GFR & Renal Hemodynamics Flashcards
kidney morphology
*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)
renal plasma flow (RPF) - definition & formula
*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
renal blood flow - definition & formula
*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)
glomerular filtration rate (GFR) - definition
*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
filtration fraction - definition & formula
*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)
clearance - definition
*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
clearance equation
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)
clearance vs. GFR
*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
3 outcomes of the relationship between clearance (Cx) and 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
if clearance of substance X (Cx) < GFR…
net tubular reabsorption and/or not freely filtered
if clearance of substance X (Cx) > GFR…
net tubular secretion of X
if clearance of substance X (Cx) = GFR…
no net secretion or reabsorption
inulin clearance
*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
using inulin clearance to determine properties of other substances
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+)
techniques for measurement of renal blood flow & renal plasma flow
*electromagnetic flow meter (lab only)
*doppler / ultrasonic flow meter
*analysis of an appropriate marker
PAH clearance for estimating renal plasma flow
*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
effective renal plasma flow (ERPF)
*ERPF = clearance of PAH (Cpah) = Upah x V / Ppah
*true RPF = Cpah / 0.9
estimating renal blood flow (RBF) using cardiac output
*the kidneys tend to receive approximately 25% of the cardiac output, so we can estimate RBF by taking 25% of the known cardiac output
factors that affect GFR
- arteriolar resistance (afferent & efferent arterioles)
- forces across glomerular filtration barrier (oncotic & hydraulic forces)
relationship between arteriolar resistance & renal plasma flow (RPF)
*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
changes in RPF & GFR due to constriction of afferent arteriole
*decreased total RPF
*decreased GFR
*decreased Pgc (hydraulic pressure in glomerular capillary)
changes in RPF & GFR due to constriction of efferent arteriole
*decreased total RPF
*INCREASED GFR
*increased Pgc (hydraulic pressure in glomerular capillary)
3 systems for governing arteriolar resistance
- renin-angiotensin-aldosterone system (RAAS)
- autoregulation
- tubuloglomerular feedback
renin-angiotensin-aldosterone (RAAS) system - overview
*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
renin-angiotensin-aldosterone (RAAS) system - pathway
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
angiotensin II - 2 major effects
*Ang II has 2 major effects:
1. systemic vasoconstriction / constriction of efferent arteriole → increased GFR, decreased RPF
2. sodium & water retention
angiotensin II → Na+/water reabsorption
*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
angiotensin II - effects on GFR
*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
effects of NSAIDs on GFR in presence of Ang II
*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
autoregulation
*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)
tubuloglomerular feedback (TGF)
*macula densa cells sense increased NaCl delivery → signaling through the JG apparatus → afferent arteriole constriction → decreased GFR
*helps prevent excessive salt & water losses
glomerular filtration barrier - overview
*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
glomerular filtration barrier - CHARGE barrier
*contains negatively charged glycoproteins (heparan sulfate) in GBM that prevent entry of negatively charged molecules (ex. albumin)
*adhesion properties between layers
glomerular filtration barrier - components of the SIZE barrier
*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)
glomerular filtration barrier - results of the SIZE barrier
*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
4 components that determine whether a filtrate is formed
- Pgc = hydraulic pressure in glomerular capillary (pressure pushing across glomerular barrier from capillary into bowman’s space)
- Pbs = hydraulic pressure in bowman’s space (pressure pushing from bowman’s space backwards)
- Πp = oncotic pressure in plasma (pressure from proteins in the plasma that draws water across the semipermeable membrane)
- Πbs = oncotic pressure in bowman’s space (effectively ZERO)
glomerular filtration rate (GFR) - equation
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)
GFR in normal physiology
*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
examples of how the GFR can change based on changes in pressures
*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
intraglomerular hypertension (hyperfiltration)
*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
ACE inhibitors / ARBs in chronic kidney disease
*reduces angiotensin II effects
*helps dilate afferent & efferent arterioles, but more so the efferent
*reduces glomerular capillary hydraulic pressure
SGLT2 inhibitors in chronic kidney disease
*block sodium glucose transporter
*sends sodium to the macula densa
*may result in increased afferent constriction and long term decreased Pgc
plasma creatinine & GFR
*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
urine clearances for estimating GFR
*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
eGFR
*estimated GFR
*equations predict better at low GFR than at high GFR
cystatin C
*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
stages of CKD
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
what “equation” provides the best estimate of GFR
non-race based creatinine + cystatin C CKD-EPI eGFR equation
