Abstract
Diabetic foot ulcers (DFUs) are chronic, difficult‐to‐heal wounds with a very high incidence of amputation. For patients with DFUs, prevention of amputation is crucial. However, the risk factors associated with DFU amputation and the extent to which different risk factors increase the risk of amputation are still uncertain. This study intends to provide a clinical basis for early intervention in DFU by retrospectively analysing the risk factors for DFU amputation. A retrospective analysis of 200 patients with DFUs admitted between October 2019 and October 2023 was conducted. Sixty‐eight of the 200 underwent amputations. The overall amputation rate was 34%. Multiple logistic regression model showed that neutrophil/lymphocyte ratio (OR = 1.943; 95% CI:1.826–2.139), white blood cell (OR = 1.143; 95% CI:1.034–1.267), C‐reactive protein (OR = 1.307; 95% CI:1.113–2.194) and Wagner grading (OR = 2.783; 95% CI: 1.751–4.302) were independent risk factors for amputation, while haemoglobin (OR = 0.742; 95% CI:0.638–0.965) and high density lipoprotein were independent protective factors for amputation (OR = 0.168; 95% CI:0.037–0.716), and further Receiver Operating Characteristic Curve curves showed that they showed high accuracy and were good predictors of amputation of DFUs.
Keywords: amputation, diabetic foot ulcers, inflammatory factors, influencing factors, wound
1. INTRODUCTION
Diabetic foot ulcer (DFU) is a common and severe complication of diabetes, affecting approximately 15% of diabetic patients during their lifetime. 1 Foot ulcers, as a kind of wound, if not treated and treated in time, may lead to infection and aggravation of ulcers, which may further lead to amputation. 2 , 3 DFU‐related amputations are a major cause of morbidity and mortality in diabetic patients. 4 , 5 Therefore, for patients with diabetes, attention should be paid to controlling blood sugar, improving blood circulation and strengthening wound care and anti‐infective treatment to promote wound healing.
Inflammation has been identified as a key factor in the onset and progression of DFU and its associated complications. 6 Inflammatory factors and markers, such as tumour necrosis factor‐α (TNF‐α), have been shown to be elevated in patients with DFUs and associated with poor wound healing and an increased risk of amputation, but there has been relatively little research on other inflammatory markers. 7 , 8 In order to further understand the levels of more inflammatory markers and their influencing factors in DFU amputation patients, it is important for clinical guidance of patient treatment. 9
This study conducted a retrospective study on the data of hospitalized DFU patients admitted to our hospital from October 2019 to October 2023, aiming to understand and analyse the levels of laboratory inflammatory factors and their influencing factors in patients with amputation of DFUs, so as to provide a feasible reference for clinical treatment and disease prevention.
2. PATIENTS AND METHODS
2.1. General information
The clinical data of 200 DFU patients admitted to our hospital from October 2019 to October 2023 in electronic medical records were collected, including demographic data, disease‐related data, laboratory indicators, etc. Patients were divided into amputation group (n = 68) and non‐amputation group (n = 132).
2.2. Inclusion and exclusion criteria
Inclusion criteria: (1) Meet the International Diabetic Foot Working Group diagnostic criteria for diabetic foot 10 ; (2) Over 18 years old, hospitalized for more than 72 h, complete medical records; (3) Sign informed consent. Exclusion criteria: (1) Patients with lower extremity thrombosis or acute arterial embolism; (2) Patients with diabetic foot whose Wagner grading is level 0; (3) Combined with other diseases causing lower limb pain, such as spinal stenosis, lumbar disc herniation accompanied by radiculopathy.
