GFR & Renal Hemodynamics

Question 1

kidney morphology

Answer 1

*nephron = subunit of kidney
*1-1.3 million nephrons per kidney
*lengths of loops of Henle vary (short in the outer cortex, long in juxtamedullary)

Question 2

renal plasma flow (RPF) - definition & formula

Answer 2

*amount of plasma delivered to both kidneys per unit time
*RPF = (Upah x V) / Ppah
*normal = 625 ml/min

note - PAH (para-aminohippuric acid) clearance is used to estimate renal plasma flow b/c it is almost completely excreted by the kidney

Question 3

renal blood flow - definition & formula

Answer 3

*amount of blood delivered to both kidneys per unit time
*renal blood flow = RPF / (1 - hematocrit)
*normal = 1.2 L/min

note - RPF is renal plasma flow (calculated by: Upah x V / Ppah)

Question 4

glomerular filtration rate (GFR) - definition

Answer 4

*flow rate of filtered fluid through the kidneys (ml/min)
*normal = 125 ml/min
*helps us define and stratify loss of kidney function due to disease

Question 5

filtration fraction - definition & formula

Answer 5

*fiiltration fraction (FF) is the fraction of plasma that enters the kidney that is actually filtered
*filtration fraction = GFR / RPF
*normal = 20% (or 0.2)

Question 6

clearance - definition

Answer 6

*amount of plasma cleared of a substance per unit time (ml/min)
*any substance (including creatinine, urea, or infused substances such as inulin)
*can be an estimate of GFR
*creatinine clearance long used to define safe drug dosing for decreased kidney function

Question 7

clearance equation

Answer 7

Cx = (Ux x V) / Px

Cx: clearance of substance X (in mL/min)
Ux: urine concentration of substance X
V: urine flow rate → (urine volume / time)
Px: plasma concentration of substance X

recall: clearance is the volume of plasma completely cleared of a substance per unit time (unit = mL/min)

Question 8

clearance vs. GFR

Answer 8

*clearance is measuring the amount in the final product (urine)
*glomerular filtration rate (GFR) is measuring the flow rate of the filtrate
*clearance may be different from GFR

*if substance X is freely filtered at the glomerulus AND:
-unaltered in the tubules: Cx = GFR
-partially reabsorbed in the tubules: Cx < GFR
-secreted by the tubules: Cx > GFR

Question 9

3 outcomes of the relationship between clearance (Cx) and GFR

Answer 9

*if substance X is freely filtered at the glomerulus AND:
-unaltered in the tubules: Cx = GFR
-partially reabsorbed in the tubules: Cx < GFR
-secreted by the tubules: Cx > GFR

Question 10

if clearance of substance X (Cx) < GFR…

Answer 10

net tubular reabsorption and/or not freely filtered

Question 11

if clearance of substance X (Cx) > GFR…

Answer 11

net tubular secretion of X

Question 12

if clearance of substance X (Cx) = GFR…

Answer 12

no net secretion or reabsorption

Question 13

inulin clearance

Answer 13

*inulin = a fructose polymer
*inulin is freely filtered and is not secreted or reabsorbed in the tubules
*therefore, inulin clearance is good for estimating GFR

Question 14

using inulin clearance to determine properties of other substances

Answer 14

for any substance, X:
*Cx / Cinulin = 1, the Cx is a good estimate of GFR
*Cx / Cinulin > 1, then X is filtered and secreted in the tubules (ex. creatinine)
*Cx / Cinulin < 1, then either:
-substance is not freely filtered (ex. albumin)
-substance is filtered but then is reabsorbed in the tubule (ex. glucose, urea, amino acids, Na+)

Question 15

techniques for measurement of renal blood flow & renal plasma flow

Answer 15

*electromagnetic flow meter (lab only)
*doppler / ultrasonic flow meter
*analysis of an appropriate marker

Question 16

PAH clearance for estimating renal plasma flow

Answer 16

*para-aminohippuric acid (PAH)
*PAH clearance:
-freely filtered
-remainder leaving the glomerulus is completely secreted
-between filtration and secretion, 90% is cleared on the first pass through the kidneys
-clearance of PAH is thus good for estimating renal plasma flow

Question 17

effective renal plasma flow (ERPF)

Answer 17

*ERPF = clearance of PAH (Cpah) = Upah x V / Ppah

*true RPF = Cpah / 0.9

Question 18

estimating renal blood flow (RBF) using cardiac output

Answer 18

*the kidneys tend to receive approximately 25% of the cardiac output, so we can estimate RBF by taking 25% of the known cardiac output

