Received: 22 September 2022 Revised: 31 October 2022 Accepted: 1 November 2022

DOI: 10.1111/iwj.14019

ORIGINAL ARTICLE

Effects of neutrophil-to-lymphocyte ratio, serum calcium,

and serum albumin on prognosis in patients with
diabetic foot

Su Xu | Yijia Wang | Zhensheng Hu | Ling Ma | Fan Zhang | Pei Liu

Department of Burn and Plastic Surgery,

Qilu Hospital of Shandong University,
Jinan, China
Correspondence
Pei Liu, Department of Burn and Plastic
Surgery, Qilu Hospital of Shandong
University, No. 107 Wenhua West Road,
Lixia District, Jinan 250012, Shandong,
China.
Email: liu_peiqilu@163.com
Funding information
Qilu Hospital of Shandong University
Abstract
The purpose of this study is to investigate the predictive value of neutrophil-to-
lymphocyte ratio (NLR), serum calcium, and serum albumin on the prognosis
of patients with diabetic foot. A total of 156 patients who were treated in the
Department of Burn and Plastic Surgery of Qilu Hospital of Shandong
University from 1 January 2014 to 1 August 2020 were selected. All the
patients were randomly divided into a healing group, minor amputation group,
major amputation group, and death group according to their treatment out-
comes. The levels of NLR, serum calcium and serum albumin in each group
were examined and compared. The correlations between NLR, serum calcium,
and serum albumin with the prognosis of diabetic foot were analysed to inves-
tigate their predictive effects on the prognosis of diabetic foot. The results of
one-way ANOVA showed that among the 4 groups of patients, the difference
in NLR values between the healing group and the minor amputation group
was slightly smaller, but they were significantly different from the major
amputation group and the death group, respectively. There was no significant
difference in serum calcium levels between the healing group and the minor
amputation group, but the serum calcium levels of the major amputation
group and the death group gradually decreased. The levels of NLR in the
4 groups gradually increased, while the albumin levels gradually decreased.
Spearman's rank correlation test indicated that NLR was significantly related
to the prognosis of patients with diabetic foot. The group with higher NLR had
a worse prognosis in diabetic foot patients. Serum calcium and serum albumin
were strongly correlated with the prognosis of patients with diabetic foot. The
group with lower serum calcium and serum albumin values had a worse prog-
nosis in diabetic foot patients. The areas under the receiver operator character-
istic curve of NLR, serum calcium and serum albumin were 0.901, 0.803, and
0.816, respectively. NLR, serum calcium and serum albumin can be used as
reliable indicators to predict the prognosis of diabetic foot. Preoperative

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XU ET AL. 1639

diabetic foot patients with higher NLR values or lower serum calcium and
serum albumin have a poorer prognosis.

KEYWORDS
diabetic foot, NLR, prognosis prediction, serum albumin, serum calcium

Key Messages
• NLR can objectively reflect the inflammatory markers in diabetic foot
patients.
• NLR has high specificity and sensitivity in predicting the prognosis of dia-
betic foot patients and can be used as a reliable indicator.
• Serum calcium and albumin are also inflammatory response values that
increase with systemic inflammation.
• The lower the serum calcium and albumin levels in diabetic foot patients,
the more severe the disease.

