Clinical Significance of Adjusting the Estimated Glomerular Filtration Rate by an Individual’s Body Surface Area from the Perspective of the Cardio-ankle Vascular Index: A Cross-sectional Study

Abstract

Aim: A decline in the estimated glomerular filtration rate (eGFR) is associated with vascular dysfunction, a cardiovascular disease (CVD) risk. However, since the eGFR is based on the standard body surface area (BSA) of 1.73 m², its reliability may be affected by body size. We aimed to clarify whether the individual’s BSA adjustment of eGFR enhances the relationship with kidney and vascular functions in the general healthy Japanese population.

Methods: This cross-sectional analysis was conducted in a total of 58,837 Japanese individuals. The BSA-adjusted eGFR (mL/min) was defined as the product of the conventional eGFR and the individual’s BSA divided by 1.73 m². Arterial stiffness was assessed by the cardio-ankle vascular index (CAVI), and a high CAVI was defined as CAVI ≥ 9.0.

Results: Compared with the eGFR, the BSA-adjusted eGFR showed higher values in males in their 20s to 50s and lower values in females of all ages. The BSA-adjusted eGFR showed a stronger negative correlation with the CAVI than the eGFR (R: –0.444 vs. –0.388 in males, –0.449 vs. –0.416 in females). In a receiver-operating characteristic curve analysis, the discriminative power for a high CAVI was stronger for the BSA-adjusted eGFR than for the eGFR (area under the curve: 0.776 vs. 0.723 in males, 0.757 vs. 0.716 in females). The upper tertile of the BSA-adjusted eGFR showed higher odds ratios for a high CAVI than that of the eGFR in both sexes, after adjusting for covariates.

Conclusions: The BSA-adjusted eGFR appropriately assesses the kidney function according to differences in sex, age and body size. Furthermore, a CAVI analysis suggested that the BSA-adjusted eGFR might facilitate the achievement of more precise preventive care for CVD.

Introduction

Several reports highlight the growing global concern of chronic kidney disease (CKD)¹⁾, indicating the need for clinicians to accurately assess kidney function for the prevention, early detection and management of CKD. Although the inulin clearance test most accurately reflects the glomerular filtration rate (GFR)²⁾, the measurement method is complicated. Consequently, the estimated glomerular filtration rate (eGFR) formula consisting of age, sex and serum creatinine concentration (or serum cystatin C concentration) is currently the most widely used simple kidney function parameter³⁾.

The eGFR formula is adapted from that for estimating inulin clearance. However, to establish the eGFR formula for epidemiological use, it is necessary to first standardize inulin clearance to a common body surface area (BSA). In this standardization, the average BSA of 1.73 m², which was the average BSA of 25-year-old American men and women in the 1920s, was adopted⁴⁾. Therefore, the accuracy of the eGFR formula is not guaranteed for individuals with a BSA deviating remarkably from 1.73 m².

The US National Institutes of Health (NIH) stated that for individuals with extreme body sizes, the eGFR should be adjusted by dividing by 1.73 m² and multiplying by the individual’s BSA⁵⁾. However, in the real world, the extent to which such individual BSA-adjusted eGFR differs from the conventional unadjusted eGFR has not been fully examined.

Vascular dysfunction manifested by systemic arterial stiffening occurs with aging and is also associated with traditional risk factors for cardiovascular disease (CVD)⁶⁾. The pulse wave velocity (PWV) is the most widely used arterial stiffness parameter, and has been shown to be associated with CVD events⁷⁾. However, an issue with the PWV is that the measured value is affected by the blood pressure (BP) at the time of measurement⁸⁾. The cardio-ankle vascular index (CAVI) is also an arterial stiffness parameter developed after the PWV to assess the stiffness of the arterial tree from the aortic origin to the ankle independent of the BP⁹⁾. This parameter is known to be high in individuals with various atherosclerotic diseases, including coronary artery disease, cerebral stroke, carotid sclerosis, and CKD¹⁰⁾. Systemic arterial stiffening, as indicated by an increased CAVI, leads to excessive pulsatile load damages small arteries and glomeruli in the kidney cortex¹¹⁾.

