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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 763-767

Value of serum tumor necrosis factor-α as an early predictor of diabetic nephropathy


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Internal Medicine, Al Shohada Central Hospital, Menoufia, Egypt

Date of Submission12-Jan-2020
Date of Decision16-Feb-2020
Date of Acceptance21-Feb-2020
Date of Web Publication18-Oct-2021

Correspondence Address:
Rasha A. E. M. A. Elsasmad
Al Shohada, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_7_20

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  Abstract 


Objective
This study was designed to evaluate serum tumor necrosis factor-α as an early predictor of diabetic nephropathy (DN).
Background
Owing to the high morbidity and mortality associated with DN, it is important to establish marker used as an early prediction of DN to overcome its complication.
Patients and methods
This study was conducted on 70 patients selected from the Inpatient Department and Outpatient Clinics of Internal Medicine Department and Medical Biochemistry and Molecular Biology Department at Menoufia University Hospital. All patients were investigated regarding urine analysis, blood urea and serum creatinine, HBA1C, lipid profile, and urine albumin-creatinine ratio.
Results
The 70 patients (55 males and 15 females) with diabetes mellitus were divided into 35 patients with normoalbuminuric and 35 patients with albuminuria (30–299 mg/g Cr). Ten healthy individuals (seven males and three females) were selected as a control group. The patients fulfilled the following criteria: age greater than 18 years, initial diagnosis of diabetes at greater than 30 years of age, no signs of renal diseases, no history of cardiovascular diseases, including stroke, heart diseases, and arteriosclerosis, and no symptoms of acute inflammatory diseases. All patients and control personnel enrolled in this study gave oral and written consent to see all of their investigations.
Conclusion
Tumor necrosis factor-α, one of the main proinflammatory cytokines, is overexpressed in DN, and this overexpression is significantly associated with evidence of renal damage.

Keywords: diabetic nephropathy, predictor, tumor necrosis factor, urine albumin-creatinine ratio


How to cite this article:
Gazareen SS, Dawood AE, Alhelbawy NG, Elsasmad RA. Value of serum tumor necrosis factor-α as an early predictor of diabetic nephropathy. Menoufia Med J 2021;34:763-7

How to cite this URL:
Gazareen SS, Dawood AE, Alhelbawy NG, Elsasmad RA. Value of serum tumor necrosis factor-α as an early predictor of diabetic nephropathy. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:763-7. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/763/328346




  Introduction Top


Diabetes mellitus comprises a group of heterogeneous disorders, which have in common an increase in blood glucose concentrations. It is a chronic illness that requires continuing medical care, and patient self-management involves maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding use of tobacco. Control of blood pressure and maintaining proper foot care are important for people with the disease to prevent acute complications and to reduce the risk long-term complications such as nephropathy and/or neuropathy [1]. Diabetic nephropathy (DN) is a serious kidney-related complication of type 1 diabetes and type 2 diabetes. It is also called diabetic kidney disease. It is the leading cause of end-stage kidney disease in North America and accounts for 44 and 34% of incident cases in USA and Canada, respectively [2]. DN is a clinical syndrome characterized by persistent albuminuria that is confirmed on at least two occasions 3–6 months apart, progressive decline in the glomerular filtration rate, and elevated arterial blood pressure [3]. Tumor necrosis factor-α (TNF-α) is an adipokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute-phase reaction. It is produced chiefly by activated macrophages, although it can be produced by many other cell types such as CD4 + lymphocytes, NK cells, and neurons [4]. The primary role of TNF-α is in the regulation of immune cells. TNF-α, being an endogenous pyrogen, is able to induce fever, apoptotic cell death, cachexia, and inflammation; inhibits tumorigenesis and viral replication; and responds to sepsis via interleukin (IL) 1-producing and IL6-producing cells. Dysregulation of TNF-α production has been implicated in a variety of human diseases including Alzheimer's disease, cancer, major depression, and inflammatory bowel disease. Recombinant TNF-α is used as an immunostimulant. TNF-α can be produced ectopically in the setting of malignancy and parallels parathyroid hormone both in causing secondary hypercalcemia and in the cancers, with which excessive production is associated [5] Diabetic patients with nephropathy have higher serum and urinary concentrations of TNF-α than nondiabetic subjects or diabetic patients without renal involvement [6]. It was suggested a direct and independent association between the levels of this cytokine and clinical markers of glomerular and tubulointerstitial damage, with a significant rise in serum and urinary TNF-α as DN progresses [7]. Therefore, this study was designed to evaluate serum TNF-α as an early predictor of DN.


  Patients and methods Top


The current study was conducted on 70 patients selected from the Inpatient Department and Outpatient Clinics of Internal Medicine Department and Medical Biochemistry and Molecular Biology Department at Menoufia University Hospital. In addition, the study included 10 normal individuals as a control group. The 70 patients (55 males and 15 females) with diabetes mellitus were divided into 35 patients with normoalbuminuric and 35 patients with albuminuria (30–299 mg/g Cr).