2.3. Data collection
The clinical data of DFU patients were recorded using a unified observation table. (1) Demographic data: age, sex, BMI, drinking history, smoking history; (2) Disease characteristics: The disease information included the course of diabetes, the course of diabetic foot disease, the location of foot ulcers (toe, back of foot, sole, ankle), the number of ulcers, the largest area, history of ulcers, Wagner grading, the number of operations, history of amputation, type of amputation (major amputation, minor amputation) and whether hypertension was complicated; (3) Laboratory inspection indicators: C‐reactive protein (CRP), white blood cell (WBC), neutrophil/lymphocyte ratio (NLR), albumin (ALB), fasting blood glucose (FBG), total cholesterol (TC), blood urea nitrogen (BUN), glycosylated serum albumin (GSP), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), haemoglobin (Hb), platelet count (PLT), fibrinogen (FIB), neutrophil percentage (NEUT%), haemoglobin A1c (HbAlc), serum creatinine (Scr), D‐dimer (D‐dimer), urinary microalbumin (U‐MA).
2.4. Statistical analysis
SPSS26.0 statistical software was used for data analysis. All analyses were bilateral tests. Measurement data were expressed as (¯x ± s), and t‐test was used for comparison. Statistical data were expressed by frequency OR rate (%), and χ2 test was used for comparison. In order to determine the independent predictors of amputation, univariate logistic regression analysis was performed for each variable and the odds ratio (OR) and 95% confidence interval (CI) were calculated using amputation as the compliance outcome. The important predictors selected in the univariate analysis are brought into the multiple regression model to test the correlation between the predictors and the outcome variables. p < 0.05 was considered statistically significant. ROC curve was used to analyse the statistically significant factors, and the influence of relevant factors on the prognosis of patients after DFU amputation was determined by the area under the curve.
3. RESULTS
3.1. Comparison of demographic data between amputation group and non‐amputation group
As shown in Figure 1, demographic data of the amputation group and the non‐amputation group showed no statistically significant differences in gender, age, working status, smoking history and drinking history. The demographic data of the two groups of patients were shown in Table 1.
FIGURE 1.
The flow chart of the study.
TABLE 1.
Comparison of demographic data between amputation group and non‐amputation group.
| Demographic indicators | Non‐amputation group (n = 132) | Amputation group (n = 68) | t/χ2 | p‐value |
|---|---|---|---|---|
| Sex | 0.013 | 0.802 | ||
| Male | 92 | 43 | ||
| Female | 40 | 25 | ||
| Age (years) | 63.84 ± 10.47 | 64.69 ± 10.57 | 0.202 | 0.679 |
| BMI (kg/m2) | 22 (18,25) | 21 (17,24) | −0.159 | 0.874 |
| Smoking history (n, %) | 1.144 | 0.266 | ||
| Yes | 32 (24.2%) | 17 (25.2%) | ||
| No | 100 (75.8%) | 51 (75.0%) | ||
| Drinking history (n, %) | 1.039 | 0.327 | ||
| Yes | 67 (50.8%) | 35 (51.5%) | ||
| No | 65 (49.2%) | 33 (48.5%) |
3.2. Comparison of disease characteristics between amputation group and non‐amputation group
There were significant differences in the course of diabetic foot disease, Wagner grading, ulcer history and ulcer site between amputation group and non‐amputation group (p < 0.05), as shown in Table 2. The comparison between minor and major amputations is shown in Figure 2. As shown in Figure 3, photographic data of a 33‐year‐old female patient with DFU before and after treatment.
TABLE 2.
Comparison of clinical characteristics between amputation group and non‐amputation group [n(%)].
