Introduction

Chronic obstructive pulmonary disease (COPD) is a major public health problem characterized by chronic respiratory symptoms such as dyspnea, cough, sputum production, and acute exacerbations. With its increasing prevalence, COPD has become a significant disease burden. It is projected that by 2030, annual deaths from COPD and related diseases worldwide will exceed 4.5 million, ranking as the third leading cause of death in China [1]. As the disease progresses, COPD can cause chronic hypoxia in multiple organs [2-3] and may induce various comorbidities. Studies have shown that COPD patients often suffer from more than one comorbid condition [4].

Due to the structural and functional characteristics of the kidneys, they are highly sensitive to hypoxia and susceptible to acute kidney injury during acute exacerbations of COPD (AECOPD) [5]. However, the symptoms of acute kidney injury are often insidious and nonspecific, making early detection difficult and potentially delaying optimal treatment while increasing healthcare burden. During AECOPD, patients' symptoms worsen significantly compared with the stable phase, with more severe systemic effects. Nevertheless, research on the factors associated with renal function impairment in AECOPD remains limited both domestically and internationally. This study investigates the factors related to renal injury in AECOPD to provide additional clinical references for protecting renal function and improving prognosis in these patients.

Methods

1.1 Study Subjects

We enrolled 192 AECOPD patients hospitalized in the Respiratory Department of the First Affiliated Hospital of Jinzhou Medical University from December 2020 to July 2023, including 132 males and 60 females. Inclusion criteria were: (1) age 50–90 years; (2) symptoms consistent with the Chinese Expert Consensus on Diagnosis and Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease (2023 Revision) [6]; and (3) hospitalization duration >1 week. Exclusion criteria were: (1) inability to cooperate with pulmonary function testing; (2) history of primary renal diseases such as glomerulonephritis; and (3) incomplete clinical data affecting statistical analysis. All participants provided informed consent, and this study was approved by the Ethics Committee (Approval No. KYLL2024187).

1.2 Data Collection

1.2.1 General Data

We collected and recorded basic information including age, sex, BMI, smoking history (continuous smoking for >1 year), and past medical history (hypertension, diabetes, coronary heart disease, COPD duration).

1.2.2 Biochemical Indicators

On the morning following admission, fasting venous blood samples were collected and sent to the laboratory of the First Affiliated Hospital of Jinzhou Medical University. Hematology parameters and biochemical indicators were measured using a Beckman hematology analyzer and an Abbott C16000 automatic biochemical analyzer. We detected white blood cell count (WBC), hemoglobin (Hb), C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), albumin (ALB), brain natriuretic peptide (BNP), troponin I (CTnI), and glucose (GLU). Midstream morning urine samples (5 mL) were collected to measure renal indicators including creatinine (Cr), cystatin C (Cys C), β2-microglobulin (β2-MG), urea (Urea), and uric acid (UA).

1.2.3 Pulmonary Function Testing

When patients' condition stabilized on the second day, pulmonary function was measured using a Shanghai CareFusion spirometer. For patients unable to complete pulmonary function testing within the first two days due to severe symptoms, testing was performed before discharge when clinically stable. Primary measurements included percentage of forced expiratory volume in one second (FEV1%) and ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC).

1.2.4 Arterial Blood Gas Analysis

After admission and following a period of quiet rest without oxygen supplementation, arterial blood gas samples were collected. pH, arterial oxygen partial pressure (PaO2), carbon dioxide partial pressure (PaCO2), and lactate (cLac) were measured in real-time using an i500 series automatic blood gas electrolyte analyzer (Shenzhen Edan Instruments Co., Ltd.).

