In chronic kidney disease staging the use of the chronicity criterion affects prognosis and the rate of progression
2007; Elsevier BV; Volume: 72; Issue: 10 Linguagem: Inglês
10.1038/sj.ki.5002472
ISSN1523-1755
AutoresBjørn O. Eriksen, Ole C. Ingebretsen,
Tópico(s)Renal Transplantation Outcomes and Treatments
ResumoThe Kidney Disease Outcomes Quality Initiative definition and staging of chronic kidney disease (CKD) have been adopted by most nephrologists but include a criterion of chronicity that has not been investigated. This criterion specifies that renal structural damage and/or reduction in glomerular filtration rate (GFR) should be present for periods lasting longer than 3 months. We examined the effects of changing this criterion to 6, 9, or 12 months on the prognosis and the rate of progression in population-based cohorts with CKD stages 3 and 4. A 12-month chronicity criterion significantly reduced the number of CKD patients relative to the 3-month criterion for both stages 3 and 4. For both stages, there were statistically significant differences in 5-year mortality between the 6- and 9-month cohorts. For stage 4, the 5-year cumulative incidence of renal failure significantly increased from 6 to 9 months, and the rate of change in GFR significantly decreased between the same two cohorts. The 5-year cumulative incidence of improvement in GFR lasting 1 year or more was significantly higher for the 3-month cohort than for the 12-month cohort in the stage 3 group. Hence, we suggest that the chronicity criterion is an important determinant of the characteristics of the population of patients with CKD stages 3 and 4. This may have practical consequences in both research and clinical work. The Kidney Disease Outcomes Quality Initiative definition and staging of chronic kidney disease (CKD) have been adopted by most nephrologists but include a criterion of chronicity that has not been investigated. This criterion specifies that renal structural damage and/or reduction in glomerular filtration rate (GFR) should be present for periods lasting longer than 3 months. We examined the effects of changing this criterion to 6, 9, or 12 months on the prognosis and the rate of progression in population-based cohorts with CKD stages 3 and 4. A 12-month chronicity criterion significantly reduced the number of CKD patients relative to the 3-month criterion for both stages 3 and 4. For both stages, there were statistically significant differences in 5-year mortality between the 6- and 9-month cohorts. For stage 4, the 5-year cumulative incidence of renal failure significantly increased from 6 to 9 months, and the rate of change in GFR significantly decreased between the same two cohorts. The 5-year cumulative incidence of improvement in GFR lasting 1 year or more was significantly higher for the 3-month cohort than for the 12-month cohort in the stage 3 group. Hence, we suggest that the chronicity criterion is an important determinant of the characteristics of the population of patients with CKD stages 3 and 4. This may have practical consequences in both research and clinical work. The increasing demand for renal replacement therapy has made the search for effective therapy for the predialytic stages of chronic kidney disease (CKD) more important. A commonly accepted definition for classifying these stages is necessary both for research and for developing clinical guidelines. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) definition and classification scheme for CKD, published in 2002, goes a long way toward fulfilling this need.1.K/DOQI clinical practice guidelines for chronic kidney disease work group. Evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar The goal of the K/DOQI Work Group was to set criteria that allowed unequivocal decisions about the diagnosis and staging of CKD.2.K/DOQI clinical practice guidelines for chronic kidney disease work group. Definition and classification of stages of chronic kidney disease.Am J Kidney Dis. 2002; 39: S46-S75Abstract Full Text PDF Google Scholar The staging scheme was based on the presence of kidney damage and/or reduced glomerular filtration rate (GFR). The more advanced stages of CKD are defined by reduced GFR alone with GFR cutoff values between stages of 60, 30, and 15 ml/min/1.73 m2. For exclusion of acute forms of kidney disease, the reduced GFR should persist for 3 months or more; however, the Work Group stated that both the cutoff levels and the 3-month criterion were chosen arbitrarily.2.K/DOQI clinical practice guidelines for chronic kidney disease work group. Definition and classification