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Clinical Nephrology |
* Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Diabetes and Arthritis Epidemiology Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona; and Division of Nephrology, Stanford University School of Medicine, Stanford, California
Address correspondence to: Dr. James H. Warram, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Phone: 617-732-2668; Fax: 617-732-2667; E-mail: james.warram{at}joslin.harvard.edu
Received for publication October 15, 2004. Accepted for publication February 4, 2005.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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In patients with CRF, trends of renal function over time are determined using one of several approximations of GFR based on serum creatinine (2–4). These approximations, however, perform adequately only in advanced disease (GFR <60 ml/min per 1.73 m2) (4–6). In patients who have normal or elevated renal function but are suspected of losing renal function over time, creatinine-based measures are unreliable for detecting trends (2).
If CRF is to be prevented, a clinically applicable method is needed for detecting negative trends in renal function when the GFR is normal or elevated. The current methods for detecting trends in renal function in this range involve direct measurements of GFR based on intravenous infusion of an exogenous marker (e.g., iothalamate, the reference method used in this study), and none is simple enough for use in clinical or epidemiologic studies (2,3). The procedures are time-consuming, costly, and susceptible to measurement error (2). For routine clinical use, a simple measure that is based on an endogenous marker is needed—similar to serum creatinine but without its limitations (1–3).
The serum concentration of cystatin C has recently been proposed as an endogenous marker of renal function that is accurate even at the low concentrations found when GFR is normal or elevated. Cystatin C is a nonglycosylated basic protease inhibitor that is produced at a constant rate by all nucleated cells (7,8). It is freely filtered by the renal glomerulus and primarily catabolized in the renal tubules (8). Furthermore, levels are reported to be independent of gender, age, and body mass (9–12). Diurnal variation is insignificant, levels are not altered by inflammatory conditions, and the concentration is stable in stored serum (13–15). Automated particle-enhanced nephelometric immunoassays are well validated and commercially available (13). Criterion validity in cross-sectional studies of renal diseases of multiple causes including diabetes has been demonstrated extensively (15–21). However, the accuracy of serum cystatin C for detecting systematic changes in GFR (slope) over time in patients with normal or elevated GFR remains to be determined.
To test this issue, we examined serial GFR measurements in Pima Indians who had type 2 diabetes and participated in the Diabetic Renal Disease Study. Their onset of type 2 diabetes was at an early age, many have elevated GFR, and their risk for developing ESRD is high (22). These characteristics make this a suitable population for studying early renal function decline that is generalizable to many type 2 diabetes populations and to the type 1 diabetes population. This study sought to determine how accurately serial determinations of serum cystatin C detect trends (particularly systematic decreases) in renal function over time that have been documented by measurements of iothalamate clearance in patients with normal or elevated GFR. For comparison, we also report how accurately the trends obtained with three commonly used creatinine-based approximations of GFR reflect the trend in iothalamate clearance.
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Materials and Methods |
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GFR was measured by the urinary clearance of iothalamate, hereafter referred to as the direct measure of renal function. Measures of renal function that are based on serum creatinine or serum cystatin C are referred to as indirect measures. To have a study group with normal or elevated GFR, we selected participants with a baseline iothalamate clearance above the median for the whole Pima study group (120 ml/min per 1.73 m2). Of the 134 participants with diabetes included in the Diabetic Renal Disease Study, 30 met these eligibility criteria: Elevated baseline iothalamate clearance, 4 yr of follow-up with measurement of iothalamate clearance at least annually, and frozen serum samples available from the clearance measurements. Other characteristics of the eligible and ineligible participants did not differ.
Protocol for the Direct Measure of GFR by Iothalamate Clearance
On the day of the iothalamate clearance study, an indwelling plastic canula was inserted into the antecubital vein of each arm, one for the collection of blood samples and the other for infusing nonradiolabeled ("cold") iothalamate (24). After the bladder was spontaneously voided, diuresis was initiated with an oral water load of 10 ml/kg (or 1500-ml maximal dose for participants >150 kg). Iothalamate (30% solution) was infused with a loading dose of 30% (300 mg plus 3 mg/kg for each kg >100 kg). Iothalamate then was delivered by an infusion pump to maintain a constant plasma concentration of 1.5 mg/dl. After a 60-min equilibration period, the bladder again was emptied by voiding, and four carefully timed urine collections, bracketed by the collection of blood samples, were made at 20-min intervals. Urinary clearance of iothalamate was estimated by the average of the four time intervals. The within-assay coefficient of variation (CV) based on the four 20-min collections is 12 ± 11% (n = 202), whereas the between-assay CV is 9 ± 8% (n = 29). In the baseline evaluation, iothalamate clearance was significantly correlated with body weight (Spearman correlation coefficient [rSp] = 0.63, P = 0.0002) but not significantly with height (rSp = 0.34, P = 0.07). Standardization of the clearance to a body surface area (BSA) of 1.73 m2 removed most of the variation caused by differences in body weight (rSp = 0.25, P = 0.19), so iothalamate clearance was analyzed after standardizing for BSA (ml/min per 1.73 m2). Given that the impact of standardization has not been examined in longitudinal studies, we analyzed both standardized and unstandardized values.
