MO609: Intrarenal TNF-α Expression in The Development of Diabetic Nephropathy

Abstract BACKGROUND AND AIMS Diabetic nephropathy (DN) develops in 40%–60% of people with type 2 diabetes mellitus (DM) and is characterized by a progressive and persistent decline in renal function, being the main cause of end-stage renal disease worldwide. TNF-α plays an important role in the development of inflammation, can lead to the destruction of connective tissue, release of lytic enzymes, has a direct effect on the processes of tissue regeneration, changing the expression of collagen types I, III and V. Also, TNF-α stimulates an increase in the synthesis of endothelin-1 by glomerular mesangial cells and has a direct cytotoxic effect on renal tissue, and increased cytokine production induces the processes of apoptosis and necrosis of glomerular cells. The aim of this work was to study the role of intrarenal TNF-α expression in the development of morphological changes in renal tissue in DN patients. METHOD We examined 50 patients with type 2 diabetes (mean age 66.58 ± 3.27 years). The duration of DM is 17.69 ± 0.35 years, and the duration of DN from the moment of detection of albuminuria to morphological examination of the renal tissue and diagnosis is 1.63 ± 0.34 years. Light and immunofluorescence microscopy of biopsy specimens of renal tissue of patients was carried out. Morphological changes were assessed in accordance with the Pathologic Classification of Diabetic Nephropathy (2010). According to light microscopy, 12 patients had class IIa (mild mesangial expansion), 13 patients had class IIb (severe mesangial expansion), 19 patients had class III (Kimmelstiel–Wilson nodular lesions) and 5 patients had class IV (extended diabetic glomerulosclerosis). In all patients, TNF-α expression in the glomerulus and in the interstitium was determined by immunofluorescence microscopy. RESULTS Correlation analysis showed the effect of TNF-α expression in the glomerulus in class IIa on the development of segmental sclerosis of the glomeruli (P = 0.04). A decrease in TNF-α expression in the glomerulus is accompanied by periglomerular sclerosis (P = 0.012), and also increases: thickening of the glomerular basement membrane (P = 0.03), expansion of the mesangium passes from soft to severe and affects more than 25% of the mesangial matrix (IIb stage) (P = 0.033), Kimmelstiel–Wilson nodular lesions are formed (P = 0.009). The interstitial expression of TNF-α remains high in the epithelium of the urinary tubules and in the interstitial cells of the kidney, regardless of the DN class and influences the development of tubulointerstitial fibrosis (P = 0.003). In order to clarify the prognostic significance of TNF-α and its role in the progression of DN, a linear regression analysis was carried out with the calculation of the coefficients of determination R2 (R Square) and using the Durban–Watson test and analysis of variance (ANOVA "Analysis of Variance") using the F criterion and calculating the standardized beta coefficient (ß) with a 95% confidence interval. It has been shown that glomerular expression of TNF-α affects the following: (i) progression of the expansion of the mesangial matrix (F = 4.817, P = 0.033; β = –0.311; CI –0.506 to –0.22, P = 0.033); (ii) the formation of Kimmelstiel–Wilson nodular lesions (F = 5.383, P = 0.025; β = –0.327; CI –1.375 to –0.97, P = 0.025). Interstitial expression of TNF-α contributes to the following: (i) the progression of arterial hyalinosis (F = 4.349, P = 0.043; β = 0.297; CI 0.009–0.497, P = 0.043); (ii) interstitial sclerosis (F = 9.541, P = 0.003; β = 0.422; CI 0.101–0.479, P = 0.003). CONCLUSION