SM_204a: CKD Pathophysiology Flashcards
Describe the pathomechanistic definition of CKD
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)
With decreases renal mass, nephron _____ progresses steadily
With decreases renal mass, nephron loss progresses steadily
The three pathomechanistic phases of CKD are _____, then _____, then _____
The three pathomechanistic phases of CKD are injury, then scarring, then progression
- Scarring: structural damage
- Progression: accelerated nephron loss, occurs before dialysis
Scarring phase of CKD involves ______
Scarring phase of CKD involves structural damage
Progression phase of CKD involves _____ and occurs before _____ begins
Progression phase of CKD involves accelerated nephron loss and occurs before dialysis begins
Describe the clinical and pathologic stages in glomerulosclerosis
Clinical and pathologic stages in glomerulosclerosis
The farther along in the progression of CKD, the more _____ the mechanism is across different conditions
The farther along in the progression of CKD, the more common the mechanism is across different conditions
Disease occurs when ____ mechanisms or misapplied or applied excessively
Disease occurs when normal biological mechanisms or misapplied or applied excessively
Why is the nephron highly vulnerable to injury?
Nephron is highly vulnerable to injury
- Concentrated toxins and metabolites
- Strong metabolic demands (transport)
- Highly vascular
- High-throughput filter
- Susceptible to inflammation
Describe the model for chronic kidney disease
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
Describe the cells contributing to renal scarring
Cells contributing to renal scarring
- Juxtaglomerular cells
- Macrophages
- Tubular cells
- Myofibroblasts
- Endothelial cells
- Pericytes
_____ is a predictor of maladaptation
Previous AKI is a predictor of maladaptation
Describe the Bricker hypothesis for pathogenesis of uremia
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
Describe the endocrinological factors in uremia
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
Describe the cycle of progressive nephron loss
Remnant hypertrophy occurs because ______
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
With nephron loss, perfusion of remaining nephrons ______
With nephron loss, perfusion of remaining nephrons increases
(want to prevent rise in ECF volume)
Describe causes of increased blood pressure in CKD
Causes of increased blood pressure in CKD
- Sodium retention
- Renal ischemia
- Increased sympathetic tone
- Maintenance of glomerulotubular balance -> activation of NSAIDs
Renin _____ single nephron GFR
Renin increases single nephron GFR
(if high renin, get sensitized to renin)
Severity of disease correlates with degree of ______
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
In glomerular disease, inhibition of TGF-beta signaling decreases _____ but not _____
In glomerular disease, inhibition of TGF-beta signaling decreases glomerulosclerosis but not proteinuria
(treatment to inhibit proteinuria also decreases glomerulosclerosis)
Increased filtered load stimulates ______
Increased filtered load stimulates tubulointerstitial fibrosis
Main function of the tubule is _____
Main function of the tubule is reclamation
(most in PCT, then TAL, then collecting duct)
___ of filtrate is reabsorbed
99% of filtrate is reabsorbed
Describe what occurs when nephrons are lost
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
Along with loss of nephrons, there is loss of _____ in CKD
Along with loss of nephrons, there is loss of vasculature in CKD
In CKD, endothelial dysfunction uremia causes ______ by ______
In CKD, endothelial dysfunction uremia causes vasoconstriction by disturbing NO-mediated vasodilation
Acid base balance in the kidney involves _____ and ______
Acid base balance in the kidney involves bicarbonate reabsorption and titratable acid excretion
Describe acidosis in CKD
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
Response to metabolic acidosis in CKD are _____ and _____
Response to metabolic acidosis in CKD are pro-inflammatory and pro-fibrotic
____ generated in CKD cause disease by reacting with lipids and proteins to alter cell membranes and generate more free radicals
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)
____ causes kidney fibrosis in CKD
Hypoxia-inducible factor causes kidney fibrosis
In CKD, kidney tissue injury, response, and demise are _____
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)
Compensation for CKD has short-term _____ but _____ in long-term
Compensation for CKD has short-term benefits for total body homeostasis but accelerates loss of kidney function in long-term
(limit Na+ intake)
