2. Diabetic nephropathy (DN) is a chronic condition
which develops over a period of many years
DN is characterized by:
Gradually increase in urinary albumin excretion (UAE)
Hyperglycemia
High blood pressure (BP)
Declining glomerular filtration rate
Absence of other renal/renal tract disease
Presence of diabetic retinopathy
Introduction
3.
4. According to US Renal Disease Registry-
According to the latest available information, the proportion of
individuals with diabetes beginning renal replacement therapy
(RRT) is 20 – 44%
The number of people with diabetes requiring RRT increased
by 50% between 1996 and 2006.
According to ICMR study-
India has largest number of diabetes cases in the world with
prevalence of 3.8% in rural and 11.8% in urban adults
25-40% of them developed End Stage Renal Disease (ESRD).
Incidence
8. The Hexosamine Pathway
In increased Glucose condition,
some Fru-6-P via GFAT is
converted to Glucosamine-6-
P and finally to UDP N-acetyl
glucosamine (UDP-GlcNAc)
UDP-GlcNAc glycosylates
serine and threonine residues of
TF
Altered gene expression
9. AGEs are proteins or lipids that become glycated as a result of
exposure of sugars
Further, it leads to-
1. Intracellular auto-oxidation of glucose to glyoxal
2. Decomposition of the Amadori product to 3-deoxyglucosone
3. Fragmentation of glyceraldehyde phosphate to
methylglyoxal (most common)
Methylglyoxal inhibits apoptosis by direct modification of heat
shock protein, repressing Cytochrome c mediated caspase activation.
AGEs inhibit lateral association of molecules of basement
membrane, increasing it’s permeability to albumin.
Advanced Glycation End products (AGEs)
10.
11. Protein Kinase C Activation
Hyperglycemia
Diacylglycerol formation
Protein kinase C activation
Vascular and neural dysfunction and
degradation
12. •Systemic hypertension causes adverse effect on renal function
through vasoconstriction and arteriolar nephrosclerosis.
•It leads to increase in glomerular hydrostatic pressure that
causes hyperperfusion, increased capillary pressure,
hyperfilteration and proteinuria.
•The direct pressure causes stretch of mesangium leads to
protien kinase C activation, which activates- TGF-β1,
fibrinonectine.
•Impaired renal autoregulation of GFR and renal plasma flow
leads to hypertension or ischemic injury to glomerular capillaries
•Succinate, provides a direct link between high glucose and
renin release in the kidney through G protein coupled receptor
for succinate.
Hemodynamic Pathway
13. It has widespread genomic and non genomic effects
Besides electrolyte and fluid homeostasis, it’s role
includes-
1. Upregulation of prosclerotic growth factors as
plasminogen activator inhibitor-1 and TGF-β
2. Promotion of macrophage infiltration
Ultimately leads to renal fibrosis
Role of Aldosterone
14.
15. Different patients with similar duration and degree of
hyperglycemia differ markedly in their susceptibility to
microvascular complications
Only 25-40% of patients with hyperglycemia and other
risk factors develop diabetic nephropathy suggesting a
genetic role
Family studies reveal that first degree relatives of
patients, has higher incidence of DN (83%) than diabetic
without these complications (17%)
Chromosome 3, 7 and 20 have shown susceptibility loci
for diabetic nephropathy
Genetics
16.
17. Major therapeutic interventions include
Control of blood glucose to near normal level
Antihypertensive treatment
Lipid lowering therapy
Restriction of dietary proteins
Cessation of smoking
Therapeutics