Conversely, CKD per se is known to exacerbate arteriosclerosis through the accumulation of uremic toxins, increased oxidative stress, chronic inflammation and altered lipoprotein metabolism¹²⁾, suggesting an interaction between systemic arterial stiffness and the kidney function. Indeed, several cross-sectional studies have revealed an association of the CAVI with the kidney function as assessed by the eGFR^{13, 14)} and serum cystatin C level¹⁵⁾, and a meta-analysis has established the longitudinal finding that an increased CAVI predicts kidney outcomes^{11, 16)}. In addition, we previously reported that the CAVI has a better predictive ability than heart-ankle PWV and the CAVI0, a variant of the CAVI, for kidney function decline¹⁷⁾. The CAVI can be improved by appropriate therapeutic interventions, and its improvement may contribute to the suppression of vascular outcomes^{18, 19)}. Therefore, applying the CAVI may be meaningful for the management of atherosclerotic diseases, including CKD, in routine clinical practice. However, no reports have examined the effect of the BSA-adjusted eGFR on the relationship between the eGFR and vascular function.

With this background, we hypothesized that the BSA-adjusted eGFR enables more appropriate management of CKD than the conventional eGFR. The present study therefore examined whether or not the eGFR adjusted for the individual BSA enhances the relationship between the kidney and vascular functions. First, we examined the detailed distribution of the BSA-adjusted eGFR in the general healthy Japanese population by gender. In addition, we compared the BSA-adjusted eGFR and conventional eGFR with respect to their association with the CAVI. If the BSA-adjusted eGFR is strongly associated with the CAVI, it may be useful for more precise preventive care for CVD through a more accurate assessment of the linkage between the kidney and vascular functions.

Materials and Methods

Study Population and Design

This research was a retrospective cross-sectional study using data from the CVD and cancer screening program organized by the Japan Health Promotion Foundation. The study population was Japanese urban residents of major cities in Japan who had undergone annual health screening between 2013 and 2018. Participants were volunteers who were not paid and were not recruited for this study (unlike subjects of a clinical trial).

Initially, all 76,720 individuals were assessed for eligibility. Since the CAVI may change due to treatments for metabolic disorders and CVD¹⁰⁾, 14,206 individuals who were receiving some kind of drug therapy; had a history of heart disease, stroke or a current diagnosis of malignant neoplasm; or were being treated for hypertension, diabetes, nephritis and gout were excluded. In addition, 3,677 individuals with missing serum creatinine concentration data were excluded. Ultimately, 58,837 individuals were included in this study.

Data Collection

All parameters were assessed by standardized methods. Height and body weight (BW) were measured, and the body mass index (BMI) was calculated as BW (kg)/height (m) squared. The BSA was calculated using the following formula²⁰⁾:

BSA = Height (cm)^0.725 × BW (kg)^0.425 × 0.007184.

The BP was measured from an upper arm cuff after resting for 5 min in a sitting position. Blood was collected from an anterior upper extremity vein in the morning after a 12-h fast for measuring fasting plasma glucose (FPG, mg/dL), total cholesterol (TC, mg/dL), triglycerides (TG, mg/dL) and high-density lipoprotein cholesterol (HDL-C, mg/dL). Low-density lipoprotein cholesterol (LDL-C, mg/dL) was calculated using Friedewald’s formula.

Two kidney function parameters were evaluated in this study. First, the conventional eGFR was calculated using the following formula developed by the Japanese Society of Nephrology²¹⁾:

eGFR (mL/min per 1.73 m²) = 194 × creatinine (mg/dL)^−1.094 × age (years)^−0.287 (× 0.739 if female).

Next, the BSA-adjusted eGFR was calculated using the following formula²²⁾:

BSA-adjusted eGFR (mL/min) = eGFR (mL/min per 1.73 m²) × individual’s BSA (m²)/1.73 (m²).

