●       Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m2)

●       Stage 3: Moderate reduction in GFR (30-59 mL/min/1.73 m2)

●       Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m2)

●       Stage 5: Kidney failure (GFR <15 mL/min/1.73 m2 or dialysis)

Stage 1&2 are often asymptomatic

If treated on time then it is reversible

- Increased intrarenal activity of RAAS contributes to initial compensatory hyperfiltration and the later maladaptive hypertrophy and sclerosis

- Angiotensin II effects: 

       - Vasoconstriction efferent arterioles → increasing glomerular hydraulic pressure and filtration fraction

       - Upregulate TGF-B (= potent fibrogenic cytokine) → increase collagen synthesis and epithelial cell transdifferentiation to myofibroblasts that contribute to excessive matrix formation 

       - Upregulate plasminogen activator inhibitor (PAI-1) → inhibits matrix proteolysis by plasmin → accumulation excessive matric and scarring in glomeruli and interstitium

- Albumin can appear in urine carrying bound fatty acids, growth factors, and cytokines 

       - When reabsorbed in proximal tubule and degraded → can cause proximal tubular cell activation and interstitial scarring 

- Early → microalbuminuria (30-300 mg/24h) 

       - 7-10 years after type 1 diabetes diagnosis

       - Can be detected by calculating albumin/creatinine ratio ACR

                  - Men → >2.5 mg/mmol

                  - Women → >3.5 mg/mmol 

- Glomerular hyperfiltration

        - Mainly bc Afferent arteriole dilation due to:

                 - Hyperglycemia and high insulin-like growth factor 1 (IGF-1) 

                 - Hyperfiltration of glucose leads to augmented sodium-glucose transport in the proximal convoluted tubule causing enhanced sodium transport

                         - Cause expansion of blood volume which leads to a rise in GFR

                         - The rise in proximal reabsorption also leads to a reduced distal fluid delivery which activates the tubuloglomerular feedback with the RAAS system which works to raise the GFR as well.

- Hyperglycemia and AGE

       - Hyperglycemia and AGE directly induce mesangial matrix production, cellular expansion and apoptosis.

       - The two have also been shown to increase basement membrane permeability to albumin.

- Cytokines

       - Elevations in vascular endothelial growth factor (VEGF), transforming growth factor beta (TFG-β), and profibrotic proteins increase damage to the nephrons at different levels; specific mechanisms are unclear.

Main Problems:
- Podocyte loss
- Scarring
- Mesangial damage

Sheer stress - stretch stress

- Peak GFR abt 120 mL/min/1.73m2

- Mean decline in the third decade of life is abt 1 mL/min/1.73m2 per year

- 70 mL/min/1.73m2 by 70 y/o

higher in men and African population