University:
Western Sydney University
Course:
MEDI 2003 | Clinical Sciences 2
Academic year:

2024
Views:

350

Pages:

2
Author:

Mariam A.

Hyperglycaemia and Advanced Glycosylation End-products (AGEs)    Both of these factors induce mesangial expansion and injury by stimulating mesangial cell matrix production and mesangial cell apoptosis. The glycosylation of tissue proteins contributes to the development of diabetic nephropathy and other microvascualr complications In chronic hyperglycaemia, excess circulating glucose combines with free amino acids on circulating or tissue proteins. This non-enzymatic process initially forms: o Reversible early glycosylation products o Irreversible advanced glycosylation end products, which accumulate in tissues and contribute to renal and microvascular complications There are several mechanisms by which AGEs (advanced glycosylation end products) may lead to diabetic complications: o Accumulation of AGEs in the extracellular matrix cause aberrant cross-linking, resulting in a decrease in elasticity of vessels o Binding of circulating AGEs to the receptor of AGEs (RAGE) on different cell types and the activation of key cell signalling pathways, such as NF-kB activation, and subsequent modulation of gene expression o Intracellular AGE formation, leading to reduction of nitric oxide and impaired function of growth factors Cytokines  The activation of cytokines, profibrotic elements, inflammation and vascular growth factors (e.g. vascular endothelial growth factor) is involved in matrix accumulation in diabetic nephropathy. Hyperglycaemia stimulates: o Increased VEGF expression – a mediator of endothelial injury in human diabetes o Increases in TGF-β expression (transforming growth factor-beta) in the glomeruli and matrix proteins o Decreased renal bone morphogenic protein-7 (BMP-7) expression which counters the profibrogenic actions of TGF-beta Risk factors for development of diabetic nephropathy    Genetic susceptibility – determinant of incidence (likelihood of developing diabetic nephropathy increased in patients with a diabetic sibling or parent with diabetic nephropathy) and severity of diabetic nephropathy Age – impact of age at onset of diabetes on risk of developing nephropathy and ESKD is unclear Blood pressure – increased systemic BP  increased intraglomerular pressure + impaired renal autoregulation       Glomerular filtration rate – In T1DM, glomerular hyperfiltration is associated with glomerular hypertrophy and increased renal size, but there are different findings with T2DM. Diabetic control – Diabetic nephropathy more likely to develop in patients with worse glycemic control Race – there is genetic influences in the racial propensity to diabetic nephropathy + also increased in blacks (3-6x compared to Caucasians), Mexican-Americans, Pima Indians with T2DM Obesity – high BMI associated with an increased risk of CKD among patients with diabetes Smoking – smoking associated with variety of adverse effects in patients with diabetes: Related to worsened glycemic control, increases in albuminuria, higher risks of ESKD, and decreased survival once dialysis is begun Contraceptives – affects/activate the Renin-angiotensin-aldosterone system