Because there are clear sex differences in the kidney function and BSA, all analyses in this study were conducted in males and females separately.

Measurement of Arterial Stiffness Parameters and BP

The CAVI was measured using a VaSera VS-1500 device (Fukuda Denshi Co., Ltd., Tokyo, Japan) according to the manufacturer’s instructions. CAVI values were automatically calculated using the following formula⁹⁾:

CAVI = a{2ρ × ln(Ps/Pd)/ΔP × haPWV²} + b,

where Ps is systolic BP; Pd is diastolic BP; ΔP is Ps ‒ Pd; ρ is blood density; haPWV denotes heart-ankle PWV; and a and b are constants.

Participants were placed in a supine position and remained still and silent during five minutes of measurement. Cuffs were placed on the arms and legs, and a heart sound microphone was attached with double-sided tape to the sternum at the second intercostal space. Individuals with an ankle-brachial index ＜0.90 were excluded from the analysis, as patients with severe arterial occlusive disease may have falsely low CAVI values⁹⁾. In addition, we defined “high CAVI” as ≥ 9.0 in all participants, which is essentially the cutoff for the presence of coronary artery stenosis¹⁰⁾.

Statistical Analyses

The SPSS software program (version 27.0.1; Chicago, IL, USA) and R software program (version 3.4.2) were used for statistical analyses. Data are expressed as the median (interquartile range) or mean±standard deviation. The Mann-Whitney U test or Fisher’s exact test was performed to examine differences between two groups. The relationship between the two kidney function parameters and age and between the age-adjusted CAVI and the two kidney function parameters were analyzed using a one-way analysis of variance (ANOVA) followed by Bonferroni’s multiple comparison test. Pearson’s correlation coefficients were compared using the cocor package in the R software program²³⁾. Sensitivity and specificity of the two kidney function parameters to predict a high CAVI were analyzed using conventional receiver-operating-characteristic (ROC) curves. The ROC curve and Youden’s J Index (J = maximum [sensitivity + specificity – 1], provides the cutoff point in the ROC curve)²⁴⁾ were generated to evaluate the discriminative power and select the cutoff value of a kidney function parameter to predict a high CAVI. Concordance statistics (C-statistics) that reflect the power of the two kidney function parameters to predict a high CAVI were compared. In addition, we calculated the continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) to compare the contribution of the parameters to a high CAVI. A multivariate logistic regression analysis was used to evaluate the contribution of the two kidney function parameters (in tertiles) to a high CAVI. While variables showing significant differences between the groups with and without a high CAVI were included as covariates in the logistic model, some variables were omitted due to the strong intraclass correlation. In all comparisons, two-sided p values ＜0.05 were considered statistically significant. In addition, the difference between two variables was also considered statistically significant if the 95% confidence intervals (CIs) of the correlation coefficients did not overlap.

Results

Clinical and Biochemical Characteristics of Male and Female Participants

A total of 58,837 Japanese urban residents (male:female = 42.0:58.0; median age 42 years old; median BMI 21.7 kg/m²) were studied in this cross-sectional study. Table 1 compares the clinical characteristics of male and female participants.

Table 1.Comparison of clinical characteristics between male and female participants