of stages of chronic kidney disease.Am J Kidney Dis. 2002; 39: S46-S75Abstract Full Text PDF Google Scholar This information raises the question of how optimal these criteria are. In particular, there is a concern that the 3-month requirement is too short to exclude conditions with subsequent improvement in GFR from stages 3 and 4. In addition, a patient could theoretically run the gamut of stage 3 from 59 to 30 ml/min/1.73 m2 in 3 months and still meet the given criteria for CKD, even though the overall rate of decrease would be 120 ml/min/1.73 m2/year. Such a scenario would not conform to the common clinical notion of a chronic condition, but whether this is a problem in practical staging needs to be clarified. Therefore, we explored how variations in this criterion affect mortality, risk of kidney failure, and rate of decrease in GFR for CKD stages 3 and 4. Data were obtained from a complete database of all serum creatinine measurements performed in a well-defined population for 10 years. Of the 38 241 patients with one or more measurements of creatinine, 1225 were categorized into CKD stage 3 (3.2%) and 138 into CKD stage 4 (0.4%), based on the 3-month criterion. The median number of creatinine measurements for the CKD stage 3 patients, including those made in the defining time interval, was 11 (interquartile range, 6–22), and for the stage 4 patients, it was 13 (interquartile range, 6–23). Table 1 shows the number of patients in the groups based on varying the duration requirement. Changing the criterion to 12 months decreased the number of identified patients by 37 and 51% for CKD stages 3 and 4, respectively, relative to the 3-month requirement.Table 1Comparision between different criteria of chronicity for CKD stages 3 and 43-month cohort6-month cohort9-month cohort12-month cohort95% confidence interval95% confidence interval95% confidence interval95% confidence intervalCKD stage 3 N12251025881774 Percent women5755–605753–605753–605653–60 Mean age76.475.8–77.176.575.8–77.276.775.9–77.577.076.2–77.8 Mean baseline GFR, ml/min/1.73 m250.950.4–51.350.850.3–51.250.650.1–51.150.750.1–51.2 5-year cumulative incidence, percent Renal failure4.22.9–5.74.12.7–5.74.63.0–6.54.52.8–6.5 Patient death45.942.6–49.244.6*41.0–48.242.1*38.3–46.140.336.3–44.6 Improvement in GFR4.8*3.5–6.23.7*2.5–5.12.81.8–4.12.31.3–3.6CKD stage 4 N1381119068 Percent women43*36–524839–574434–554634–58 Mean age74.571.8–77.174.8*71.7–77.573.369.8–76.572.568.2–76.2 Mean baseline GFR, ml/min/1.73 m224.824.0–25.524.824.0–25.524.623.7–25.525.124.0–26.0 5-year cumulative incidence, percent Renal failure43.1*33.6–53.047.5*36.9–59.059.547.8–72.564.051.1–78.5 Patient death43.734.3–53.343.0*32.6–54.331.521.0–43.527.116.1–39.8 Improvement in GFR0.00.00.00.0CKD, chronic kidney disease; GFR, glomerular filtration rate.*P<0.05 for difference from the next cohort Open table in a new tab CKD, chronic kidney disease; GFR, glomerular filtration rate. *P<0.05 for difference from the next cohort Table 1 shows the cumulative incidences of each of the three competing end points. Although the 5-year mortality was similar for the 3-month cohorts from both stages 3 and 4 (45.9 vs 43.7%), there was a statistically significant decrease between the 6- and 9-month cohorts for both stages. Mortality for the 12-month cohort was higher for stage 3 than for stage 4 (40.3 vs 27.1%). To explore this difference, an ordinary Kaplan–Meier survival analysis with death as the only end point and censoring at the end of study was performed for both 12-month cohorts. The 5-year mortality was then 43.9 and 58.8% for CKD stages 3 and 4, respectively, indicating that patients having reached the renal failure end point in stage 4 had a high mortality. Although the cumulative incidence of renal failure remained at the 4% level for all cohorts of stage 3, there was a sharp increase from 47.5 to 59.5% between the 6- and 9-month cohorts for stage 4. No patient with CKD stage 4 experienced the improvement end point. For stage 3, the cumulative incidence of this end point decreased gradually from 4.8% for the 3-month cohort to 2.3% for the 12-month cohort. The differences between both the 3- and 6-month cohorts and between the 6- and 9-month cohorts at stage 3 were statistically significant. Table 2 shows the results of the Cox regression for each end point. For CKD stage 3, the hazard ratios were significantly lower for all three end points in patients who satisfied the 12-month criterion. Also, there were statistically significant linear trends for a decrease in hazard ratio for each end point from the 3- to the 12-month criterion (P<0.001). Analysis of the composite end point of death or renal failure, and of death alone, showed similar results as for death in Table 2 (data not shown).Table 2Cox regression analyses of the competing end points death, renal failure, and improvement in GFR for CKD stages 3 and 4DeathRenal failureImprovement in GFRaNo patient with the CKD stage 4 experienced the improvement end point.Hazard ratio95% confidence intervalP-valueHazard ratio95% confidence intervalP-valueHazard ratio95% confidence intervalP-valueCKD stage 3 (n=1225) Female gender0.560.47–0.67<0.0010.460.27–0.810.0071.520.78–2.950.22 Age, 10-year increment1.901.71–2.12<0.0010.780.64–0.960.020.830.65–1.050.12 Baseline GFR, 10 ml/min/ 1.73 m2 increment0.820.74–0.91<0.0010.610.45–0.820.0011.400.90–2.170.13 Longest duration criterion satisfied 3 month1.00Reference1.00Reference1.00Reference 6 month1.200.89–1.620.220.790.26–2.430.680.690.26–1.810.45 9 month0.840.60–1.170.300.570.19–1.710.310.640.24–1.680.36 12 month0.260.20–0.33<0.0010.160.07–0.37<0.0010.150.07–0.31<0.001 Linear trend<0.001<0.001<0.001CKD stage 4 (n=138) Female gender1.110.60–2.050.740.850.46–1.580.62 Age, 10-year increment2.011.49–2.71<0.0010.910.79–1.060.21 Baseline GFR, 10 ml/min/ 1.73 m2 increment0.640.31–1.320.130.680.35–1.340.27 Longest duration criterion satisfied 3 month1.00Reference 6 month1.700.74–3.890.211.00bThe 3- and 6-month category combined because of few end points.Reference 9 month0.570.22–1.470.25 12 month0.370.17–0.800.012.22cThe 9- and 12-month category combined.0.94–5.270.07 Linear trend<0.001CKD, chronic kidney disease; GFR, glomerular filtration rate.a No patient with the CKD stage 4 experienced the improvement end point.b The 3- and 6-month category combined because of few end points.c The 9- and 12-month category combined. Open table in a new tab CKD, chronic kidney disease; GFR, glomerular filtration rate. In stage 4, there was also a significant linear trend for a decreasing hazard ratio for death with a longer duration criterion (P<0.001) (Table 2). For renal failure, there was a strong tendency toward a higher hazard ratio for those satisfying the longest criteria (P=0.07). There were no significant differences between the patient groups for the composite end point, probably because its two-component end points showed opposite tendencies. Increased age was associated with an increased hazard ratio for death for both CKD stages 3 and 4, whereas a decreased hazard ratio for renal failure for stage 3 was found. Female gender and increased baseline GFR had a positive effect only for death and renal failure in stage 3. Some patients were censored before they had creatinine measurements to allow determination of whether they belonged to the 6-, 9-, or 12-month cohorts. There were 92 of these patients in stage 3 and 10 in stage 4. All analyses were repeated after they were excluded, and the results did not differ materially from those presented in the tables. Table 3 shows the estimated mean change in GFR (ΔGFR) for each stage and each of the four nested cohorts. For CKD stage 3, there was a change from -1.5 ml/min/1.73m2/year for the 3-month cohort to -2.1 ml/min/1.73m2/year for the 12-month cohort. The minus sign indicates a decrease in GFR. The percentage of patients with a decrease in GFR increased from 71 to 80. In the two-level multivariate linear regression analysis with dummy variables for the longest duration criterion satisfied as covariates, there was a significant linear trend of lower ΔGFR with a longer duration criterion. Female gender was associated with a slower decrease (Table 4).Table 3Change in GFR for different criteria of chronicity in CKD stages 3 and 43-month cohort6-month cohort9-month cohort12-month cohort95% confidence interval95% confidence interval95% confidence interval95% confidence intervalCKD stage 3 N12251025881774 ΔGFR, ml/min/1.73 m2/yearaΔGFR, change in GFR, negative values denote a decrease in GFR. Mean-1.5-1.7 to -1.3-1.6-1.8 to -1.4-1.8-2.0 to -1.6-2.1-2.4 to -1.9 Standard deviation4.23.63.53.4 Patients with ΔGFR <0, percent7169–747572–777774–808078–83CKD stage 4 N1381119068 ΔGFR, ml/min/1.73 m2/yearaΔGFR, change in GFR, negative values denote a decrease in GFR. Mean-2.7-3.4 to -2.1-3.3-3.9 to -2.6-4.1-4.8 to -3.5-4.2-4.9 to -3.4 Standard deviation3.73.62.93.1 Patients with ΔGFR <0, percent8478–908679–929084–969184–98CKD, chronic kidney disease; GFR, glomerular filtration rate.a ΔGFR, change in GFR, negative values denote a decrease in GFR. Open table in a new tab Table 4Effects on change in GFR (ΔGFR) of age, gender, and chronicity criterion for CKD stages 3 and 4 in two-level multivariate linear regression analysesRegression coeffcient, ml/min/1.73 m2/year95% confidence intervalP-valueCKD stage 3 (n=1225) ΔGFR for 60-year-old male satisfying only the 3-month criterionaΔGFR, change in GFR, negative values denote a decrease in GFR.