| Clinical characteristics | Non‐amputation group (n = 132) | Amputation group (n = 68) | t/χ2 | p‐value |
|---|---|---|---|---|
| Duration of diabetes, yr | 10 (7.0,19.2) | 10 (6.3,18.5) | −0.214 | 0.812 |
| Duration of Diabetic foot, months | 29 (16,62) | 30 (17,61) | −2.305 | 0.037 |
| Ulcer area, cm 2 | 4.92 (2.38,9.21) | 3.92 (2.06,7.32) | −1.692 | 0.211 |
| Wagner grading | 321.33 | <0.001 | ||
| Grade 1 | 93 | 0 | ||
| Grade 2 | 16 | 9 | ||
| Grade 3 | 13 | 21 | ||
| Grade 4 | 6 | 35 | ||
| Grade 5 | 4 | 3 | ||
| History of amputation | 2.243 | 0.152 | ||
| Yes | 73 (55.30%) | 39 (57.35%) | ||
| No | 59 (44.70%) | 22 (32.35) | ||
| Type of amputation | ||||
| Minor amputation | ‐ | 53 (77.9%) | ||
| Major amputation | ‐ | 15 (22.1%) | ||
| History of ulcer (n) | 20.526 | <0.001 | ||
| Yes | 21 | 31 | ||
| No | 111 | 37 | ||
| Location, n (%) | 26.452 | <0.001 | ||
| Toe | 59 | 45 | ||
| Dorsalis pedis | 32 | 6 | ||
| Plantar | 7 | 12 | ||
| Heel | 8 | 3 | ||
| Ankle | 26 | 2 | ||
| Number of ulcers | 0.053 | 0.784 | ||
| 1 | 93 (70.45%) | 47 (69.12%) | ||
| ≥2 | 39 (29.55%) | 21 (30.88%) | ||
| Number of procedures | 1.569 | 0.285 | ||
| ≤3 | 83 (62.88%) | 42 (61.76%) | ||
| >3 | 49 (37.12%) | 26 (38.24%) | ||
| Hypertension | 3.257 | 0.063 | ||
| Yes | 85 (64.39%) | 43 (63.24%) | ||
| No | 47 (35.61%) | 25 (36.76%) | ||
FIGURE 2.
Classification diagram of amputation.
FIGURE 3.
Photographic data of a 33‐year‐old female patient with diabetic foot ulcer before and after treatment: (A) preoperative appearance; (B) intraoperative view; (C) 14 days postoperative appearance.
3.3. Comparison of levels of inflammatory factors between amputation group and non‐amputation group
The comparison of laboratory indicators between the amputation group and the non‐amputation group showed that CRP, WBC, NLR, ALB, FBG, TG, HDL‐C, Hb, PLT, FIB, NEUT, HbA1c, D‐dimer and U‐MA were significantly different between the two groups (p < 0.05). Other indicators had no statistical significance (p > 0.05), as shown in Table 3.
TABLE 3.
Comparison of laboratory parameters between amputation group and non‐amputation group.
| Clinical characteristics | Non‐amputation group (n = 132) | Amputation group (n = 68) | t/Z | p‐value |
|---|---|---|---|---|
| CRP, mg/L | 8.23 (4.12–11.27) | 83.91 (17.93–135.46) | −11.231 | <0.001 |
| WBC count, ×109/L | 6.82 ± 3.13 | 13.76 ± 8.21 | −8.762 | <0.001 |
| NLR | 2.83 (1.79–3.16) | 6.39 (3.27–11.95) | −9.831 | <0.001 |
| ALB, g/L | 36.23 ± 5.37 | 30.35 ± 6.14 | 7.925 | <0.001 |
| FBG, mmol/L | 10.03 ± 3.38 | 12.37 ± 6.29 | −2.534 | 0.016 |
| TC, mmol/L | 3.92 ± 0.63 | 3.61 ± 1.02 | 1.231 | 0.219 |
| BUN, mmol/L | 6.03 ± 1.34 | 6.82 ± 3.25 | −1.832 | 0.083 |
| GSP, mmol/L | 2.25 ± 0.27 | 2.37 ± 0.41 | −1.389 | 0.167 |
| TG, mmol/L | 1.39 (0.89–2.17) | 1.03 (0.91–1.72) | −2.431 | 0.015 |
| LDL‐C, mmol/L | 2.39 ± 0.53 | 2.03 ± 0.96 | 1.362 | 0.175 |
| HDL‐C, mmol/L | 1.07 (0.81–1.46) | 0.79 (0.53–0.87) | −2.648 | 0.006 |
| Hb, g/L | 117.32 ± 29.37 | 97.61 ± 21.63 | 2.459 | <0.001 |
| PLT, ×109/L | 279.43 ± 101.23 | 446.95 ± 152.04 | 5.403 | <0.001 |
| FIB, g/L | 4.77 ± 1.03 | 5.92 ± 1.45 | 2.568 | 0.032 |