	Male	Female	p value
Number	24,732	34,105	-
Age (years)	39 (32, 50)	44 (36, 55)	＜0.001
Height (m)	1.71 (1.67, 1.75)	1.57 (1.54, 1.61)	＜0.001
Wight (kg)	66.8 (60.7, 74.0)	51.6 (47.2, 57.0)	＜0.001
BMI (kg/m2)	22.95 (21.09, 25.17)	20.75 (19.10, 22.87)	＜0.001
BSA (m2)	1.78 (1.69, 1.88)	1.51 (1.44, 1.58)	＜0.001
Systolic BP (mmHg)	124 (116, 132)	118 (108, 128)	＜0.001
Diastolic BP (mmHg)	74 (66, 80)	68 (62, 76)	＜0.001
the CAVI	7.3 (6.8, 8.0)	7.3 (6.8, 8.0)	0.018
FPG (mg/dL)	85 (81, 91)	82 (78, 87)	＜0.001
TC (mg/dL)	206 (184, 231)	214 (188, 240)	＜0.001
HDL-C (mg/dL)	58 (49, 69)	74 (63, 86)	＜0.001
LDL-C (mg/dL)	122 (101, 145)	120 (98, 144)	＜0.001
Triglyceride (mg/dL)	96 (66, 146)	66 (49, 92)	＜0.001
Uric acid (mg/dL)	6.0 (5.2, 6.7)	4.2 (3.7, 4.8)	＜0.001
Creatinine (mg/dL)	0.83 (0.76, 0.90)	0.61 (0.56, 0.67)	＜0.001
eGFR (mL/min per 1.73m2)	83.3 (74.5, 92.9)	83.5 (74.1, 94.0)	0.005
the BSA-adjusted eGFR (mL/min)	85.9 (76.1, 96.7)	73.0 (64.2, 82.9)	＜0.001

Cross-sectional data are expressed as median (interquartile range). Comparison of two groups was performed using Mann–Whitney U test. BMI, body mass index; BSA, body surface area; BP, blood pressure; the CAVI, cardio-ankle vascular index; FPG, fasting plasma glucose; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate.

Compared with females, males had a significantly higher BMI, BP, FPG, TC, LDL-C, TG, uric acid, creatinine and BSA-adjusted eGFR and lower age and HDL-C. Despite the significant difference, the CAVI and eGFR values were almost the same in males and females (male vs. female: median the CAVI = 7.3 vs. 7.3 in, median eGFR = 83.3 vs. 83.5 mL/min per 1.73 m²).

Relationship of the BSA and Kidney Function Parameters with Aging in Male and Female Participants

We first examined the impact of individual BSA adjustment on the evaluation of the kidney function.

Fig.1 shows the relationship of two kinds of kidney function parameters by age group and by sex. Males in the 20- to 50-year age groups showed a significantly higher BSA-adjusted eGFR than eGFR in the corresponding age groups (Fig.1A). Conversely, males ≥ 70 years old showed a lower BSA-adjusted eGFR than eGFR. In contrast, females in all age groups showed a lower BSA-adjusted eGFR than eGFR in all age groups (Fig.1B). These results are attributed to the fact that the BSA in young middle-aged men is higher than 1.73 m², while the BSA in women of all age groups is lower. Furthermore, a trend toward a significant decrease in the kidney function with age was confirmed by a one-way ANOVA analysis for both the BSA-adjusted eGFR and eGFR in males and females (Fig.1A, B).

Fig.1. Relationship of two kidney function parameters with aging in male and female participants

Bar charts of the eGFR or the BSA-adjusted eGFR stratified by age in (A) males and (B) females are presented. p＜0.001 comparing the BSA-adjusted eGFR with the eGFR in the same age group (Mann-Whitney U test). All data are expressed as the mean±standard deviation. BSA, body surface area; eGFR, estimated glomerular filtration rate.

The Comparison of Correlation Coefficients of the CAVI with the Conventional and BSA-Adjusted eGFR

Next, the relationship of the kidney function with the vascular function is presented. First, the strength of the correlation coefficient between the two kidney function parameters and the CAVI is compared by sex in Table 2.

Table 2.Comparison of correlation coefficients of the CAVI with eGFR and the CAVI with the BSA-adjusted eGFR in male and female participants

	R (95% CI) between eGFR and the CAVI	R (95% CI) between the BSA-adjusted eGFR and the CAVI	p value
Male	–0.388 (–0.399, –0.378)	–0.444 (–0.454, –0.434)	＜0.001
Female	–0.416 (–0.425, –0.408)	–0.449 (–0.457, –0.440)	＜0.001

R, Pearson’s correlation coefficient; CI, confidence interval; the CAVI, cardio-ankle vascular index; eGFR, estimated glomerular filtration rate; BSA, body surface area.

Both kidney function parameters correlated significantly and inversely with the CAVI in males and females, although the BSA-adjusted eGFR correlated more strongly with the CAVI than did the eGFR.

