This study aimed to explore the relationship between the blood urea nitrogen/creatinine (BUN/Cre) ratio and all-cause or cause-specific mortality in the general population. Participants were enrolled from the National Health and Nutrition Examination Survey (NHANES) during 1999 to 2014. Baseline variables were acquired from questionnaires and examinations. Death status were ascertained from National Death Index records. Cox proportional hazards models with cubic spines were used to estimate hazard ratios (HRs) and 95% confidence interval (CI) of all-cause mortality, cardiovascular and cancer mortality. A total of 42038 participants were enrolled in the study with a median 8.13 years of follow-up. Older people and women tend to have a higher BUN/Cre ratio. After multivariable adjustment, BUN/Cre ratio between 11.43 and 14.64 was associated with the lowest all-cause mortality compared with the participants with the lowest quartile (HR 0.83 [0.76, 0.91]; p < 0.001). The highest quartile of BUN/Cre ratio was associated with the lowest risk of cancer mortality (HR 0.64 [0.53, 0.78]; p < 0.001). Restricted cubic splines showed BUN/Cre was nonlinearly associated with all-cause mortality and linearly associated with cancer mortality. This study confirmed a U-shape relationship between BUN/Cre ratio and all-cause mortality in the general population.
Keywords: Blood urea nitrogen; creatinine; BUN/Cre ratio; all-cause mortality; NHANES
The blood urea nitrogen/creatinine (BUN/Cre) ratio is a simple and widely used indicator for the assessment of renal function in clinic [[
Recently, it has been proposed as an effective prognostic factor for severe diseases, such as chronic heart failure [[
The National Health and Nutrition Examination Survey (NHANES) is a nationwide survey designed to assess the health and nutritional status of adults and children in the United States. The study used data from NHANES during 1999 to 2014. After excluding participants with missing data on BUN and Cre, age <18 years old and unavailable mortality status, 42038 participants were enrolled in the study (Figure 1). The study was approved by the institutional review board of Nanjing University (2020AE01065) and all participants provided written informed consent.
Graph: Figure 1. The flow chart of participant selection.
The blood urea nitrogen was assessed using an enzymatic conductivity rate method. Serum Cre was measured using the kinetic Jaffe rate method. The main outcomes of the study were all-cause mortality, cardiovascular mortality and cancer-related mortality. Mortality status was obtained by linkage to the National Death Index by 31 December 2015. Cardiovascular disease was defined as ICD-10 codes I00-I09, I11, I13, or I20-I51. Malignant neoplasm was defined as ICD-10 codes C00-C97.
The baseline characteristics of participants were acquired by questionnaires and examinations, including demographics (such as sex, age, race, educational level, and family poverty income ratio), lifestyle information (such as physical activity, drinking and smoking), medical history (hypertension and cardiovascular diseases) and mediations use (antihypertensive drugs, hypoglycemic drugs and lipid-lowering drugs). Race was classified as non-Hispanic white, non-Hispanic black, Mexican American, other Hispanic or others. Education level was categorized as less than high school, high school, equivalent and college or above. Family poverty income ratio (PIR) was stratified as <1, 1–3, and > 3. Smoking status were defined as current, past and never. Physical activity status was classified as vigorous, moderate and inactive. Hypertension was defined as a history of hypertension or blood pressure ≥140/90 mmHg or taking anti-hypertensive medications. The cardiovascular disease (CVD) was defined as self-reported congestive heart failure, coronary heart disease, angina pectoris, heart attack and stroke. The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Multiple imputation (n = 5) using predictive mean matching (PMM) was performed for covariates with missing values, including education level, race, PIR, body mass index, smoker, drinker, physical activity, high blood pressure, diabetes mellites, cardiovascular diseases, antihypertensive drugs, hypoglycemic drugs, and lipid-lowering drugs.
