.on.ca
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Abstract |
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Cr72h) and the percentage 72-h change in calculated (Cockcroft-Gault equation) Cr clearance (%CrCl72h). We randomly selected 2000 individuals who underwent aortocoronary bypass, valve surgery, or both at the Toronto General Hospital between May 1999 and August 2000. The variables were analyzed with frequency histograms and normal probability plots. Their association with dialysis, mortality, and prolonged intensive care unit stay was determined by using receiver operating characteristic (ROC) curves. Cr72h was skewed to the right, whereas %CrCl72h was normally distributed. ROC curve areas showed Cr72h to be a good predictor of dialysis (0.98), death (0.83), and prolonged hospitalization (0.74). %CrCl72h had similar ROC curve areas for predicting dialysis (0.97), death (0.82), and prolonged hospitalization (0.74). ROC curve areas did not differ significantly with respect to mortality (P = 0.89), dialysis (P = 0.49), or prolonged hospitalization (P = 0.85). Both variables were correlated with patient-relevant outcomes. Mathematical transformation of Cr72h to %CrCl72h results in a normal distribution that is amenable to parametric statistical tests. Cr72h and %CrCl72h may be used as surrogate outcomes in future trials. IMPLICATIONS: A convenient surrogate measure of renal function is needed for evaluating renal-protective therapies in cardiac surgery. We evaluated the performance of serum creatinine concentration and calculated creatinine clearance for predicting dialysis, mortality, and prolonged hospitalization. Both measures were correlated with clinical outcomes. Creatinine clearance had the advantage of a distribution suitable for parametric statistical tests.
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Introduction |
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Surrogate measures of perioperative renal dysfunction are therefore needed for the preliminary evaluation of new renal-protective therapies using feasible sample sizes. The ideal surrogate measure should be easily measured and correlate with patient-relevant outcomes. It should also have distributional properties suited to parametric statistical tests, which are generally more powerful than nonparametric equivalents (3). If a therapy beneficially alters an ideal surrogate measure, there is justification for then studying its effects on patient-relevant outcomes (dialysis, mortality, and length of stay) in an adequately powered larger study. The surrogate measures presently in use include urinary protein markers, serum creatinine (Cr) concentration, and Cr clearance (CrCl) (measured and calculated).
Urinary levels of 
1-microglobulin, ß2-microglobulin, and N-acetyl-ß-D-glucosaminidase are sensitive markers of real tubular injury. However, there is no evidence that perioperative increases of these markers are associated with postoperative morbidity or mortality (4). Furthermore, antifibrinolytics (e.g., 
-aminocaproic acid, tranexamic acid, and aprotinin) cause microglobulinuria independent of renal injury (5).
Serum Cr concentration has been used as a measure of overall renal function. It is easily measured and has a small interassay coefficient of variation (<5% at our institution). However, Cr concentrations are affected by factors aside from renal function, namely, sex, age, and muscle mass (6). Investigators have usually either used Cr concentration as a continuous variable or dichotomized it to define clinically significant changes in renal function. Definitions of clinically significant perioperative changes in Cr concentration have been largely arbitrary. The most common definition, an increase more than 44.2 µmol/L (0.5 mg/dL) over 48 to 72 h (7,8), was obtained from the contrast-induced nephropathy literature (9). The significance of a 44.2 µmol/L perioperative increase in serum Cr is unknown.
Measured CrCl has been used to estimate glomerular filtration rate (GFR), but its accuracy and precision have generally been low (10). Other disadvantages include increased personnel time and costs that are needed for accurate collection of timed urine samples. The shorter collection times used in perioperative trials (11) may further magnify inaccuracies in urine volume measurement.
GFR can also be estimated by calculated CrCl. The latter estimates GFR through an equation that accounts for an individual’s age, sex, weight, and serum Cr (12). It has advantages over both measured Cl and serum Cr. Calculated Cl estimates GFR and measured Cl in critically ill patients admitted to medical and cardiac surgical ICUs (13,14), even during conditions of changing renal function (14). Furthermore, calculated Cl does not require the collection of cumbersome timed urine samples.