Question 19

factors that affect GFR

Answer 19

1. arteriolar resistance (afferent & efferent arterioles)
2. forces across glomerular filtration barrier (oncotic & hydraulic forces)

Question 20

relationship between arteriolar resistance & renal plasma flow (RPF)

Answer 20

*changes in afferent and efferent arteriole diameter result in changes in overall RPF
*resistance to flow across arterioles = 85% of total vascular resistance
*peritubular capillaries & renal veins: remaining 15% of total vascular resistance

*constriction of afferent arteriole → decreased total RPF and decreases GFR
*constriction of efferent arteriole → decreased total RPF but increases GFR

Question 21

changes in RPF & GFR due to constriction of afferent arteriole

Answer 21

*decreased total RPF
*decreased GFR
*decreased Pgc (hydraulic pressure in glomerular capillary)

Question 22

changes in RPF & GFR due to constriction of efferent arteriole

Answer 22

*decreased total RPF
*INCREASED GFR
*increased Pgc (hydraulic pressure in glomerular capillary)

Question 23

3 systems for governing arteriolar resistance

Answer 23

1. renin-angiotensin-aldosterone system (RAAS)
2. autoregulation
3. tubuloglomerular feedback

Question 24

renin-angiotensin-aldosterone (RAAS) system - overview

Answer 24

*the afferent arteriole contains specialized juxtoglomerular (JG) cells:
-renin is stored & released from secretory granules

*stimuli for renin release:
1. renal hypoperfusion: hypotension or volume depletion
2. decreased NaCl delivery to macula densa
3. increased sympathetic activity

Question 25

renin-angiotensin-aldosterone (RAAS) system - pathway

Answer 25

hypotension / hypovolemia → renal hypoperfusion → decreased afferent arteriolar stretch, decreased NaCl delivery to macula densa, & increased sympathetic tone → **renin release** → conversion of angiotensinogen to Angiotensin I → conversion to Angiotensin II (by the ACE enzyme, located in lung, endothelium, and glomerulus) → 1. increased aldosterone secretion → increased renal Na+ reabsorption → extracellular volume expansion 2. increased systemic blood pressure

Question 26

angiotensin II - 2 major effects

Answer 26

*Ang II has 2 major effects: 1. systemic vasoconstriction / **constriction of efferent arteriole → increased GFR, decreased RPF** 2. sodium & water retention

Question 27

angiotensin II → Na+/water reabsorption

Answer 27

*2 mechanisms by which angiotensin II → Na+/water reabsorption: 1. direct stimulation of proximal tubule → **increased activity of Na+/H+ antiporter** 2. increased secretion of **aldosterone** from the adrenal cortex → enhances Na+ transport in the cortical collecting tubule

Question 28

angiotensin II - effects on GFR

Answer 28

*Ang II causes constriction of afferent & efferent arterioles, plus interlobular arteries *net effect: reduction in renal blood flow & maintenance (**increase) of GFR**, even if there is a drop in systemic BP note - vasoconstrictive effects of Ang II is balanced by vasodilatory **prostaglandins**, which preferentially **dilate the afferent arteriole**

Question 29

effects of NSAIDs on GFR in presence of Ang II

Answer 29

*NSAIDs inhibit production of prostaglandins *prostaglandins are usually helping to attenuate the vasoconstrictive effects of Ang II *in patients with high Ang II (such as very low salt intake), **NSAIDs cause an acute decline in GFR** (due to inability to vasodilate afferent arteriole) *note - NSAIDs produce minimal effects on renal function in normo-volemic subjects with low prostaglandin production

Question 30

autoregulation

Answer 30

*ability to keep GFR & RPF constant over a wide range of arterial pressures *myogenic stretch receptors in the afferent arteriole play an important role: -afferent arteriole constricts or dilates in response to stretch to keep intra-glomerular pressure stable *system is impaired below MAP of 70 mmHg (increased risk of acute kidney injury)

Question 31

tubuloglomerular feedback (TGF)

Answer 31

*macula densa cells sense increased NaCl delivery → signaling through the JG apparatus → afferent arteriole constriction → decreased GFR *helps prevent excessive salt & water losses

Question 32

glomerular filtration barrier - overview

Answer 32

*responsible for filtration of plasma according to size & charge selectivity (smaller & more cationic molecules more likely to be filtered) *3 layers: 1. fenestrated endothelial cell 2. glomerular basement membrane 3. epithelial cell (attached to the GBM by discrete foot processes) *pores between foot processes (**slit pores**) are closed by a slit diaphragm