Continuous variables were described as the mean ± standard deviation and categorical variables were presented as numbers and proportions. Sample weight were used to estimate the representative distribution using the supplied masked variance pseudo-stratum and masked variance pseudo-primary sampling units. Differences between groups were explored by one-way analysis of variance (ANOVA), or chi-square tests. Univariate survival analysis was performed with Kaplan–Meier analysis and Log rank test. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence interval (CI) for all-cause, cardiovascular, and cancer mortality. Model 1 was adjusted for age and gender. Model 2 was adjusted for age, gender, education level, race, PIR, body mass index, smoker, drinker, physical activity. Model 3 was adjusted for age, gender, education level, race, PIR, body mass index, smoker, drinker, physical activity, high blood pressure, diabetes mellites, cardiovascular diseases, antihypertensive drugs, hypoglycemic drugs, lipid-lowering drugs and eGFR. Restricted cubic spline with 3 knots (0.10, 0.50, and 0.90 respectively) based on the Model 3 was used to describe the nonlinear relationship between BUN/Cre ratio and mortality with Wald χ2 test. Subgroup analyses was used to explore the interactive effect of gender, age, race, education, PIR, and comorbidities. All statistical analyses were performed using R version 3.6, and p < 0.05 was considered as statistically significant.
The study included 42038 participants with a median 8.13 years of follow-up. Compared to participants with lower BUN/Cre ratio, population with higher BUN/Cre ratio were older, more females, more drinkers and had more percentage of hypertension, diabetes and cardiovascular diseases (Table 1).
Table 1. Characteristics of the study population.
Variable BUN/Cr BUN/Cr BUN/Cr BUN/Cr Male (%) 6050 (57.5) 5853 (55.5) 4870 (46.8) 3602 (34.1) <0.001 Age, years 40.61 (17.46) 45.04 (18.75) 49.07 (19.40) 53.70 (19.44) <0.001 Race (%) <0.001 Non-Hispanic white 4165 (39.6) 4865 (46.1) 5150 (49.5) 5089 (48.1) Non-Hispanic black 3774 (35.9) 2406 (22.8) 1459 (14.0) 984 (9.3) Mexican American 1392 (13.2) 1789 (17.0) 2115 (20.3) 2792 (26.4) Others 1183 (11.3) 1482 (14.1) 1688 (16.2) 1705 (16.1) Education (%) <0.001 Less than high school 2408 (25.8) 2441 (25.1) 2715 (27.7) 3466 (34.6) High school or equivalent 2318 (24.8) 2219 (22.8) 2236 (22.9) 2238 (22.4) College or above 4609 (49.4) 5052 (52.0) 4834 (49.4) 4308 (43.0) PIR (%) <0.001 <1 2628 (26.7) 2069 (21.2) 1938 (20.3) 1936 (20.4) 1 ∼ 3 3979 (40.4) 3975 (40.7) 3887 (40.7) 4115 (43.4) >3 3249 (33.0) 3711 (38.0) 3733 (39.1) 3428 (36.2) BMI, kg/m2 28.32 (6.77) 28.55 (6.64) 28.70 (6.66) 28.55 (6.58) 0.001 Drinking (%) 28.32 (6.77) 28.55 (6.64) 28.70 (6.66) 28.55 (6.58) 