S2: Renal Plasma Flashcards
What is glomerular filtration rate (GFR)?
How much filtrate is removed from the blood each minute
What is the equation for the net filtration pressure?
, PGC – (PBS + ΠGC) = 16mmHg
Glomerular capillary pressure - (hydrostatic pressure in Bowman’s space and oncotic force of plasma protein
Equation for urinary excretion rate
GFR - reabsorption rate + secretion rate
What factors determine GFR?
GFR contributes to the rapid removal of waste products
GFR is determined by a combination of factors
- The hydrostatic and oncotic pressures across capillary membranes
The permeability of capillary filtration barrier and surface area available
How do we measure GFR?
We don’t measure GFR directly, instead we measure it using the excretion of a marker substance.
What substance is best used to measure GFR (and why)?
A substance that is freely filtered and no absorbed/secreted for example creatinine.
This is because nothing is done to it so the rate of which this substance is appearing in urine matches the rate it is being filtered
What is the Inulin Method?
- Gold standard for measuring GFR
- Not used clinically
Inulin is an inert polysaccharide that is freely filtered through glomerular membrane and is not absorbed, secreted or metabolised
Rate of filtration through glomerular membrane per min = rate of entry into bladder per minute
List the steps of the inulin method
- We do not make inulin so it would have to be infused in blood via IV until plasma levels (Pin) becomes steady. This is checked by doing repeated blood samples.
- Container given to person to collect all their urine in a defined period of time
- Concentration of inulin in urine worked out (Uin)
- Rate of filtration (of that substance) through glomerular membrane per minute is equal to the rate of entry (of S) into the bladder per minute.
Calculate GFR eq. using equations and inulin method
GFR = Glomerular filtration rate (ml.min-1) Pin = plasma inulin concentration (mg.ml-1) Uin = urine inulin concentration (mg.ml-1) V* = urine flow rate (ml.min-1)
Rate of filtration = [Pin] x GFR
[Pin] x GFR = [Uin] x V*
GFR= [Uin] x V* / [Pin]
What is renal clearence?
Volume of plasma that is completely cleared of the substance by the kidney per unit of time, (in other words excreted in urine each minute), expressed in ml/min.
Why is renal clearance not the same as GFR?
Because many substances are modified as they go through the renal tubule, some is reabsorbed and some is secreted. So if we just looked at GFR it wouldn’t tell us what is happening with the substance while it is going through.
What is the formula for working out renal clearacne?
Cs= Clearance rate of substance (s) Ps= Plasma concentration of s Us= Urinary concentration of s V*= Urine flow rate
Cs x Ps = Us x V*
Cs = Us x V*/Ps
What are the negative with using inulin as the gold standard?
- Prolonged infusion (as it isn’t made in the body)
- Repeated plasma samples needed (to check if it is stable)
- Difficult for routine clinical use
What is used to measure GFR clinically?
Why??
Clinically creatinine is used for GFR measurement
- It is an intrinsic, inert substance
- Released at steady level in plasma from skeletal muscle so no infusion needed unlike inulin
- Freely filtered and no re absorption in the tubule
What is the disadvantage with using creatinine to measure GFR?
Some creatinine is secreted into the tubule so the
Ccr (creatinine clearance) will be slightly greater than GFR
What is Trimethoprim?
Trimethoprim, an antibiotic is a competitive inhibitor (competes for the transport channel) of creatinine secretion, so may cause an artificial increase in plasma creatinine.
Where does creatinine come from?
Creatinine is made in the skeletal muscles and released at a steady state. It is released at a steady state from creatine and phosphocreatine. There are two sources of creatine, de-novo synthesis in the liver and what you take in through your diet.
What enzyme turns creatine to phosphocreatine?
Creatine kinase
Why do people take creatine supplements?
Phosphocreatine is useful in excersize
Explain the relationship between serum creatinine and creatinine clearance
with graphs etc
We can see that the serum creatinine is inversely proportional to creatinine clearance. I.e. high serum creatinine means lower GFR and lower kidney function.
GFR= Ccr = Ucr x V*/PCr
We assume GFR =Ccr
Ccr = 1/Pcr
We can plot this relationship - graph is curvilinear
This can however be difficult to calculate the percentage drop in GFR when creatinine rises
So mathematically we can combat this by plotting 1/[Cr], then this becomes a linear relationship. Then you can more easily read of what is happening.
So if patient comes in and we see creatinine level has gone up, then 1/[Cr] will go down (because plasma Cr has increased).
So if GFR drops from 100->67% and 1/[Cr] goes from 1-> 0.67mg/dl, the actual plasma creatinine has gone up from 1 -> 1.5mg/dl (reciprocal) (1/0.67)
Explain variation in GFR and creatinine with different people
- Men have higher creatinine level
- Men have higher GFR level
- More muscle mass increases creatinine level
So as you get older, muscle mass decreases so creatinine will decrease, as well as there is normal loss in renal function so this could hide a loss of renal function (because Pin is low you assume GFR is okay).
What is eGFR?