-1.1-3.1 to 0.80.26 Female gender1.30.2 to 2.40.02 Age, 10-year increment-0.1-0.5 to 0.40.73 Longest duration criterion satisfied 6 month-0.2-3.1 to 2.60.87 9 month0.6-2.0 to 3.30.64 12 month-1.6-3.4 to 0.20.09 Linear trend0.03CKD stage 4 (n=138) ΔGFR for 60-year-old male satisfying only the 3-month criterion-1.9-5.0 to 1.20.24 Female gender-0.1-2.3 to 2.10.92 Age, 10-year increment0.1-0.6 to 0.70.81 Longest duration criterion satisfied 6 month6.21.1 to 11.20.02 9 month-2.2-6.4 to 1.90.29 12 month-2.4-5.7 to 0.90.16 Linear trend0.01CKD, chronic kidney disease; GFR, glomerular filtration rate.a ΔGFR, change in GFR, negative values denote a decrease in GFR. Open table in a new tab CKD, chronic kidney disease; GFR, glomerular filtration rate. CKD, chronic kidney disease; GFR, glomerular filtration rate. For CKD stage 4, mean ΔGFR varied from -2.7 to -4.2 ml/min/1.73 m2/year from the 3-month to the 12-month cohort, and the percentage of patients with decreasing GFR increased from 84 to 91 (Table 3). In the regression analysis, the 6-month criterion had a significantly higher regression coefficient than the reference, and the linear trend of lower ΔGFR with a longer duration was significant (Table 4). Nonlinear relationships between ΔGFR and time were explored with inclusion of quadratic and cubic terms in the models for both stages, but were not statistically significant. The importance of agreeing on definitions of nosological entities can hardly be overstated. Progress in clinical work and research depends on a solid conceptual foundation, and new definitions should be tested under field conditions before they are accepted. In this study, we applied the K/DOQI definitions of CKD stages 3 and 4 to a clinical database of creatinine measurements to examine the criterion of chronicity. Because the database included all detected kidney disease in a well-defined population, the results show the spectrum of disease that can be expected from ordinary use of the definitions. Results for the 3-month cohort of CKD stage 3, corresponding to the established definition, showed a high mortality and a low risk of renal failure at 5 years and a low rate of decrease in GFR. This patient population has been discussed in more detail in a separate publication.3.Eriksen B.O. Ingebretsen O.C. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.Kidney Int. 2006; 69: 375-382Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar It is noteworthy that for this group, the risk of re-establishing GFR at a level greater than 60 ml/min/1.73 m2 was about the same as that of developing renal failure. On the other hand, the 3-month cohort from the stage 4 group had both a high risk of renal failure and death and a steeper decrease in GFR. The most important consequence of increasing the time period was a reduction in the number of patients by 16–37% for stage 3 and by 20–51% for stage 4 (Table 1). Analyses of the competing end points showed statistically significant differences between the cohorts. In both stages, the shorter duration criteria included patients with a higher mortality (Table 2) and a slower decrease in GFR (Tables 3 and 4). For stage 3, they also had a significantly higher chance of improvement in GFR to a level greater than 60 ml/min/1.73 m2. For stage 4, there was a marked increase in the cumulative incidence of renal failure and a decrease in the cumulative mortality between the 6- and 9-month cohorts (Table 1). The regression analyses demonstrated that the effects of varying the duration criterion were independent of age, gender, and baseline GFR. The 12-month cohort from the stage 4 group exhibited a lower mortality than the 12-month cohort from the stage 3 group, which may seem paradoxical. This outcome arose from the increased hazard of renal failure for stage 4 patients, which preempted the mortality end point. Many patients in stage 4 who reached the renal failure end point first subsequently died, as demonstrated in an ordinary Kaplan–Meier survival analysis in which death was analyzed as the only end point. Because creatinine is assumed to vary little in non-hospitalized patients, some epidemiological surveys have not included the chronicity criterion in estimates of CKD prevalence.4.Culleton B.F. Larson M.G. Evans J.C. et al.Prevalence and correlates of elevated serum creatinine levels: the Framingham Heart Study.Arch Intern Med. 1999; 159: 1785-1790Crossref PubMed Scopus (172) Google Scholar,5.Iseki K. Ikemiya Y. Fukiyama K. et al.Risk factors of end-stage renal disease and serum creatinine in a community-based mass screening.Kidney Int. 1997; 51: 850-854Abstract Full Text PDF PubMed Scopus (102) Google Scholar In the third National Health and Nutrition Examination Survey, the prevalence of different CKD stages was estimated from one measurement of creatinine in each patient.6.Coresh J. Astor B.C. Greene T. et al.Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey.Am J Kidney Dis. 2003; 41: 1-12Abstract Full Text Full Text PDF PubMed Scopus (2211) Google Scholar However, a repeat measurement of a random sample of the subjects found that only 77% of those classified as <60 ml/min/1.73 m2 were classified similarly on the repeat measurement. Classification based on a single measurement would therefore tend to inflate the prevalence estimates. This indicates that a chronicity criterion should also be used in population surveys. For epidemiologic studies based on creatinine measured in patients, this criterion is indispensable and was used in recent studies by both Keith et al.7.Keith D.S. Nichols G.A. Gullion C.M. et al.Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.Arch Intern Med. 2004; 164: 659-663Crossref PubMed Scopus (1282) Google Scholar and Drey et al.8.Drey N. Roderick P. Mullee M. et al.A population-based study of the incidence and outcomes of diagnosed chronic kidney disease.Am J Kidney Dis. 2003; 42: 677-684Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar Unfortunately, it is not possible to determine from these papers how use of this criterion affected the number of patients identified for the studies. The CKD definitions are also used as inclusion criteria in clinical trials. Estimating the necessary sample size depends on the expected frequency of the primary end point. In studies of interventions to slow the progression of CKD, a high percentage of patients with stable GFR would necessitate an increase in the number of patients required. A longer duration criterion would lessen this problem because the 12-month cohorts of both stages exhibited the lowest mean and standard deviations of ΔGFR. An alternative solution would be to specify additional inclusion criteria, such as proteinuria, to limit the number of patients without progressive disease; however, this tactic would prevent generalization of the results to all patients with CKD, which again would make the definition less useful. In addition, including CKD stage 4 patients from the 3- and 6-month cohorts would result in selection of study populations with very high mortality, a potential problem in some types of studies. The K/DOQI CKD definition has played an important role in the development of practice guidelines.9.National Kidney Foundation.National Kidney Foundation. Clinical Practice Guidelines, New York2006http://www.kidney.org/professionals/kdoqi/guidelines.cfmGoogle Scholar The results of this study show that definitions based on short duration criteria result in identification of large cohorts including many patients with poor prognosis. Although these patients must also receive treatment and care, they probably have other needs than, for example, a patient with a decreasing GFR and a longer life expectancy. Practice guidelines target groups of patients, but should nevertheless be as specific as possible. This need for specificity is an argument for making the target populations as homogeneous as possible and accordingly for the use of a definition with a longer duration criterion. The mean age in our cohort of CKD patients was high. This is a consequence of the natural decrease in GFR with age and the application of the same GFR cutoffs to all age groups in the definition. Other studies have made similar findings and advocated different cutoffs for the elderly.10.O'Hare A.M. Bertenthal D. Covinsky K.E. et al.Mortality risk stratification in chronic kidney disease: one size for all ages?.J Am Soc Nephrol. 2006; 17: 846-853Crossref PubMed Scopus (298) Google Scholar Population surveys have also found a very high prevalence of CKD stages 3 and 4 in the older age groups, even though elderly and diseased people are probably underrepresented in surveys.11.Coresh J. Byrd-Holt D. Astor B.C. et al.Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999–2000.J Am Soc Nephrol. 2005; 16: 180-188Crossref PubMed Scopus (624) Google Scholar, 12.Chadban S.J. Briganti E.M. Kerr P.G. et al.Prevalence of kidney damage in Australian adults: The AusDiab kidney study.J Am Soc Nephrol. 