SM 204 CKD Pathophysiology

Question 1

What is the endocrine function of the kidney?

Answer 1

Hematopoiesis (EPO)

Question 2

How does the kidney relate to bone metabolism?

Answer 2

Calcium/Phosphorus reabsorption

Vitamin D Activation

Question 3

What is the clinical definition of CKD?

Answer 3

Persistent loss of function, through four stages of varying severity which need intervention and may progress to end stage renal disease

Question 4

What is the pathomechanistic definition of CKD?

Answer 4

Persistent loss of function that invokes compensatory mechanisms to maintain homeostasis at a new steady state, which will eventually progress to end-stage renal disease

Question 5

What % of kidney function results in dialysis?

Answer 5

< 10% kidney function requires dialysis

Question 6

Describe the progression to CKD in terms of kidney function (Creatinine levels) over time?

Answer 6

For most patients, kidney function falls linearly with time; however, there can be temporary increases in function with time as well

Question 7

What are the 3 pathomechanistic phases of CKD and what do they represent?

Answer 7

The 3 phases are: injury, scarring, and progression

They represent the path taken by the kidney as it declines over time

Question 8

Broadly speaking, how does the specificity and commonality of mechanisms involving CKD vary with time?

Answer 8

Early in CKD, during the injury stages, mechanisms that give rise to CKD are very specific to each patient, based on his/her unique injury

Later in CKD, during the maladaptive stages, mechanisms that advance the CKD are common to all patients, regardless of their initial injury

Question 9

Why is CKD considered maladaptive?

Answer 9

Normally, the adaptations in CKD are beneficial and help maintain function in the short-run, but over time they fall apart and lead to disease

Question 10

What characteristics about the kidney make it susceptible to injury?

Answer 10

Highly vascular and strong metabolic demand
High throughput filter that concentrates toxins
Susceptible to inflammation

Question 11

Describe the steps that broadly model CKD?

Answer 11

Injury causes an initial response which results in a repair process
If the repair process is successful, return to health
If the repair process is unsuccessful, adaptation occurs
Adaptation results in a new steady state or abnormal physiology that leads to CKD

Question 12

Which cells in the Kidney can contribute to renal injury/scarring?

Answer 12

All of them, including:

Juxtaglomerular cells
Myofibroblasts
Endothelial cells
Macrophages
Pericytes
Tubular cells

Question 13

Why does AKI predict CKD?

Answer 13

AKI predicts CKD because it can lead to damage/repair cycles that cause maladaptation

Question 14

How does GFR stay normal during the development of uremia in CKD?

Answer 14

GFR stays normal during the initial phases of uremia in CKD due to compensation that increase the single nephron GFR

Question 15

How do Phosphate and Calcium levels relate to the development of GFR and the development of uremia during CKD?

Answer 15

As GFR falls, phosphate levels in the blood rise which lowers calcium levels in the blood

PTH and FGF23 are released and maintained at a higher level to lower phosphate and raise calcium

As GFR continues to fall, PTH and FGF23 levels are released and maintained at higher levels until eventually cells stop responding to them, Phosphate levels skyrocket and Calcium levels plummet

Question 16

What effects does the continually declining GFR and induction of elevated PTH and FGF23 have on extra-renal systems?

Answer 16

PTH and GFR cause:

Elevated bone resorption
Cardiovascular disease
Pruritis

Question 17

What effects do PTH and FGF23 have on the surviving nephrons in CKD?

Answer 17

After the initial injury results in the less of some nephrons, the surviving nephrons compensate by:

Hyperfiltration
Hypertrophy
Intraglomerular HTN

These lead to further injury and nephron loss

Question 18

What is remnant hypertrophy?

Answer 18

After an injury to the kidney, surviving neurons hypertrophy to compensate for those that were lost and maintain a steady state

Results in a higher single nephron filtered load for the surviving nephrons

Question 19

How does the total filtered load change during CKD?

Answer 19

For most of CKD, the total filtered load is normal and kidney function appears normal

Question 20

How does the single nephron filtered load change during CKD?

Answer 20

Over the course of CKD, single nephron filtered load rises as surviving nephrons are forced to compensate for the nephrons that die

Question 21

What is the cycle of nephron loss in CKD?

