SM 204: CKD Pathophysiology

Question 1

Definition of CKD

Answer 1

1. Persistent Loss of fx, unlikely to return to normal

2. Compensatory mechanisms invoked to improve physiological homeostasis, eventually will fail

Question 2

Phases of CKD

Answer 2

Genetic Predisposition - Injury - Initial Lesion - Resistant FSGS - Maladaptation - Progression to CKD

Question 3

Why is the nephron so vulnerable to damage?

Answer 3

1. Concentrates toxins/metabolites
2. Strong Metabolic Demands for transport
3. Highly Vascular
4. High Throughput Filter
5. Susceptible to Inflammation

Question 4

Progression of CKD Pathogenesis (PTH/FGF)

Answer 4

Low GFR = High blood P, low blood Ca = high PTH and high FGF23 = lower P, raise Ca to normal = works until GFR declines too far, Ca falls, P rises, PTH rises

Question 5

Steps in Progressive Nephron Loss (following injury)

Answer 5

1. Remnant Nephron Hypertrophy (high SNGFR)
2. High Filtered Load
3. High Tubular Transport Work
4. High O2 Utilization
5. Tissue Hypoxia + Endothelial Dysfunction
6. Acidosis, ROS/HIF, Cell Stress, Inflammation
7. Fibrosis and more nephron loss

Question 6

How do acidosis, ROS/HIF, and cell stress contribute to fibrosis?

Answer 6

Acidosis: worsened in CKD by ischemia + anaerobic metabolism; adaptive response is to increase H+ secreting channels; maladaptive response is proinflammatory/profribrotic = more nephron loss = more acidosis

ROS - generated in hypoxia, off-target oxidation, free radical formation - cell membrane damage
HIF - profibrotic

Cell Stress - Inflammation, abnormal protein folding, protein catabolism, apoptosis

Question 7

Factors that influence per-nephron load

Answer 7

1. Low birth weight (low # nephrons)
2. Obesity (more metabolism = high GFR)
3. HTN (high GFR)
4. Hx of AKI (high risk of CKD)
5. Anemia (poor O2 delivery)