Cr concentrations and calculated CrCl are convenient, reproducible, and inexpensive surrogate mea-sures. However, the prognostic significance and distributional properties of perioperative changes in these measures remain unclear. We therefore evaluated the surrogate measures in 2000 patients undergoing coronary artery bypass grafting, valve surgery, or both. We also sought to identify the appropriate perioperative changes in Cr and CrCl for defining clinically significant changes in renal function. We limited postoperative measurements of renal function to the 72 h after surgery, a previously defined period (15) that would capture changes in function attributable to surgery itself. We used the percentage change in CrCl to better relate the perioperative change in Cl to preoperative renal function.
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Methods |
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Assuming a dialysis rate of 0.75%, the sample size of 2000 was estimated to provide sufficient outcomes (death or dialysis) for logistic regression modeling (i.e., 10 outcomes per independent variable) (17) and 95% confidence intervals (CI) more precise than ±0.10 during receiver operating characteristic (ROC) curve analysis. CIs were calculated by using the methods of Hanley and McNeil (18), assuming a ROC curve area of 0.90. The sample size was also deemed to be feasible for manual retrieval of laboratory data. We randomly selected 2000 individuals from the 3077 patients identified previously, by using a computer-generated random-number table (SAS 8.02; SAS Institute, Cary, NC).
The Cr concentrations of patients undergoing cardiac surgery at TGH are routinely measured before surgery (within 30 days) and then daily after surgery until discharge or the fifth postoperative day. After obtaining approval from the TGH Research Ethics Board, we manually reviewed medical charts to obtain these results. The preoperative Cr concentration (Crpreop) was defined as the value recorded closest to surgery but not on the day of the procedure itself. The maximal 72-h Cr concentration (Cr72hmax) was defined as the largest postoperative measurement between Days 0 and 3. All in-hospital measurements were performed at Toronto Medical Laboratories (Toronto, ON, Canada) with the Bayer Advia 1650 autoanalyzer (Bayer Inc., Tarrytown, NY), which has an interassay coefficient of variation <5%. Of Crpreop measurements, 97% were measured at Toronto Medical Laboratories. The overall results were not qualitatively altered when we excluded the 3% with preoperative measurements at facilities other than Toronto Medical Laboratories. Preoperative measurements were performed on the day before surgery for 63% (n = 1267) of the study sample. The duration between the preoperative measurement and surgery ranged from 1 to 27 days (mean, 5 days; 25th percentile, 1 day; 75th percentile, 11 days).
The 72-h change in Cr concentration (Cr72h) was defined as the difference between preoperative and postoperative concentrations (Cr72h = Cr72hmax - Crpreop). Preoperative (CrClpreop) and smallest 72-h postoperative (CrCl72h) CrCl were calculated with the Cockcroft-Gault equation (12):
Units for age, weight, and Cr were years, kilograms, and micromoles per liter, respectively. The Cockcroft-Gault equation was selected given its superior performance relative to other equations (19). The absolute 72-h change in CrCl (CrCl72h) was calculated by using preoperative and postoperative CrCl: CrCl72 h = (CrCl72 h - CrClpreop). The percentage 72-h change in CrCl (%CrCl72h) was subsequently determined: %CrCl72 h = (CrCl72 h/CrClpreop) x 100%.
Patients who needed postoperative dialysis received either intermittent hemodialysis or continuous venovenous hemodialysis. Decisions on implementing dialysis were made by a consulting nephrologist.
Analyses were performed with SAS 8.02. All tests of significance were two tailed, with P values less than 0.05 considered statistically significant.
The distributions of Cr72h and %CrCl72h were assessed by using frequency histograms and normal probability plots. We assessed the distributions of the percentage change in Cr concentration, %Cr (%Cr = Cr72 h/Crpreop x 100%), and the absolute change in CrCl (CrCl72h) to ensure that differences in their distributions were not due to %CrCl72h being a percentage. We also determined whether any mathematical trans-formations (logarithmic, etc.) converted Cr72h or %CrCl72h to symmetric, bell-shaped distributions.
