Glomerular filtration and its determinants

Question 1

Describe paradoxical aciduria

Answer 1

• low urine pH in cases of metabolic alkalosis
• this occurs if volume loss occurs with hydrogen loss, as in vomiting
• therefore, bicarbonate excretion **does not occur
• this is because sodium reabsorption, or volume correction is stimulated, and takes priority over acid-base balance
• in turn this increases HCO3 reabsorption as a result of enhanced H secretion
• elevated aldosterone levels stimulate hydrogen secretion int he collecting duct, as well as modulating Na levels

Additional complication - elevated aldosterone levels stimulate H+ secretion in collecting duct

Question 2

Describe how filtration barrier works

Answer 2

• fenestrated endothelial cell has 50 to 100 nm gaps, and can only really keep cells out
• basement membrane carries a negative charge due to the presence of heparan sulphate PGs, and thus repels larger polyanionic plasma proteins, and excludes albumin (despite its small size)
• podocyte foot processes or pedicels have slits between them, and are likely the major barrier to protein loss

N.B. Microscopic haematuria - inflammation of very few glomeruli

See also nephron slides for details

Question 3

Describe GFR and eGFR

Answer 3

GFR
- is the factor which largely determines stage of kidney disease
- it is typically calculated with renal blood flow

eGFR
- is the only test used to measure GFR, as opposed to mGFR (which uses an exogenous marker)
- calculated by CKD-EPI equation and is automatically reported with plasma lab creatinine
- based on age, sex, plasma creatinine ^[not diet, race. Note that the US used to consider race, and recently removed this]

Question 4

Describe creatinine

Answer 4

Creatinine
- is the basis of reported eGFR in Australia
- comes from flesh or muscle
- fluctuates about 8% day to day
- some is always secreted and can be variable
- usual excretion is about 10 mmol (found in 500g of meat)

Question 5

List some considerations when using any marker to assess kidney function

Answer 5

• a person with normal body weight and diet, has normal eGFR and kidney function
• change in diet can affect mGFR substantially, and degree of effect is dependent on amount of renal reserve ^[aka are they already working hard? or not?]
• diet also adds a creatinine load
• normal kidneys, and weight with dominant vegetable diet will have normal eGFR, and kidney function may be low or normal
• non-scarred kidneys in obesity = increases filtration demand, thus eGFR can be normal or reduced; kidney function high resulting in hyperfiltration and albuminuria
• scared kidneys in obesity may have normal or reduced eGFR, while kidney function is normal. Albuminuria is present
• very scarred kidneys in obesity = reduced eGFR and kidney function. Albuminuria is present

Question 6

Describe body surface correction for GFR

Answer 6

• body surface area correction is the standard, with exceptions
• expressed as mL/min/1.73 m2
• in theory, if a person gets fatter, and GFR is changed, corrected GFR will fall
• other things that should* *be a consideration for GFR, missed

Question 7

What is CKD-EPI?

Answer 7

• the best for routine use
• the equation is accurate to within 30% of mGFR about 80% of the time
• but is even less accurate in those with unusual diets and obesity
• Note: a normal eGFR does NOT mean kidney is NOT damaged

Question 8

Describe autoregulation of filtration

Answer 8

• All organs autoregulate - if they didn’t, then BP would have to be exactly the same all the time
• Afferent arterioles govern perfusion pressure
• Ratio of resistance between afferent and efferent arterioles governs filtration fraction
• Mechanisms:
• Systemic BP fall stimulates SNS which directly raises BP and stimulates RAAS to raise BP
• Myogenic reflex in afferent arterioles - more stretching (↑ BP) causes contraction, so if BP rises, then afferent arteriole will contract
  and keep perfusion pressure stable
• Tubuloglomerular feedback (specific to kidney)
• Controlled by juxtaglomerular apparatus
• Macula densa (part of distal LOH)
• Extraglomerular mesangium
• Terminal afferent arteriole containing renin-producing cells
• Early efferent arteriole
• Adenosine release from macula densa cells in response to increased tubular chloride - adenosine leads to contraction of
  afferent arteriole ∴ GFR ↑ leads to ↑ tubular chloride → ↓ GFR
• High chloride fluids may have worse outcomes for resuscitation because of less inhibition of GFR
• What may be good for kidney function in the short term (by raising GFR) may not be good in the long run
• What is good for the kidney in the long run (lowering hyperfiltration) may not be good in the short term

Question 9

Describe tubuloglomerular feedback

Answer 9

• The tubule (ascending limb) loops back up briefly to run right next to the glomerulus
• JGA plays a major role, with four key components:
  
  • macula densa: part of distal looop of Henle*
  • extraglomerular mesangium
  • terminal afferent arteriole, which contains renin-producing cells
  • early efferent arteriole
• detects NaCl at macula densa
• uses this as a proxy for volume
• an increase in sodium or chloride in the tubule at macula densa results in the following changes
  
  • adenosine release, leading to direct constriction of afferent arteriole to lower intraglomerular pressure and reduce GFR
  • inhibition of renin release, to lower blood pressure and lessen the efferent arteriole constriction. This lowers intraglomerular pressure and reduces GFR. The net effect is a lower renal plasma flow, filtration fraction and lower GFR

Note: anything that suddenly raises GFR, or impaired proximal tubule function, feeds back to a lower GFR
- this not great if someone is recovering from kidney failure