1 | INTRODUCTION recurrence rate of ulcers is also an important factor con-

Diabetes mellitus (DM) is a systemic metabolic disease
caused by defective insulin secretion or impaired biologi-
cal function.1 At present, the prevalence of diabetes has
increased significantly worldwide. It is estimated that the
global prevalence will reach 10.0% by 2045, and the num-
ber of patients will rise to 693 million.2 Diabetic foot
(DF) with neuropathy or diabetic vasculopathy is one of
the most important and serious chronic complications in
diabetic patients. Diabetic foot is an infection, ulcer, or
deep tissue destruction of the foot caused by nerve abnor-
malities and different degrees of vascular lesions in the
distal lower extremities of diabetic patients. Diabetic foot
ulcer (DFU) is one of the most important and serious
chronic complications of diabetes patients.2,3 According
to the definition of “Chinese Guidelines for the Preven-
tion and Treatment of Diabetic Foot”, DFU refers to
lesions involving skin damage and epithelial loss in DM
patients. The lesions can extend into the dermis and dee-
per layers, even deep into bone and muscle, and are a
prevalent global problem, with severe consequences lead-
ing to amputation and even death.4 The incidence of
DFU in China was 8.1%, and the recurrence rate of
healed patients was 31.6%.5 Lipsky et al indicated that
even with the treatment of medical institutions, the
amputation rate of diabetic foot patients is still 23.0%,
which is the main cause of non-traumatic amputation of
diabetes.6 The 5-year mortality rate of diabetic foot
patients is 2.5 times that of diabetic patients without foot
disease.7 In developed countries, the probability of DFU
only two-thirds of the time within 12 months. One of the
potentially serious consequences of incurable DFU is an
infection, which occurs in 40.1% of patients, leading to
persistent foot ulcers and disease progression. The high
tributing to the high rate of diabetic foot amputation. It
has been reported that the recurrence rate of DFU after
cure is 40% at 1 year, 50% at 3 years, and up to 65% at
5 years.8 Amputation and death have a huge impact and
trauma on patients and their families and also brought
huge economic burdens to the country and families.9
Therefore, it is very important to identify the high-risk
groups of diabetic foot in the early stage and carry out
targeted prevention and treatment in time.
There are many risk factors for diabetic foot, includ-
ing foot pressure, vascular neuropathy, and so on. On this
basis, many scholars have proposed predictive indicators
for the prognosis of diabetic foot. Neutrophils and lym-
phocytes can be used as important indicators to routinely
assess the severity of inflammation in patients. Neutro-
phil count and lymphocyte count are common inspection
items in clinical blood tests. However, due to the differ-
ences in detection methods and detection machines, the
normal range will also be slightly different, and relatively
speaking, the obtained neutrophil-to-lymphocyte ratio
(NLR) values will also be slightly different. The normal
proportion of neutrophils is 0.40–0.75 (40%–75%), and the
normal value of the number is (1.80–6.30)  109/L.
The normal proportion of lymphocytes is 0.20–0.40 (20%–
40%), and the normal value of the number is (0.8–3.5) 
109/L. Lymphocytes have protective and regulatory
effects during inflammation, promoting tissue repair,
pro-IL-10 expression, and anti-atherosclerotic activity.10
A high NLR may contribute to a poor prognosis in dia-
betic foot amputation patients.11 Patients with higher
NLR values have more severe diabetic foot infections and
are at higher risk of amputation; therefore NLR predicts
diabetic foot infections and amputations.10 Patients who
required amputation had higher NLRs than those who

