SM_204a: CKD Pathophysiology

Question 1

Describe the pathomechanistic definition of CKD

Answer 1

Pathomechanistic definition of CKD

• Persistent loss of function, unlikely to return to normal
• Compensatory mechanisms invoked to improve physiological homeostasis
• New steady state or progression to end-stage renal disease (dialysis or transplantation)

Question 2

With decreases renal mass, nephron _____ progresses steadily

Answer 2

With decreases renal mass, nephron loss progresses steadily

Question 3

The three pathomechanistic phases of CKD are _____, then _____, then _____

Answer 3

The three pathomechanistic phases of CKD are injury, then scarring, then progression

• Scarring: structural damage
• Progression: accelerated nephron loss, occurs before dialysis

Question 4

Scarring phase of CKD involves ______

Answer 4

Scarring phase of CKD involves structural damage

Question 5

Progression phase of CKD involves _____ and occurs before _____ begins

Answer 5

Progression phase of CKD involves accelerated nephron loss and occurs before dialysis begins

Question 6

Describe the clinical and pathologic stages in glomerulosclerosis

Answer 6

Clinical and pathologic stages in glomerulosclerosis

Question 7

The farther along in the progression of CKD, the more _____ the mechanism is across different conditions

Answer 7

The farther along in the progression of CKD, the more common the mechanism is across different conditions

Question 8

Disease occurs when ____ mechanisms or misapplied or applied excessively

Answer 8

Disease occurs when normal biological mechanisms or misapplied or applied excessively

Question 9

Why is the nephron highly vulnerable to injury?

Answer 9

Nephron is highly vulnerable to injury

• Concentrated toxins and metabolites
• Strong metabolic demands (transport)
• Highly vascular
• High-throughput filter
• Susceptible to inflammation

Question 10

Describe the model for chronic kidney disease

Answer 10

If repair process is insufficient or excessive, adaptation is required

Functional outcome

• Best-case scenario: perfect repair -> normal function
• Minor permanent damage: mild loss of function -> stable physiology
• Severe permanent damage: significant nephron loss -> temporary stabilized physiology, further response/repair cycles -> maladaptation

Question 11

Describe the cells contributing to renal scarring

Answer 11

Cells contributing to renal scarring

• Juxtaglomerular cells
• Macrophages
• Tubular cells
• Myofibroblasts
• Endothelial cells
• Pericytes

Question 12

_____ is a predictor of maladaptation

Answer 12

Previous AKI is a predictor of maladaptation

Question 13

Describe the Bricker hypothesis for pathogenesis of uremia

Answer 13

Bricker hypothesis for pathogenesis of uremia

• GFR stays normal at first but then decreases due to further nephron loss
• Phos remains normal for a while, so Ca does as well
• As Ca decreases, signals for PTH and FGF23 to rise, normalizing Ca and Phos: PTH and FGF23 rise with each cycle until they exceed ability to keep Phos from rising

Question 14

Describe the endocrinological factors in uremia

Answer 14

Endocrinological factors in uremia lead to nephron loss

• Effect of excess PTH and FGF23 on extra-renal systems: bone resorption, cardiovascular disease, pruritis, inflammation
• Effects on remaining nephrons: hyperfiltration, hypertrophy, and intraglomerular HTN

Question 15

Describe the cycle of progressive nephron loss

Answer 15

Question 16

Remnant hypertrophy occurs because ______

Answer 16

Remnant hypertrophy occurs because each nephron works harder to maintain homeostasis

• Rapid response (24 hours) to tissue loss
• Increased single neprhon GFR
• Critical for maintaining adequate renal function
• Major mediator: RAAS system
• Tubular response to maintain glomerulotubular balance
• Immediate benefit, long-term problem

Question 17

With nephron loss, perfusion of remaining nephrons ______

Answer 17

With nephron loss, perfusion of remaining nephrons increases

(want to prevent rise in ECF volume)

Question 18

Describe causes of increased blood pressure in CKD

Answer 18

Causes of increased blood pressure in CKD

• Sodium retention
• Renal ischemia
• Increased sympathetic tone
• Maintenance of glomerulotubular balance -> activation of NSAIDs

Question 19

Renin _____ single nephron GFR

Answer 19

Renin increases single nephron GFR

(if high renin, get sensitized to renin)

Question 20

Severity of disease correlates with degree of ______

Answer 20

Severity of disease correlates with degree of proteinuria

• In children, glomerular disease more rapid than tubulointerstitial disease
• In all patients, severity of proteinuria is proportional to rate of progression

Question 21

In glomerular disease, inhibition of TGF-beta signaling decreases _____ but not _____

Answer 21

In glomerular disease, inhibition of TGF-beta signaling decreases glomerulosclerosis but not proteinuria

(treatment to inhibit proteinuria also decreases glomerulosclerosis)

Question 22

Increased filtered load stimulates ______

Answer 22

Increased filtered load stimulates tubulointerstitial fibrosis

Question 23

Main function of the tubule is _____

Answer 23

Main function of the tubule is reclamation

(most in PCT, then TAL, then collecting duct)

Question 24

___ of filtrate is reabsorbed

Answer 24

99% of filtrate is reabsorbed

Question 25

Describe what occurs when nephrons are lost

Answer 25

When nephrons are lost

• Increased single nephron GFR
• Increased tubular reabsorption
• More energy and more oxygen consumption is required: renal oxygen extraction increases
• Loss of peritubular vessels worsens oxygen delivery

Question 26

Along with loss of nephrons, there is loss of _____ in CKD

Answer 26

Along with loss of nephrons, there is loss of vasculature in CKD

Question 27

In CKD, endothelial dysfunction uremia causes ______ by ______

Answer 27

In CKD, endothelial dysfunction uremia causes vasoconstriction by disturbing NO-mediated vasodilation

Question 28

Acid base balance in the kidney involves _____ and ______

Answer 28

Acid base balance in the kidney involves bicarbonate reabsorption and titratable acid excretion

Question 29

Describe acidosis in CKD

Answer 29

Acidosis in CKD

• Worsened by ischemia and anaerobic metabolism
• Bicarbonate feeding decreases renal tubular peroxide production and damage in CKD mice
• Bicarbonate supplementation slows CKD progression in humans even in abscence of defined acidosis

Question 30

Response to metabolic acidosis in CKD are _____ and _____

Answer 30

Response to metabolic acidosis in CKD are pro-inflammatory and pro-fibrotic

Question 31

____ generated in CKD cause disease by reacting with lipids and proteins to alter cell membranes and generate more free radicals

Answer 31

ROS generated in CKD cause disease by reacting with lipids and proteins to alter cell membranes and generate more free radicals

(uremia: carbamylated LDL promote oxidative stress in endothelial cells, ROS activity associated with HTN, tissue hypoxia causes local ROS generation)

Question 32

____ causes kidney fibrosis in CKD

Answer 32

Hypoxia-inducible factor causes kidney fibrosis

Question 33

In CKD, kidney tissue injury, response, and demise are _____

Answer 33

In CKD, kidney tissue injury, response, and demise are heterogeneous

(need to know where in disease course before treatment, many factors affect per-nephron load)

Question 35

Compensation for CKD has short-term _____ but _____ in long-term

Answer 35

Compensation for CKD has short-term benefits for total body homeostasis but accelerates loss of kidney function in long-term

(limit Na⁺ intake)