1.3 Grouping

Based on the Chinese Expert Consensus on Diagnosis and Treatment of Chronic Kidney Disease in the Elderly (2018) [7], we calculated each patient's estimated glomerular filtration rate (eGFR) using the formula: eGFR [ml/(min·1.73m²)] = 186 × [Cr]⁻¹·¹⁵⁴ × [age]⁻⁰·²⁰³ × 1.233 (×0.742 for females). Patients were divided into three groups: normal renal function group (eGFR ≥ 90 ml/min, n=92), mild renal impairment group (60 ml/min ≤ eGFR < 90 ml/min, n=66), and severe renal impairment group (eGFR < 60 ml/min, n=34).

1.4 Statistical Analysis

Data were analyzed using SPSS 26.0 statistical software. Normally distributed continuous variables were expressed as mean ± standard deviation (x̄±s) and compared using one-way ANOVA. Non-normally distributed variables were expressed as median (interquartile range) [M(P25, P75)] and compared using Kruskal-Wallis H test, with pairwise comparisons performed using rank-sum tests. Categorical variables were expressed as percentages and compared using chi-square tests. Pearson correlation analysis was used to evaluate correlations between variables. Multivariate logistic regression analysis was performed to identify predictive factors. ROC curves were generated using SPSS 26.0 to evaluate the predictive value of various indicators for renal function impairment in AECOPD patients.

Results

2.1 Comparison of General Characteristics Among Three Groups

Age, hypertension, and coronary heart disease differed significantly among the three groups (P<0.05). Both the mild and severe renal impairment groups had higher age and higher proportions of hypertension and coronary heart disease compared with the normal renal function group (P<0.05). The severe renal impairment group also had a higher proportion of coronary heart disease than the mild impairment group (P<0.05). See Table 1 [TABLE:1].

2.2 Comparison of Blood Gas, Pulmonary Function, Hb, and ALB Among Three Groups

Hb, ALB, FEV1%, and PaO2 differed significantly among groups (P<0.05). The mild impairment group had lower ALB than the normal group (P<0.05). The severe impairment group had lower Hb, ALB, FEV1%, and PaO2 compared with the normal group (P<0.05), and lower FEV1% and PaO2 compared with the mild impairment group (P<0.05). See Table 2 [TABLE:2].

2.3 Comparison of WBC, CRP, IL-6, and PCT Among Three Groups

CRP and IL-6 differed significantly among groups (P<0.05). The mild impairment group had higher IL-6 and CRP than the normal group (P<0.05). The severe impairment group had higher CRP and IL-6 than the normal group (P<0.05), and higher IL-6 than the mild impairment group (P<0.05). See Table 3 [TABLE:3].

2.4 Comparison of BNP, CTnl, and Renal Indicators Among Three Groups

BNP, CTnl, Cr, Cys C, β2-MG, Urea, and UA differed significantly among groups (P<0.05). The mild impairment group had higher BNP, CTnl, Cr, Cys C, β2-MG, and Urea than the normal group (P<0.05). The severe impairment group had higher BNP, CTnl, Cr, Cys C, β2-MG, Urea, and UA than the normal group (P<0.05), and higher Cr, Cys C, β2-MG, Urea, and UA than the mild impairment group (P<0.05). See Table 4 [TABLE:4].

2.5 Correlation Analysis of eGFR and Cys C with PaO2, FEV1%, and IL-6

Cys C was negatively correlated with PaO2 and FEV1% (P<0.01, r=-0.379, -0.254) and positively correlated with IL-6 (P<0.01, r=0.641). eGFR was positively correlated with PaO2 and FEV1% (P<0.01, r=0.470, 0.286) and negatively correlated with IL-6 (P<0.01, r=-0.456). See Table 5 [TABLE:5] and Figure 5 [FIGURE:5]-1~6.

2.6 Multivariate Logistic Regression Analysis of Factors Associated with Renal Impairment in AECOPD

Using renal impairment severity as the dependent variable (normal=0, mild=1, severe=2) and variables with significant differences in univariate analysis as independent variables, multivariate logistic regression analysis showed that age, hypertension, PaO2, IL-6, Cr, UA, Cys C, and β2-MG were predictive factors for renal impairment in AECOPD patients. See Table 6 [TABLE:6].