Relationship of the Age-Adjusted CAVI with Kidney Function Parameters

The relationship between the two kidney function parameters and vascular function was then analyzed by sex (Fig.2). Since the CAVI is strongly dependent on age, the age-adjusted CAVI was used in the analysis.

Fig.2. Relationship of the age-adjusted CAVI with kidney function parameters in male and female participants

Bar charts of the age-adjusted CAVI stratified by the eGFR in (A) males and (B) females, and stratified by the BSA-adjusted eGFR in (C) males and (D) females were analyzed using a one-way ANOVA followed by Bonferroni multiple comparison test. ^＊p＜0.001 versus the lowest stratified group (＜50 mL/min). All data are expressed as the mean±standard deviation. the CAVI, cardio-ankle vascular index; BSA, body surface area; eGFR, estimated glomerular filtration rate; ANOVA, analysis of variance.

In males, the age-adjusted CAVI was not significantly associated with the eGFR (p = 0.111 for trend, Fig.2A). Conversely, females showed a significant decreasing trend with an increase in the eGFR (p = 0.008 for trend, Fig.2B). However, no significant differences in the age-adjusted CAVI were detected between the groups stratified by the eGFR. By contrast, the age-adjusted CAVI decreased significantly with increasing BSA-adjusted eGFR values in both males and females (p＜0.001 for trend). Furthermore, in the BSA-adjusted eGFR groups of ≥ 100 mL/min in males (Fig.2C) and ≥ 80 mL/min in females (Fig.2D), the age-adjusted CAVI was significantly lower than that in the lowest BSA-adjusted eGFR group (＜50 mL/min).

The Comparison of Clinical Characteristics in Participants with and without a High CAVI

Finally, the relationship between the kidney function parameters and a high CAVI (defined as ≥ 9.0) was examined. Table 3 compares the clinical characteristics of participants with and without a high CAVI. Compared with participants without a high CAVI, those with a high CAVI had a higher male ratio as well as age and BMI, BP, FPG, TC, LDL-C, TG, uric acid, and creatinine values and lower BSA, HDL-C, eGFR, and BSA-adjusted eGFR values.

Table 3.Comparison of clinical characteristics in participants with and those without a high CAVI

	the CAVI ≥ 9.0	the CAVI ＜9.0	p value
Number (Male %)	3938 (51.0)	54899 (41.4)	＜0.001＊
Age (years)	66 (61, 71)	41 (34, 51)	＜0.001
Height (m)	1.60 (1.53, 1.67)	1.62 (1.57, 1.70)	＜0.001
Wight (kg)	56.1 (49.2, 64.1)	57.4 (50.2, 66.9)	＜0.001
BMI (kg/m2)	22.1 (20.1, 24.0)	21.7 (19.7, 24.0)	＜0.001
BSA (m2)	1.57 (1.45, 1.71)	1.61 (1.49, 1.77)	＜0.001
Systolic BP (mmHg)	135 (124, 146)	120 (110, 129)	＜0.001
Diastolic BP (mmHg)	78 (70, 86)	70 (63, 78)	＜0.001
the CAVI	9.3 (9.1, 9.6)	7.2 (6.7, 7.8)	＜0.001
FPG (mg/dL)	91 (85, 98)	84 (79, 89)	＜0.001
TC (mg/dL)	227 (202, 250)	210 (186, 237)	＜0.001
HDL-C (mg/dL)	65 (53, 77)	67 (56, 80)	＜0.001
LDL-C (mg/dL)	137 (116, 158)	120 (98, 143)	＜0.001
Triglyceride (mg/dL)	98 (71, 139)	74 (53, 111)	＜0.001
Uric acid (mg/dL)	5.2 (4.3, 6.1)	4.8 (4.0, 5.9)	＜0.001
Creatinine (mg/dL)	0.72 (0.61, 0.83)	0.68 (0.59, 0.81)	＜0.001
eGFR (mL/min per 1.73m2)	73.0 (65.1, 82.1)	84.1 (75.1, 94.2)	＜0.001
the BSA-adjusted eGFR (mL/min)	66.7 (57.6, 76.3)	79.1 (69.0, 90.4)	＜0.001

Cross-sectional data are expressed as median (interquartile range). Comparison of two groups was performed using ^＊Fischer’s exact test or Mann–Whitney U test. the CAVI, cardio-ankle vascular index; BMI, body mass index; BSA, body surface area; BP, blood pressure; FPG, fasting plasma glucose; TC, total cholesterol; HDL-C, high -density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate.

