GFR - Yagil

Question 1

Structural components of the glomerulus

Answer 1

1. Capillaries
2. Mesangium (material between capillaries gluing them together, contracted by AngII, area of least resistance)
3. Visceral Bowman’s epithelium-podocytes
4. Parietal Bowman’s epithelium

For filtration: capillary–>endothelium (fenestrated with pores and glycocalyces contributing to preventing large molecule passage)–> glomerular basal membrane (fusion of podocytes and endothelial cell, type IV collagen, proteoglycans, negatively charged)–>visceral epithelium (podocyte) with slit diaphragm

Question 2

Layers and properties of the podocytes

Answer 2

Podia/feet processes/extensions sit on capillaries

Meets endothelium at basement membrane

3 layers:
1. Lamina rara interna
2. Central dense layer
3. Lamina rara externa
Thickness: 350 nm

Thin membrane disease causes hematuria without any other impairment in kidney function.

In between: slit diaphragm containing proteins forming the final barrier for molecular passage.
Key components: Nephrin or Podocin. Lack causes loss of slit diaphragm.

Question 3

Sieving Curve: Fractional Clearance

Answer 3

To what degree a molecule crosses the membrane based on size

If 100% of molecules cross through membrane their fractional clearance is 1. If no molecules cross their FC is 0.

The larger the molecule, the fewer pass. More cationic and fewer anionic molecules pass given the same size.

Question 4

Pathological conditions in GBM

Answer 4

Charge selectivity:

Minimal change nephropathy
Diabetic nephropathy
damage to podocytes results in:
Diminished synthesis of heparan sulfate
Fewer anionic sites
Loss of charge barrier
Proteinuria

Size selectivity: membranous nephropathy, diabetic nephropaty (both)

Question 5

Role and activity of the Parietal Epithelial Cells of Bowman’s Capsule

Answer 5

Active role in handling of albumin that is filtered across the glomerular filtration barrier (hypothesis that damage occurs when overloaded)
Local source of new podocytes

Question 6

Equation and components for determination of GFR

Answer 6

GFR=LpS (deltaPhydraulic - deltaPioncotic)

GFR=LpS ([Pgc-Pbs]-ð[(pi)p-(pi)bs])

Lp: Normally constant permeability of capillary wall

S: Can vary functionally and anatomically, inner filtration surface. Reduced functionally by AngII by constriction. Also diminished structurally in disease (sclerosis of glomerular tufts)

Pgc: Glomerular capillary pressure (determined by aortic/perfusion pressure, resistance at afferent/efferent arterioles). Constant along glomerular capillaries between afferent and efferent.

Pbs: Hydraulic pressure in Bowman’s Space. Normally constant, increases with intratubular or ureteral obstruction (stones in renal parenchyma, beyond renal tubules in pelvis or in urethra).

Sigma: reflection coefficient, permeability of glomerular capillary to proteins. Normally impermeable (1), 0 if freely permeable.

Pi (p): Plasma oncotic pressure. Determined by plasma protein concentration (in particular albumin) and rate of filtration of blood through glomerular microcirculation. Normally constant up to the afferent arteriole, then rises progressively in glomeerular capillaries because of filtration of fluid. Increases in dehydration and multiple myeloma, macroglobulinemia (paraproteinemias).

Pi(bs): Oncotic pressure in Bowman’s space. Insignificant unless protein leaks into Bowman’s space (nephritic syndrome, diabetic nephropathy).

Question 7

How do Angiotensin II and ACE inhibitors affect the GFR?

Answer 7

Decrease AngII, preventing constriction of (dilating) the efferent arteriole, decreasing GFR.

Side note: AngII can cause decreased GFR if it sufficiently decreases the RPF and osmotic pressure predominates.

Question 8

Control of resistance at the afferent and efferent arterioles

Answer 8

Renal nerves - mostly SNS

Humoral factors:
Angiotensin II (mostly EA)
Norepinephrine (AA and EA)

Tubuloglomerular feedback

Question 9

Filtration fraction- definition and calculation and normal values

What affects it?

Answer 9

Ratio of glomerular filtration rate (GFR) to renal plasma flow (RPF)

FF=GFR/RPF

Increased:
Constriction of the efferent arteriole
Decreased plasma protein concentration

Decreased:
Increased plasma protein concentration
Constriction of ureter or urinary tract obstruction (increased Pbs)

Normal GFR = 125 mL/min
RPF = 600 mL/min
FF = 20%

Question 10

What happens if 50% of the nephrons stop functioning (nephrectomy)?

Answer 10

If 50% of functioning nephrons cease functioning:
GFR declines
20-30% and not 50%
Compensatory hyperfiltration of remaining nephrons unless there is parenchymal disease. Compensation abilities decrease with age.

Fluid and electrolyte balance maintained
urinalysis normal- 70-80% loss before symptom reduction is noticed.
Reduction in GFR may go clinically unnoticed
Lab measurement of GFR may be earliest and only clinical sign of renal disease

Question 11

What are the various measurement methods of GFR?

What is the most common measuring technique of GFR?

How it is measred?

Calculation

Answer 11

Inulin
Creatinine
Urea – BUN
Iothalamate, CrEDTA
Cystatin

Creatinine clearance: endogenous but constant unless muscle breakdown or eating lots of meat. Secreted from peritubular capillaries into tubule lumen and > inulin excretion by 10-20% but measurement in plasma creatinine cancels it out. May overestimate by as much as 100%. Measured in 24h urine collection.

CrCl = Uvol (ml) x [Cr]u (mg/dL) / ([Cr]p (mg/dL) x 1440 (min))

Alternative: measure Pcr only. Caution: Initial minor elevation, Subsequent major rise. 120-80 GFR huge loss only indicated by a small change in Cr within normal limits. Not reliable in acute setting, needs to accumulate and rises steadily. Also dependent on age and body size, a skinny old woman with a Pcr within normal lab limits may be pathologically high.

The MDRD calculates based on PCR, gender, race and age. Used for progression of disease (normal patients will appear in failure).

Question 12

What are the limitations of the use of BUN and urea to estimate GFR?

Answer 12

Urea formed by hepatic metabolism of amino acids. Decreases with low protein diet.
BUN increased with high protein diet and enhanced tissue breakdown, without change in GFR (endogenous, excreted by glomerular filtration like Cr). Partially reabsorbed
BUN diminished by severe liver disease or low protein intake, without change in GFR.

40-50% of filtered urea is normally passively reabsorbed along with tubule water and sodium
 In hypovolemia (dehydration), more urea is reabsorbed and as result, urea clearance is 50-70% of inulin clearance and cannot be used as a reliable indicator of GFR

Always secondary to Pcr.

Question 13

What is Cystatin C and what is its use?

Answer 13

Low molecular weight protein
Filtered and not reabsorbed
Metabolized in tubules (doesn’t reach urine, measured only in plasma)

Produced by all nucleated cells
Rate of production constant, not affected by diet
Plasma concentration may correlate more closely with GFR than PCr
Problem: Plasma levels appear to be affected by age and gender. Also expensive.

Better than BUN.