2.7 Diagnostic Performance Evaluation of Different Factors

ROC curve analysis demonstrated that UA (AUC=0.646, 95%CI: 0.569–0.724), Cys C (AUC=0.895, 95%CI: 0.852–0.939), β2-MG (AUC=0.822, 95%CI: 0.764–0.879), IL-6 (AUC=0.743, 95%CI: 0.674–0.812), and PaO2 (AUC=0.676, 95%CI: 0.601–0.751) had predictive value for renal function impairment in AECOPD patients (all P<0.05). Cys C showed higher sensitivity, specificity, accuracy, and AUC (89.50%) compared with β2-MG, IL-6, and PaO2 (82.20%, 74.30%, 67.60%, respectively), with statistically significant differences (P<0.05). See Table 7 [TABLE:7] and Figure 6 [FIGURE:6].

Discussion

As the global population ages, the number of COPD patients continues to increase. This progressive disease can ultimately lead to multi-organ failure. In recent years, research on COPD complicated by renal function impairment has attracted increasing attention [8]. MAPEL et al. [9] studied clinical data from 2,284 COPD patients and found that the incidence of chronic renal failure (CRF) was 2.89%, nearly three times higher than in the general population (0.79%). TERZANO et al. [10] conducted a 7-year follow-up study of 288 Italian COPD patients, reporting a CRF incidence of 26.3%, second only to hypertension (64.2%). The National Health and Nutrition Examination Survey also demonstrated that decreased renal function was associated with increased COPD prevalence [11]. These studies indicate a strong association between COPD and renal injury, though the relationship requires further clarification.

COPD patients experience chronic hypoxia that stimulates immune function and triggers systemic inflammatory responses. During acute exacerbations, more inflammatory cytokines are released, and their accumulation causes renal damage. CHEN Xin [12] reported that renal injury is primarily manifested by elevated inflammatory markers such as CRP and IL-6. IL-6 is valuable for early diagnosis and assessment of inflammation and infection. CRP is an acute-phase protein and a common inflammatory marker that serves as a sensitive indicator for assessing inflammatory status and disease severity [13-14]. It is closely related to airway hyperresponsiveness and inflammatory regulation and can effectively reflect disease status. Cys C is a cysteine protease inhibitor expressed in many organs and tissues. It freely passes through the glomerular filtration membrane at physiological pH and is catabolized or reabsorbed in the proximal tubule, with its concentration primarily affected by eGFR. Therefore, measuring blood Cys C levels can reflect the degree of renal injury [15]. β2-MG is a metabolite mainly derived from lymphocytes that undergoes renal filtration and excretion. It is synthesized and secreted in a stable state in the human body. When renal injury occurs with decreased glomerular filtration or impaired tubular reabsorption, its blood concentration increases, making it a sensitive indicator of renal function impairment. UA is almost 100% filtered in the glomerulus, with reabsorption and secretion occurring mainly in the proximal tubule. If tubular function is impaired, blocked UA excretion leads to elevated serum uric acid, which may in turn aggravate renal injury, creating a vicious cycle.

This study found that age, hypertension, and coronary heart disease were associated with renal impairment in AECOPD patients, indicating that older AECOPD patients with comorbid hypertension or coronary heart disease are more susceptible to renal dysfunction. The mechanisms include progressive degenerative changes in renal structure with aging; cardiac disease can cause secondary renal damage through hemodynamic disturbances and abnormal neurohumoral activation; hypertension induces mechanical injury to vascular endothelium and vessel walls, causing vasodilation imbalance and overactivation of the renin-angiotensin system (RAS). Multiple factors including low vWF-cleaving protease and various chronic inflammatory markers target vascular endothelial cells and walls, leading to glomerular endothelial cell proliferation, swelling, ischemic shrinkage, and sclerotic changes that result in renal function impairment [16].