0.001 Smoking (%) <0.001 Current 2537 (33.4) 1830 (24.6) 1405 (19.7) 1115 (15.5) Past 436 (5.7) 424 (5.7) 338 (4.7) 285 (4.0) Never 4621 (60.9) 5183 (69.7) 5406 (75.6) 5786 (80.5) Activity (%) <0.001 Vigorous 2954 (45.1) 2749 (42.6) 2411 (40.2) 2017 (37.0) Moderate 2470 (37.7) 2558 (39.7) 2553 (42.6) 2510 (46.0) Inactive 1133 (17.3) 1144 (17.7) 1028 (17.2) 924 (17.0) Medical history (%) HBP 1637 (16.3) 1749 (17.3) 1836 (18.4) 2410 (23.9) <0.001 DM 1043 (9.9) 1295 (12.3) 1608 (15.4) 2059 (19.5) <0.001 CVD 612 (6.5) 761 (7.8) 916 (9.4) 1093 (10.9) <0.001 Cancers 598 (5.9) 778 (7.4) 937 (9.0) 1134 (10.7) <0.001 Antihypertensive drugs 2113 (77.8) 2541 (81.5) 2891 (85.3) 3620 (89.1) <0.001 Hypoglycemic drugs 476 (45.0) 675 (51.3) 903 (56.1) 1224 (61.3) <0.001 Lipid-lowering drugs 1060 (77.5) 1403 (79.7) 1632 (80.8) 2016 (82.2) 0.004 Systolic BP, mmHg 121.99 (17.76) 123.02 (19.33) 124.24 (20.12) 127.01 (22.12) <0.001 Diastolic BP, mmHg 70.15 (13.61) 69.85 (13.41) 69.50 (13.43) 68.73 (14.38) <0.001 HbA1c, % 5.50 (0.91) 5.58 (0.93) 5.67 (1.03) 5.79 (1.21) <0.001 Cholesterol, mg/dL 70.15 (13.61) 69.85 (13.41) 69.50 (13.43) 68.73 (14.38) <0.001 eGFR, ml/min per 1.73 m2 91.73 (26.13) 92.86 (26.63) 96.18 (31.12) 105.53 (44.57) <0.001 BUN, mg/dL 8.86 (4.55) 11.92 (3.70) 14.19 (4.57) 17.79 (6.83) <0.001 Cre, mg/dL 0.99 (0.76) 0.91 (0.28) 0.86 (0.27) 0.78 (0.28) <0.001 BUN/Cre ratio 9.16 (1.80) 13.09 (0.90) 16.47 (1.09) 23.15 (4.60) <0.001
1 Data are presented as mean (SD) or n (%). PIR: poverty income ratio; BMI: body mass index; HBP: high blood pressure; DM: diabetes mellites; CVD: cardiovascular diseases; eGFR: estimated glomerular filtration rate; BUN: blood urea nitrogen; Cre: creatinine.
As shown in Figure 2, Kaplan-Meier analysis suggested that lower BUN/Cre ratio was associated with a lower all-cause mortality in the whole population. After adjusting for demographics, lifestyles and medical history, we found that BUN/Cre ratio between 11.43 and 14.64 was associated with the lowest all-cause mortality compared with the lowest quartile (HR 0.83[0.76, 0.91]; p<0.001; Table 2). In addition, a negative correlation was observed between BUN/Cre ratio and cancer-related mortality. The highest quartile of BUN/Cre ratio was associated with the lowest risk of cancer mortality (HR 0.64 [0.53, 0.77]; p < 0.001). However, the relationship between BUN/Cre ratio and cardiovascular mortality disappeared after multivariable adjustment.
PHOTO (COLOR): Figure 2. The Kaplan–Meier analysis between the BUN/Cre ratio quartiles and all-cause mortality (A), cardiovascular mortality (B) and cancer mortality (C). BCrcat represented BUN/Cre quartiles. The P values were calculated by the log-rank test.
Table 2. Association of BUN/Cre ratio with all-cause and cause specific mortality.
