|Year : 2022 | Volume
| Issue : 4 | Page : 234-239
Role of neutrophil-to-lymphocyte ratio in predicting microvascular complications in type 2 diabetes mellitus
Nandita Gollakota1, Swaroopa Deme1, Bhaskar Kakarla2, M Nageswara Rao1, Y Sathyanarayana Raju1, Megha Uppin3, Noorjahan Mohammed4
1 Department of General Medicine, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Respiratory Medicine, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
3 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
4 Department of Biochemistry, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
|Date of Submission||05-Feb-2022|
|Date of Decision||25-Mar-2022|
|Date of Acceptance||28-Mar-2022|
|Date of Web Publication||04-Oct-2022|
Associate Professor, Department of General Medicine, Nizams Institute of Medical Sciences, Hyderabad 500 082, Telangana
Source of Support: None, Conflict of Interest: None
Background: Tools for early recognition to enable timely intervention and prevention of micro and macrovascular complications are needed in diabetes mellitus. Our study was aimed at assessing the role of neutrophil-to-lymphocyte ratio (NLR) as a tool to identify individuals at risk for microvascular complications in type 2 diabetics, i.e., diabetic nephropathy, retinopathy and neuropathy.
Methods: This was a cross-sectional study conducted at a tertiary care hospital in south India that included 98 patients with type 2 diabetes mellitus. NLR was calculated; clinical and laboratory work-up was done in all patients. This was done by quantifying albuminuria by albumin-creatinine ratio (ACR), fundus examination and nerve conduction studies. Correlation between NLR, ACR and other variables was studied in individuals with or without microvascular complications.
Results: The NLR in patients with increased ACR was found to be significantly higher when compared to patients with normal ACR (P < 0.001) with a correlation coefficient of 0.783 between ACR and NLR. Receiver operater characteristic curve analysis suggested an NLR cut-off value of 2.032 with a sensitivity and specificity of 89.1% and 81.2%, respectively. A statistically significant higher NLR value was observed in patients with diabetic retinopathy (P = 0.0005) and neuropathy (P < 0.0001).
Conclusions: NLR can be used as an early predictor of diabetic nephropathy, neuropathy and retinopathy. It, being an easier tool, can be routinely measured in diabetic individuals to identify at-risk individuals, so that early intervention with appropriate measures can be instituted.
Keywords: Diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, neutrophil lymphocyte ratio
|How to cite this article:|
Gollakota N, Deme S, Kakarla B, Rao M N, Raju Y S, Uppin M, Mohammed N. Role of neutrophil-to-lymphocyte ratio in predicting microvascular complications in type 2 diabetes mellitus. J Clin Sci Res 2022;11:234-9
|How to cite this URL:|
Gollakota N, Deme S, Kakarla B, Rao M N, Raju Y S, Uppin M, Mohammed N. Role of neutrophil-to-lymphocyte ratio in predicting microvascular complications in type 2 diabetes mellitus. J Clin Sci Res [serial online] 2022 [cited 2022 Dec 7];11:234-9. Available from: https://www.jcsr.co.in/text.asp?2022/11/4/234/357838
| Introduction|| |
Diabetes is a metabolic condition characterised by hyperglycaemia resulting from alterations in insulin secretion, insulin action or both. The chronic hyperglycaemia of diabetes is associated with long-term damage to different organ systems, including the eyes, kidneys, nerves, heart and blood vessels. Long-term microvascular complications of diabetes include retinopathy with the potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, Charcot's joints and autonomic neuropathy causing gastrointestinal, genitourinary, sexual dysfunction and cardiovascular symptoms. Poor glycaemic control, duration of diabetes and uncontrolled blood pressure are risk factors for microvascular complications. Genetic susceptibility and other accelerating factors such as hypertension and hyperlipidaemia and smoking also play a role. It has been noted that inflammation plays a key role in inciting vascular damage in both micro- and macrovascular complications of diabetes. Diabetes mellitus is a state of chronic inflammation. Many inflammatory markers are related to diabetic nephropathy, such as, interleukin (IL)-1, IL-6, IL-8, transforming growth factor-beta 1, tumour necrosis factor-alpha (TNF-α) and cytokines. However, their measurement is not used routinely as it is costly and not easy to do. Multiple studies have pointed the role and importance of inflammatory molecules including adipokines, chemokines, adhesion molecules and cytokines and endothelial dysfunction in the development of insulin resistance, diabetes and its various complications. White blood cell (WBC) count and its subtypes are amongst these, being easily available and inexpensive. Multiple studies have established that inflammatory markers such as neutrophilia and relative lymphocytopenia are independent markers of many diseases, especially complications of diabetes mellitus, such as diabetes nephropathy. But using WBC count, neutrophil, or lymphocyte counts alone has its own bias, while neutrophil-to-lymphocyte ratio (NLR) has a better predictive value as it is a dynamic parameter. NLR is a novel marker of chronic inflammation that exhibits a balance between neutrophils that are the active non-specific inflammatory mediators that form the first line of defense, whereas lymphocytes are the regulatory or protective component of inflammation.