| NEUT, % | 8.32 ± 3.76 | 19.37 ± 7.02 | 9.352 | <0.001 |
| HbA1c, % | 8.21 (7.02–9.17) | 9.36 (8.34–12.36) | −4.471 | <0.001 |
| SCr,μmoI/L | 78.32 (56.36–125.87) | 77.37 (58.34–99.35) | −1.458 | 0.163 |
| D‐dimer | 369.35 ± 102.73 | 621.03 ± 401.59 | 4.672 | <0.001 |
| U‐MA, mg/L | 4.69 (3.21–5.67) | 6.38 (4.37–7.39) | −3.276 | 0.004 |
Abbreviations: ALB, albumin; A1c, Scr, serum creatinine; BUN, blood urea nitrogen; CRP, C‐reactive protein; D‐dimer, D‐dimer; FBG, fasting blood glucose; FIB, fibrinogen; GSP, glycosylated serum albumin; Hb, haemoglobin; HbAlc, haemoglobin; HDL, high density lipoprotein; LDL, low density lipoprotein; NEUT, Neutrophil; NLR, neutrophil/lymphocyte ratio; PLT, platelet count; TC, total cholesterol; TG, triglyceride; U‐MA, urinary microalbumin; WBC, white blood cell.
3.4. Multivariate logistic regression was performed with amputation as the dependent variable
Multivariate logistic regression analysis was conducted with amputation as dependent variable and univariate analysis as independent variable, and the result showed that only six indicators were independent influencing factors for DFU; NLR (OR = 1.943; 95% CI:1.826–2.139), WBC (OR = 1.143; 95% CI:1.034–1.267), CRP (OR = 1.307; 95% CI:1.113–2.194) and Wagner grading (OR = 2.783; 95% CI: 1.751–4.302) were independent risk factors for amputation, while Hb (OR = 0.742; 95% CI:0.638–0.965) and HDL were independent protective factors for amputation (OR = 0.168; 95% CI: 0.037–0.716), as shown in Table 4. The indicators of these six independent influencing factors are drawn as a forest map, as shown in Figure 4.
TABLE 4.
Results of the logistic regression analysis.
| Variable | p‐value | OR | 95% CI |
|---|---|---|---|
| WBC | 0.003 | 1.143 | 1.034–1.267 |
| CRP | 0.037 | 1.307 | 1.113–2.194 |
| Wagner | <0.001 | 2.783 | 1.751–4.302 |
| Hb | 0.023 | 0.742 | 0.638–0.965 |
| NLR | 0.003 | 1.943 | 1.826–2.139 |
| HDL | 0.018 | 0.168 | 0.037–0.716 |
FIGURE 4.
Multivariate analysis forest plot for amputation.
3.5. ROC curve diagnostic efficiency evaluation
ROC curve was used to analyse the predictive ability of NLR level, WBC level, CRP level, Wagner grade, Hb and HDL levels. The results showed that the AUC of NLR under ROC curve was 0.837 (95% CI: 0.797–0.876), the predicted sensitivity and specificity were 83.6% and 91.5%, respectively. The AUC of WBC level under ROC curve was 0.742 (95% CI: 0.685–0.799), and the predicted sensitivity and specificity were 0.783% and 0.758%, respectively. The AUC of CRP level under ROC curve was 0.789 (95% CI: 0.741–0.837), and the predicted sensitivity and specificity were 64.2% and 79.3%, respectively. The AUC of Wagner grading under ROC curve was 0.866 (95% CI: 0.741–0.837). The predicted sensitivity and specificity were 60.9% and 72.1%, respectively, and the AUC of Hb under ROC curve was 0.669 (95% CI: 0.604–0.735), the predicted sensitivity and specificity were 78.5% and 65.3%, respectively, and the AUC of HDL under the ROC curve was 0.615 (95% CI: 0.553–0.678), the predicted sensitivity and specificity were 80.3% and 72.1%, respectively, as shown in Table 5 and Figure 5.
TABLE 5.