Ethical consideration

The study was approved by the Ethical Committee of Menoufia Faculty of Medicine. An informed consent obtained from all participants before the study was commenced.

The patients fulfilled the following criteria: age greater than 18 years, initial diagnosis of diabetes at greater than 30 years of age, no signs of renal diseases, no history of cardiovascular diseases, including stroke, heart diseases, and arteriosclerosis, and no symptoms of acute inflammatory diseases. All patients and control personnel enrolled in this study gave oral and written consent to examine all of their investigations.

All patients were subjected to the following: history taking including duration of diabetes mellitus and type of drug therapy either oral hypoglycemic or insulin; complete clinical examination; and laboratory tests, including complete blood count using Sysmex KX-21 automatized hematology analyzer (Sysmex Corporation, Kobe, Hyogo, Japan), urine analysis, kidney functions, including blood urea and serum creatinine using the open system autoanalyzer synchron CX5 (Beckman, Brea, California, United States), urine albumin and creatinine ratio, fasting blood glucose using Sysmex KX-21 automatized hematology analyzer (Sysmex Corporation), HbA1c, lipid profile using the open system autoanalyzer synchron CX5 (Beckman), abdominal ultrasound, and measurement of urinary TNF-α with human TNF-α Sunredbio ELISA Kit (BaoshanDistrict,Shanghai,China). TNF-α uses a double-antibody sandwich enzyme linked immune-sorbent assay (ELISA) to assay human TNF-α in samples. Add TNF-α to monoclonal antibody enzyme which is precoated with human TNF-α monoclonal antibody, incubate, then add TNF.

Statistical analysis

Results were tabulated and statistically analyzed by using a personal computer using Microsoft Excel 2016 and SPSS v. 21 (SPSS Inc., Chicago, Illinois, USA). Statistical analysis was done using descriptive, for example percentage, mean, and SD, and analytical, which includes χ2 and one-way analysis of variance test. A value of P less than 0.05 was considered statistically significant.


  Results Top


Our study included 70 patients, comprising 55 male (70%) 15 female (30%). There was no significant differences regarding age and sex (P > 0.05), as well as years of diabetes (P = 0.035), and highly significant difference regarding drug therapy (P < 0.001) [Table 1]. There were statistically highly significant differences between group I and group III and between group II and group III and non-significance between group I and group II regarding kidney function tests, including urea and creatinine (P < 0.001). [Table 2]. There were statistically high significant differences between the three studied groups regarding glycated hemoglobin and fasting blood sugar (P < 0.001). There was a highly statistically significant difference among the three studied groups regarding urine albumin creatine ratio (UACR) (P < 0.001), [Table 3]. Among the studied cases, there were statistically high significant positive correlations between TNF-α and years of diabetes mellitus, creatinine, fasting blood glucose, and UACR (P < 0.001); significant correlations regarding urea and glycated hemoglobin (P < 0.05); and non-significant correlations regarding age, cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein (P > 0.05) [Table 4].
Table 1: Comparison of the studied groups regarding demographic data

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Table 2: Comparison of the studied groups regarding Kidney function tests

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Table 3: Comparison of the studied groups regarding hemoglobin A1c, fasting blood glucose, and urine albumin creatine ratio

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Table 4: Correlation between tumor necrosis factor-α and laboratory investigations among studied cases

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  Discussion Top


Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Various genetic and environmental factors can result in the progressive loss of b-cell mass and/or function that manifests clinically as hyperglycemia [3]. Chronic kidney disease is diagnosed by the persistent presence of elevated urinary albumin excretion (albuminuria), low estimated glomerular filtration rate, or other manifestations of kidney damage [8]. In addition, among people with type 1 or 2 diabetes, the presence of chronic kidney disease markedly increases cardiovascular risk and health care costs [9]. One of the most important changes is related to the participation of immune-mediated inflammatory processes in the pathophysiology of diabetes mellitus and its complications [10]. TNF-α is a proinflammatory cytokine with a wide range of biologic effects including the stimulation of the production of prostaglandins, platelet-activating factor, and plasminogen activator inhibitor; chemotaxis; the induction of adhesion molecules expression; and the synthesis of other inflammatory mediators. Renal cells are capable of synthesizing TNF-α, which may act in a paracrine or autocrine manner to induce a variety of effects on different renal structures [11]. There is growing evidence that proinflammatory cytokines play a significant role in the development and progression of several renal disorders, including DN [12].

In this study, we aimed to evaluate serum TNF-α as an early predictor of DN. This study included 70 subjects, and they are divided into two groups: group II included 35 patients with diabetes and without proteinuria and group III included 35 patients with diabetes and albuminuria. In addition, a 'control group' (group I) was included, which comprised 10 patients without diabetes, and was age and sex matched with the cases.

