Physiology: Glomerular Filtration & Renal Blood Flow

Front 1

Sagittal and Coronal sections of renal anatomy:

Back 1

Front 2

Renal Anatomy and Microcirculation:

Back 2

Front 3

Anatomy of The Nephron and Renal Microcirculation:

Back 3

*Note two types.
*Two capillary networks in series with each other: the glomerular capillary network followed by the peritubular capillary network.

Front 4

Segments of the nephron:

Back 4

Front 5

What drives glomerular filtration?

Back 5

*Starling forces!

Front 6

What are Starling forces?

Back 6

*Forces that drive the ultrafiltration of fluid across a capillary wall.
*Forces that FAVOR filtration across a capillary wall.

Front 7

How do you calculate the single nephron GFR?

Back 7

*Single nephron GFR is forces FAVORing filtration minus forces OPPOSING filtration multiplied by an ultrafiltration coefficient representing permeability traits and surface area of a particular capillary.
*Reduces!

Front 8

SNGFR calculation with real life numbers:

Back 8

Front 9

Where is hydrostatic pressure the highest in the nephron?

Where is colloid π the highest?

Back 9

*In renal artery, hydrostatic pressure = BP. Big pressure drop at afferent and efferent arterioles. GLOMERULAR CAPILLARY FORCES FAVOR FILTRATION.
*π rises once you've passed into the peritubular capillary network. These are more favorable forces for REABSORBING SALT AND WATER. PERITUBULAR CAPILLARY FORCES FAVOR REABSORPTION.

Front 10

What's the consequence of opposing forces in the glomerular and peritubular capillaries?

Back 10

Front 11

What is The Filtration Fraction?

What happens if GFR is constant and renal plasma flow decreases?

Back 11

*Filtration fraction = GFR÷RPF (renal plasma flow) = 120 ml/min÷600 ml/min = 0.20 or 20%

*Where GFR is glomerular filtration rate and RPF is renal plasma flow. Hence, 20% of RBF is filtered, 80% remains. 

*If RPF decreases and GFR remains the same, the filtration fraction increases, e.g. RPF decreases to 500 ml/min and GFR remains 120 ml/min, FF = 0.25 or 25%. In this situation, peritubular π increases, favoring salt and water retention (this happens in heart failure).

Front 12

Relation between glomerular and peritubular capillaries:

Back 12

Front 13

If renal blood flow is reduced (as often happens with heart failure or hypovolemia) and GFR is preserved, filtration fraction (FF) increases. What occurs “downstream” in peritubular capillaries?

Back 13

*As FF increases, filtration equilibrium is reached prior to the end of glomerular capillaries, and colloid osmotic pressure (πGC) rises.

*The πGC rises in peritubular capillaries.

*This favors reuptake of water and solute from the tubules.

Front 14

Mr. Corleone is 78 year-old man with a prior history of coronary disease, is admitted to the hospital with dyspnea and is found to have heart failure. On examination, his blood pressure is 90/40 and he is diffusely edematous.

What kind of level do you expect for his GFR, RPF, and urinary sodium? Why?

Back 14

*GFR-moderately low, RPF-low, urinary sodium-low.

*By virtue of autoregulation, GFR is preserved while RPF is low in heart failure. Hence FF (GFR/RPF) is elevated and colloid osmotic pressure (πGC) rises in the terminal glomerular capillaries and downstream peritubular capillaries.

*Thus, uptake of reabsorbed sodium is enhanced and urinary sodium (for this and other reasons) falls.

Front 15

How does GFR remain constant??

Back 15

*The answer lies in the anatomy of the glomerulus.
*The resistance of the afferent and efferent arterioles can be regulated.

Front 16

Discuss the process of Autoregulation of GFR in hypoperfusion:

Back 16

*Angiotension II works preferentially at the EFFERENT arteriole.
*Vasodilatory elements act preferentially at the AFFERENT arteriole.

Front 17

In the setting of renal hypoperfusion, what is the effect of ACE-Is and ARBs on GFR and why?