Predictive values of the independent correlation factors.
| Independent factors | Sensitivity | Specificity | AUC | 95% CI of AUC |
|---|---|---|---|---|
| WBC | 0.783 | 0.758 | 0.742 | 0.685–0.799 |
| CRP | 0.642 | 0.793 | 0.789 | 0.741–0.837 |
| Wagner | 0.609 | 0.721 | 0.866 | 0.829–0.904 |
| Hb | 0.785 | 0.653 | 0.669 | 0.604–0.735 |
| NLR | 0.836 | 0.915 | 0.837 | 0.797–0.876 |
| HDL | 0.803 | 0.721 | 0.615 | 0.553–0.678 |
FIGURE 5.
ROC curve of six predictive indexes affecting amputation of diabetic foot ulcer.
4. DISCUSSION
At present, clinical evaluation of DFU infection is mostly based on the local infection manifestations of the foot wound, bacterial culture results of secretions, etc. 11 Although it has high diagnostic value, some patients have unclear local infection symptoms and cannot quantitatively analyse the risk of infection, and its application is limited. 12 Related studies have pointed out that various inflammatory indicators are related to the occurrence and development of infections in the body, and can be used to early evaluate the risk of infection. 13 This study retrospectively studied the clinical data of DFU and explored the risk factors related to DFU amputation, aiming to provide theoretical basis for the prevention and treatment of DFU. 14 Binary logistic regression analysis showed that the independent risk factors for DFU amputation include elevated CRP, elevated WBC count, elevated NLR and elevated Wagner grading. The independent protective factors for DFU amputation include decreased Hb levels and decreased HDL levels.
This study's univariate analysis showed that the inflammation index CRP in the amputation group was higher than that in the non‐amputation group, with statistical significance, indicating a close relationship between CRP and amputation risk. Multivariate regression analysis showed that CRP is an independent risk factor for amputation, indicating that the higher CRP, the greater the likelihood of amputation, which is consistent with previous reports. 15 , 16 Therefore, in clinical practice, CRP can be used to make timely and effective judgements on amputation. The reason may be that CRP increased gradually in the early stage of infection injury, reached the peak at 48 hours and decreased to the normal level as the inflammation subsided. Therefore, it is often used for the identification and diagnosis of infectious diseases. Compared with unamputated DFU patients, the CRP level of DFU amputation patients is significantly higher.
In this study, the WBC count of the amputated group was higher than that of the non‐amputated group, and the difference was statistically significant. The inclusion of binary regression analysis showed that an increase in WBC count was an independent risk factor for DFU amputation, indicating that the higher the WBC count, the more severe the DFU infection, and the greater the risk of amputation, which is basically consistent with previous studies. 17 The possible reason may be that after the occurrence of DFU infection, it stimulates the body to produce nonspecific immune response, and the mobilization of neutrophils from bone marrow increases compensatively, which indirectly causes the increase of peripheral blood leukocytes and plays an anti‐infective role.
Wagner grading is currently the most commonly used DFU grading method, which is widely used in clinical practice due to its simplicity, practicality and inclusion of high‐risk feet for DFU. Previous studies have shown a close correlation between DFU amputation and Wagner grading, with a significantly increased risk of amputation for Wagner 4–5 grade foot ulcers compared to 0–3 grade ulcers. 18 , 19 , 20 In this study, as the Wagner grading increased, the amputation rate also showed an upward trend. Through multiple regression analysis, it was found that the Wagner grading was an independent risk factor for DF amputation, which is consistent with previous research results. 21 , 22 This suggests that as the Wagner grading increases, the risk of amputation increases. Therefore, it is necessary to assess the severity of ulcers as early as possible, in order to adopt scientific and effective treatment. For unavoidable amputations, decisions should be made as early as possible.
