SM 204a/206a - CKD, CKD Clinical Flashcards
Describe the cycle of progressive nephron loss
- Initial nephron loss
- Hypertrophy of remaining nephrons
- Increased filtered load for the remaining nephrons
- May lead to scarring
- Increased tubular transport work, increased O2 utilization of these nephrons
- May lead to tissue hypoxia
- Cascade of acidosis, ROS generation, cellular stress, inflammation
- Leads to fibrosis and further nephron loss
How does increased tubular transport demand lead to nephron loss?
More tubular transport = increased metabolic demand
- More energy, oxygen consumption is required
- Can lead to hypoxia and endothelial dysfunction if perfusion cannot keep up
- It is hard for perfusion to keep up because an individual cell will have such high oxygen demand – diffusion may be maxed out even if blood flow is normal
- Uremia can cause vasoconstriction, decreasing blood flow
- -> further damage, apoptosis, loss of perfusion
- This can eventually cause nephron loss :(
What factors contribute to increased BP in CKD?
- Na+ retention
- Renal ischemia
- Increased sympathetic tone
- Maintenenance of glomerulotubular balance through activation of RAAS
ESRD disproportionally affects people of __________, __________, and __________ descent
ESRD disproportionally affects people of, Hispanic** , **African American** and **Native American descent
What aspects of diet are problematic for patients with CKD?
- Potassium
- Phosphorous
- Sodium
- Water
- Protein
If GFR is decreased, kidneys cannot clear whatever is extra or unnecessary
(Pepole with normal kidneys can adjust to increases and decreases in these nutrients)
In response to renal injury, the remaining nephrons increase their function by which of the following?
A. Increasing single-nephron GFR
B. Producing parathyroid hormone
C. Undergoing apoptosis
D. Producing coagulation factors
E. Decreasing total renal blood flow
A. Increasing single-nephron GFR
The following patient is at greatest risk for progression of their chronic kidney disease
- 35 year old male with a history of membranous nephropathy with an MDRD eGFR of 55ml/min/ 1.73m2 and 7 grams of protein on two 24 hour urine collections.
- 45 year old female with a history of IgA nephropathy and MDRD eGFR of 40 ml/min/1.73m2 and less than <30 mg of protein on two 24 hour urine collections.
- 60 year old male with a history of heart failure with MDRD eGFR of 50 ml/min/ 1.73m2 and 300 mg of protein on two 24 hour urine collections.
- 35 year old male who has a creatinine increase from 1.0 mg/dl (MDRD eGFR 90 ml/min/1.73m2) baseline to 1.9 mg/dl after a gastrointestinal illness who has now fully recovered from his illness.
a.
35 year old male with a history of membranous nephropathy with an MDRD eGFR of 55ml/min/ 1.73m2 and 7 grams of protein on two 24 hour urine collections.
Proteinuria = predictor of CKD progression
What is the Bricker hypothesis?
A hypothesis to explain the pathogenesis of uremia
- When you first begin to lose nephrons, GFR is fine
- As nephrons decrease, GFR decreases
- Phosphorous and Ca2+ remain normal until ~60% of nephrons remain (GFR is continuing to decline)
- Initial drop in Ca2+, increase in phosphorous
- > increase in PTH, FGF-23
- > Ca2+ and phosphorous return to normal
- However, as you continue to lose nephrons, it takes a larger and larger increase in PTH to try to normalize Ca2+ and phosphorous
- Eventually, you max out the body’s response to PTH, and it can no longer normalize Ca2+ and phosphorous
- Eventually, dialysis is necessary
What defines “rapid” progression of CKD?
Sustained decline in eGFR of more than 5 ml/min/yr
What is the major mediator of nephron hypertrophy?
RAAs system
- Works to increase GFR of nephrons that neighbor damaged nephrons
- Critical for maintaining adequate renal function
- Leads to a tubular response to maintain glomerulotubular balance
-
-> Immediate benefit, but long term problem
- Benefit = maintained function
- Long term problem = scarring
Which patients with stage 3 CKD are most likely to develop stage 4 or 5 CKD?