The Comparison of the Discriminative Power of two Kidney Function Parameters for a High CAVI

ROC curves were generated to assess the discriminative power and select the cutoff value of each kidney function parameter for a high CAVI, as shown in Table 4. Both parameters had C-statistics above 0.7 and therefore had good discriminative power. The discriminative powers of the two parameters were further compared using NRI and IDI. Results of the analyses showed that the BSA-adjusted eGFR was superior to the eGFR (p＜0.001 for both NRI and IDI) in predicting a high CAVI.

Table 4.Comparison of discriminative power of the two kidney function parameters for a high CAVI

(A) Male
	C-statistics (95% CI)	p value	Cut-off	Sensitivity	Specificity	p value for C-statistics	NRI (95% CI)	p value for NRI	IDI (95% CI)	p value for IDI
eGFR	0.723 (0.711–0.735)	＜0.001	78.7	0.664	0.661	＜0.001	0.675 (0.632–0.717)	＜0.001	0.041 (0.039–0.044)	＜0.001
the BSA-adjusted eGFR	0.776 (0.766–0.787)	＜0.001	78.8	0.693	0.717
(B) Female
	C-statistics (95% CI)	p value	Cut-off	Sensitivity	Specificity	p value for C-statistics	NRI (95% CI)	p value for NRI	IDI (95% CI)	p value for IDI
eGFR	0.716 (0.705–0.728)	＜0.001	76.9	0.618	0.700	＜0.001	0.547 (0.503–0.590)	＜0.001	0.021 (0.020–0.023)	＜0.001
the BSA-adjusted eGFR	0.757 (0.747–0.768)	＜0.001	66.8	0.684	0.703

Discriminative power and cut-off value of kidney function parameter for the CAVI ≥ 9.0 in (A) male and (B) female participants. Youden index was used to select the optimum cut-off point for the CAVI ≥ 9.0. the CAVI, cardio-ankle vascular index; CI, confidence interval; eGFR, estimated glomerular filtration rate; BSA, body surface area; NRI, net reclassification improvement; IDI, integrated discrimination improvement.

Odds Ratios for a High CAVI in Each Tertile of Kidney Function Parameters

A logistic regression analysis was conducted to clarify the independent involvement of the two kidney function parameters in a high CAVI in males and females, as shown in Fig.3. Both parameters converted to tertiles were used as explanatory variables. Covariates were FPG, systolic BP, LDL-C and TG, focusing on factors that showed significant differences in Table 3. Age was not included as a covariate because it is incorporated in the eGFR formula, and the BMI was not adopted because it correlated strongly with the BSA (Rs = 0.671, p＜0.001).

Fig.3. Odds ratios for a high CAVI in tertiles of (A) eGFR and (B) the BSA-adjusted eGFR in male and female participants

Multivariate logistic regression analyses. Odds ratios (95% CIs) were calculated using T3 (upper tertile) as reference. FPG, SBP, LDL-C and triglycerides were included as covariates. the CAVI, cardio-ankle vascular index; eGFR, estimated glomerular filtration rate; BSA, body surface area; CI, confidence interval; FPG, fasting plasma glucose; SBP, systolic blood pressure; LDL-C, low-density lipoprotein cholesterol.

When the upper tertile (T3) was used as the reference, the lower tertile (T1) showed the highest odds ratio for both kidney parameters. Furthermore, the odds ratios for T1 of the BSA-adjusted eGFR (12.8 in males, 18.8 in females, Fig.3B) were significantly higher compared with the odds ratios for T1 of eGFR (6.2 in males, 5.5 in females, Fig.3A).