All cause and cause specific mortality Cases Model 1 HR(95% CI) Model 2 HR(95% CI) Model 3 HR(95% CI) All causes Q1 867 10514 Ref Ref Ref Q2 986 10542 0.76 [0.70, 0.84]*** 0.82 [0.75, 0.90]*** 0.83 [0.76, 0.91]*** Q3 1281 10412 0.77 [0.70, 0.84]*** 0.87 [0.79, 0.95]*** 0.87 [0.80, 0.95]** Q4 1923 10570 0.84 [0.77, 0.92]*** 0.97 [0.89, 1.06] 1.03 [0.94, 1.12] Continuous 5057 42038 1.00 [0.99, 1.00] 1.01 [1.00, 1.01]* 1.01 [1.01, 1.02]*** Cardiovascular Q1 139 865 Ref Ref Q2 165 984 0.88 [0.70, 1.10] 0.82 [0.75, 0.90]*** 0.87 [0.69, 1.09] Q3 235 1278 0.81 [0.66, 1.01] 0.87 [0.79, 0.95]** 0.83 [0.66, 1.03] Q4 335 1918 0.74 [0.60, 0.91]** 0.97 [0.89, 1.06] 0.82 [0.65, 1.02] Continuous 874 5045 0.98 [0.97, 0.99]** 0.99 [0.98, 1.00] 0.99 [0.98, 1.01] Malignant neoplasms Q1 220 705 Ref Ref Ref Q2 231 744 0.86 [0.72, 1.04] 0.88 [0.73, 1.06] 0.88 [0.72, 1.06] Q3 249 1016 0.63 [0.53, 0.76]*** 0.67 [0.55, 0.81]*** 0.66 [0.55, 0.80]*** Q4 359 1537 0.58 [0.49, 0.69]*** 0.62 [0.52, 0.75]*** 0.64 [0.53, 0.77]*** Continuous 757 4002 0.96 [0.95, 0.97]*** 0.97 [0.96, 0.98]*** 0.99 [0.98, 1.01] ***
- 2 Model 1 was adjusted for age and gender.
- 3 Model 2 was adjusted for age, gender, education level, race, poverty income ratio, body mass index, smoker, drinker, physical activity.
- 4 Model 3 was adjusted for age, gender, education level, race, poverty income ratio, body mass index, smoker, drinker, physical activity, high blood pressure, diabetes mellites, cardiovascular diseases, cancers, antihypertensive drugs, hypoglycemic drugs, lipid-lowering drugs, sBP, dBP, HbA1c, cholesterol and eGFR.
- 5 *p < 0.5, **p < 0.01, ***p < 0.001; HR, hazard ratio; CI, confidence interval.
To explore the nonlinear relationship between BUN/Cre ratio and all-cause mortality as well as cancer mortality, restricted cubic spines based on Cox regression models were performed (Figure 3). We found a nonlinear association existed in all-cause mortality (Figure 3(A)) while a linear relationship in cancer mortality (Figure 3(B)). Subgroup analysis (Table 3) showed that the association was consistent across groups except for the history of CVD. The BUN/Cre ratio was U-shaped associated with the risk of all-cause mortality in participants without CVD while increased the risk of mortality in participants with CVD.
Graph: Figure 3. The restricted cubic regression between the BUN/Cre ratio with all-cause mortality (A), and cancer mortality (B) in Model 3. The P values were calculated by the Wald χ2 test.
Table 3. Subgroup analysis of association of BUN/Cre ratio with all-cause mortality.