Patients with higher degrees of proteinuria
Even if GFR is mild to moderately decreased, severe proteinuria predicts progression of CKD
Why is IV iron important for the treatment of CKD?
Patients with CKD have reduced iron absorption and recycling, plus blood loss due to dialysis
(Reduced absorption and reycling due to buildup of hepcidin, which inhibits ferroportin)
Why is RAAs inhibition useful in the treatment of diabetic nephropathy?
Early stage renal disease is characterized by hyperfiltration due to increased glucose load
Initially, this is adaptive but eventually leads to hypertrophy and damage
Blocking RAAs decreases hyperfiltration and reduces the negative effects of angiotensin II, which leads to better outcomes for patients with diabetic nephropathy
What is the role of atriovenous fistula in patients on hemodialysis?
Removes need for catheter
Arteriolizes a vein so it can be used for dialysis
What is the role of ferroportin in iron homeostasis?
Ferroportin is a protein channel through which iron gets from cells to blood
- Gets iron from the enterocyte to the blood
- After intestinal reabsorption
- Releases iron from the macrophages in the spleen
- After RBC breakdown
If ferroportin is inhibited, how is iron homeostasis effected?
Iron cannot be reabsorbed in the intestine or recycled in the spleen
- Cannot be released from the enterocytes (intestine) or macrophages (spleen)
This leads to low iron in the blood
Which patient with Stage 3 CKD is at a higher risk of progression to ESRD?
- Patient A
- GFR = 55 mL/min (mildy to moderately decreased)
- Albuminuria >30 mg/mmol (severely increased)
- Patient B
- GFR = 45 mL/min (moderately to severly decreased)
- Albuminemia <3 mg/mmol (mildly increased)
Patient A is at a higher risk
Even though their GFR is better, their severe albuminuria (proteinuria) indicates a high risk of progression to CKD
What is the mechanism of SGLT2 inhibitors?
Where do they act?
Which patients will benefit most from them?
SGLT2 inhibitors block Na+ and glucose absorption in the proximal tubule
This increases solute delivery to the macula densa
- -> Downregulation of RAAS
- -> Less Angiotensin II
- -> Less efferent arteriolar vasoconstriction
- -> Prevents intra-glomerular hypertension
- -> Decreased Na+ uptake along the rest of the tubule
- -> Decreased filtration
What is the effect of Renin on single-nephron GFR?
Renin release leads to…
- Angiotensin II synthesis
- Efferent arteriole vasoconstriction
- -> Increased single nephron GFR
For a patient with ESRD…
What is the 5-year survival rate on dialysis?
What is the 5-year survival rate with transplant?
Dialysis: <40%
Transplant: 85-90%
Which cells of the kidney contribute to renal scarring?
All of them!
Any one of the kidney cells can activate the others, leading to the production of scar tissue
- Juxtaglomerular cells
- Macrophages
- Inflammatory mediators, proteases, procoagulants
- Tubular cells
- Antigen-presentation, apoptosis, profibrotic cytokines
- Endothelial cells
- Apoptosis, procoagulants, end-MT
- Pericytes
- May differentiate into fibroblasts
Potential steps to improve renal function or delay progression in CKD include which of the following interventions:
A. Blood pressure reduction
B. Smoking cessation
C. A low-sodium diet
D. Restricted protein intake
E. Correction of acidosis
All of the above
How does metabolic acidosis contribute to the progression of CKD?
CKD = decreased ability to secrete acid
- -> Decreased interstitial and intracellular pH
- -> Increased ammoniagenesis
- Via ET-1 and RAAS production
- Adaptive response
- Tubular hypotrophy, increased active transport
- -> Increased acid secretion
-
Maladaptive response
- Activation of complement
- Proinflammatory and profibrotic mediators
- -> Tubular interstitial injury and fibrosis
- -> Loss of functioning nephrons
- -> CKD progression
- -> Worse acid retention
- Activation of complement
Donald E. Wesson et al. JASN 2020;31:469-482
What are the criteria for diagnosing CKD?
- Abnormal GFR
- Usually demonstrated by a higher than normal serum creatinine
- Abnormal for ≥ 3 months
- Abnormal urinalysis
- Proteinuria or hematuria
- Abnormal for ≥ 3 months
- Structural abnormality
- Cystic kidney disease
- Congenital solitary kidney
How does peritoneal dialysis work?