ROC curves (18) were plotted for the relationship of Cr72h and %CrCl72h with postoperative dialysis, in-hospital mortality, and prolonged ICU length of stay. Prolonged ICU stay was defined as more than or equal to 5 days (95th percentile for the study sample). The methods of Hanley and McNeil (18) were used to calculate areas under each ROC curve with 95% CI. The ROC curve area gives a global assessment of the performance of Cr72h or CrCl72h in discriminating between individuals who do or do not have an outcome. Measures that perform no better than chance have ROC curve areas of 0.50; measures with perfect discrimination have areas of 1.0. The measures’ ROC curve areas were compared by using the methods of Hanley and McNeil (20).
We developed several alternative definitions of clinically significant changes in perioperative renal function by dichotomizing Cr72h and %CrCl72h along convenient cut-points, including a 72-h increase in Cr concentration more than 44.2 µmol/L (0.5 mg/dL). We used the ROC curves to identify the cut-points that resulted in the optimal balance of sensitivity and specificity for predicting postoperative dialysis.
We also measured the correlation of Cr72h and %CrCl72h with dialysis, mortality, and prolonged ICU stay by using univariate logistic regression modeling. The statistical significance of the relationship of Cr72h or %CrCl72h (as continuous variables) with these outcomes was assessed by using the Wald statistic (21). Odds ratios with 95% CI were calculated. The discrimination and calibration of the regression models were determined with the c statistic and the Hosmer-Lemeshow goodness-of-fit statistic, respectively (21). Discrimination refers to a model’s ability to assign higher probabilities to individuals who sustain outcomes as opposed to those who do not (22). Calibration describes the degree to which models’ predicted probabilities compare against actual outcomes (22).
The effect of perioperative changes on renal function may be affected by the presence of preoperative renal dysfunction. We therefore determined the predictive performance of Cr72h and %CrCl72h in two strata defined by CrClpreop. Only two strata were used, given the limited statistical power of a 2000-patient sample. We initially plotted an ROC curve comparing CrClpreop and postoperative dialysis; this curve was subsequently used to identify the CrClpreop value with the optimal balance of sensitivity and specificity for predicting dialysis. The sample was then divided into two strata (normal and reduced preoperative renal function) on the basis of this CrClpreop value. ROC curves were subsequently plotted comparing Cr72h and %CrCl72h with dialysis within each stratum.
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Results |
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Cr72h (Fig. 1) was skewed to the right (median, 3 µmol/L; 25th percentile, -5 µmol/L; 75th percentile, 14 µmol/L). The variable was not normally distributed on a normal probability plot. The transformation to %Cr (median, 3%; 25th percentile, -5%; 75th percentile, 15%) was also skewed to the right and not normally distributed. Transformation of Cr72h to the difference between the reciprocals of preoperative and postoperative Cr concentrations (1/Crpreop - 1/Cr72hmax) resulted in a more symmetric, bell-shaped distribution.
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Cr72h was correlated with postoperative dialysis (ROC area, 0.98; 95% CI, 0.94–1.00), mortality (ROC area, 0.83; 95% CI, 0.72–0.94), and prolonged ICU stay (ROC area, 0.74; 95% CI, 0.69–0.79). The sensitivity, specificity, and prevalence of several cut-points in Cr72h are presented in Table 2. The cut-point that resulted in the optimal balance of sensitivity and specificity was an increase in Cr concentration more than 50 µmol/L, which had a prevalence of 5.5%. Cr72h was also associated with clinical outcomes in univariate logistic regression models (Table 3). All models had good discrimination (Table 3). The models were also well calibrated, aside from the model predicting prolonged ICU stay (Table 3).
