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      Inflammatory cytokines as predictive markers for early detection and progression of diabetic nephropathy

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          Abstract

          Diabetic nephropathy is a major complication of diabetes mellitus and the leading cause of end-stage renal disease. Both hyperglycemia and hypertension (systemic and/or intraglomerular) are established causal factors for diabetic nephropathy. Nonetheless, there is growing evidence that activated innate immunity and inflammation are also contributing factors to the pathogenesis of diabetic nephropathy. This notion is based on increasing evidence indicating that both cytokines-chemokines and pro-fibrotic growth factors are important players in the progression of diabetic nephropathy, effectively accelerating and exacerbating inflammatory and fibrotic processes leading to end-stage renal disease. In this review, we focus on several predominant cytokines-chemokines as potential predictive markers for diabetic nephropathy. These cytokines-chemokines may also be helpful as biomarkers to monitor the progression of the disease and the impact of interventional modalities aimed at halting eventual manifestation of end-stage renal disease in diabetic patients.

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          Most cited references131

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          The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis.

          Stress influences circulating inflammatory markers, and these effects may mediate the influence of psychosocial factors on cardiovascular risk and other conditions such as psoriasis and rheumatoid arthritis. Inflammatory responses can be investigated under controlled experimental conditions in humans, and evidence is beginning to emerge showing that circulating inflammatory factors respond to acute psychological stress under laboratory conditions. However, research published to date has varied greatly in the composition of study groups, the timing of samples, assay methods, and the type of challenge imposed. The purpose of this review is to synthesize existing data using meta-analytic techniques. Thirty studies met inclusion criteria. Results showed robust effects for increased levels of circulating IL-6 (r=0.19, p=0.001) and IL-1beta (r=0.58, p<0.001) following acute stress, and marginal effects for CRP (r=0.12, p=0.088). The effects of stress on stimulated cytokine production were less consistent. Significant variation in the inflammatory response was also related to the health status of participants and the timing of post-stress samples. A number of psychobiological mechanisms may underlie responses, including stress-induced reductions in plasma volume, upregulation of synthesis, or enlargement of the cell pool contributing to synthesis. The acute stress-induced inflammatory response may have implications for future health, and has become an important topic of psychoneuroimmunological research.
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            The role of inflammatory cytokines in diabetic nephropathy.

            Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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              Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications.

              Recent developments indicate that pathophysiological mechanisms leading to beta-cell damage, insulin resistance, and the vascular complications of diabetes include an activation of the inflammation cascade, endothelial dysfunction, and procoagulant imbalance. Their circulating biomarkers may therefore provide opportunities for early diagnosis and targets for novel treatments. Circulating biomarkers of these pathways such as TNFalpha, IL-6, C-reactive protein (CRP) (inflammation), vascular cellular adhesion molecule-1, interstitial cellular adhesion molecule-1, E-selectin, von Willebrand factor (endothelial dysfunction), plasminogen activator inhibitor-1, fibrinogen, P-selectin (procoagulant state), and adiponectin (antiinflammation) may be associated with development of both type 1 and type 2 diabetes and some studies, particularly in type 2 diabetes, have demonstrated that certain biomarkers may have independent predictive value. Similarly studies have shown that these biomarkers may be associated with development of diabetic nephropathy and retinopathy, and again, particularly in type 2 diabetes, with cardiovascular events as well. Finally, the comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to ameliorate them. Increased CRP, IL-6, and TNFalpha, and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with nephropathy, retinopathy, and cardiovascular disease in both type 1 and type 2 diabetes. Whereas further work is needed, it seems clear that these biomarkers are predictors of increasing morbidity in prediabetic and diabetic subjects and should be the focus of work testing their clinical utility to identify high-risk individuals as well as perhaps to target interventions.
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                Author and article information

                Contributors
                +1-706-7212748 , +1-706-7216252 , aelmarakby@mail.mcg.edu
                Journal
                EPMA J
                EPMA J
                The EPMA Journal
                Springer Netherlands (Dordrecht )
                1878-5077
                1878-5085
                13 March 2010
                March 2010
                : 1
                : 1
                : 117-129
                Affiliations
                [1 ]Department of Oral Biology, School of Dentistry, Medical College of Georgia, Augusta, GA 30912 USA
                [2 ]Department of Oral Health and Diagnostic Sciences, School of Dentistry, Medical College of Georgia, Augusta, GA 30912 USA
                Article
                4
                10.1007/s13167-010-0004-7
                3405301
                23199046
                ea443939-4b65-4644-ba7f-4f5421556c09
                © European Association for Predictive, Preventive and Personalised Medicine 2010
                History
                : 28 December 2009
                : 28 January 2010
                Categories
                Review Article
                Custom metadata
                © European Association for Predictive, Preventive and Personalised Medicine 2010

                Molecular medicine
                renal disease,major complication of diabetes,cytokines/chemokines,advanced predictive diagnostics,disease monitoring,personalized patient treatment

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