Laboratory Procedures and the Protocol for the Indirect Measures of GFR
All urine and serum samples were stored at –70°C until the day of assay, which for all measures except cystatin C were performed within 30 d of the sample collection. The concentration of urinary albumin was determined by immunonephelometry, whereas urine creatinine was measured by a modified picrate method of Jaffe. An HPLC system with a sensitive ultraviolet light detector was used to assay iothalamate at 236 nm (Instrumentation Shimadzu #6A, Kyoto, Japan). Ultrafiltrate of plasma and diluted urine were injected onto a reverse-phase column (#C18, 5µ Ultrasphere; Beckman, San Ramon, CA). The mobile phase was 3.5% acetonitrile in 10 mM triethylamine at a pH of 3.5, and the flow rate was 1.0 ml/min. Iothalamate concentration was determined from its solute peak, corresponding to column retention times of 14 min. Serum creatinine was measured by a modified picrate method of Jaffe on a Ciba Corning Express Plus Chemistry Analyzer. Serum creatinine was calibrated to Modification of Diet in Renal Disease (MDRD) laboratory values by comparing measurements in 186 paired specimens in the Phoenix and Cleveland laboratories. The between-assay CV in samples from the lowest and highest quartiles of the creatinine distribution were 2.76 and 1.76%, respectively. Serum cystatin C was measured by a single operator (B.E.P.O.) at the Joslin Diabetes Clinic using thawed samples by an immunoassay based on rabbit monospecific anti-human cystatin C antiserum (Dade Behring Diagnostics) conducted on a BN Prospec System nephelometer (Dade Behring Inc., Newark, DE). The between-assay CV in samples from the lowest and highest quartiles of the cystatin C distribution was 3.8 and 3.0%, respectively. As serum cystatin C concentration was independent of height and weight (rSp = –0.05, P = 0.78; and rSp = –0.2, P = 0.30, respectively), no standardization was required for this variable.
Statistical Analyses
Descriptive statistics and estimates of linear trends in renal function were obtained using SAS (SAS 8.02 for Windows; SAS Institute, Cary, NC). Serum cystatin C was transformed to the reciprocal multiplied by 100 (100/cystatin C in mg/L). Three serum creatinine-based estimates of GFR were calculated: The reciprocal multiplied by 100 (100/creatinine in mg/dl), the modified Cockcroft-Gault formula (2), and the MDRD equation (25). In studies of renal function, serum concentrations of creatinine and cystatin C are commonly transformed to their reciprocals for analysis (26). This serves to make changes over time have the same direction as the changes in iothalamate clearance, whereas untransformed serum concentrations change in the opposite direction. Pairwise comparisons between measures were made by the method of Bland and Altman (27). For longitudinal analysis, measures of renal function were transformed to the logarithmic scale. For each individual, five estimates of the trend in renal function over time were obtained by regression analysis: One for the direct measurement by iothalamate clearance and four for the indirect methods based on serum cystatin C and serum creatinine. A linear term adequately captured the temporal variability within the 4-yr span, so the trends could be represented as a slope and expressed as annual percentage change (the terms trend, slope, and annual percentage change are used interchangeably throughout this article). Error variance for each method of estimation of trend was calculated from the regression mean square error and expressed as a percentage of the mean (the within-individual residual SD). For evaluating the accuracy of trends based on the four indirect methods, each was compared with the trend based on iothalamate clearance (the reference method) using Spearman correlation coefficients and paired t test. Sensitivity and specificity of each measure for detecting declining renal function, defined as a negative annual percentage change in iothalamate clearance, were calculated.
