Diabetic nephropathy and Causes of tissue damage by hyperglycemia:

Diabetic nephropathy:

Diabetes mellitus is a chronic hyperglycemia sufficient to cause multisystem dysfunction but mostly retina, kidney, nerves and arteries. Type 1 DM is due to autoimmune destruction of pancreatic islet beta cells causing loss of insulin. Type 2 diabetes is due to combination of cellular resistance to insulin and beta cell failure.

Diabetic nephropathy (DN) there is finding of proteinuria in patient with diabetes with no evidence of UTI. Overt nephropathy occurs when albumin excretion of around 300 mg/day. Albumin measurement in urine is the recommended for detecting and monitoring kidney damage in adults. Patients with albuminuria 30-300 mg/day are said to be having microabluminuria.

In DN, there is kidney necrosis, contraction, thickened basement membrane and other abnormalities. Clinical progression is defined in terms of change in urinary albumin excretion rate and decline in GFR and blood pressure. In type 1 DM, microabluminuria develops later after 5 years of diagnosis or at any time after 40 years of age. So annual monitoring or urine albumin is recommended after 5 years disease duration. Type 2 DM are usually older at presentation and defining the date of onset is difficult and annual monitoring of urine albumin is recommended from the time of diagnosis.

Hyperinfiltration with progressive increase in UAE with decrease in GFR can lead to hypertension and finally cause ESRD with uraemic syndrome.

To this date the best available predictor for development of nephropathy in kidney disease and in diabetics, is microabluminuria as UAE represents generalized vascular damage than renal microvascular injury alone.

The exact mechanism for hyperglycemic tissue damage probably includes

a.      Formation of Advanced glycation end products (AGE)

b.    Overactivity of polyol pathway. Polyols are sugar alcohols formed from their respective sugars under the action of aldose reductase.

c.       Generation of ROS

Glucose is preferentially shunted through the polyol pathway under hyperglycemic conditions generating sorbitol that accumulates within cells. Abundance of glucose and its product in ECM of glomerulus and interstitium is a key step in pathogenesis. There is excess of ECM within glomeruli and interstitium. E.g. TGF-β is stimulated by hyperglycemia, AGE, angiotensin II and ROS this TGF-β cause the upregulation of insulin independent GLUT-1 transporter in mesangial cells. Glucose is transported to cells through GLUT-1 and metabolized mainly be glycolytic pathway. Activation of other signaling pathways like PKC, DAG, MAPK, etc. induces expression of ECM proteins. Hypersclerotic and hypertrophic effect of glucose are largely mediated by TGFβ which is seen to be overproduced in DN patients.

The receptors for AGE has been identified (RAGE) which is selectively expressed in glomerular epithelial cells (podocytes). Increased accumulation of AGE in diabetes engages podocyte RAGE and may lead to increased glomerular permeability. Vascular permeability a hallmark of diabetes can be suppressed by inhibiting RAGE in animal model.