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B4W2 Flashcards

1
Q

Fasting blood glucose for Diabetic Kidney Disease Dx

A

> 126 mg/dL

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2
Q

Random blood glucose for DKD Dx

A

> 200 mg/dL

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3
Q

Hba1c for circulating Hb DKD dx

A

> 7.0%

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4
Q

Differentiate T1DM from T2DM

A

T1DM: (juvenile) auto immune attack on pancreatic B cells with complete loss of insulin production cells
T2DM: (adult onset) initial insulin resistance followed by failure of B cells in the pancreas for decreased insulin secretion

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5
Q

What would the GFR be of kidney disease

A

there would be a lowered GFR around < 60 mL/min (while the normal would be around 125 mL/min

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6
Q

albumin value for microalbuminuria

A

> 30 mg albumin/g creatinine in urine

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7
Q

How would you measure macroalbuminuria

A

> 300 mg albumin/g creatinine in urine

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8
Q

Clinical factors that are risk factors for DKD

A

race, genetics, obestiy, poor glycemic control, hypertension, other diabetic microvascular end organ complications (retinopathy/neuropathy)

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9
Q

DKD has slightly higher rates in ……

A

women

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10
Q

What can we see changing on kidney histology to diagnose ESRD

A

tubules (atrophy) and interstitial fibrosis

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11
Q

What are the three components of the glomerulus

A

podocytes, endothelial cells, mesangial cells

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12
Q

What are the histological changes in the mesangial cells in DKD

A

they secrete cytokines and growth factors which contribute to profibrotic conditions

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13
Q

What are the histological changes in the podocytes during ESRD

A

they have an increased thickened basement membrane, and disrupted foot processes

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14
Q

What are Kimmelstiel Wilson lesions

A

they increase mesangial matrix and cause damage by glycation of proteins - this causes arteriolar hyalionsis

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15
Q

What is arteriolar hyalinosis

A

Thickening of vessels via hyalin deposits

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16
Q

What are the 4 stages of progression of DKD

A
  1. hyperfiltration and GFR increase
  2. microalbuminuria
  3. macroalbuminuria
  4. increasing albuminuria leading to GFR decrease
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17
Q

As GFR ________, albumin excretion rate in the urine _________.

A

decreases, increases

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18
Q

What are some of the proposed pathological mechanisms of DKD

A

hemodynamic changes ( in HTN or hyperfiltration), hyperglycemia, inflammation, ROS toxicity, cellular senescence, ER stress, SGLT2 activity, impaired autophagy, Lipotoxicity

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19
Q

What are the two main factors that contribute to T1DM and T2DM in animal models respectively?

A

T1: SZN
T2: leptin mice

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20
Q

What is the mechanism of using SZN to induce diabetes

A

T1DM – (rats) it is injected via an intraperitoneal injection and it accelerates glomerular lesions to cause a decrease in GFR

(mice) mice need a second hit of SZN to allow for decrease in GFR

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21
Q

What was SZN used for, and what is it used for now

A

then: antibiotics (but induces diabetes)
now: inducing DM for animal models, and treating pts with insulinomas

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22
Q

What is leptin

A

satiety hormone that tell us we are full

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23
Q

How does KO of leptin lead to DM

A

continuing to eat, leads to obesity, DM and hyperlipidemia

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24
Q

What is the mechanism of leptin mice developing DM

A

obesity and hyperlipidemia leads to development of glomerular lesions, mesangial expansion and arteriolar hyalinosis