2003; 14: S131-S138Crossref PubMed Google Scholar, 13.Nitsch D. Dietrich D.F. von Eckardstein A. et al.Prevalence of renal impairment and its association with cardiovascular risk factors in a general population: results of the Swiss SAPALDIA study.Nephrol Dial Transplant. 2006; 21: 935-944Crossref PubMed Scopus (63) Google Scholar As our cohort included all patients with detected CKD in a well-defined population, it is more representative of the CKD patients who are met by the nephrologists in clinical practice. However, similar studies need to be done in populations with different ethnic compositions and health-care systems before the optimal chronicity criterion can be defined. The limitations of estimating GFR from serum creatinine are well known.14.Stevens L.A. Coresh J. Greene T. et al.Assessing kidney function – measured and estimated glomerular filtration rate.N Engl J Med. 2006; 354: 2473-2483Crossref PubMed Scopus (2160) Google Scholar One of the most significant limitations is the lack of calibration of creatinine analysis across laboratories; this limitation is illustrated by the differences in some of the results presented here for CKD stage 3 compared with those in a previous publication based on the same database.3.Eriksen B.O. Ingebretsen O.C. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.Kidney Int. 2006; 69: 375-382Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar The recalibration of the Modification of Diet in Renal Disease equation for isotope dilution mass spectrometry traceable creatinine measurement methods and the recalculation of creatinine values measured with Jaffe's method for the enzymatic method in our laboratory represent a substantial improvement in the accuracy of the estimates. This improvement was confirmed by comparison of a sample of the estimates to 51CrEDTA clearance. We conclude that the choice of chronicity criterion in the CKD definitions for stages 3 and 4 was a determinant of the characteristics of the identified patient populations, particularly of the number of patients identified. This finding may have important implications for how the definitions are applied. An increase in the duration requirement should be considered. The database of the Department of Medical Biochemistry at the University Hospital of North Norway contains all measurements of serum creatinine performed on inhabitants of the municipality of Tromsø in northern Norway. In the 10-year study period from January 1, 1994 to December 31, 2003, there were 248 560 measurements of creatinine in these subjects as part of routine clinical activities. These activities included all healthcare in the municipality, both primary care and hospital in- and outpatients, and amounted to 0.43 measurements per person-year in the total population.3.Eriksen B.O. Ingebretsen O.C. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.Kidney Int. 2006; 69: 375-382Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar The mean population of Tromsø in the study period was 58 086. The University Hospital of North Norway is the sole provider of nephrology and laboratory services, ensuring the completeness of the database; the distance to the next laboratory and hospital is 300 km by road. The study population and the database have been described in more detail previously.3.Eriksen B.O. Ingebretsen O.C. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.Kidney Int. 2006; 69: 375-382Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Serum creatinine analyses were performed with instruments from Roche Diagnostics (Mannheim, Germany). The model Hitachi 917 was used from 1994 to 2002, with a switch in 2002 to the Modular model from Hitachi. A Jaffe method with reagents and calibrators purchased from the same company also was used. Control samples with three levels of creatinine were analyzed for every 100 patient samples. For internal quality control, we used an analytical coefficient of variation of 2%. The rejection rule was the occurrence of two consecutive control observations exceeding the same mean±2 s.d. Calibrations were performed when necessary. The laboratory participated in an External Quality Assessment Program provided by Labquality (Helsinki, Finland). At the end of 2003, a new enzymatic method for creatinine analysis was introduced in our laboratory (CREA Plus, Roche Diagnostics), which has been standardized against isotope dilution mass spectrometry. The linear relationship between the old and the new methods was established and permitted recalculation of all of the old creatinine values to the enzymatic method. Levey et al.15.Levey A.S. Coresh J. Greene T. et al.Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.Ann Intern Med. 2006; 145: 247-254Crossref PubMed Scopus (3693) Google Scholar recently published a new version of the abbreviated Modification of Diet in Renal Disease formula recalibrated for isotope dilution mass spectrometry traceable creatinine measurement methods. The formula estimates GFR from creatinine, gender, and age as 175 × (serum creatinine)-1.154 × age-0.203 × 0.742 for women and × 1.21 if African-American.15.Levey A.S. Coresh J. Greene T. et al.Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate.Ann Intern Med. 2006; 145: 247-254Crossref PubMed Scopus (3693) Google Scholar GFR was estimated using this formula for all the recalculated creatinine measurements in the database. Only measurements before initiation of first-time renal replacement therapy (RRT) were included. The database included date of birth and a person number encoding gender. Age at the time of measurement was used for each estimate. The number of inhabitants of African descent in Tromsø is negligible, and this last factor was ignored. To validate the GFR estimates, these values were compared with all available concurrent measurements of 51CrEDTA clearance. Because the abbreviated Modification of Diet in Renal Disease formula is known to be imprecise for higher GFR values, only 51CrEDTA clearances below 100 ml/min/1.73 m2 were included. A total of 80 measurements were found. When the difference between estimated GFR and 51CrEDTA clearance was expressed as percentage of 51CrEDTA clearance, the median of the distribution of differences was 16.3%, the 75th percentile was 27.3%, and the 90th percentile was 40%. Although these values are somewhat higher than those published by Levey for the original, abbreviated Modification of Diet in Renal Disease formula (the same percentiles were 12.1, 20.5, and 29.7%), this precision was deemed sufficient for the purposes of this study (Levey AS, Greene T, Kusek JW et al. J Am Soc Nephrol 2000; 11: A0828, abstract). In a previous publication regarding CKD stage 3 from this project, estimated GFR values from Jaffe creatinine measurements were used, and some of the results for the CKD stage 3, 3-month cohort presented here differ somewhat from our previous estimates.3.Eriksen B.O. Ingebretsen O.C. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.Kidney Int. 2006; 69: 375-382Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar The most important difference is a decrease in the number of patients classified as CKD stage 3. According to the K/DOQI definition, GFR from 30 to 59 ml/min/1.73 m2 is classified as CKD stage 3, and from 15 to 29 ml/min/1.73 m2 as CKD stage 4.2.K/DOQI clinical practice guidelines for chronic kidney disease work group. Definition and classification of stages of chronic kidney disease.Am J Kidney Dis. 2002; 39: S46-S75Abstract Full Text PDF Google Scholar For each stage, all GFR estimates in the corresponding interval were identified. When an identified measurement was followed by a second measurement in the same interval 3 months or more after the first, the patient was classified as being in the corresponding stage if there were no measurements outside the interval in the time period between these two. This process was then repeated three times, but with the requirement of a second measurement at 6, 9, and 12 months after the first, instead of at 3 months. Because all patients who satisfied, for example, the 9-month criterion also satisfied the 3- and 6-month criteria, we had four nested cohorts of patients (Figure 1). The observation time of each patient was defined as starting 3, 6, 9, or 12 months after the date of the first registered measurement that satisfied these criteria. Death, renal failure, and improvement were considered competing risks. Renal failure was defined as either initiation of RRT or CKD stage 5, and the date of the event that occurred first was registered. CKD stage 5 is defined as GFR <15 ml/min/1.73 m2 and was ascertained from the database as the first date of a GFR below this level with no subsequent values of 15 or greater before RRT, death, or censoring.1.K/DOQI clinical practice guidelines for chronic kidney disease work group. Evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar Improvement was registered as the first date with estimated GFR equal to or greater than 60 ml/min/1.73 m2 followed by a second measurement above this level at least 1 year later with no values below this level in the interim. Patients were censored at the end of the