1640
required debridement/drainage.12,13 The serum calcium
and albumin values of patients with diabetic foot
decreased and gradually decreased with the severity of
the disease. There is a correlation between serum calcium
and albumin, which is an important indicator to predict
the prognosis of diabetic foot. Among them, serum cal-
cium has a significant advantage in predicting poor prog-
noses such as diabetic foot amputation. Almost all of the
calcium in human blood exists in serum (plasma), which
is classified as non-diffusive and diffusive types. Non-
diffusing calcium accounts for 40–50% of total serum cal-
cium, 81% of which is present in the form bound to albu-
min. Diffused ionised calcium is also called free calcium
and calcium salts account for about 50% of total calcium.
At present, most clinical chemistry laboratories mainly
detect serum total calcium. We also discovered that dia-
betic foot patients with infection, severe necrosis, and
poor prognosis had higher NLR, lower serum albumin,
and often hypocalcemia. This study was conducted to fur-
ther investigate the predictive significance of NLR, serum
calcium and albumin on the prognosis of diabetic foot.
2 | C L IN I C A L D AT A AN D
METHODS
2.1 | General information
Patients who were treated by the Department of Burn
and Plastic Surgery, Qilu Hospital of Shandong Univer-
sity from 1 January 2014 to 1 August 2020 and met the
inclusion criteria. Inclusion criteria: Patients who meet
the diagnostic criteria for diabetes and diabetic foot.
Patients over 18 years of age, hospitalised for more than
72 hours, and with complete medical records. Patients
and their family members or patient guardians gave
informed consent to the treatment and signed the
informed consent form. Exclusion criteria: Patients with
type I diabetes mellitus (DM). Patients with DM in preg-
nancy. Paraplegic patients and patients with acute com-
plications of DM. Patients with comorbidities that may
affect the course of the diabetic foot, such as neoplastic
or immune disorders. Patients with incomplete data, and
could not be completed by follow-up. Patients with multi-
ple hospitalizations with repeated medical records.
Patients who refuse limb salvage treatment due to eco-
nomic conditions directly choose amputation. Patients
who refuse certain important treatments during treat-
ment. Patients with other malignancies, autoimmune dis-
eases, and underlying haematological diseases. Patients
using glucocorticoids. Patients with other active infec-
tions. Patients who died during follow-up from other
causes unrelated to diabetic foot.
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XU ET AL.
The enrolled patients were divided into a healing
group, minor amputation group, major amputation
group, and death group according to the prognosis of
patients. The relationship between patients and the prog-
nosis of diabetic foot was investigated according to serum
calcium and serum albumin levels. The amputation plan
was decided by a physician according to the clinical man-
ifestations of the patient, the results of related auxiliary
examinations and the intraoperative exploration. Minor
amputations are defined as amputations below the ankle,
including toe amputations and transmetatarsal amputa-
tions. Major amputation is defined as amputation of the
limb above the ankle joint, including the ankle joint.
Major amputation and death can be considered poor
prognoses for patients with diabetic feet. All the speci-
mens of this study were got informed consent from
patients and were approved by the Ethical Committee of
our hospital.
2.2 | Research methods
The clinical data of the patients who met the criteria
were analysed statistically. Clinical data included patient
name, gender, serum calcium, serum albumin, and
6-month follow-up prognosis after discharge.
2.3 | Postoperative treatment
The patients were given anti-inflammatory and symp-
tomatic supportive treatment after operation, and the
prognosis of the patients was followed up for 6 months.
2.4 | Laboratory parameter
determination
A fasting routine blood test was drawn the next morning
after admission. Counts of circulating immune cells are
obtained from routine blood tests. Peripheral blood sam-
ples were collected in ethylene diamine tetraacetic acid
for routine blood testing using a BC-7500 automated
blood analyser (Mindray, Shenzhen, China). The normal
ranges for these cell counts are as follows: 1.8 to
6.3  109/L for neutrophils and 1.1 to 3.2  109/L for
lymphocytes.
2.5 | Statistical methods
Statistic Package for Social Science (SPSS) 25.0 statistical
software was used for statistical analysis of medical

