Introduction
Chronic heart failure (CHF) is a clinical syndrome of cardiac output and/or elevated intracardiac pressures at rest or during stress due to structural and/or functional cardiac abnormality [
1]. The prevalence of heart failure increases with age: from around 1% for those aged < 55 years to > 10% in those aged 70 years or over [
2], which had become a global clinical and public health challenge.
CHF patients often have complications [
3], the most important comorbidity was kidney damage [
4]. As early as 1836, Robert Bright had decribed the interdependent relationship between heart and kindey [
5], with the continuous development of research, the mechanism of kidney disease in patients with heart failure (HF) is gradually concluded to be mostly related to the hemodynamic interactions, neurohormonal activation and so on [
6]. In the meantime, blood urea nitrogen (BUN) and serum creatinine (Scr) are the classic indicators of renal function. Nevertheless, BUN is not an accurate index of renal function because excess protein intake, body fluid depletion, heart failure, increased catabolism, and use of diuretics increase BUN levels [
7], besides, Scr has been shown to underestimate renal function [
8]. In brief, BUN and Scr alone have their limitations. Fortunately, BUN/Scr ratio are recognized indicators of renal insufficiency and there are a few previous reports have shown that the BUN/Scr ratio is associated with prognosis of CHF and is an independent predictor of all-cause mortality [
7,
9,
10]
The insufficient renal perfusion, due to the dysfunction of ventricular systolic and/ or diastolic function in patients with CHF, leads to pre-renal acute kidney injury. Activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) decreased urea excretions, and activation of neurohormones increased urea absorption, while creatinine could pass freely through the glomerulus without absorption, increasing BUN/Scr. On the contrary, intrinsic renal disease is the irreversible nephron loss, urea clearance rate, and glomerular filtration rate were decreased simultaneously, resulting in normal BUN/Scr [
11]. BUN/Scr can better reflect renal function and evaluate the prognosis of patients with CHF.
In consequence, we conducted the retrospective study to explore the relationship between the BUN/Scr ratio and the prognosis of patients with HF complicated with renal injury.
Discussion
The retrospective analysis of this study concluded that: the results of this study reveals that BUN/Scr ratio is associated with all-cause mortality, and BNU/Scr ≥ 19.37 as the best cutoff points for all-cause mortality, and also associated with higher mortality even after adjustment for other prognostic factors, could be a convenient marker for clinical work.
Scr and BUN are two important indicators for clinical evaluation of renal function. Scr is the product of creatine metabolism with a small molecular weight, most of which passes through glomerular filtration, and almost all of the Scr formed in the body can be excreted by urine. Reduced cardiac output and decreased blood volume due to diuretic use, resulting in renal insufficiency, decreased glomerular filtration rate, increased Scr. BUN is absorbed by renal tubular filtration, in patients with heart failure, decreased cardiac output and insufficient arterial filling lead to the release of sympathetic nervous system (SNS) and RAAS, and increased sodium reabsorption in proximal renal tubules, resulting in increased urea concentration. Activation of SNS is a major cause of cardiac dysfunction and vascular injury and can significantly worsen the prognosis [
14,
15]. In addition, insufficient arterial filling leads to the release of baroreceptor mediated arginine vasopressin (AVP) and upregulates the urea transporter in the intramedullary collecting tube. In addition, creatinine is not reabsorbed, which causes a disproportionate increase in BUN and Scr [
16].
Considering these mechanisms, elevated BUN/Scr level on admission reveals activation of neurohormones and deterioration of renal function, elevated BUN/Scr ratio is associated with poor prognosis in patients with CHF and is an independent predictor of all-cause mortality. This may be because this ratio represents decreased cardiac output, reduced circulating blood volume, insufficient renal perfusion, unstable hemodynamics, and poor prognosis. There are some similarities between our results and those of others.
According to the median ratio, 557 acute decompensated heart failure patients were divided into high BUN/Scr ratio group and low BUN/Scr ratio group, and the relationship between ratio and long-term mortality was evaluated. During the median follow-up period of 1.9 years, patients with high ratio had higher mortality (
P = 0.006) [
17]. Matsue et al. showed that the median BUN/Scr ratio was 15.0 in 4484 general population without cardiovascular complications, and 21.2 in 2033 patients with acute heart failure. Moreover, the increased ratio was related to more severe heart failure symptoms, and the mortality rate was higher [
18]. Kaplan–Meier survival analysis of a prospective cohort study showed that all-cause mortality was higher in patients with a higher BUN/Scr ratio (
P < 0.0001) [
19]. In our study, the tangent value of 19.37 was found by ROC curve at first, and then verified and analyzed by Kaplan−Meier survival curve. The results showed that the survival rate of patients with BUN/Scr ratio ≥ 19.37 was lower than that of patients with BUN/Scr ratio < 19.37.
Multiple studies showed that the BUN/Cr value was still statistically significant after adjusting for multiple factors by COX analysis [
20‐
22]. Even after adjustment for the clinical model including both BUN and Scr, higher than normal range of BUN/Scr ratio group was an independent predictor for all-cause death [HR = 1.86 (1.29–2.66)] [
18]. Hao Qian et al. conducted a prospective observational study, in which patients with HF complicated with AMI were included and followed up for 1 year to evaluate the predictors related to mortality. After multivariate COX hazard analysis, BUN/Cr > 15.34 was still < 0.05 [
23]. In univariate analysis, the all-cause mortality of BUN/Scr ratio ≥ 25.09 is 90% higher than that of the group with ratio < 25.09 [HR = 1.90 (1.30–2.77)]. Further analysis using multivariate Cox proportional hazard regression, after adjusting the baseline variables (including age, current smokers, LVEF < 40%, atrial fibrillation, MAP, sodium, uric acid, albumin, cystatin C, hemoglobin, RDW, D-dimer, free triiodothyronine, log NT-pro BNP, eGFR, NYHA functional grade, the results showed that BUN/Scr ratio ≥ 25. 09 group [HR = 1.52 (1.03–2.24)] is an independent predictor of long-term death of AHF patients [
9]. Similarly, after adjusting the multivariate, this study found that the ratio ≥ 19.37 was significantly related to all-cause mortality in patients with chronic heart failure [HR = 1.885 (1.298, 2.737)], which was consistent with previous research results.
NYHA is a valuable clinical tool, which is related to the potential severity of heart disease and the medium and long-term mortality [
24]. In this study, a subgroup analysis of long-term mortality was conducted. The results of BUN/Scr in evaluating the long-term prognosis of patients with chronic heart failure were influenced by NYHA. Furthermore, among patients with IV grade, the prognosis of patients with high BUN/Scr is worse. Among the three subgroups of NYHA, BUN/Scr is statistically significant in predicting the long-term prognosis of patients with CHF (interaction
P < 0.05).
Many studies have shown that eGFR is a powerful prognostic indicator of CHF [
25,
26]. The results of this study show that BUN/Scr has statistical significance in predicting the long-term prognosis of chronic heart failure among the three subgroups of eGFR (Interaction
P = 0.022).
This study has some limitations. First, it was a retrospective observational study conducted at a single center, with a selection bias due to the data availability, and does not represent all patients with HF. Second, since this study was observational in nature, other confounding factors affecting the results cannot be excluded even after adjusting the analysis. Despite these limitations, our study emphasizes that CHF patients with BUN/Scr ≥ 19.37 at admission have poorer long-term outcomes, and has predictive value for the prognosis of patients with CHF.
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