Discussion

This study examined the clinical significance of the BSA-adjusted eGFR compared with the conventional eGFR in a healthy general Japanese population. Our results showed that the conventional eGFR underestimated the kidney function in middle-aged and younger men and overestimated the kidney function in women of all ages compared with the BSA-adjusted eGFR. Furthermore, BSA adjustment revealed the detailed relationship of the eGFR with the CAVI, suggesting the usefulness of the kidney function parameter as an indicator of arteriosclerosis.

In general, an early decline in the kidney function precedes changes in systemic arteriosclerosis and warns of increased cardiovascular risk before the onset of clinical outcomes¹²⁾. The BSA-adjusted eGFR is expected to improve the management of systemic arteriosclerosis by enhancing the accuracy of the kidney function assessment. In addition, the CAVI can detect early vascular dysfunction in real time. Utilizing these tools therefore enables early detection of high-risk patients, support for preventive strategies, and assistance in decision-making regarding treatment options. However, while the predictive ability of a high CAVI for kidney function decline has been known, the efficacy of kidney function improvement on improving the vascular function has not yet been fully elucidated, and the causality should be established in the future.

The present study may contribute to resolving the following two issues with the conventional eGFR formula: (1) the eGFR in individuals with a body size deviating from BSA 1.73 m² has reduced reliability, and (2) the eGFR calculated from serum creatinine is also affected by skeletal muscle mass. First, the significance of the BSA-adjusted eGFR formula for correcting deviated body sizes is described. The inulin clearance test that most accurately reflects GFR is expressed by the following formula:

Inulin clearance (mL/min) = U × V/P,

where U is the urinary inulin concentration (mg/dl), V is the urine volume (mL/min), and P is the plasma inulin concentration (mg/dl). Subsequently, considering that the kidney function is proportional to the BSA, the GFR is normalized to a fixed BSA of 1.73 m^{2 25)}, as shown in the following formula:

Standardized inulin clearance (mL/min per 1.73 m²) = U × V/P × 1.73/individual’s BSA

This method was originally developed in the field of comparative animal physiology and later applied to human nephrology, allowing clinicians to compare GFR estimates between different body types. The eGFR is a regression equation established using age, sex and serum creatinine concentration (or serum cystatin C concentration) to estimate standardized inulin clearance. In other words, while the eGFR formula does not include any anthropometric indicator, it is based on the assumption that the subject’s BSA is 1.73 m². Therefore, the process of multiplying the conventional eGFR by the subject’s BSA divided by 1.73 in effect cancels out the standardization by the BSA of 1.73 m² and estimates the inulin clearance before standardization, i.e. U × V/P (mL/min). The BSA-adjusted eGFR thus reflects the original inulin clearance, which improves the accuracy of the kidney function assessment, leading to more appropriate drug dosing decisions, and may be useful for identifying specific kidney diseases related to body composition.

Second, the significance of correcting the eGFR formula calculated from serum creatinine, which is affected by skeletal muscle mass, is discussed. Glomerular hyperfiltration indicated by a markedly elevated GFR is mainly caused by increased glomerular capillary pressure, glomerular hypertrophy, and impaired tubular-glomerular feedback²⁶⁾. In a meta-analysis of 11 general population studies including over 90,000 participants²⁷⁾, increased mortality was observed among those with an eGFR ≥ 105 mL/min/1.73 m² calculated by the creatinine-based equation. However, the increased mortality risk was diminished when using the cystatin C-based eGFR. In addition, a similar phenomenon was observed in a longitudinal study utilizing the BSA-adjusted eGFR²⁸⁾. In that 14-year follow-up study of 1747 individuals in Finland with cardiovascular risk, the highest category of the creatinine-based eGFR was associated with an increased standardized mortality ratio (SMR), but the highest category of the BSA-adjusted eGFR showed an SMR at the population level. These results suggest that patients diagnosed with glomerular hyperfiltration with an increased creatinine-based eGFR may include individuals with a low BSA and overestimated kidney function. In other words, the conventional creatinine-based eGFR formula has a risk of misdiagnosing glomerular hyperfiltration in slim individuals with low serum creatinine. Since the BSA is strongly correlated with skeletal muscle mass²⁹⁾, BSA adjustment can correct a falsely high eGFR caused by low skeletal muscle mass. As shown in the present study, the eGFR may be overestimated in older individuals and females in Japan, and our proposed BSA adjustment is clinically relevant.