XU ET AL.
TABLE 1 Content comparison of NLR, serum calcium, and albumin in diabetic foot patients
Groups N NLR
Healing group 35 3.227 ± 1.437
Minor amputation group 71 5.436 ± 5.853
Major amputation group 38 11.315 ± 10.307
Death group 12 23.653 ± 15.685
T A B L E 2 Correlation between
Groups
levels of NLR, serum calcium, and
albumin and prognosis of diabetic foot Correlation coefficient
P 0.012
record data. Measurement data conforming to a normal
distribution were expressed as mean ± standard devia-
tion (SD), grouped according to NLR value, serum cal-
cium, and serum albumin value. Correlations between
NLR, serum calcium and serum albumin, and prognosis
of diabetic foot were analysed using Spearman's rank cor-
relation test. The receiver operator characteristic (ROC)
curve was used to further evaluate the diagnostic value
and efficacy of NLR value, serum calcium, and albumin
in the prognosis of diabetic foot. Three replicates were
performed for each experiment.
3 | R E SUL T S
3.1 | Comparison of NLR, serum
calcium, and albumin levels in diabetic
foot patients
The results showed that the higher the levels of NLR or
the lower the serum calcium and albumin in the four
groups of diabetic foot patients, the worse the prognosis.
With the gradual increase of NLR level, or the gradual
decrease of TCA and ALB levels in diabetic foot patients,
the patient's condition gradually became serious, and the
prognosis also changed from healing to minor amputa-
tion, major amputation, and even death.
3.2 | Correlation between levels of NLR,
serum calcium, and albumin and prognosis
Through spearman correlation analysis, we discovered
that the levels of NLR, serum calcium, and albumin were
closely correlated with the prognosis of diabetic foot, with
correlation coefficients of 0.547, 0.483, and 0.543,
respectively. Therefore, we believe that NLR, serum
calcium, and serum albumin have a strong correlation
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1641
Serum calcium (mmol/L) Serum albumin(g/L)
2.2760 ± 0.11366 39.1857 ± 4.78872
2.2251 ± 0.13479 35.5324 ± 5.29498
2.1153 ± 0.13380 30.8474 ± 5.63856
1.9333 ± 0.09642 27.5500 ± 3.38862
NLR Serum calcium (mmol/L) Serum albumin(g/L)
0.547 0.483 0.543
0.022 0.016
with the prognosis of patients with diabetic foot (Tables 1
and 2).
3.3 | ROC curve of NLR, serum calcium,
and albumin in predicting prognosis of
diabetic foot
The results of the ROC curve indicated that the area
under the ROC curve of NLR was 0.901 (P < 0.01), and
the 95% confidence interval was 0.828 to 0.974. Through
ROC analysis, the area under the ROC curve of serum
calcium was 0.803 (P < 0.01), and the 95% confidence
interval was 0.729 to 0.877. The area under the ROC
curve of serum albumin was 0.816 (P < 0.01), and the
95% confidence interval was 0.744 to 0.889 (Figure 1,
Table 3). It can be seen that NLR, serum calcium, and
serum albumin can be used as more reliable predictors of
the prognosis of patients with diabetic foot, and have
great guiding significance for guiding treatment, preoper-
ative and postoperative intervention (Figures 2 and 3).
4 | TYPICAL CASES
Case 1. The patient is a 56-year-old male
patient with right foot ulceration and exuda-
tion for more than 3 months, who has not
been diagnosed and treated before. The
patient was diagnosed with type II diabetes
and diabetic foot. The results showed that the
patient had high NLR, hypoalbuminemia and
hypocalcemia, and he underwent right calf
amputation. Exploration revealed extensive
necrosis of the soft tissue behind the right
lower extremity, and debridement and nega-
tive pressure suctions were performed. After

1642
FIGURE 1 The ROC curve of NLR, serum calcium, and albumin in predicting adverse prognosis of diabetic foot
TABLE 3 The detailed data of ROC curve
Test outcome variables Area under the curve
NLR 0.901
Serum albumin 0.816
Serum calcium 0.803
that, skin grafting was used to repair the
wound, and the patient recovered well after a
6-month follow-up.
Case 2. A 53-year-old male patient was admit-
ted to the hospital for more than 1 month of
right foot ulceration and exudation of pus. The
patient was diagnosed with type 2 diabetes mel-
litus and diabetic foot. The results showed that
the patient had high levels of NLR, hypoalbumi-
nemia, and hypocalcemia. Intraoperative explora-
tion revealed extensive necrosis of the soft tissue
of the right foot, and the limb salvage effect was
poor. He underwent a second surgical amputa-
tion and recovered well 6 months after surgery.
5 | DISCUSSION
With the global rise in the incidence of diabetes, poor
long-term glycemic control in diabetic patients leads to
rupture and occlusion of distal microvessels, abnormal
sensations in distal limbs, and finally a gradual increase
in the incidence of diabetic foot. DFU is one of the most
important and serious chronic complications in diabetic
patients. If DFU develops in diabetic foot, surgical
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XU ET AL.
95% Confidence interval
Standard error P Lower limit Upper limit
0.037 <0.01 0.828 0.974
0.037 <0.01 0.744 0.889
0.038 <0.01 0.729 0.877
intervention is generally required. For patients with
high-risk factors, DFU often has a poor prognosis, which
brings huge pain and economic burden to patients. The
annual mortality rate of DFU in China was 14.4%, and it
gradually increased. The 5-year survival rate for ampu-
tees is less than 60%.2 In this study, the death rate of dia-
betic foot patients was 7.7%, the amputation rate was
69.9%, the major amputation rate was 24.4%, the minor
amputation rate was 45.5%, and the healing rate was
22.4%. Different previous studies have reported that the
amputation rate of diabetic feet varies greatly, which may
be connected to different regions, social environments,
and the selection of survey subjects. Most reports' ampu-
tation rates were lower than the results of this study. For
example, Jeong et al. reported that the risk of lower limb
amputation in patients with type 2 DM was as high as
58.9%, especially the proportion of minor amputations
was high, accounting for 50.5%, and the proportion of
major amputations was only 8.3% of.14 Patients with dia-
betic feet who required inpatient surgery were selected
for this study, therefore excluding some patients with
mild, early diabetic feet who could only be cured by out-
patient or medical inpatient dressing changes. And most
of the hospitalised patients are engaged in manual
labour, patients are prone to foot injuries. In addition,
limited by economic conditions and cultural levels,

