CKD: Pathophysiology & Nephroprotective Agent Pharmacology

CKD can be defined as having kidney damage for greater than _____ months, as defined by a _______ or ________ abnormality of the kidney, with or without decreased __________

3, structural, functional, GFR

There are two ways for CKD to manifest:

1) evidence of kidney damage. What would this look like?

2) GFR less than ______ for 3 months. With or without kidney damage.

abnormal biopsy or albuminuria; 60

A patient in the GFR category of G1 would have a GFR of _________. This illustrates a __________ to ___________ GFR

greater than 90; normal to high

A patient in the GFR category of G2 would have GFR of _______ to _______. This illustrates a ________ GFR

60-89; mildly decreased

A patient in the GFR category of G3a would have a GFR of ______ to _____. This illustrates a ______ to _______ GFR.

45-59; mild to moderately decreased

A patient in the GFR category of 3Gb would have a GFR of ______ to ______. This illustrates a ______ GFR.

30-44; moderately decreased

A patient in the GFR category of G4 would have a GFR of _____ to ______. This illustrates a _______ GFR

15-29; severely decreased

A patient in the GFR category of G5 would have a GFR of less than _______ or need _______. This illustrates ___________

15; dialysis; end-stage renal disease/kidney failure

Starting in which GFR category would renal adjustments need to be made?

starting in G3a (going through G5)

True or false: CKD can also be staged based on urine output

false; albuminuria

What is ACR? What is it also known as?

albumin to creatine ratio (spot urine sample)

What is AER? What is it also known as?

albumin excretion rate (24 hour urine collection)

A patient in the category A1 would have an ACR of _______. This illustrates ________ albuminuria.

less than 30; normal to mildly increased

A patient in the category A2 would have a ACR of ______ to _____. This illustrates ___________.

30-300; microalbuminuria

A patient in the category A3 would have an ACR of _______. This illustrates _______.

greater than 300; macroalbuminuria

True or false: AER uses the same parameters as ACR

true

What are some risk factors that can make a patient susceptible to CKD?

advanced age, african american, low income, low birth weight, CKD family history, inflammation, dyslipidemia

What are the top two risk factors for the initiation of CKD?

diabetes and HTN

What are some risk factors for the progression of CKD?

uncontrolled glucose, uncontrolled BP, proteinuria, hyperlipidemia, smoking, obesity, AKI

What percent of adults (aged 20 and older) have CKD in the United States?

15%

A 51 year old man with an eGFR of 37 ml/min/1.73m2 and an albumin to creatinine ration of 27.3 mg/g would be classified as what albuminuria and KDIGO category of CKD?

3a; A1
3a; A2
3b; A1
3b; A2

3b; A1

JT, a 67 YO male (5'7 and 65kg) has a history of type II DM. He drinks alcohol everyday, and smokes half a pack per day. His medications included metformin 500 mg BID as well as a multivitamin.

BP: 152/94
A1c: 7.8
eGFR: 50 ml/min
Scr: 4 mg/dL


What is his eCrCl? Which current condition can contribute to a decline in JT's kidney function?


- smoking
- advanced age
- elevated BP
- alcohol intake
- A&C

16; smoking and elevated BP

What is uremia? What lab parameter will be affected by this?

the retention of waste products due to decreased renal function; BUN will increase

Patients are often asymptomatic until which stage of CKD?

4 and 5

What are some symptoms that manifest in stages 4 and 5 of CKD?

fatigue, SOB, weakness, abnormal bleeding, loss of appetite, cold intolerance

What are some signs that manifest in stages 4 and 5 of CKD?

edema, weight gain, bubbly urine (proteinuria), abdominal distension

Which lab values would be elevated in CKD?

phosphate
eGFR
Scr
hemaglobin
bicarb
BUN
K
albumin

phosphate, Scr, BUN, K,

which lab values would be decreased in CKD?

phosphate
eGFR
Scr
hemaglobin
bicarb
BUN
K
albumin

hemaglobin, bicarb, albumin

Which of the following is not associated with the pathogenesis of CKD?