Other studies have shown the NLR to be an independent predictor of major adverse cardiac events in patients with myocardial infarction and were also associated with poor survival rates after coronary artery bypass grafting. In chronic kidney disease patients, the NLR has shown to be an easy and inexpensive laboratory parameter that provides significant information regarding inflammation. NLR was found to be significantly elevated in patients with increased albuminuria pointing towards a relationship between inflammation and endothelial dysfunction in diabetics with nephropathy. Thus, this study is aimed at investigating the relationship between NLR with urinary albumin excretion in patients with diagnosed type 2 diabetes mellitus.
| Material and Methods|| |
This cross-sectional observational study was conducted in a tertiary care centre at Hyderabad in southern India. Institutional Ethics Committee approval had been taken. Patients with type 2 diabetes mellitus were screened for inclusion in the study. Ninety eight patients fulfilling inclusion criteria were recruited. Patients with type I diabetes, patients with uncontrolled hypertension, patients having diseases affecting urinary protein excretion as nephritis/nephrotic syndrome, urolithiasis, renal artery stenosis, low glomerular filtration rate <30 mL/min without microalbuminuria, dehydration and infections, autoimmune disorders, malignancy, and those on anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers were excluded. Clinical and laboratory data were collected and analysed Urinary albumin was quantified by an albumin creatinine ratio (ACR). According to the American Diabetes Association, patients with ACR <30 mg/g are normoalbuminuric, values between 30 and 300 mg/g are considered microalbuminuria, and values above 300 mg/g are quantified as macroalbuminuria.
DR was defined as progressive dysfunction of retinal blood vessels caused by chronic hyperglycaemia. All patients were examined by a qualified ophthalmologist and subjected to a detailed fundus examination. Diabetes retinopathy was diagnosed on the following findings: retinal capillary microaneurysms, dot and blot haemorrhages, hard exudates, retinal oedema, cotton wool spots (non-proliferative diabetic retinopathy) and presence of neovascularisation and vitreous retinal haemorrhages (proliferative diabetic retinopathy). DN was defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. Patients who had positive findings on the clinical examination such as the loss of ankle tendon reflexes, reduced pinprick sensation, reduced joint position and vibration sensation were referred to neurological for electrophysiological studies. It is diagnosed based on electrophysiological criteria, namely, decreased sensory nerve action potential amplitudes, distal latencies, absence of H reflex and presence of fibrillations in lower extremity muscles. The NLR was calculated in each of the groups separately and a comparison between the groups was made. The relation between albuminuria and elevated NLR was assessed. Total patients were divided into three groups: normoalbuminuric, microalbuminuric and macroalbuminuric groups. Micro and macroalbuminuric groups were compared with normoalbuminuric group, i.e., control group. Furthermore, the cut-off value of NLR beyond which diabetic nephropathy could be suspected was determined. Patients were also divided into groups based on whether they have developed neuropathy and retinopathy, and a comparison of NLR was made between patients with and without these complications.
Data were collected and entered in Microsoft Excel (Microsoft Corporation, Redmond, WA). with Statistical analysis was performed using Student unpaired t-test and analysis of variance for normally distributed variables, Mann–Whitney U test done for non-normally distributed variables. Spearman rank correlation coefficient was used for establishing an association between NLR and urine microalbuminuria. The Pearson correlation coefficient was used for the normally distributed variable to assess the correlation between study variables. Receiver-operator characteristic (ROC) curve analysis was done to determine the NLR value with its sensitivity and specificity for the detection of early-stage diabetic nephropathy. The statistical software IBM SPSS Statistics version 26 (IBM Corp. Somers NY, USA) was used for statistical calculations.