study period. All initiation of RRT for inhabitants of the municipality is administered by the University Hospital of North Norway, and the date was recorded from hospital databases. Initiation of RRT in patients who had moved from the municipality was assumed to be negligible, as migration in people over 40 years of age to and from the municipality was very low during the period.16.Statistics Norway.StatBank Norway. Statistics Norway, Oslo2006http://statbank.ssb.no/statistikkbanken/default_fr.asp?PLanguage=1Google Scholar As an additional validation of the completeness of the creatinine database, it was matched with all patients from Tromsø having initiated RRT in the study period. Only four of 55 patients did not have any creatinine measurement in the 3 months before the start of RRT. In two of these, RRT was started within 3 months of the beginning of the study period. Date of death was registered from the hospital's database, which is regularly updated against the Norwegian Central Population Register. Identical and separate statistical analyses were done for the CKD stage 3 and 4 groups. ΔGFR expressed in ml/min/1.73 m2/year was estimated for each patient with a two-level multivariate linear regression model. ΔGFR was modeled as a linear function of time incorporating age and gender as covariates. A negative change denoted a decrease in GFR, and a positive change an improvement. Compared to using ordinary least-square estimates of change in GFR for each individual patient, this method avoids high variability in estimates for patients with short follow-up. The model has been described in more detail previously.3.Eriksen B.O. Ingebretsen O.C. The progression of chronic kidney disease: a 10-year population-based study of the effects of gender and age.Kidney Int. 2006; 69: 375-382Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar First, separate analyses were done for each of the four cohorts which included all measurements made after the respective defining time intervals until death, initiation of RRT, or end of follow-up. These estimates were used for calculating the mean ΔGFR with confidence intervals for each cohort. Secondly, an analysis was done including all patients where dummy variables for the longest duration criterion satisfied by each patient were added as covariates. Linear trends were investigated with the chronicity criterion entered as a continuous variable. PROC MIXED in SAS was used for estimating the parameters of the model (SAS Institute, Cary, NC). Survival analysis of the competing risks of death, renal failure, and improvement was performed using non-parametric, maximum likelihood estimates of the cumulative incidence of each end point in the presence of the other end points, as suggested by Kalbfleisch and Prentice.17.Kalbfleisch J.D. Prentice R.L. The Statistical Analysis of Failure Time Data. 2nd edn. John Wiley & Sons, Inc., Hoboken, New Jersey2002Crossref Scopus (3277) Google Scholar This analysis was done separately for each of the cohorts. Because of statistical dependences between these four nested cohorts, ordinary statistical tests of differences could not be used. Instead, 95% confidence intervals for the outcomes of each cohort and differences between them were estimated with the bootstrap algorithm using 20 000 resamples of the original observations.18.Efron B. Tibshirani R.J. An Introduction to the Bootstrap. Chapman & Hall, New York1993Crossref Google Scholar The differences in hazard rates were analyzed in Cox regression of time until each of the three end points. Independent variables were age, gender, baseline GFR, and dummy variables for the longest duration criterion satisfied by each patient. For each analysis, patients were censored when experiencing any of the competing end points or at the end of follow-up.17.Kalbfleisch J.D. Prentice R.L. The Statistical Analysis of Failure Time Data. 2nd edn. John Wiley & Sons, Inc., Hoboken, New Jersey2002Crossref Scopus (3277) Google Scholar Because patients might experience death or renal failure after the improvement end point, additional Cox regressions were performed of the composite end point of renal failure or death, and of death alone, with patients censored only at end of follow-up. The independent variables were the same. Statistical significance was set at P<0.05. This study was approved by the Norwegian Data Inspectorate and the Regional Ethics Committee of North Norway. The authors are grateful to Åshild Halvorsen, Department of Clinical Chemistry, University Hospital of North Norway, for extracting data from hospital databases.
Referência(s)