Question 33

glomerular filtration barrier - CHARGE barrier

Answer 33

*contains **negatively charged glycoproteins (heparan sulfate) in GBM** that **prevent entry of negatively charged molecules** (ex. albumin) *adhesion properties between layers

Question 34

glomerular filtration barrier - components of the SIZE barrier

Answer 34

*combination of: 1. fenestrated capillary endothelium (prevents entry of large molecules & blood cells) 2. effective pore size in GBM 3. slit diaphragm in epithelium (prevents entry of medium-sized molecules)

Question 35

glomerular filtration barrier - results of the SIZE barrier

Answer 35

*allows passage of small molecules (sodium, urea) *solutes up to size of inulin (MW 5200) are freely filtered *myoglobin (MW 17000) less completely *albumin (MW 69000) should not be in the urine

Question 36

4 components that determine whether a filtrate is formed

Answer 36

1. Pgc = hydraulic pressure in glomerular capillary (pressure pushing across glomerular barrier from capillary into bowman's space) 2. Pbs = hydraulic pressure in bowman's space (pressure pushing from bowman's space backwards) 3. Πp = oncotic pressure in plasma (pressure from proteins in the plasma that draws water across the semipermeable membrane) 4. Πbs = oncotic pressure in bowman's space (effectively ZERO)

Question 37

glomerular filtration rate (GFR) - equation

Answer 37

GFR = Kf x (Pgc - Pbs - Πp) Kf: filtration coefficient Pgc: hydraulic pressure in glomerular capillary Pbs: hydraulic pressure in bowman's space Πp: oncotic pressure in plasma *changes in GFR result from: -anything that changes these values -change in renal plasma flow (RPF)

Question 38

GFR in normal physiology

Answer 38

*hydraulic pressures remain constant *capillary oncotic pressure progressively rises as we progress through the capillary bed due to filtration of protein-free fluid *gradient starts around 13 mmHg and falls to zero

Question 39

examples of how the GFR can change based on changes in pressures

Answer 39

*reduction in surface area available in glomerulonephritis → decreased GFR *increased Pbs in obstruction → decreased GFR *increased Πp in volume depletion → decreased GFR *increased Πp in multiple myeloma (high levels of Ig light chains) → decreased GFR *decreased Πp in nephrotic syndrome → increased GFR

Question 40

intraglomerular hypertension (hyperfiltration)

Answer 40

*starts with nephron loss (due to any kidney disease) *compensatory rise in filtration in other nephrons, driven by afferent dilation *plays a major role in diabetic nephropathy

Question 41

ACE inhibitors / ARBs in chronic kidney disease

Answer 41

*reduces angiotensin II effects *helps dilate afferent & efferent arterioles, but more so the efferent ***reduces glomerular capillary hydraulic pressure**

Question 42

SGLT2 inhibitors in chronic kidney disease

Answer 42

*block sodium glucose transporter *sends sodium to the macula densa *may result in increased afferent constriction and long term decreased Pgc

Question 43

plasma creatinine & GFR

Answer 43

***plasma creatinine should vary inversely (exponential) with GFR** (ex: creatinine 1.5 = GFR 67; creatinine 2 = GFR 50; creatinine 4 = GFR 25) *limitations: loss of nephrons leads to compensatory hyperfiltration; when GFR begins to fall, tubular secretion of creatinine increases *result: creatinine remains stable despite a drop in true GFR *a stable creatinine does not necessarily mean stable GFR

Question 44

urine clearances for estimating GFR

Answer 44

*inulin clearance is the gold standard for GFR measurement, but is only used in experiments due to expense & difficulty *another option: check 24 hour urine for expected creatinine excretion *urine creatinine clearance tends to OVERestimate GFR *urine urea clearance tends to UNDERestimate GFR *therefore, we can take the **average of creatinine clearance and urea clearance**

Question 45

eGFR

Answer 45

*estimated GFR *equations predict better at low GFR than at high GFR

Question 46

cystatin C

Answer 46

*low molecular weight protein produced by all nucleated cells *not altered in the tubules to a large extent *great for boosting accuracy of creatinine-based equations ***great for low muscle mass situations**

Question 47

stages of CKD

Answer 47

stage 1: eGFR 90+ (with other sign of kidney damage) stage 2: eGFR 60-89 stage 3a: eGFR 45-59 stage 3b: eGFR 30-44 stage 4: eGFR 15-29 stage 5: eGFR < 15 also - take into account albuminuria

Question 48

what "equation" provides the best estimate of GFR

Answer 48

non-race based creatinine + cystatin C CKD-EPI eGFR equation