Question 10

Describe filtration demand

Answer 10

• filtration is affected by diet, obesity and nephron mass
• obesity or meat intake increases filtration
• similarly, reduced renal mass increases filtration on the remaining kidney ^[e.g. in donors, people born with one kidney]
• kidneys cannot generate more glomeruli i.e. you are stuck with what you are born with
• increase filtration to compensate for fewer glomeruli
  
  • requires increase in intraglomerular pressure = damage and run out of renal capacity
  • raised filter pressure leads to leaking filter and albuminuria
• hyperfiltration is why donors do not halve their GFR (although it does decrease), and high mGFRs are often seen in severe obesity
• note: a higher is not always good if there are not enough glomeruli/overworking

Question 11

List the hormone and paracrine substances relevant for GFR

Answer 11

• adenosine, which works to constrict the afferent arteriole. Therapeutically targeted with SGLT2i
• angiotensin II which constricts the efferent arteriole, increasing proximal Na reabsorption some. Therapeutically targeted by ARBs and ACEi
• aldosterone, which is responsible for sodium retention in the distal nephron, increasing blood pressure. This is targeted by several drugs, including spironolactone. eplerenone, finerenone
• Prostaglandins which relax the afferent arteriole in stress, therapeutically targeted with NSAIDs
• SNS which stimulates renin and angiotensin

N.B. drugs that interfere with these substances
e.g. ACE, ARB, SGLT2i (indicated in diabetes, heart failure, preserve kidney function– more sodium to macula densa – feedback GFR reduction. Less albuminuria, slower scarring) ^[note, this would constitute a separate question]

Question 12

Describe the effect of SGLT2 inhibitors in diabetes

Answer 12

more sodium to macula densa – feedback GFR reduction. Less albuminuria, slower scarring

Question 13

Describe what happens at macula densa in diabetes

Answer 13

• hyperglycaemia
• retains glucose and sodium
• sodium loss appears to macula densa as hypovolaemia (could be in truth overloaded)
• relaxes efferent, constricts afferent, stretch of filter
• albuminuria, scarring and LOF

Question 14

Describe renal plasma flow

Answer 14

Renal plasma flow and filtration fraction
RPF = RBF * (1-HCT) ^[Hb/3 ~ HCT]
The kidneys get about 25% of cardiac output and usually 10% to 25% of the (plasma) flow is filtered off as glomerular filtrate.
- intraglomerular pressure changes filtration fraction

Renal plasma flow: non-clinical
- infuse a substanvce that is filtered and secreted such taht every drop of plasma that passes through kidney is cleared of the substance
- PAH is a good approcimate
- as some parts of the kidney do not contribute to secretion it meaures effective RPF, which is slightly less than true RPF
-

Question 15

Describe renal blood flow

Answer 15

• Flow is proportional to pressure drop across the kidney and inversely proportional to vascular resistance of the kidney
• Flow is pressure divided by resistance

Question 16

Describe the determinants of single nephron filtration

Answer 16

snGFR = Kf [(Pgc - Pbs) -(πgc πbs)]
- Kf is ultrafiltration coefficient
- Hydrostatic pressure between capillary and Bowman’s space
- Oncotic difference between capillary and Bowman’s spcae (note usually πbs will be zero)

P change = afferent vs efferent
Oncotic changes minimal, as Bowman’s is usually zero

Front afferent to efferent arteriole
- oncotic pressure rises and resists filtration (relevant for dialysis)
- in nephrotic syndrome, oncotic pressure lower, will affect GFR

Question 17

Describe mGFR

Answer 17

Traditionally by inulin infusion at equilibrium, as inulin is completely filtered and not secreted
or reabsorbed. In this case the infusion flow is equal to the urinary appearance.

• mGFR= Clearance of inulin in L/min
  = Inulin Flow (mmol/min) / Plasma Inulin conc. (mmol/L)
  = Glomerular filtration rate in L/min
  Can be measured by single injection and multiple blood samples, plus fudge factors.

Canberra uses 99Tc labelled diethylenetriaminepentaacetic acid (Tc-DTPA)

Question 18

Explain how GFR is calculated with creatinine clearance

Answer 18

Creatinine clearance in L/min
= urine creatinine mmol/min / plasma creatinine conc. mmol/L
The equation is usually written as
C = UxV/P
- Where C is the clearance
- U is the urinary concentration in a timed (24hr) specimen
- V is the urinary volume in the timed (24hr) specimen
- P is the plasma concentration

• recall: will always be higher than true clearance due to secretion

Question 19

Describe the Cockcroft-Gault equation

Answer 19

Cockcroft- Gault
* Still the standard for many renally cleared drugs, even though it is a rubbish equation. It is standard purely for historical reasons
* Cockcroft Gault equation (simplifies to)
* Weight*(140-age)/Creatinine
* Multiply by 1.23 for men and 1.04 for women
* Gives an unindexed calculated creatinine clearance

• Unknown whether lean or actual body weight should be used
• Very little actual outcome data (toxicity/effectiveness) to support any particular adjustment
• When possible (usually is not) it is good to measure drug levels or clinical effect in low therapeutic index drugs
• Developed in white men, original creatinine assay lost in the mists of time
• Used extensively for drug dosing, not used much for anything else

Question 20

Describe albuminuria

Answer 20

Three different processes cause albuminuria:
- a hole in the filter (GN)
- a leaky filter (e.g. disease affecting podocytes)
i.e. nephritic or nephrotic syndromes

• an overpressurised filter (high filtration fraction)