- Peritoneal membrane and its capillary network acts as a filter
- Pump dialysis fluid into the cavity
- Waste diffuses into fluid
- Fluid and waste are drained out
- This can be done at home, and needs to be done every day (usually at night while the patient sleeps)
Therapy to slow or delay the progression of chronic kidney disease includes…
- Treatment with phosphate binders to lower phosphate to below normal range to prevent vascular calcification
- Treatment with fluids and albumin to improve hemodynamics
- Treatment with sodium/glucose cotransporter 2 inhibitors in patients with an eGFR of 45 ml/min/1.73m2
- Treatment with erythropoietin to keep hemoglobin 14 mg/dl
- Treatment of secondary hyperparathyroidism with parathyroidectomy
c. Treatment with sodium/glucose cotransporter 2 inhibitors in patients with an eGFR of 45 ml/min/1.73m2
Other treatments may protect against complications, but will not slow progression
On reviewing monthly labs on a patient on hemodialysis, you notice that his serum potassium value is 6.5 mg/dl (elevated). He tells you that he ate at an all-you-can-eat breakfast.
Which of the following is least likely to contribute to his hyperkalemia?
a. Fruit bowl with mangos, bananas, and oranges
b. Apple Juice
c. Oatmeal with raisins
d. Breakfast potatoes
b. Apple Juice
What is the role of bicarbonate therapy in the management of CKD?
Bicarbonate therapy to treat metabolic acidosis can slow the progression of CKD
- Beneficial even if acidosis is not apparent
- Improves GFR
What factors cause the generation of ROS in CKD?
What are the consequences?
- Uremia -> oxidative stress
- Hypertension
- Tissue hypoxia
- TBG-beta
- Angiotensin
- Macrophages
ROS at low concentrations act as signaling molecules
Moderate concentration: off-target signaling effects
High concentration: Reacting with lipids and proteins to alter cell membrane and generate more ROS
-> Cell damage :(
What factors can increase a person’s per-nephron load?
What are the consequences?
- Low birth weight
- Prematurity
- Obesity
- Hypertension
- History of AKI
- Anemia
All of these thing increase the filtrate load of each nephron
- > Hypertrophy because the tubular cells must work harder
- > Risk of hypoxia -> cell death -> nephron loss
- > Even further increased load for surrounding nephrons
What is the role of bicarbonate in patients with CKD?
Giving bicarbonate slows CKD progression in humans even in the absence of defined acidosis
- Patients with CKD are prone to acidosis
- Exacerbated by ischemia and anerobic metabolism
- Bicarbonate can prevent these things from developing?
What are the acute (emergent) indications for starting dialysis?
AEIOU
- Acidosis
- Electrolytes (Hyperkalemia)
- Ingestions (Lithium, ASA)
- Overload (Volume overload)
- Uremia
- Nutrition (in pediatrics)
Usually dialysis is not started unless the patient is in distress/discomfort/generally is not doing well
Where is most of the phosphorous in your body stored?
Bone
When serum phosphate levels start to rise, we know that CKD is advanced.
Why?
At earlier stages of CKD, the body can upregulate phosphate excretion (via increased PTH) so that phosphate levels remain low, despite decreased GFR
CKD -> Increase in FGF-23
- Calcitriol (1,25-hydroxy-D3) production decrease
- -> Lower Ca2+
- -> PTH secretion increases
- -> Ca2+ levels recover
- Phosphate levels increase (due to decreased clearance)
- -> Increased PTH and FGF-23
- -> Phosphaturia to restore phosphate levels
This is known as the Bricker hypothesis
Eventually, PTH will “max out” and it will no longer be able to keep serum phosphate low - This is how we know CKD is really bad at this point
What is the effect of increased filtered load on the kidney?
Increased filtered load
-> Hypertrophy due to a tubular response
The tubule must work harder to reabsorb and secrete things
This causes the release of…
- Inflammatory mediators
- Proteases
- Cytotoxic agents
- Mitogens
- ECM proteins
- ECM protease inhibitors
Eventually, this can lead to nephron loss
-> Neighboring nephrons increase GFR -> cycle continues
Why do we get increased filtration in early-stage diabetic renal disease?
