The Modified Chronic Kidney Disease Epidemiology Collaboration Equation For The Estimated Glomerular Filtration Rate Is Better Associated With Comorbidities Than Other Equations in Living Kidney Donors in Japan Ⅱ

Results 

Baseline data are presented in Table 1. We compared the mean eGFR for the three types of equations between the elderly (age >70 years old) and non-elderly groups and between the comorbidity-positive and comorbidity-negative groups (Table 2) and observed significant differences between the elderly and non-elderly groups for all three eGFRs. When comparing mean eGFR/Jm-eGFR, obesity, hypertension, and CVD exhibited significant differences. When comparing the mean eGFR/Jm-MDRD, significant differences were detected only in obesity. When comparing the mean eGFR/Jm-CKD-EPI, obesity, hypertension, diabetes, and CVD exhibited significant differences. No significant differences in the mean eGFR were observed for stroke using each equation.

The positive rates of the 5 comorbidities in the elderly (age >70 years old) and non-elderly groups are shown in Fig. 2. The positive rates for hypertension, diabetes, stroke, and CVD were two to three times higher in the elderly than in the non-elderly group. Chi-square tests for an older age (>70 years old) and comorbidity rates exhibited significant differences (p<0.001).

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The correlations between the age and eGFR calculated using the 3 equations were significant (p<0.001). The R2 of the eGFR/Jm-CKD-EPI (R2 =0.509) was larger than that of the eGFR/Jm-eGFR (R2 =0.150) and eGFR/Jm-MDRD (R2 = 0.083).

Fig. 3a shows the ROC analysis between the eGFRs calculated using the three equations and the five comorbidities of obesity, hypertension, diabetes, CVD, and stroke. The ROC curves of the eGFR/Jm-CKD-EPI exhibited a leftward shift compared with those of the eGFR/Jm-eGFR and eGFR/ Jm-MDRD about the comorbidities. In particular, regarding the relationship with older age (>70 years old), the area under the ROC curve (AUROC) for the eGFR/JmCKD-EPI was much larger, (0.859) than that for the eGFR/ Jm-eGFR (0.674) and eGFR/Jm-MDRD (0.636). Fig. 3b shows the results of the ROC analysis between the eGFR calculated using the 3 equations and the 5 comorbidities, excluding an older age (>70 years old), (n=798). The ROC curves of the eGFR/Jm-CKD-EPI presented a leftward shift compared with those of the eGFR/Jm-eGFR and eGFR/JmMDRD about the comorbidities. The comorbidity rates, namely <70 mL/min/1.73 m2, 70- 80 mL/min/1.73 m2, and  80 mL/min/1.73 m2, in the 3 eGFR groups are presented in Table 3. All five comorbidities showed significant differences only in the group with eGFR/Jm-CKD-EPI, and the comorbidity rates in the group with eGFR/Jm-CKD-EPI <70 mL/min/1.73 m2 were higher than those in the group with eGFR - 70 mL/min/1.73 m2.

Discussion 

Of the three eGFRs, the eGFR/Jm-CKD-EPI correlated most sensitively with the comorbidities. The eGFR/Jm-CKD-EPI, eGFR/Jm-eGFR, and eGFR/Jm-MDRD detected significant differences in four, three, and one of the five comorbidities, respectively (Table 2). In the ROC analyses (Fig. 3), the eGFR/Jm-CKD-EPI was superior in terms of the relationship between comorbidities. A trend analysis (Table 3) revealed the superiority of the eGFR/Jm-CKD-EPI in the decline of the eGFR (Fig. 3).

During donor candidate evaluation before transplantation, the eGFR/CKD-EPI can be used for the initial assessment. Extra care should be provided to patients who have received donations from donors with a low eGFR/CKD-EPI (<70 mL/min/1.73 m2 ), which is most strongly associated with the five comorbidities and an older age (Table 3). Compared to donations from healthy living donors, those from living donors with medical conditions (so-called expanded criteria donors) exhibited a high incidence of overall and death-censored graft loss according to multivariable Cox proportional hazards analyses (hazard ratios=2.16 and 3.25, p= 0.015 and 0.004, respectively) (7).

Figure 3. a: The AUROC using the ROC analysis for the relationship with comorbidities calculated by the eGFR using the three equations of Jm-eGFR, Jm-MDRD, and Jm-CKD-EPI. The AUROC is shown graphically for each ROC analysis between the eGFR and comorbidities. n=8,176. b: The AUROC using the ROC analysis for the relationship with comorbidities calculated by the eGFR using the three equations of Jm-eGFR, Jm-MDRD, and Jm-CKD-EPI, excluding the elderly (age >70 years old). n=7,378. AUROC: area under the receiver operating characteristics curve, ROC: receiver operating characteristics, AUC: area under the curve, BMI: body mass index, eGFR: estimated glomerular filtration rate, HT: hypertension, DM: diabetes, CVD: cardiovascular disease, Jm: Japanese modified, MDRD: Modification of Diet in Renal Disease, CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration. The red line is Jm-CKD-EPI, the blue line is Jm-eGFR, and the green line is Jm-MDRD.

In cross-sectional studies, a lower eGFR/CKD-EPI showed a better association with the prevalence of comorbidities than eGFR/MDRD in Caucasian community-dwelling populations. Tarantini et al. (4) reported that in patients with CVD, the prevalence of CVD was higher when evaluating the eGFR/CKD-EPI than when evaluating the eGFR/MDRD in the low eGFR group. Juutilainen et al. (13) evaluated the rates of comorbidities, namely hypertension, obesity, diabetes, and CVD, in patients with CKD and observed a significantly higher prevalence of patients with comorbidities when the evaluation was performed using the eGFR/CKD-EPI than when it was performed using the eGFR/MDRD.