| Results|| |
A total of 98 individuals were studied; of which 4 patients were excluded as they required dialysis because of biopsy-proven diabetic nephropathy. The mean age in the study group was 55.7±19.6 years, the mean NLR was 9.88±5.6 and the mean ACR was 199.6, the median value being 23.5, thus suggesting a skewed non-normal distribution [Table 1]. Patients were divided into groups based on urine albumin quantification. 48 (51.1%) patients had normoalbuminuria, 46 (48.9%) patients had an increased urine albumin, of which 29 (31%) patients had microalbuminuria and 17 (18%) patients had macroalbuminuria [Figure 1]. The mean age of normoalbuminuric, microalbuminuric and macroalbuminuric patients was 53.1±9.9, 59.9±8.2 and 55.9±10.6 years, respectively. A positive correlation was observed between NLR and ACR (correlation coefficient 0.783; P < 0.0001). The comparison of study variables including the NLR, ESR, HbA1C, total leucocyte count and albumin was made in patients with normoalbuminuria and patients with micro or macroalbuminuria. Except for the TLC which was similar in both the populations, the other variables such as NLR, ESR and HbA1C were higher, while serum albumin was lower in patients with albuminuria P < 0.05 [Table 2]. Significant differences were noted between the NLR in patients with normoalbuminuria versus micro and macroalbuminuria, micro versus macroalbuminuria [Table 3]. On comparison of urine microalbumin between the three tertiles of NLR, significant differences in ACR between the lowest and highest NLR tertile (P < 0.001) were evident. ROC curve analysis was performed to determine the cut-off value for NLR for diabetic nephropathy.A cut-off of 2.032 had a sensitivity of 89.1% and specificity of 81.2% (P < 0.001) [Figure 2]. In normoalbuminuric individuals, 3 (6%) had retinopathy and 9 (18%) had neuropathy in contrast to individuals with increased urinary albumin, 21 (45%) had retinopathy and 17 (37%) had neuropathy. In patients with albuminuria a significantly higher proportion of patients with DR and DN were noted [Table 4]. A statistically significant higher NLR value was observed in patients with diabetic retinopathy (P = 0.0005) and neuropathy (P < 0.0001).
|Table 3: Comparison of neutrophil-to-lymphocyte ratio in patients with normoalbuminuria, microalbuminuria and macroalbuminuria|
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|Figure 2: Receiver-operator characteristic curve along with 95% confidence limits for calculating the cut off value of neutrophil-to-lymphocyte ratio in predicting diabetic nephropathy. The area under the receiver operator characteristic curve = 0.911, standard error = 0.0318, 95% confidence intervals ranging from 0.835 to 0.960, z statistic = 12.925, significance level P (Area = 0.5) ≤0.0001|
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|Table 4: The proportion of individuals with retinopathy and neuropathy in cases and controls|
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| Discussion|| |
The main aim of the study was to establish an association between NLR and ACR in diabetic individuals, to depict whether NLR could be used as a surrogate marker for the prediction of diabetic nephropathy. Similarly, the role of NLR in the prediction of DR and diabetic neuropathy also was studied. The key findings of this study include the positive correlation between NLR and urine albumin, a higher NLR in patients with micro- and macroalbuminuria compared to normoalbuminuria. The mean NLR in patients without albuminuria was 1.79±0.8 and with albuminuria was 3.96±4 (P < 0.001). This was similar to the finding observed in another study. In that study, the mean NLR for normal group and diabetic nephropathy group were 1.94±0.65 and 2.83±0.85, respectively. In a study, NLR was significantly elevated in patients with increased albuminuria pointing towards a relationship between inflammation and endothelial dysfunction in diabetes mellitus patients with nephropathy. In another study NLR values were significantly higher in patients with diabetic nephropathy (2.48±0.59) than in patients with diabetes mellitus without nephropathy (2.20±0.62) and healthy controls (1.80±0.64). A study conducted in the geriatric population also suggested that increased NLR levels were in itself an independent predictor for microvascular complications of diabetes mellitus. In this study, NLR was higher in the patients with diabetes mellitus (2.21±1.14) than in the controls (2.18±0.76). Furthermore, there was a statistically significant difference between NLR levels in diabetic patients with and without complications (2.46±1.26 Vs 2.04±0.51), respectively (P < 0.001). NLR cut-off point microvascular complications was 2.89 with 96.7% specificity, 94.4% positive predictive value, while it was 2.032 with 89.1% sensitivity and 81.2% specificity. The difference could be because ROC-curve analysis was performed for all the microvascular complications in the other study, while in our study, it was analysed only for diabetic nephropathy. In the other study, the correlation coefficient comparing the NLR was 0.39, while in our study, it was 0.783. It has been have shown that NLR could be related to DN and is also correlated as an indicator of ESRD.