Correlation analysis showed that eGFR was negatively correlated with IL-6, suggesting that higher inflammatory levels correspond to lower eGFR and more severe renal injury. This occurs because COPD patients are more prone to infection, which dramatically increases inflammation. The major inflammatory cytokine IL-6 not only causes lung pathology but also acts as an inflammatory mediator promoting mesangial cell proliferation. In glomerular inflammatory responses, IL-6 has autocrine and paracrine functions that damage vascular endothelium and reduce peritubular capillaries. Since the kidneys have limited detoxification capacity, they cannot tolerate excessive inflammatory mediators, making them vulnerable to injury in AECOPD patients [17].

Logistic regression analysis revealed that PaO2 was not only a predictive factor for renal impairment in AECOPD patients but also positively correlated with eGFR. The mechanism involves hypoxia-induced elevation of endothelin-1 (ET-1) levels in the kidney [18] and activation of phospholipase A2 (PLA2), which can directly damage renal tubular epithelial cells and cause functional disorders. Severe hypoxia can also lead to tubular degeneration and necrosis, ultimately causing acute renal failure [19]. Additionally, reactive oxygen species (ROS) serve as important second messengers that participate in multiple signaling pathways, resulting in cellular injury [20-21]. In summary, chronic hypoxia causes early renal function impairment, consistent with findings by REIHMAN et al. [22].

Recent studies have begun focusing on the relationship between Cys C and COPD. One study found that elevated plasma Cys C levels in COPD patients could predict lung function status, suggesting that monitoring plasma Cys C may be useful for diagnosing and assessing disease severity [23]. Our findings are similar, showing that Cys C is a predictive factor for renal impairment in AECOPD patients, consistent with research by LUO Hongyan et al. [24]. Cys C was negatively correlated with PaO2 and FEV1% and positively correlated with IL-6, aligning with YU's research [25] and CHAI et al.'s findings that serum Cys C levels are associated with COPD exacerbations and negatively correlated with FEV1% predicted values [26]. This is because Cys C is secreted into the bloodstream by inflammatory cells, particularly alveolar macrophages, and serves as an important endogenous cysteine protease inhibitor and marker of various chronic inflammatory conditions. AECOPD patients experience chronic mild hypoxia, and macrophages under hypoxic conditions secrete large amounts of Cys C that bind β2-MG. UA can cause renal damage through inflammatory responses, oxidative stress, RAS activation, and promotion of renal fibrosis [27]. Our previous research found that Cys C is significantly elevated in patients with renal insufficiency and is valuable for early diagnosis and therapeutic evaluation of renal injury [28]. These studies further demonstrate that more severe COPD increases the likelihood of renal function impairment.

This study has limitations. As a single-center retrospective study with a limited sample size, most subjects were from western Liaoning Province, and the sample balance was suboptimal, which may introduce bias. Future multi-center, prospective studies with larger sample sizes are needed to further clarify the factors associated with renal impairment in AECOPD.

In conclusion, age, hypertension, IL-6, Cys C, β2-MG, UA, and PaO2 can affect eGFR and are predictive factors for renal impairment in AECOPD patients. Among these, Cys C has high predictive value and diagnostic utility, making it an important indicator for assessing the risk of renal injury in AECOPD patients. These findings can help clinicians detect and manage these indicators early during hospitalization, protect renal function, and prevent further renal damage.

Author Contributions: TIAN Ying conceived the study, designed the protocol, conducted literature searches, collected and verified data, performed statistical analysis, and wrote the manuscript. PAN Dianzhu supervised the research, managed quality control, proofread the manuscript, and oversaw the entire project, taking overall responsibility for the paper.

Conflict of Interest: The authors declare no conflicts of interest.

ORCID: PAN Dianzhu https://orcid.org/0009-0002-5720-5886

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(Received: April 7, 2025; Revised: July 20, 2025)
(This article was edited by CHENG Sheng)