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CrCl72h used here was a mathematical transformation of Cr72h. The distribution of %CrCl72h (Fig. 1) was approximately normal (mean, -5.1%; SD, 16.4%). The distribution of the absolute change in CrCl, CrCl72h, was more symmetric and bell shaped than that of Cr72h. However, normal probability plots showed that the transformation of CrCl72h to %CrCl72h resulted in a closer approximation to the normal distribution.
%CrCl72h was correlated with postoperative dialysis (ROC area, 0.97; 95% CI, 0.91–1.00), mortality (ROC area, 0.82; 95% CI, 0.71–0.93), and prolonged ICU stay (ROC area, 0.74; 95% CI, 0.69–0.79). The ROC curve areas were not significantly different from Cr72h with respect to death (P = 0.89), dialysis (P = 0.49), or prolonged ICU stay (P = 0.85). The sensitivity, specificity, and prevalence of several cut-points in %CrCl72h are presented in Table 2. The cut-point that resulted in the optimal balance of sensitivity and specificity was a decrease in CrCl more than 25%, which had a prevalence of 10.2%.
%CrCl72h was also associated with clinical outcomes in univariate logistic regression models (Table 3). All models had good discrimination (Table 3). The models were well calibrated, except the model predicting prolonged ICU stay (Table 3).
The area under the ROC curve relating CrClpreop and postoperative dialysis was 0.77 (95% CI, 0.65–0.90). The optimal definition of preoperative renal dysfunction was a CrCl <60 mL/min, which had a prevalence of 27% (n = 538). The relative risk for dialysis among individuals with preoperative renal dysfunction was 5.0 (95% CI, 2.0–12.6; P = 0.0001). The ROC curves relating Cr72h and %CrCl72h with postoperative dialysis in the entire cohort and two subgroups are presented in Figures 2 and 3.
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Cr72h and %CrCl72h were 0.99 (95% CI, 0.95–1.00) and 0.99 (95% CI, 0.94–1.00), respectively. An increase in Cr concentration more than 50 µmol/L, which had a prevalence of 4% (n = 53), was associated with a sensitivity and specificity for dialysis of 97% and 100%, respectively. By comparison, a decrease in CrCl larger than 25%, which had a prevalence of 9% (n = 127), had a sensitivity of 92% and specificity of 100%.
The ROC curve areas relating postoperative dialysis with Cr72h and %CrCl72h for individuals with preoperative renal dysfunction were 0.96 (95% CI, 0.89–1.00) and 0.95 (95% CI, 0.86–1.00), respectively. An increase in Cr concentration more than 50 µmol/L, which had a prevalence of 11% (n = 57), was associated with a sensitivity of 91% and a specificity of 92%. A decrease in CrCl more than 25%, which had a prevalence of 14% (n = 76), had a sensitivity and specificity of 88% and 92%, respectively.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1: Definitions of...References |
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Calculated CrCl is a mathematical transformation of Cr concentration. Nonetheless, this transformation resulted in a normally distributed and clinically meaningful variable that retained high correlation with patient-relevant outcomes. The other mathematical transformation that resulted in a symmetric, bell-shaped distribution was the difference between the reciprocals of preoperative and postoperative Cr concentrations. This alternative transformation is difficult to interpret. We suspect that clinicians will more readily interpret 95% CI for a proportionate change in calculated CrCl than for a difference in reciprocals.
Both Cr concentrations and calculated CrCl may be used as continuous outcome variables. In this situation, CrCl has an important advantage over Cr concentration. Parametric statistical tests (e.g., Student’s t-tests and analysis of variance) all assume that the outcome variable conforms to an approximately normal distribution. Whereas CrCl has a symmetric, bell-shaped distribution, serum Cr has a skewed distribution. The symmetric distribution of CrCl did not simply reflect its use as a percentage. The percentage change in Cr concentration (%Cr72h) did not have a normal distribution. When performing statistical analyses on Cr concentration, one must therefore either apply nonparametric tests or transform the data such that they follow a normal distribution. The SD and 95% CI from analyses of transformed data are often difficult to interpret (23). In contrast, one can immediately apply convenient parametric statistical tests to CrCl and derive results that are readily understandable to clinicians. This difference in distributions will therefore simplify statistical analyses during preliminary sample size calculations and final data analyses (3).