BUN/Cre Q1 Q2 Q3 Q4 P for interaction 0.721 Female 16.6 ± 6.28 Ref 0.79 [0.67, 0.93]** 0.76 [0.65, 0.89]*** 0.95 [0.82, 1.10] Male 14.3 ± 4.87 Ref 0.85 [0.76, 0.96]** 0.94 [0.84, 1.05] 1.05 [0.94, 1.18] 0.188 <60 14.6 ± 5.42 Ref 0.87 [0.74, 1.03] 0.77 [0.65, 0.92]** 0.82 [0.68, 0.99]* ≥60 17.3 ± 6.02 Ref 0.80 [0.71, 0.89]*** 0.86 [0.77, 0.96]** 1.05 [0.94, 1.17] 0.054 Non-Hispanic white 15.8 ± 5.56 Ref 0.77 [0.68, 0.88]*** 0.81 [0.72, 0.92]** 0.94 [0.83, 1.06] Non-Hispanic black 12.8 ± 4.80 Ref 0.84 [0.70, 1.00]* 0.91 [0.75, 1.10] 1.38 [1.12, 1.69]** Mexican American 17.1 ± 6.28 Ref 0.95 [0.74, 1.22] 0.90 [0.72, 1.14] 1.01 [0.80, 1.26] Others 16.1 ± 5.57 Ref 0.70 [0.48, 1.02] 0.61 [0.42, 0.88]** 0.81 [0.57, 1.17] 0.534 Less than high school 16.3 ± 6.37 Ref 0.86 [0.75, 1.00]* 0.92 [0.80, 1.06] 1.11 [0.97, 1.27] High school or equivalent 15.2 ± 5.67 Ref 0.75 [0.62, 0.90]** 0.83 [0.69, 1.00]* 0.88 [0.74, 1.06] College or above 15.1 ± 5.34 Ref 0.86 [0.73, 1.01] 0.83 [0.71, 0.98]* 1.01 [0.86, 1.19] 0.053 <1 15.0 ± 5.96 Ref 0.91 [0.76, 1.10] 0.94 [0.79, 1.13] 1.01 [0.84, 1.22] 1 ∼ 3 15.6 ± 5.86 Ref 0.80 [0.70, 0.90]*** 0.86 [0.76, 0.97]* 1.05 [0.93, 1.19] >3 15.6 ± 5.47 Ref 0.88 [0.72, 1.07] 0.82 [0.67, 0.99]* 0.98 [0.81, 1.18] 0.578 No 15.3 ± 5.60 Ref 0.84 [0.75, 0.95]** 0.89 [0.79, 1.00]* 1.03 [0.92, 1.16] Yes 16.3 ± 6.26 Ref 0.79 [0.69, 0.92]** 0.80 [0.69, 0.93]** 0.99 [0.86, 1.14] 0.393 No 15.2 ± 5.64 Ref 0.85 [0.76, 0.94]*** 0.87 [0.78, 0.97]* 0.98 [0.88, 1.09] Yes 17.0 ± 6.16 Ref 0.82 [0.68, 0.99]* 0.88 [0.74, 1.05] 1.13 [0.95, 1.34] No 15.5 ± 5.72 Ref 0.83 [0.74, 0.92]*** 0.87 [0.78, 0.96]** 0.93 [0.84, 1.04] Yes 16.7 ± 6.09 Ref 0.87 [0.72, 1.06] 0.93 [0.77, 1.12] 1.30 [1.08, 1.57]**
Our study found a U-shape association between the BUN/Cre ratio and all-cause mortality, namely a lower BUN/Cre ratio and higher BUN/Cre ratio were all related to a higher all-cause mortality. Besides, a higher BUN/Cre ratio was linearly associated with the lower risk of cancer mortality.
BUN and Cre are the end products of nitrogen metabolism in human body, whose change reflect the renal function, nutritional and metabolic status. BUN/Cre ratio is one of the common indices used to separate pre-renal azotemia and acute tubular necrosis, with a threshold of 20 [[
We have also observed a negative relationship between BUN/Cre ratio and cancer mortality. A retrospective study reported that elevated Cre was related to increased mortality in patients with malignant fibroblastic and myofibroblast sarcomas [[
Some limitations existed in our study. Firstly, the disease history was self-reported by participants, which may cause recall errors. Secondly, one-time measurement of BUN/Cre would vary by the participants' condition and was not a long-term reflection.
In conclusion, we reported a U-shape relationship between BUN/Cre ratio and all-cause mortality in general population. Conversely, BUN/Cre ratio was negatively correlated with cancer mortality. Further studies will be needed to determine whether interfering BUN/Cre ratio will improve the long-term prognosis in general population.
The study was approved by the institutional review board of Nanjing University (2020AE01065) and all participants provided written informed consent.
The authors have no conflicts of interest to declare.
X B designed this study; S S wrote the manuscript; Y XD performed statistical analysis.
The data supporting our results were available in NHANES.
By Song Shen; Xudong Yan and Biao Xu
Reported by Author; Author; Author