Back 17

*Autoregulation fails--> decreased GFR.
*NSAIDs decrease GFR, too, by inhibiting prostaglandin synthesis.
*This is clinically only a concern in people who are profoundly hypovolemic, have HF, or have high grade renal artery stenosis.

Front 18

*Mr. Stenson is a 65 year-old cigarette smoker with HTN. Recently, his blood pressure has been more difficult to control and his physician added lisinopril, an ACEI, to his regimen.

*One week later, the patient returns to his physician and BP is 120/80.

*However, he is complaining of fatigue and GFR has dropped by 50%. What happened?

Back 18

Answer: bilateral renal artery stenosis

Front 19

Back 19

*Molecular Sieving by the Glomerulus.
*Mesangium is surrounded by capillaries.

Front 20

What are the Barriers to molecular passage through the glomerulus?

3 barrier types:

Back 20

Front 21

What are the three layers of the glomerular capillary wall?

Back 21

1: Endothelial surface with fenestrations.
2: BM.
3: Podocyte-projected foot processes. The slit diaphragm is between the foot processes.

Front 22

Back 22

*This is what the glomerular capillaries would look like if you were standing in Bowman's space.
*Podocyte body is smooth looking. Its foot processes are rougher looking.

Front 23

What key Podocyte Proteins help Regulate Macromolecular Passage?

Back 23

*Slit diaphragm (nephrin) is key to limiting passage of macromolecules.
*Finnish nephrotic syndrome = nephrin mutation leading to escape of macromolecules--> proteinuria--> severe form leads to nephrotic syndrome.

Front 24

What's the effect of molecular size on glomerular filtation?

Back 24

More radius = less clearance of that molecule. In nephrotic syndrome, more protein escapes!

Front 25

What's the Impact of charge on glomerular sieving?

Back 25

*Cations = enhanced clearance.
*Anions = diminished clearance.

Front 26

Describe the equation for Clearance:

Back 26

*Clearance is the volume of plasma removed of a substance per unit time.
*Expressed as Volume per Time.

Front 27

What would be the clearance for a substance that is freely filtered?

What is this substance?

Back 27

*This is a basic (old school, important for STEP 1) way to measure GFR.

Front 28

What do we use instead of inulin to measure GFR?

Back 28

*Unlike inulin, creatinine is an endogenous substance which can be substituted to estimate GFR. 

*While creatinine is freely filtered and not reabsorbed, like inulin, a small proportion of creatinine is secreted. 

*Therefore, creatinine slightly OVERestimates GFR.

Front 29

Back 29

*Red line = idealized inulin-like clearance.
*Dots = actual CREATININE clearance.
*Creatinine slightly OVERestimates GFR.

Front 30

How does creatinine vary by gender?

Back 30

Front 31

What is the Effect of GFR Decline on Plasma Creatinine?

Back 31

*Plasma creatinine rises when excretion drops. You have to measure creatinine in the steady state, not during a change.

Front 32

How do we figure out Estimated GFR (eGFR) using the MDRD Equation?

Back 32

I don't have to know this I don't think. The lab will do this for me.

Front 33

What are the problems with the eGFR-based CKD Staging System?

Back 33

*There may be an overestimation of chronic kidney disease in some populations, particularly in the elderly, where there is less muscle mass.

*There are problems with the markers we use to measure GFR.

*Urinary albumin may be useful as a predictor of future kidney problems.

Front 34

What's the significance of Cystatin C?

Back 34

*Cystatin C is a 13-kDa protein, synthesized and secreted at a nearly constant rate by virtually all nucleated cells.

*Cystatin C is freely filtered by the glomeruli.

*In contrast to creatinine, cystatin C is not excreted in the urine but is metabolized by the proximal tubule.

*Hence, timed urine collections are not needed.

*Cystatin C is particularly useful for estimating kidney function when creatinine production is variable or unpredictable, e.g. in the elderly.

*May be better than creatinine as an estimator of GFR and as a predictor of loss of kidney function! We may see more of this and less of creatinine in the future.