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25
What type of DM is KW seen in
T1DM
26
Leptin mice see ________ in GFR
no decline in GFR unless there is a 2nd hit
27
Explain hyperfiltration (beginning to end)
afferent arteriole dilation leads to ANG II release, ANG II activation leads to vasoconstriction of efferent arterioles, which increases P(gc) causing hyperfiltration and HTN -- HTN leads to leaky capillaries, an increase in mesangial cell ECM secretion and hypertrophy of vessels causing permanent damage
28
What are some of the growth factors/cytokines associated with DKD
ANGII, Transforming GF(Beta), endothelin, PDGF, Insluin like GF, tumor necrosis factor, IL-1
29
What are cytokines and GF role in DKD
They are normally expressed in the kidney but overexpression can lead to loss of control of renal matrix composition, cell hypertrophy, proliferation, modulation of cells of the immune cells and enzymes development in glucose metabolism
30
How are ACEi used with DM treatment
ACEi allow for a decrease in P(gc) which causes a reduction of GFR and reduced hyperfiltration
31
What is the study ACEi that allowed for a decrease in GFR
Enalapril
32
What are the two DKD pathophysiological pathways
TGF-beta DKD pathway Endothelin in DKD pathway
33
What is the TGF-beta DKD pathway
(transforming growth factor) is a profibrotic cytokine which stimulates the secretion of ECM proteins **there were only changes in TGFb in diabetic mice
34
What were mice treated with to go against the TGFbeta affects
monoclonal antibodies **humans do not have any results following mAB tx
35
What is the endothelin DKD pathway
potent vasoconstriction leads to profibrotic environment and stimulation of ROS. Additionally affects Na absorption (via ETA and ETB receptors)
36
How do ET Receptor antagonists aid in treatment of DKD
reduce albuminuria, but exacterbate peripheral edema and can lead to the development of CHF (due to increased Na retention)
37
What is the transport rate of SGLT2
1:1 transporter of Na/glucose on the apical membrane of PCT
38
How is SGLT 2 affected in DM
Because there is more glucose filtered, then there is an increase in SGLT2 activity which causes increased Na, decreasing macula densa Na conc., leading to the activation of the TGF, leading to afferent dilation, leading to efferent constriction, leading to hyperfiltration and glomerular HTN
39
How do we treat in regards to SGLT targeting
SGLT2 inhibition and GLP-1 agonist (which stimulate insulin release)
40
What are the effects of SGLT-2 KO mice in regards to hyperglycemia
observed to have lower blood glucose levels when compared to normal DM mice, and demonstrated higher glucosuria
41
What are the effects of SGLT-2 KO mice in regards to GFR and albuminuria
GFR : DM mice: high GFR and blood glucose leading to hyperfiltration KO mice: decrease in blood glucose leading to decrease in GFR Albuminuria: no difference
42
What are some of the failed treatment therapies (4)
1. Aminoguanidine (ACEi)(effective for proteinuria decrease, but no GFR decrease) 2. Vit B6 (prevents scarring, but not in humans) 3. Targeting ROS (PKC inhibitors) 4. Genetic treatment
43
Describe Lipotoxicity
-FATP2 is expressed in the PT and uptakes fatty acids -via GFB disruptions, glucose and FA react to link together and allow for albumin to travel into the cells -increase FA uptake leads to overload and cell death -pathogenesis
44
What happens in KO FATP2 mice
restoration of GFR
45
What are the current biomarkers for DKD diagnosis
eGFR, ACR (augmented renal clearance)
46
what are the values of biomarkers that would lead to an increased risk of DKD
ACR (30- >300) eGFR (15-45)
47
How does soluble TNF receptors work into pathogenesis
(soluble tumor necrosis factor) is an inflammatory cytokine which increases the risk of disease -- patients with high sTNF can be associated with high rates of ESRD
48
Treatments for DKD
glucose level monitoring, BP treatment, SGLT2 inhibitor, ACEi, ARB, GLP-1 receptor agonists
49
What is the goal of treatment for DKD
to lower the A1c to < 7%
50
Side effects of ACEi
dry cough, hyperkalemia
51
How does glucose monitoring treat DKD
strict glucose control can lead to less impairment of lesion development can decrease GFR changes, and chance of albuminuria
52
How does Blood pressure monitoring treat DKD
improves microvascular outcomes to lessen risk of hyperfiltration
53
How does SGLT2 inhibitors treat DKD
more beneficial for restoration of TGF than decreasing the Na/glucose transport
54
How does GLP-1 receptor agonists treat to DKD
stimulation of insulin at the pancreas to improve albuminuria but does not change GFR significantly
55
What is the mechanism of a GLP-1 agonist
- inhibits the NHE, stimulating TGF, to increase TGF, increasing arteriole tone, decreasing efferent tone, reducing P(gc), and reducing GFR to allow for less hyperfiltration
56
What was the conclusion of the MRFIT study
ESRD was greater in AA men then white men when age was adjusted
57
What was the conclusion of the JAMA study
HTN control leads to the slowing of progression of kidney disease but does not stop or eliminate it
58
What is the conclusion of kidney disease and family hx
biology contributes to kidney disease and those who have family with kidney disease have a higher rate of risk
59
What are the two variants of APOL-1 that lead to ESRD
APOL1-G1 and APOL1-G2
60
Where were APOL1 variants discovered
FSGS (focal segmental glomerulosclerosis) and HIV-ESRD (second hit)
61
How does APOL-1 circulate
via HDL cholesterol and normally protects against african sleeping sickness
62
if someone is heterozygous for APOL1 variant, vs someone who is homozygous, what are their respective protections against african sleeping sickness and risk of ESRD
heterozygous: protection against ASS, and has normal risk of ESRD homozygous: protection against ASS, elevated risk of ESRD
63
You have more risk for ESRD when you have _______ APOL-1 G mutations
two
64
Are APOL-1 genes powerful
yes. uncharacteristically powerful
65
Do APOL-1 levels change when there is ESRD
no. there is no change in level when ESRD is present
66
What is seen in the mouse model of ESRD and APOL-1
podocyte depletion
67
Does APOL-1 level or expression cause kidney disease
the expression of APOL-1 in the kidneys is what leads to disease
68
MOA of APOL-1 pathogenesis
APOL1 creates a pore like cation channel leading to Na and K entry into cells, leading to a loss of K, activation of stress kinases (JNK MAPK, P38 MAPK, ERK MAPK), increasing cytotoxicity
69
What is the best target for gene therapy when treating APOL1
VX-147 reduces proteinuria
70
What are the three types of genetic targeted therapies at this time and what do they target on the genome
1. CrispR (targets DNA to repair sequences and to interrupt gene) 2. Antisense RNA (targets RNA to reduce transcript abundance and prevent translation) 3. Small molecules (target APOL1 proteins to block channel formation, prevent oligomerization, and to alter transport)
70
What are the three types of genetic targeted therapies at this time and what do they target on the genome
1. CrispR (targets DNA to repair sequences and to interrupt gene) 2. Antisense RNA (targets RNA to reduce transcript abundance and prevent translation) 3. Small molecules (target APOL1 proteins to block channel formation, prevent oligomerization, and to alter transport)
71
How likely are African Americans to get HTN ESRD when compared to White American
2x more likely

Translational Physiology (8 decks)

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