In this study, there were statistically high significant differences between the three studied groups regarding drug therapy and age and significant differences regarding sex and years of diabetes. In this study, there were statistically high significant differences among the three studied groups regarding kidney function tests including urea and creatinine, glycated hemoglobin, and fasting blood glucose. In a study done by Navarro et al. [13], glucose concentration was significantly higher in diabetic than in nondiabetic animals. The blood glucose concentration did not differ significantly between diabetic rats treated with enalapril and untreated diabetic rats.

In this study, there were no significant differences among the three studied groups regarding lipid profile. TNF-α is one of the main proinflammatory cytokines and may be produced intrinsically in renal cells. It is important to note that increased urinary and renal interstitial concentrations of TNF-α precede the rise in albuminuria. TNF-α is cytotoxic to glomerular, mesangial, and epithelial cells, and may induce direct renal damage. Moreover, TNF-α has a direct effect on the protein permeability barrier of the glomerulus, independent of alterations in hemodynamic factors or effects of recruited inflammatory cells [14].

In this study, there was a statistically highly significant difference among the three studied groups regarding UACR. Hasegawa et al. [15] reported that peritoneal macrophages incubated with glomerular basement membranes from diabetic rats produced greater levels of TNF-α and IL-1 than macrophages incubated with membranes from normal rats. They suggested that proinflammatory cytokines might be involved in the development of DN [16]. They determined whether there was an association between Ang-2, TNF-α, and reactive oxygen species (8-OHdG and SOD) in type 2 diabetes patients with albuminuria. They concluded that increased levels of TNF-α and 8-OHdG and decreased SOD activity were associated with a worsening of albuminuria. Serum TNF-α and 8-OHdG predicted serum Ang-2 levels. Urinary TNF-α and 8-OHdG predicted urinary Ang-2 levels. TNF-α and 8-OHdG were associated with elevated urinary Ang-2 levels in type 2 diabetes patients with albuminuria.


  Conclusion Top


From the present study, we concluded that TNF-α is overexpressed in DN, and that this overexpression is significantly associated with evidence of renal damage, such as UAE; thus, it can be considered as a predictor of DN. Therefore, we recommend the facilitation of future methods to use this marker as a predictor for DN.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
International Diabetes Federation. IDF diabetes atlas 8th edition. 2017. Available from: https://www.idf.org/e-library/epidemiology-research/diabetes-atlas.html. [2018]. [ Last Retrieved on 2020 Jul 19].  Back to cited text no. 1
    
2.
Tang SC, Chan GC, Lai KN. Recent advances in managing and understanding diabetic nephropathy. F1000Res 2016; 3:5–12.  Back to cited text no. 2
    
3.
Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA 2016; 316:602–610.  Back to cited text no. 3
    
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Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry 2012; 68:930–941.  Back to cited text no. 4
    
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Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67:446–457.  Back to cited text no. 5
    
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Domingueti CP, Dusse LM, das Graças Carvalho M, de Sousa LP, Gomes KB, Fernandes AP. Diabetes mellitus: the linkage between oxidative stress, inflammation, hypercoagulability and vascular complications. J Diabetes Complic 2016; 30:738–745.  Back to cited text no. 6
    
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Donate-Correa J, Martín-Núñez E, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF. Inflammatory cytokines in diabetic nephropathy. J Diabetes Res 2015; 2015:9.  Back to cited text no. 7
    
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Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 2013; 24:302–308.  Back to cited text no. 8
    
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United States Renal Data System. Annual Data Report: Epidemiology o kidney disease in the United States. Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2016.  Back to cited text no. 9
    
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Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress – A concise review. Saudi Pharm J 2016; 24:547–553.  Back to cited text no. 10
    
11.
Navarro-González JF, Mora-Fernández C, de Fuentes MM, Chahin J, Méndez ML, Gallego E, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol 2015; 26:220–229.  Back to cited text no. 11
    
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Elsherbiny NM, Al-Gayyar MM. The role of IL-18 in type 1 diabetic nephropathy: the problem and future treatment. Cytokine 2016; 81:15–22.  Back to cited text no. 12
    
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Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 2008; 19:433–442.  Back to cited text no. 13
    
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Willebrords J, Crespo Yanguas S, Maes M, Decrock E, Wang N, Leybaert L, et al. Connexins and their channels in inflammation. Crit Rev Biochem Mol Biol 2016; 51:413–439.  Back to cited text no. 14
    
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Hasegawa G, Nakano K, Sawada M, Uno K, Shibayama Y, Ienaga K, et al. Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int 1991; 40:1007–1012.  Back to cited text no. 15
    
16.
He FF, Li HQ, Huang QX, Wang QY, Jiang HJ, Chen S, et al. Tumor necrosis factor-alpha and 8-hydroxy-2'-deoxyguanosine are associated with elevated urinary angiopoietin-2 level in type 2 diabetic patients with albuminuria. Kidney Blood Pressure Res 2015; 40:355–365.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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