Diabetes
- -> Increased glucose load
- -> More SGLT2 channels = increased Na+ and glucose absorption in the proximal tubule
- -> less Na+ delivery to macula densa
- -> less Adenosine released
- -> Afferent vasodilation
- Macula densa mediates increased filtration
- -> Intraglomerular hypertension, increased filtration
SGLT2 inhibitors prevent afferent vasodilation and efferent vasoconstriction, thus reducing hyperfiltration and reducing intraglomerular hypertension
What are the three pathomechanism phases of CKD?
Injury
Scarring (structural damage)
Progression (accelerated nephron loss)
What is the first alteration in mineral metabolism in CKD?
Increased FGF-23
- > Decline in 1,25-hydroxy-D3 production
- > Stimulates PTH secretion (Secondary hyperparathyroidism)
- > Phosphate excretion
When phosphate levels begin to rise, effect of PTH has maxed out
FGF-23 is adaptive early in CKD, but eventually leads to systemic problems like heart failure (cardiac remodeling)
Why are patients with CKD at increased risk of free iron deficiency?
CKD = buildup of hepcidin
Hepcidin inhibits ferroportin, a protein necessary for iron reabsorption and recycling
CKD -> Hepcidin -> Decreased free iron
(Ferroportin is the channel through which iron is released from enterocytes and macrophages)
Hyperfiltration is most likely to occur in which CKD?
Diabetic kidney disease
What are the treatment goals for each stage of CKD?
- Early stages (1 -3)
- Slow progression
- CVD risk reduction
- Stage 4
- Symptom control
- Preparation for renal replacement therapy
- Arteriovenous fistula procedure
- Evaluate for placement on the transplant list
- Stage 5 (GFR < 15)
- Renal replacement therapy
The main reason that the renal tubule in progressive chronic kidney disease is rendered susceptible to hypoxic injury is:
A. Circulating toxins
B. Albumin sensitivity
C. Increased per-nephron transport activity
D. Erythrocytosis
E. Cigarette smoking
C. Increased per-nephron transport activity
At what stage of CKD do patients begin to have trouble controlling electrolyte levels and micronutrients
Advanced CKD
Stage 3b and beyond (GFR <40 mL/min)
Why is calcitriol used to treat hyperparathyroidism?
Calcitriol = 1,25-hydroxy-D3 = active vitamin D3
It is produces by the kidneys
Patients with CKD have reduced calcitriol production, which leads to decreased calcium reabsorption, which leads to PTH secretion
Supplementing with calcitriol can help to restore mineral balance, and reduce PTH secretion
Decreased PTH -> decreased FGF-23
Lower FGF-23 protects the heart from CVD
Why does PTH increased as CKD progresses?
As kidney function declines, FGF-23 increases
This leads to…
- Calcitriol (1,25-hydroxy-D3) production decrease
- -> Lower Ca2+
- -> PTH secretion increases
- -> Ca2+ levels recover
- Phosphate levels increase (due to decreased clearance)
- -> Increased PTH and FGF-23
- -> Phosphaturia to restore phosphate levels
This is known as the Bricker hypothesis
Eventually, PTH will “max out” and it will no longer be able to increase Ca2+ and lower phsophate - this is bad
(nobody knows why)
What is the ideal form of renal replacement therapy?
Transplant
What defines chronic kidney disease?
Kidney damage for ≥ 3 months
OR
GFR <60 mL/min for ≥ 3 months
=> Can have CKD without GFR <60 mL/min
What is hepcidin?
How does it affect iron homeostasis?
Hepcidin is a hormone that builds up in patients wtih CKD due to reduced renal clearance
- Hepcidin causes internalization of ferroportin
- Ferroportin is necessary for absorption and recycling of Iron
- Patients with CKD are at risk for free iron deficiency due to build up of hepcidin
What are the leading causes of End-Stage Renal Disease (ESRD)?
Diabetes
Hypertension
Glomerulonephritis
Cystic/hereditary congenital disease