Front 35

Why is para-aminohippurate useful?

Back 35

*Para-aminohippurate is a substance which is both freely filtered and highly secreted so that most of the PAH is “extracted” in one pass through the renal circulation.

*CPAH estimates the effective renal plasma flow. Since extraction is of PAH is not quite complete, the true RPF is 10% higher.

*To determine RBF, one must also know the hematocrit (Hct) and the calculation is as follows: RBF = RPF ÷ (1-Hct)

Front 36

What do the kidneys do to glucose?

How do you calculate reabsorption rate?

Back 36

Tmax = maximal tubular reabsorption of glucose.

Front 37

How do you calculate secretion rate? What is an example substance where this would happen?

Back 37

Front 38

urine flow rate 1 mL/min
plasma concentration of inulin 100 mg/mL
urine concentration of inulin 12 gm/mL
renal artery concentration of PAH 1.2 mg/mL
renal vein concentration of PAH 0.1 mg/mL
urine concentration of PAH 650 mg/mL
plasma concentration of A 10 mg/mL
urine concentration of A 2 gm/mL
hematocrit 45%

What is the GFR?

Back 38

Cin = Uin x V ÷ Pin
= 12,000 mg/ml x 1 ml/min ÷ 100 mg/min
= 120 ml/min

Front 39

urine flow rate 1 mL/min
plasma concentration of inulin 100 mg/mL
urine concentration of inulin 12 gm/mL
renal artery concentration of PAH 1.2 mg/mL
renal vein concentration of PAH 0.1 mg/mL
urine concentration of PAH 650 mg/mL
plasma concentration of A 10 mg/mL
urine concentration of A 2 gm/mL
hematocrit 45%

What is the renal plasma flow?

Back 39

RPF = UPAH x V ÷ PPAH = CPAH
= 650 mg/ml x 1 ml/min ÷ 1.2 mg/ml
= 542 ml min

(True RPF is 10% higher or 596 ml/min)

Front 40

urine flow rate 1 mL/min
plasma concentration of inulin 100 mg/mL
urine concentration of inulin 12 gm/mL
renal artery concentration of PAH 1.2 mg/mL
renal vein concentration of PAH 0.1 mg/mL
urine concentration of PAH 650 mg/mL
plasma concentration of A 10 mg/mL
urine concentration of A 2 gm/mL
hematocrit 45%

What is the renal blood flow?

Back 40

RBF = RPF ÷ (1-Hct)
RBF = 596 ÷ (0.55)
RBF = 1084 ml/min

Front 41

Assuming that substance A is freely filtered, how is substance A handled by the nephron?

Back 41

Front 42

Which of the following individuals has a normal GFR?

An 80 year-old woman with a serum creatinine of 1.2 mg/dl
A 6 month-old girl with a serum creatinine of 1.2 mg/dl
A 7 year-old boy with a serum creatinine of 1.2 mg/dl
A 76 year-old man with a serum creatinine of 1.2 mg/dl
A 30 year-old male weight lifter with a serum creatinine of 1.4 mg/dl

Back 42

*The weight lifter has the greatest muscle mass and therefore is likely to synthesize the most creatinine.

*Hence, serum creatinine of 1.4 represents a normal GFR.

*All of the other individuals probably have a LOW GFR.

Front 43

Take Home Points from this lecture:

Back 43

1) Glomerular filtration is governed by Starling forces in specialized capillaries with high porosity and permselectivity for macromolecules.

2) Permselectivity is a function of physical occlusion of large molecules by the slit pore and molecular charge.

3) Low glomerular plasma flow augments the filtration fraction and results in physical forces favoring reabsorption downstream near the proximal nephron.

4) Autoregulation protects GFR in conditions of low renal artery pressure by a combination of afferent arteriolar dilation and efferent constriction.

5) Glomerular filtration can be measured in human subjects by clearance techniques. Clearance can also be used to evaluate the filtration as well as net reabsorption or secretion of other low molecular weight substances.