SM 204 CKD Pathophysiology Flashcards
What is the endocrine function of the kidney?
Hematopoiesis (EPO)
How does the kidney relate to bone metabolism?
Calcium/Phosphorus reabsorption
Vitamin D Activation
What is the clinical definition of CKD?
Persistent loss of function, through four stages of varying severity which need intervention and may progress to end stage renal disease
What is the pathomechanistic definition of CKD?
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
What % of kidney function results in dialysis?
< 10% kidney function requires dialysis
Describe the progression to CKD in terms of kidney function (Creatinine levels) over time?
For most patients, kidney function falls linearly with time; however, there can be temporary increases in function with time as well
What are the 3 pathomechanistic phases of CKD and what do they represent?
The 3 phases are: injury, scarring, and progression
They represent the path taken by the kidney as it declines over time
Broadly speaking, how does the specificity and commonality of mechanisms involving CKD vary with time?
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
Why is CKD considered maladaptive?
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
What characteristics about the kidney make it susceptible to injury?
Highly vascular and strong metabolic demand
High throughput filter that concentrates toxins
Susceptible to inflammation
Describe the steps that broadly model CKD?
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
Which cells in the Kidney can contribute to renal injury/scarring?
All of them, including:
Juxtaglomerular cells Myofibroblasts Endothelial cells Macrophages Pericytes Tubular cells
Why does AKI predict CKD?
AKI predicts CKD because it can lead to damage/repair cycles that cause maladaptation
How does GFR stay normal during the development of uremia in CKD?
GFR stays normal during the initial phases of uremia in CKD due to compensation that increase the single nephron GFR
How do Phosphate and Calcium levels relate to the development of GFR and the development of uremia during CKD?
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
What effects does the continually declining GFR and induction of elevated PTH and FGF23 have on extra-renal systems?
PTH and GFR cause:
Elevated bone resorption
Cardiovascular disease
Pruritis
What effects do PTH and FGF23 have on the surviving nephrons in CKD?
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
What is remnant hypertrophy?
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
How does the total filtered load change during CKD?
For most of CKD, the total filtered load is normal and kidney function appears normal
How does the single nephron filtered load change during CKD?
Over the course of CKD, single nephron filtered load rises as surviving nephrons are forced to compensate for the nephrons that die
What is the cycle of nephron loss in CKD?
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
How does initial scarring in CKD setup hypoxia?
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
How long does remnant hypertrophy take to occur following a kidney injury?
Rapidly - 24 hours
What is the major mediator of remnant hypertrophy?
Remnant hypertrophy is controlled by the RAAS system
How does kidney function change after the initial stage of remnant hypertrophy?
Kidney function is normal initially, but declines over time
What happens when salt intake exceeds output?
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
What causes increased blood pressure in CKD?
Renal ischemia leads to increased sympathetic tone, activating RAAS and causing sodium retention, raising ECF and BP
How does renin increase single nephron GFR?
Renin causes RAAS activation = release Ang II
Ang II = contract efferent arteriole
Contracted efferent arteriole = Raise GFR
Why can high levels of renin release be maladaptive?
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
How does proteinuria relate to CKD?
Severity of proteinuria correlates with severity of CKD
How does the increased filtered load in CKD promote tubulointerstitial fibrosis?
Increased filtration of toxins = increased macrophage + cytokine + lipid recruitment = fibrosis via Mitogens and ECM proteins
Why does the kidney have a high oxygen demand?
Active transport mechanisms for a high perfusion
How does nephron loss increase the metabolic demand of the kidney?
Nephron loss causes:
Increased single nephron GFR
Increased tubular reabsorption per nephron
= more O2 demand
How does the renal vasculature change in CKD?
CKD is associated with a loss in renal vasculature?
How does uremia cause endothelial dysfunction?
Uremia disturbs NO-mediated vasodilation, causing vasoconstriction and further loss of nephron perfusion
How does acidosis effect CKD progress?
Acidosis is common in CKD and may be due to ischemia forcing anaerobic metabolism
Bicarbonate supplementation can slow CKD progression by relieving acidosis
Why does bicarbonate supplementation slow CKD progression?
Bicarbonate supplementation alleviates the acidosis that accompanies CKD, slowing CKD progression
What maladaptive response follows metabolic acidosis in CKD?
Activation of proinflammatory mediators
How does hypoxia cause ROS generation?
Hypoxia leads to mitochondrial dysfunction, which causes ROS accumulation
How do ROS cause disease?
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
What mediates hypoxic signal transduction in CKD?
HIF (Hypoxia Inducible Factor) leads to Fibrosis
Is kidney tissue injury in CKD homogenous?
No, injury and recovery cycles are heterogenous, so some portions of the kidney function better than others
How is increased single nephron GFR maintained in the kidney?
Increased single nephron GFR is maintained through increased circulation and intraglomerular blood pressure