NLR is an emerging research hotspot in inflammation indicators in recent years. Compared with other inflammation indicators, NLR is cheaper and relatively simple to detect and calculate. 23 Neutrophils often reflect the inflammatory response that causes damage, while lymphocytes often reflect the immune response of the body. Compared to analysing the two indicators separately, NLR can better reflect the imbalance of the proportion of the two types of cells in chronic inflammation, which is less affected by various physiological and pathological factors, and the results are more convincing. Research has reported that NLR is closely related to various diseases such as cardiovascular disease, tumours and acute pancreatitis. Some studies also suggest that NLR has good predictive value for peripheral arterial lesions and amputation in DFU. Some studies suggest that the admission NLR value is positively correlated with the severity of infection in DFU patients, and the higher the value, the greater the risk of amputation. 24 , 25 The univariate analysis of this study showed that the NLR value of the amputation group was higher than that of the non‐amputation group, and the difference was statistically significant. The inclusion of binary logistic regression analysis showed that the NLR value was an independent protective factor for DFU amputation, indicating that the lower the NLR value, the lower the risk of DFU amputation. The higher the NLR value, the higher the risk of DFU amputation. Therefore, in clinical practice, the risk of DFU amputation can be predicted early through the admission NLR value. This further confirms the results of the two studies mentioned above.
The results of this study indicate that Hb and HDL levels are protective factors for DFU amputation, and the possible reasons for this may be that red blood cell membrane proteins are affected by oxidative stress, endotoxin toxicity and glycosylation mediated effects, prolonging the destructive effect of high glucose toxicity on red blood cell function and morphology. Two recent studies have shown that low haemoglobin can cause insufficient oxygen supply to local tissues, microcirculatory disorders, and lead to local malnutrition, which is not conducive to wound healing and can result in amputation, this is consistent with the results of this study. 22 , 26 HDL can transport cholesterol from surrounding tissues to the liver for metabolism, thereby reducing the accumulation of cholesterol in surrounding tissues, reducing vascular and neurological disorders caused by cholesterol accumulation and reducing the risk of DFU amputation.
In this study, the curve was used to analyse the predictive ability of NLR level, WBC level, CRP level, Wagner grade, Hb and HDL levels. The results showed that these six indicators can predict the adverse prognosis of patients after DFU amputation to a certain extent, and have good sensitivity and specificity in predicting the occurrence of amputation in DUF. This is similar to recent findings published by Su et al.24
4.1. Limitations
This study also has certain limitations. Firstly, it is a retrospective study and may have some bias compared to prospective studies. The obtained clinical data is mainly collected from electronic medical records, and doctors describe and organize them. There are subjective differences in the description and grading of ulcers among doctors, which may lead to biased results. Secondly, this study did not conduct follow‐up and lacked data on the long‐term prognosis of patients. Again, although this study collected relatively complete clinical data from patients and timely inquired and supplemented medical history, due to the different diagnostic and treatment methods of different clinical physicians, and although there is a relatively complete clinical pathway process, there are still relevant indicators that have not been included in the research. In the future, it is urgent to carry out a multi‐center prospective epidemiological survey with a large sample size in order to more comprehensively reflect the clinical characteristics of diabetes foot patients and the influencing factors of amputation.
5. CONCLUSION
In summary, the independent risk factors for DFU amputation are elevated NLR, elevated CRP, elevated WBC count and elevated Wagner grading, while the independent protective factors are decreased Hb and HDL levels. The results of this study will help clinicians identify high‐risk patients who may undergo amputation, and develop timely appropriate individualized treatment programmes to reduce the amputation rate of diabetes foot patients.
FUNDING INFORMATION
This work was supported by the project of Hunan Provincial Department of Education (20C1427); The China Postdoctoral Science Foundation (2022M711125); Hunan Provincial Natural Science Foundation of China (2023JJ30370); The Science and Technology Innovation Program of Hunan Province (2021SK51110); Scientific Research Project of Hunan Provincial Health Commission (20233549).
CONFLICT OF INTEREST STATEMENT
The authors declare that there is no competing interest associated with the manuscript.
ACKNOWLEDGEMENTS
Not applicable.
Zhang X, Li Q, Zhou X, Xu Y, Shu Z, Deng H. Risk factors for amputation in diabetic foot ulcers: A retrospective analysis. Int Wound J. 2024;21(4):e14832. doi: 10.1111/iwj.14832
Xiaoyu Zhang is the Lead author.
DATA AVAILABILITY STATEMENT
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.