Both Cr and CrCl can also be dichotomized to define clinically significant changes in perioperative renal function. We analyzed the most common definition of perioperative renal dysfunction, a 0.5 mg/dL (44 µmol/L) increase in serum Cr, and determined its predictive performance for dialysis (sensitivity, 95.0%; specificity, 61.9%), mortality (sensitivity, 61.9%; specificity, 94.1%), and prolonged ICU stay (sensitivity, 37.3%; specificity, 95.6%). ROC analysis suggested that a clinically significant change in renal function should be defined as either an increase in serum Cr concentration more than 50 µmol/L or a decrease in CrCl more than 25%. The latter definition is more conveniently used during clinical trials because of its higher prevalence (10.2% vs 5.5%). A clinical trial that defines clinically significant renal dysfunction as a decrease in CrCl more than 25% would therefore need only half as many patients to develop statistical power equivalent to that in a trial that defines clinically significant dysfunction as an increase in serum Cr more than 50 µmol/L.
There is limited prior information on surrogate measures of perioperative renal function. Charlson et al. (24) used ROC analysis to evaluate the performance of changes in serum Cr concentrations. However, they related changes in Cr to postoperative measured CrCl, not clinical end-points (e.g., death, dialysis, or prolonged ICU stay).
There are several limitations to this study. First, postoperative CrCl was calculated by using preoperative weights. Given that the Cockcroft-Gault equation uses weight to estimate muscle mass, our calculations assumed that muscle mass did not significantly change over the first 72 postoperative hours. However, surgical stress increases protein catabolism. The urinary excretion of 3-methylhistidine, a marker of skeletal muscle protein catabolism, increases up to 40% in the early postoperative period after elective surgery (25). Nonetheless, it is unlikely that remeasuring weight on each postoperative day would have significantly improved the accuracy of our results. Immediate postoperative weight increases above preoperative values because of IV fluid administration. The Cockcroft-Gault equation would interpret this additional weight as increased muscle mass, when muscle mass is likely to have decreased. Using preoperative weights will therefore lead to less overestimation of postoperative GFR than using serial postoperative weights.
Second, these results demonstrate a close statistical association of these outcome measures with dialysis, death, and prolonged ICU stay. Although the relationship has biological plausibility, a cause-effect relationship must be validated prospectively. Future clinical trials of interventions that alter Cr or CrCl must also demonstrate similar changes in these clinical outcomes.
In conclusion, both Cr concentration and calculated CrCl are surrogate measures of perioperative renal function that are convenient, inexpensive, and highly correlated with patient-relevant clinical outcomes (mortality, dialysis, and prolonged hospitalization). Other surrogate outcomes now in use (e.g., measured CrCl and urinary protein markers) do not share all these characteristics. CrCl has the additional advantage of a symmetric, bell-shaped distribution amenable to parametric statistical tests. Either measure may be used to define a clinically significant change in perioperative renal function. The most appropriate definitions appear to be either an increase in serum Cr concentration >50 µmol/L or a decrease in CrCl more than 25%.
We propose that that Cr concentration and calculated CrCl be used as surrogate measures of renal function during initial clinical trials of novel renal-protective drugs. Demonstration of the benefit of such drugs on these surrogate measures is necessary before progressing to the large studies needed for evaluating effects on the outcomes themselves.
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Appendix 1: Definitions of Perioperative Variables |
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Acknowledgments |
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Footnotes |
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Presented in part at the meeting of the Canadian Cardiovascular Congress, Edmonton, AB, Canada, October 27, 2002.
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References |
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1- and ß2-microglobulinuria poor markers of postcardiac surgery renal dysfunction. Anesthesiology 1999; 90: 928–9.[ISI][Medline]
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