XU ET AL.
F I G U R E 2 Disease progression in Case 1. A, Diabetic foot ulcer before surgery. B, Intraoperative exploration revealed extensive
lesions. C, Examination showed infection and necrosis extending to the posterior part of the right thigh. D and E, Follow-up photos taken
6 months after discharge
patients often lack good disease management ability,
medical awareness, and compliance, and cannot receive
correct treatment in a timely manner. As a result, the
amputation rate is higher than that at home and abroad.
Thus, the prevention and prediction of diabetic foot are
particularly important.
It has become an urgent problem to find reliable indi-
cators to predict the prognosis of diabetic foot, including
neutrophils, lymphocytes, monocytes, serum albumin,
serum calcium, NLR, platelets/Lymphocyte ratio
(Platelet/lymphocyte ratio), neutrophil/albumin ratio
(Neutrophil/albumin ratio). Among these numerous indi-
cators, we discovered that patients with higher preopera-
tive NLR tended to have poorer prognoses, and further
research was conducted. Neutrophils have been found to
infiltrate the vessel walls and secrete superoxide free radi-
cals, cytokines, and various proteolytic enzymes, leading
to endothelial damage. And lymphocytes can regulate the
effect of neutrophils and have the effects of resisting arte-
riosclerosis. Higher NLR indicates higher neutrophil
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1643
activity leading to endothelial damage and dysfunction,
possibly leading to poorer prognosis in vascular-related
diseases.15 Studies have shown that severe inflammation
occurs in the context of ischemic tissue injury and that
neutropenia and lymphocytopenia caused by inflamma-
tion are associated with cortisol-induced stress, with
increased NLR.16-18 The study by Feist et al. suggested
that NLR values are a potential disease-related risk factor
for mortality in the entire population. Postoperative NLR
value is considered to be a strong predictor of early mor-
tality.19 Sefil and Hussain indicated that NLR is a reliable
biomarker for diabetes monitoring and glycemic control,
closely related to fasting blood glucose and glycated hae-
moglobin (HbA1c).20,21 Patients with higher NLR values
on admission had more severe diabetic foot infections, a
higher risk of amputation, and required long-term hospi-
talisation and aggressive treatment. However, they also
have a greater chance of benefiting from treatment.22 As
a prognostic indicator to evaluate the prognosis of inflam-
mation, lower extremity arterial disease, prognosis of

1644
FIGURE 3 Disease progression in Case 2. A, B, Preoperative photos. C, D, Extensive tissue necrosis was observed during intraoperative
exploration
non-small cell lung cancer and many diseases.12 NLR
also has a good performance in predicting the prognosis
of patients with diabetic foot. By spearman correlation
analysis, we found a strong correlation between NLR and
the prognosis of diabetic foot. We, therefore, believe that
NLR is strongly associated with the prognosis of patients
with diabetic foot. With the gradual increase of NLR
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XU ET AL.
value in diabetic foot patients, the patient's condition
gradually became more serious. Through ROC analysis, it
can be seen that NLR has high sensitivity and specificity
as a prognostic indicator of diabetic foot.
In clinical practice, we found that some patients with
severe diabetic foot have severe hypocalcemia, which is
difficult to correct by supplementing calcium and