Answer 21

Injury = initial nephron loss
Surviving nephrons = remnant hypertrophy
Remnant nephrons = higher filtered load
Higher filtered load = increased tubular transport
Increased tubular transport = increased oxygen demand
Hypoxia ensues, causing more tissue loss

Question 22

How does initial scarring in CKD setup hypoxia?

Answer 22

Initial scarring typically results in the loss of blood supply to the nephron, which exacerbates hypoxia causes by the increased oxygen demand of surviving nephrons that undergo remnant hypertrophy to compensate

Question 23

How long does remnant hypertrophy take to occur following a kidney injury?

Answer 23

Rapidly - 24 hours

Question 24

What is the major mediator of remnant hypertrophy?

Answer 24

Remnant hypertrophy is controlled by the RAAS system

Question 25

How does kidney function change after the initial stage of remnant hypertrophy?

Answer 25

Kidney function is normal initially, but declines over time

Question 26

What happens when salt intake exceeds output?

Answer 26

Salt drives ECF volume expansion, which causes arteriolar vasodilation and lower Renal vascular resistance to promote salt excretion

Ultimately raises the GFR/nephron burden to maintain normal electrolyte levels

Question 27

What causes increased blood pressure in CKD?

Answer 27

Renal ischemia leads to increased sympathetic tone, activating RAAS and causing sodium retention, raising ECF and BP

Question 28

How does renin increase single nephron GFR?

Answer 28

Renin causes RAAS activation = release Ang II
Ang II = contract efferent arteriole
Contracted efferent arteriole = Raise GFR

Question 29

Why can high levels of renin release be maladaptive?

Answer 29

Normal levels of renin = normal Ang II levels which only contract the efferent arteriole = raise GFR = lower serum solute

Very high renin = very high Ang II levels = contract efferent and afferent arteriole = lower GFR = raise serum solute

Question 30

How does proteinuria relate to CKD?

Answer 30

Severity of proteinuria correlates with severity of CKD

Question 31

How does the increased filtered load in CKD promote tubulointerstitial fibrosis?

Answer 31

Increased filtration of toxins = increased macrophage + cytokine + lipid recruitment = fibrosis via Mitogens and ECM proteins

Question 32

Why does the kidney have a high oxygen demand?

Answer 32

Active transport mechanisms for a high perfusion

Question 33

How does nephron loss increase the metabolic demand of the kidney?

Answer 33

Nephron loss causes:

Increased single nephron GFR
Increased tubular reabsorption per nephron
= more O2 demand

Question 34

How does the renal vasculature change in CKD?

Answer 34

CKD is associated with a loss in renal vasculature?

Question 35

How does uremia cause endothelial dysfunction?

Answer 35

Uremia disturbs NO-mediated vasodilation, causing vasoconstriction and further loss of nephron perfusion

Question 36

How does acidosis effect CKD progress?

Answer 36

Acidosis is common in CKD and may be due to ischemia forcing anaerobic metabolism

Bicarbonate supplementation can slow CKD progression by relieving acidosis

Question 37

Why does bicarbonate supplementation slow CKD progression?

Answer 37

Bicarbonate supplementation alleviates the acidosis that accompanies CKD, slowing CKD progression

Question 38

What maladaptive response follows metabolic acidosis in CKD?

Answer 38

Activation of proinflammatory mediators

Question 39

How does hypoxia cause ROS generation?

Answer 39

Hypoxia leads to mitochondrial dysfunction, which causes ROS accumulation

Question 40

How do ROS cause disease?

Answer 40

At low concentrations, ROS act as a signaling molecule, but at higher concentrations, ROS have off-target oxidizing effects and can even produce more ROS

Question 41

What mediates hypoxic signal transduction in CKD?

Answer 41

HIF (Hypoxia Inducible Factor) leads to Fibrosis

Question 42

Is kidney tissue injury in CKD homogenous?

Answer 42

No, injury and recovery cycles are heterogenous, so some portions of the kidney function better than others

Question 43

How is increased single nephron GFR maintained in the kidney?

Answer 43

Increased single nephron GFR is maintained through increased circulation and intraglomerular blood pressure