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Results |
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For each individual, regression slopes (expressed as annual percentage change) were calculated for iothalamate clearance and for the four indirect measures of renal function. The slopes fitted to the standardized and unstandardized iothalamate clearance were identical (the regression models differed only in the intercepts), so the unstandardized values were not considered further. The annual percentage change in standardized iothalamate clearance was –4.4%. The annual percentage change in 100/cystatin C closely approximated this value and was not significantly different from it. The pairwise differences between the slopes for iothalamate clearance and each of the other indirect measures were also not statistically significant, but the magnitude of the differences was much larger (Table 2). In the subgroup of greatest interest, the 20 patients with declining renal function (negative slope for iothalamate clearance), the average slope for 100/cystatin C was still close to the slope for iothalamate clearance and not significantly different from it, whereas the average slope for 100/creatinine and the Cockcroft-Gault formula significantly underestimated it. The slope for estimates based on the MDRD equation also underestimated the slope for iothalamate clearance, but the difference was not quite significant.
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The sensitivity and specificity of trends in serum cystatin C to detect declining renal function were 100 and 70%, respectively. The positive predictive value and negative predictive value were 87 and 100%, respectively. The overall accuracy of this method, defined as the measure of true findings (sum of the true-positive and true-negative results) divided by all test results, was 90%. The corresponding data for the creatinine-based estimates are detailed in the legend to Figure 2.
Analysis of the Precision of the Annual Percentage Change in GFR
To explain the observed advantage of cystatin C over the creatinine-based estimates for accurately reflecting trends in renal function, we sought to determine whether cystatin C is associated with less error variance than the other measures. The within-individual residual SD for the four methods of GFR estimation was smallest for 100/cystatin C. For the 30 participants, the mean residual SD for 100/cystatin C was 9.0% as compared with 13.8% for 100/creatinine (paired t test, P = 0.01), 14.2% for the Cockcroft-Gault formula (paired t test, P = 0.01), and 16.6% for the MDRD equation (paired t test, P = 0.002). Furthermore, the mean residual SD for standardized iothalamate clearance (12.1%) tended to be greater than that of cystatin C (paired t test, P = 0.10).
In Figure 3, we present four examples that illustrate the observation that trends in 100/cystatin C have a smaller error variance than direct measurements of iothalamate clearance. The first example is a clear illustration of the observation (Figure 3A). Although the annual percentage change in GFR based on iothalamate clearance and cystatin C are similar (–21 and –18%, respectively), the mean residual SD was larger for the trend in iothalamate clearance than for the trend in cystatin C (14 and 10%, respectively). Similarly, in the three participants in which the direction of change in 100/cystatin C was discrepant with iothalamate clearance (the "false-positives" in Figure 2A), the mean residual SD was larger for iothalamate clearance in all instances (Figure 3, B through D).
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Discussion |
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The implications of this feature of cystatin C are of great importance. First, it permits early identification of patients who are at risk for (but before) the development of CRF—at a stage of disease when interventions may be most effective. Second, it carries the important research implication that a practical tool now exists for studying renal function decline as a biologic end point. Before now, the available creatinine-based methods provided poor estimation of longitudinal trends in renal function in this range of GFR.
Two very important aspects of the performance of serum cystatin C were demonstrated in this study. First, it confirms cross-sectional correlation of cystatin C with iothalamate clearance (the reference method) across the full range of GFR values. Although this correlation has been reported extensively, the patients studied have tended to have renal function in the normal or impaired renal function ranges (15–21). The current results extend these previous findings by allowing generalization to the range of hyperfiltration, a range in which creatinine-based estimates are known to perform poorly. Second and of greater importance, this study demonstrates the predictive validity of serial measures of cystatin C for detecting declining renal function.
The findings of this study also suggest that measurement of serum cystatin C has scientific as well as practical advantages over direct measurement of GFR by one of the reference methods, such as iothalamate clearance. A difficulty with the direct measurement of GFR by one of the reference methods is the surprising variability inherent in replicate measurements (28–30). This variability in iothalamate clearance may arise from technical error or reflect short-term variability in true GFR. In the former case, variability may arise from both human and technical error during repeated timed urine collections and multiple assays for the calculation of iothalamate clearance (2,4,28,31). In this study, these factors were minimized by the skill and extensive training of the technical staff. In contrast, measurement of an endogenous marker such as cystatin C requires only a single assay and no critical timing in the sample collection.
Alternatively, the large variability in measurements of iothalamate clearance may be due to short-term excursions in true GFR. These excursions may result from physiologic variation related to dietary factors or glycemic control among other things (32,33). That similar variability is not seen with serum cystatin C suggests that the serum concentration reflects the cumulative effect of the GFR over a period of time, akin to glycated hemoglobin A1c as a time-averaged measure of plasma glucose. Rather than a shortcoming, this hypothesized feature would make serial measurements of cystatin C an attractive representation of persistent change for the purposes of evaluating long-term trends in renal function. This explanation for the superior reproducibility of estimates of GFR based on serum cystatin C requires further study.