XU ET AL.
vitamin D, and the prognosis is usually poor. The results
of this study demonstrated that the mean serum calcium
value of the diabetic foot patients was 1.93 mmol/L in
the death group, 2.12 mmol/L in the major amputation
group, 2.23 mmol/L in the minor amputation group, and
2.28 mmol/L in the healing group. The levels of serum cal-
cium were not significantly different between the healing
group and the minor amputation group but were signifi-
cantly different from those of the major amputation group
and the death group (P < 0.05). Major amputations and
death can be classified as poor outcomes, and our results
are consistent with lower serum calcium in patients with
poor outcomes, such as diabetic foot amputation. Research
data have shown that severe hypocalcemia can predict the
poor prognosis of the diabetic foot and is one of the risk
factors for diabetic foot amputation. However, there is no
literature report that low calcium can predict poor progno-
sis such as diabetic foot amputation.
In recent years, some studies have reported that
serum albumin had certain significance in predicting dia-
betic foot amputation, and this study also indicated that
hypoalbuminemia may be one of the risk factors for
amputation.14 Our results showed that the mean serum
albumin value of the diabetic foot patients enrolled is
27.55 g/L in the death group, 30.85 g/L in the major
amputation group, 35.53 g/L in the minor amputation
group, and 39.19 g/L in the healing group. The differ-
ences among the four groups were statistically signifi-
cant, which was lower than the reference range of
normal adult albumin. Studies have demonstrated that
low protein can predict the prognosis of patients with
diabetic feet. In many studies, serum calcium positively
correlated with albumin, which is consistent with our
findings. The overall nutritional status of diabetic foot
patients is poor, especially in patients with amputation.
Coupled with the increased protein consumption and
reduced synthesis of diabetic foot patients, the nutritional
risk is higher. Low serum albumin not only reflects the
nutritional status of patients but also can be used as one
of the indicators reflecting the severity of the disease in
clinical patients. The exudation of diabetic foot wounds
itself carries away a large amount of protein, and the
speed of albumin synthesis is insufficient. Frequent dress-
ing changes and surgeries will further promote the loss of
albumin, the patient's immunity will be weakened, and
pathogens can easily invade. At the same time, wound
healing requires a large amount of protein consumption,
and patients are often trapped in a vicious circle of
hypoalbuminemia-infection-wound non-healing.23 The
stimulation of surgery may result in lower and lower
levels of albumin in patients. Therefore, the dynamic
monitoring of albumin levels in patients should be
strengthened in clinical practice, and timely
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1645
replenishment of albumin is of great significance to pre-
vent disease progression. The mechanism of serum cal-
cium reduction is very complex, not necessarily related to
albumin alone, but is affected by multiple factors, which
may be related to various factors such as fat metabolism
soap theory, calcium salt deposition, and vitamin D
deficiency.
In conclusion, NLR can objectively reflect the inflam-
matory indicators of patients with diabetic foot, and
reflect the immune status and comprehensive physical
fitness of the body. NLR has high specificity and sensitiv-
ity in predicting the prognosis of patients with diabetic
foot, which can be used as a reliable indicator. Similar to
NLR, serum calcium and albumin are also inflammatory
values, which increase with the aggravation of systemic
inflammation. The lower the serum calcium and albumin
levels in diabetic foot patients, the more severe the dis-
ease. However, its mechanism of action and internal con-
nection mechanism still needs to be further researched.
The patients are often severe, and the data of some mild
patients may be ignored, which is a limitation of this
study. It is our key task and the direction of future devel-
opment to establish a relatively complete diabetic foot
disease management and two-way referral system and a
multidisciplinary team of intra-hospital and inter-
hospital cooperation for diabetic foot disease.
A C KN O WL ED G EME N T S
The authors have no support to report.
CONFLICT OF INTEREST
All authors declare that they have no financial or other
conflicts of interest in relation to this research and its
publication.
DA TA AVAI LA BI LI TY S T ATE ME NT
The datasets used and/or analyzed during the current
study are available from the corresponding author on rea-
sonable request.
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How to cite this article: Xu S, Wang Y, Hu Z,
Ma L, Zhang F, Liu P. Effects of neutrophil-to-
lymphocyte ratio, serum calcium, and serum
albumin on prognosis in patients with diabetic
foot. Int Wound J. 2023;20(5):1638‐1646. doi:10.
1111/iwj.14019