Observations of the present study are in concordance with another study where ACR was a significant predictor of poor renal outcome. In our study, a comparison of NLR values were similar in patients with and without hypertension. This is in contrast to another study where there was a difference in the NLR values in patients with and without hypertension. The proportion of individuals with hypertension was higher in the middle and highest tertile of NLR as compared to the lowest tertile (18.2% and 16.1% compared to 11.8%).
In the present study, a significantly higher NLR value was observed in patients with diabetic neuropathy (P < 0.0001). This was similar to another study which also showed a higher NLR in patients with diabetic neuropathy. In that study, after adjusting for potentially related factors, NLR was still related to the status of diabetic neuropathy in the logistic regression (r = 1.743, P = 0.001). The area under ROC was 0.619 (P < 0.001). Moreover, a recent study in Egyptian patients has shown that NLR values were significantly higher in patients with diabetes mellitus with retinopathy (P < 0.001), neuropathy (P = 0.025) and nephropathy (P < 0.001) than those without any microvascular complications and healthy controls.
In the present study NLR was significantly higher in patients with retinopathy (P < 0.0001). A study demonstrated NLR to be a quick and reliable prognostic marker for DR and its severity. In this study, NLR values of the diabetes mellitus patients were significantly higher than those of the healthy control group (P < 0.001), and NLR levels of the patients with DR were higher than those of the patients without DR (P < 0.001). Furthermore, NLR values were correlated with the presence of DR and DR grades (r = 0.466, P < 0.001; and r = 0.630, P < 0.001, respectively). Another recent study concluded that NLR can be considered a predictive and prognostic marker for sensorineural hearing loss in diabetic patients.
In addition to the NLR, a full blood count can include measurements such as mean platelet volume, platelet distribution width, red cell distribution width and platelet-to-lymphocyte ratio. These indices have also been used as inflammatory markers and are independent predictors of cardiovascular disease and have been compared with the NLR in various clinical situations.,,, The results have been variable, but the NLR has been usually the best marker of disease progression. One key issue is to establish whether combinations of these markers are more effective predictors of the progression of several diseases than using a single marker. There are many other biomarkers of kidney injury in diabetes mellitus, these being markers of glomerular injury, tubular injury, markers of inflammation, markers of oxidative stress. Of interest are the markers of inflammation apart from NLR and other blood indices. Biomarkers of inflammation, such as, tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), which are cytokines involved in the onset and progression of diabetic neuropathy, also play predictive roles., A study was the first to suggest that these pro-inflammatory cytokines could participate in the development of diabetic neuropathy. In this study, macrophages incubated with glomerular basement membranes from diabetic rats produced significantly greater levels of IL-1 β and TNF-α than macrophages incubated with membranes of normal non-diabetic rats. Similarly, the findings from clinical studies indicate a direct and significant relationship between urinary protein excretion and serum TNF-α in diabetic patients with normal renal function and microalbuminuria on one hand, as well as in patients with overt nephropathy and ESKD on the other hand., Other biomarkers of inflammation, which are also glomerular markers, include interleukin-18 (IL-18), interferon-gamma-induced protein (IP-10), monocyte chemoattractant protein 1 (MCP-1), granulocyte colony-stimulating factor (G-CSF), regulated on activation, normal T-cell expressed and secreted or C-C chemokine ligand 5 (CCL-5) and orosomucoid. Moreover, serum and urinary levels of IP-10 and MCP1 proinflammatory cytokines were found to be positively correlated with albumin excretion rate and intima-media thickness, suggesting that microinflammation may be a common risk factor for diabetic neuropathy and atherosclerosis in type 2 diabetes mellitus. Studies have also found that urine cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) levels increase with the progression of DN and are positively correlated to urine ACR and negatively correlated to GFR.,, In diabetes with glomerular hyperfiltration urine NGAL levels were raised and positively correlated to and GFR.
Thus, various biomarkers have been identified for the progression of diabetic nephropathy, of which NLR is a sensitive and easily available marker. Larger follow-up studies have to be conducted to accurately assess the role of NLR in the prediction of diabetic nephropathy and other complications of diabetes, to aid us in initiating early treatment with drugs like angiotensin converting enzyme inhibitors and angiotensin receptor blockers to halt the disease process.
Inflammation has been known to play a major role in the pathogenesis of diabetic nephropathy and also other complications of diabetes. Hence, in our study, NLR which is a marker of inflammation was studied concerning ACR (a marker of diabetic nephropathy), and other complications of diabetes. NLR was found to be significantly higher in individuals with diabetic microvascular complications. Thus, NLR can be used in routine clinical practice to assess if individuals are at risk of developing complications, to halt their progression by appropriate measures, to reduce morbidity and mortality in diabetic individuals.
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Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]