There exists some controversy over the accuracy of cystatin C. Contrary to previous reports, a large cross-sectional study suggests that factors other than renal function (age, weight, gender, smoking, and levels of c-reactive protein) may influence serum cystatin C levels independent of GFR (34). This conclusion can be questioned, however, because GFR was estimated in that study by the creatinine clearance, a measure that is recognized to have its own biases and lack of precision relative to gold standard methods such as inulin or iothalamate clearance (2). Thus, the associations seen in that study may be the result of the performance of creatinine clearance rather than problems with cystatin C. It is important to recognize that factors associated with systematic differences between 100/cystatin C and GFR in cross-sectional comparisons may not affect the accuracy of determination of trends in renal function, given that the latter analysis depends on the change in cystatin C over time rather than its absolute value.
In conclusion, this first study of the longitudinal behavior of cystatin C provides convincing evidence that sequential measurements of cystatin C are an accurate and precise alternative to gold standard methods for measuring the urinary clearance of exogenous markers to quantify trends in renal function and detect declining renal function. This finding has major implications for clinical research because it demonstrates the existence of a practical, inexpensive, and accurate alternative for investigating trends in renal function in epidemiologic studies. Although creatinine-based estimates may provide sufficient accuracy for diagnosing the presence of CRF, unlike cystatin C, they do not have sufficient precision for detecting longitudinal trends in GFR in the normal and hyperfiltration ranges. Validation of cystatin C in this range of renal function permits epidemiologic research into the timing and determinants of the initiation of early renal function decline and the early intervention to prevent chronic kidney disease in patients with type 1 or type 2 diabetes, for whom hyperfiltration is a common feature of the early stages of kidney complications.
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Acknowledgments |
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We are indebted to Linda H. Ficociello, MSc, for significant contributions to the analysis and presentation of the data and to Dr. Camille Jones for expert advice on manuscript content. We are also indebted to Lois Jones, RN, for performing the GFR measurements and to the members of the Gila River Indian Community for participating in this investigation.
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Footnotes |
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P. Rossing, K. Rossing, P. Gaede, O. Pedersen, and H.-H. Parving Monitoring Kidney Function in Type 2 Diabetic Patients With Incipient and Overt Diabetic Nephropathy Diabetes Care, May 1, 2006; 29(5): 1024 - 1030. [Abstract] [Full Text] [PDF]
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A. D. Rule, V. E. Torres, A. B. Chapman, J. J. Grantham, L. M. Guay-Woodford, K. T. Bae, S. Klahr, W. M. Bennett, C. M. Meyers, P. A. Thompson, et al. Comparison of Methods for Determining Renal Function Decline in Early Autosomal Dominant Polycystic Kidney Disease: The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease Cohort J. Am. Soc. Nephrol., March 1, 2006; 17(3): 854 - 862. [Abstract] [Full Text] [PDF]
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M. L. Caramori, P. Fioretto, and M. Mauer Enhancing the Predictive Value of Urinary Albumin for Diabetic Nephropathy J. Am. Soc. Nephrol., February 1, 2006; 17(2): 339 - 352. [Abstract] [Full Text] [PDF]
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M. G. Shlipak, C. L. W. Fyr, G. M. Chertow, T. B. Harris, S. B. Kritchevsky, F. A. Tylavsky, S. Satterfield, S. R. Cummings, A. B. Newman, and L. F. Fried Cystatin C and Mortality Risk in the Elderly: The Health, Aging, and Body Composition Study J. Am. Soc. Nephrol., January 1, 2006; 17(1): 254 - 261. [Abstract] [Full Text] [PDF]
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 A. Berghout, R. W. Wulkan, J. G. den Hollander, L. Risch, H. Drexel, A. R. Huber, B. A. Perkins, R. G. Nelson, A. S. Krolewski, M. G. Shlipak, et al. Cystatin C and the risk of death. N. Engl. J. Med., August 25, 2005; 353(8): 842 - 844. [Full Text] [PDF]
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0 ml/min per 1.73 m2). Operating characteristics for trends in renal function estimated by cystatin C (A) are described in the text. The operating characteristics (sensitivity and specificity) of trends estimated by 100/creatinine (B), Cockcroft-Gault formula (C), and MDRD equation (D) were 50% and 70%, 60% and 60%, and 50% and 70%, respectively.