- increased glomerular permeability
- hyperfiltration at glomerulus
- tubulointersitital fibrosis
- hydronephrosis
- activation of RAAS

hydronephrosis

Explain how increased glomerular permeability and hyperfiltration at the glomerulus can contribute to the pathogenesis of CKD

Nephrons are the filtering units of the kidneys. When nephrons become damaged, healthy ones have to compensate in order to maintain about the normal GFR. When healthy nephrons compensate, they often become more porous- this allows proteins and other things that aren't normally found in the urine to be excreted

Explain how tubulointerstitial fibrosis can contribute to the pathogenesis of CKD

as CKD progresses there tends to be an accumulation of extracellular matrix proteins- also known as fibrosis. Fibrosis disrupts tubular function and reduces blood flow to the nephrons. This is a hallmark sign of advanced kidney damage

Explain how the activation of RAAS can contribute to the pathogenesis of CKD

In CKD there is typically reduced blood flow, and increased sodium delivery to the distal tubules of the nephron. This detection causes the RAAS system to kick in and increase blood pressure. Increased blood pressure in kidneys that are already experiencing damage can cause further inflammation and fibrosis.

What are goals of CKD management?

slow progression, prevent a CV event, and need for dialysis

What kind of change signifies progression in CKD?

- change in GFR category (such as G3a and G3b)
- drop in GFR category and greater than 25% drop in GFR
- sustained GFR drop (greater than 5 in a year)

change in GFR category (G3a to G3b)

What kind of change signifies a "certain drop" in CKD?

- change in GFR category (such as G3a and G3b)
- drop in GFR category and greater than 25% drop in GFR
- sustained GFR drop (greater than 5 in a year)

drop in GFR category and greater than 25% in GFR

What kind of change signifies "rapid progression"

- change in GFR category (such as G3a and G3b)
- drop in GFR category and greater than 25% drop in GFR
- sustained GFR drop (greater than 5 in a year)

sustained GFR drop (greater than 5 in one year)

What are three nephroprotective drugs?

ACEs/ARBs, SGLT2 Inhibitors, and finerenone

Why are ACEs and ARBS are considered to be nephroprotective?

What arteriole do they work on?

they decrease blood pressure. Therefore it will decrease glomerular capillary pressure, GFR, and albuminuria

dilate the efferent arteriole (this will decrease GFR and allow blood to exit the kidneys)

______________ (overstimulation/understimulatio) of mineralocorticoid receptors will lead to an increase in reactive oxygen species and cause inflammation/fibrosis- which lead to damage and progression of CKD

overstimulation

What drug class does finerenone belong to?

non-steroidal selective MRA

Explain the MOA of finerenone and why it is considered to be nephroprotective?

aldosterone is a hormone that likes to bind to mineralocorticoid receptors and causes the retention of sodium and water- this increases the BP. Increased blood pressure can be damaging to the kidneys. Finerenone binds to the mineralocorticoid sites and prevents overactivation. Without overactivation, sodium isn't retained and reduces fibrosis and inflammation in the kidneys

Spironolactone and eplerenone are drugs that work similarly to finerenone. Why is finerenone preferred?

It is both potent and selective (remember that spironolactone is non-selective and has a more harmful side effect profile). It also interferes with cofactor binding!!

In the use of finerenone, what electrolyte should we watch closely?

potassium; since sodium is being excreted it will stay inside the cell

What region of the nephron are sodium-glucose cotransporters located in?

proximal convoluted tubule

How does the sodium-glucose transporter move glucose?

against the concentration gradient; it gets energy from the movement of Na from the lumen to the inside of the cell

What is the MOA of SGLT2 Inhibitors?

blocks transport of glucose in the PCT (so that it can't enter into cells) and promotes it to be lost in the urine

Why are SGLT2 Inhibitors considered to be nephroprotective?

Promotes natiuresis as well as glycosuria (the excretion of sodium prevents sodium and water retention that would increase BP)

In the use of SGLT2 inhibitors what is the goal reduction of HbA1C?

0.7-1%

In the use of SGLT2 inhibitors, what is the goal for weight reduction?

2-4 kg

In the use of SGLT2 inhibitors, what is the goal for blood pressure reduction?

2-4 mmHg

What are some adverse effects of SGLT2 Inhibitors?

genital fungal infefctions, AKI, hypovolemia, hypotension, diabetic ketoacidosis