Regarding other benefits of BSA adjustment in addition to resolving the issues of conventional eGFR formula, first, by adjusting the eGFR with the BSA, more appropriate selection and dosage adjustment of drugs that are metabolized in the kidney may be achieved. The risk of inappropriate excessive drug administration is more likely to occur in females, whose kidney function is overestimated by the conventional eGFR formula, so the use of the BSA-adjusted eGFR is therefore preferrable. Another benefit is that the use of the BSA-adjusted eGFR may guide more appropriate decision regarding hemodialysis initiation. However, since this study targeted a healthy general population, the usefulness of the BSA-adjusted eGFR in end-stage kidney disease could not be verified. In the future, it would be desirable to compare the discriminative power between the conventional and BSA-adjusted eGFR values in terms of the occurrence of uremia.

An issue with the proposed BSA adjustment for eGFR estimation is that the cutoff value has to be reconsidered. The conventional eGFR cutoff for CKD, i.e. 60 mL/min/1.73 m², is explained in the meta-analysis conducted by the CKD Prognosis Consortium³⁰⁾. That analysis demonstrated the associations of eGFR ＜60 mL/min/1.73 m² with increased risk of all-cause and cardiovascular mortality as well as CKD progression in both general and high cardiovascular risk populations. However, the fact that this cutoff was defined without taking aging into account has been debated in the nephrology community³¹⁾. Several reports have demonstrated that the BSA changes with age^{32, 33)}, and it may be meaningful to re-determine the eGFR threshold with consideration of the rate of decline in the eGFR, albuminuria, and the BSA-adjusted eGFR.

One limitation of this study is the cross-sectional design, which cannot address causal relationships. In addition, using serum cystatin C instead of serum creatinine may have yielded a more accurate estimation of kidney function²⁷⁾. Finally, as this study was conducted in Japanese individuals, the eGFR formula proposed by the Japanese Society of Nephrology was used, with other types of formula not examined.

In conclusion, the use of the BSA-adjusted eGFR appropriately assesses the kidney function according to differences in sex, age and body size. Furthermore, the CAVI analysis revealed that the BSA-adjusted eGFR could facilitate the achievement of more precise preventive care for CVD.

Acknowledgements

We would like to thank all staff members of our department who contributed to this study. In particular, we are grateful to Dr. Kentaro Fujishiro, Mr. Kenji Suzuki and the Japan Health Promotion Foundation, to which they belong, for their enormous contribution to this manuscript.

Conflict of Interest Statement

All authors declare no conflict of interest.

Institutional Review Board Statement

The protocol of the study was prepared in accordance with the Declaration of Helsinki, and this study was reviewed and approved by the Institutional Review Board and Ethics Committee of Sakura Hospital, School of Medicine, Toho University (No. S24011; date of approval, June 2024). Written informed consent for the examinations was obtained by an opt-out method.

Funding Sources

This research was supported by the Japan Health Promotion Foundation, but the foundation had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ Contributions

Conceptualization, D.N.; Data acquisition, D.N.; Data curation and formal analysis, D.N.; Data interpretation, Y.W., A.S. and K.S.; Writing—original draft preparation, D.N.; Writing—review and editing, Y.W., M.O., K.S. and A.S. All authors have read and agreed to the published version of the manuscript.

Availability of Data and Materials

The data that supports the findings of this study are not publicly available because they contain information that could compromise the privacy of research participants. Further enquiries may be directed to the corresponding author.

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