We confirmed the accuracy of the eGFR/Jm-CKD-EPI in the literature. Rule et al. (14) reported that the CKD-EPI equation was more accurate than MDRD in low-risk populations, including pre-donation and post-donation kidney donors. Murata et al. (15) reported that the creatinine-based eGFR/CKD-EPI demonstrated less bias than the eGFR/ MDRD in potential LKT donors (−8% vs. −18%). Burballa et al. (16) and Gaillard et al. (17) compared the values of the creatinine-based eGFR/CKD-EPI, eGFR/MDRD, and mGFR with isotopes in preoperative LKT donors and concluded that the eGFR/CKD-EPI correlated better with mGFR than did the eGFR/MDRD. Horio et al. (18) compared the accuracy of the eGFR/Jm-CKD-EPI and eGFR/ Jm-MDRD with the measured inulin GFR in a health checkup population in Japan. In the rage of measured inulin GFR  60 mL/min/1.73 m2, the biases (mGFR-eGFR) were 7.3±20.6 mL/min/1.73 m2 in the eGFR/Jm-CKD-EPI and 7.8 ±22.2 mL/min/1.73 m2 in the eGFR/Jm-MDRD, respectively (p<0.001). Horio et al. (19) evaluated the accuracy of the eGFR/Jm-eGFR in potential LKT donors in Japan who received the inulin clearance test and observed a bias (mGFReGFR) of 18.3±16.4 mL/min/1.73 m2. Thus, the eGFR/JmeGFR underestimated the true GFR of LKT donors. Based on the two studies of Horio et al. (18, 19), the eGFR/JmCKD-EPI appears accurate for comparing measured inulin GFR values.

We explored why the eGFR/Jm-CKD-EPI was superior regarding its relationship with the five evaluated comorbidties, as the reasons have not been examined in-depth in previous reports. The comorbidity rates were 2 to 3 times higher in the elderly group (age >70 years old) than in the non-elderly group (age  70 years old) among the LKT donors (Fig. 3). An ROC analysis revealed that the eGFR/JmCKD-EPI was better associated with older age (>70 years old) compared to the eGFR/Jm-eGFR and eGFR/JmMDRD (Fig. 3a). We thus believe that the equation characteristic of age sensitivity is responsible for the superiority of the eGFR/Jm-CKD-EPI.

Ji et al. studied the relationship between the eGFR and preclinical target organ damage in hypertension using a ROC analysis and reported that the eGFR/Chinese CKD-EPI equation was better associated with hypertensive complications than the eGFR/Chinese and Asian- modified MDRD equations (20). The eGFR/CKD-EPI was better associated than the eGFR/MDRD with intra-media thickness, ankle-brachial index, left ventricular mass index, urine albumin-to-creatinine ratio, and aortic pulse wave velocity. In our study, discounting elderly cases, the eGFR/CKD-EPI was better associated with comorbidities in LKT donors than the eGFR/ Jm-eGFR and eGFR/Jm-MDRD (Fig. 3b). Thus, the eGFR/ CKD-EPI might be sensitive for hypertensive or atherosclerotic complications, excluding the older age factor. The eGFR/Jm-CKD-EPI is recommended for use in risk evaluations, not only for renal damage but also systemic organ damage, reflecting hypertensive complications in LKT donors.

The eGFR/CKD-EPI has been reported to be superior to the eGFR/MDRD in the prediction of CVD events or mortality in Caucasian participants (1-3). In Chinese participants, the eGFR/CKD-EPI was a better predictor of stroke recurrence and death than the eGFR/MDRD (21). Consistent, Matsushita, et al. (22) reported that the eGFR/JmCKD-EPI was a better predictor of the risk of all-cause and cardiovascular mortalities than the eGFR/Jm-MDRD in the range of the eGFR  60 mL/min/1.73 m2 in Japanese participants. Terawaki et al. (3) used an ROC analysis to compare the predictive values for CVD and stroke between the eGFR/Jm-CKD-EPI and eGFR/Jm-MDRD and reported that the AUROCs for CVD events in the eGFR/Jm-CKD-EPI and eGFR/Jm-eGFR were 0.596 and 0.562, respectively. The eGFR/CKD-EPI was more closely associated with CVD incidence in 241,159 Japanese participants (mean age, 64 years old) who were undergoing a general health checkup. Ohsawa et al. (23) reported a better prediction for all-cause mortality, myocardial infarction, and stroke with the eGFR/ Jm-CKD-EPI than with the eGFR/Jm-MDRD in a health checkup cohort. Thus, the eGFR/CKD-EPI is superior for predicting CVD events and mortality in community-dwelling populations. We should carefully follow up with donors with a low eGFR/CKD-EPI after transplantation.

Several limitations associated with the present study warrant mention. The registry data had no data on the measured GFR, so we could not directly compare the accuracy of the three eGFR equations. We unfortunately had to exclude many cases with missing data from the analysis. These limitations might have resulted in the data being misclassified; however, our study has some important insights derived from its involvement of a large cohort of LKT donors (> 8,000 cases). 

Conclusion 

The eGFR/Jm-CKD-EPI was better associated with comorbidities, including obesity, hypertension, diabetes, CVD, and stroke than the eGFR/Jm-eGFR and eGFR/JmMDRD in low-risk populations, such as Japanese LKT donors. For the initial assessment of the renal function of LKT donor candidates, the eGFR/Jm-CKD-EPI is recommended, particularly for expanded criteria donors with comorbidities.