How is it measured?
Estimated glomerular filtration rate
- Less accurate than clincially measuring GFR e.g. 24 hr urine collection
- Much simpler as it requires just one blood test so kidney disease can be spotted earlier
What equation can be used to estimate eGFR?
The MDRD equation uses blood tests, age, sex and sometimes other information to estimate the GFR.
What factors make the eGFR unreliable?
- People in extremes of body types .e.g. malnourished, amputees
- Pregnant women
- Children
- Patients older than 70
- Racial groups -afrocaribbean
Describe CKD stages
The stages of CKD (chronic kidney disease) are mainly based on estimated GFR (e.g. 90+ you are in stage1). There are five stages but kidney function is normal in stage 1 and minimally reduced in stage 2.
What is the CKD-EPI?
CKD-EPI is an equation that is more accurate MDRD, less biased at GFR and performs better in elderly people
The equation has many variables that help combat the variation seen in eGFR to be more accurate
Compare what would have happened to substances with clearance =< or > than inulin (GFR)
= Inulin (=GFR)
- Freely filtered, not reabsorbed/metabolised/secreted and has been excreted out into urine
- Urine conc will equal plasma conc
- flow rate = 125ml/min
> Inulin (>GFR)
- Secretion into tubule
What is the average GFR?
125ml/min
Give examples of substances with clearance < inulin
- Not freely filtered e.g. albumin with clearance ml/min
- Drugs bound to albumin e.g. digoxin and warfarin
- Substance that is filtered by reabsorbed
e. g. glucose with clearance 0ml/min
How would we investigate glucose filtration rate?
So to investigate, we would set up an IV line, get our patient and infuse them with both glucose and inulin. We do both, because we can use the inulin to work out the GFR for that particular test subject.
Rate of filtration= plasma glucose conc x GFR
Describe glucose handling by kidney - graph plotting glucose filtration/excretion/reabsorption against plasma glucose
- As increasing glucose is infused, rate of glucose filtration will increase as plasma conc of glucose increases
- After renal threshold of plasma glucose is reached (15mM) glucose starts to appear in urine
- This is because the SGLT2 transporters are unable to keep up with increase in plasma glucose as all the transport carriers are saturated (Tm) - reabsorption line plateus
- The reason we see glucose start to appear in the urine before the transport maximum is reached, is because we have over a million nephrons in each kidney so each one is slightly different and each one may have a slight difference in Tm
What is Tm (transport maximum) of glucose?
20 mM
Will glucose filtration of glucose ever reach that of inulin?
No
So as long as the SGLT2 transporters are working effectively, the clearance of glucose will never reach the clearance of inulin. This is because some is ALWAYS reabsorbed by the carrier mechanism whereas inulin is literally just filtered and leaves (125ml/min).
It is only if we completely stopped the reabsorption, we would reach the same level.
List some substances that are actively reabsorbed
- All amino acids (no clearance unless
excess is filtered) - Ca2+. Na+. PO42-, Mg2+
- Water soluble vitamins
All of these substances that are actively reabsorbed will display Transport Maximums (Tm)
What happens to amino acid clearance in myeloma?
Bence-Jones proteins (small antibody fragments) are present in urine as they are filtered through
List some substances that are passively reabsorbed
- Cl
- Urea
- Lipophilic drugs (only lipid soluble can passively cross tubular wall - hydrophilic drugs tend to be lost in urine)
These passively reabsorbed substances will NOT display Tm because their rate of transport is determined by other factors e.g. electrochemical gradient, permeability.
As the glomerular filtrate flows down the tubule and more of its water is reabsorbed, the solutes are more concentrated providing a conc. gradient down which they can diffuse.
Name some substances where clearance >GFR
This is a substance that would be freely filtered through and is then secreted actively against an electrochemical gradient.
- Endogenous substances e.g. weak organic acids and bases
- Adrenaline, dopamine
- Steriods
- Exogenous substances e.g. penicillin
Explain penicillin secretion
If we give a patient penicillin IV into plasma it is very quickly secreted into the filtrate so plasma levels fall rapidly. This can be counteracted by giving probenecid which competes with penicillin for the same transport carriers and thus slows excretion of penicillin and prolongs its actions.
What is renal plasma flow RPF?
How is it related to renal blood flow RBF?
Renal plasma flow is the rate at which plasma flows through the kidney.
Blood consists of 55% plasma and 45% cellular components.
So when estimating RPF through the kidneys, we can also estimate total blood flow through the kidneys.
How can RPF be measured?
Using paramminohippuric acid PAH
If you keep the conc. of PAH lower than the Tm, you are able to measure the renal plasma flow
What is paramminohippuric acid PAH?
Describe its path down the renal tubule
PAH is a weak acid metabolite found in horse’s urine. It is filtered freely and enters the glomerular filtrate. But large amounts are still in plasma.
The majority is secreted back into the PCT and excreted in urine. Which is why the clearance is greater than GFR
Carriers will not be saturated and PAH will virtually be completely cleared in a single pass through kidney.
Clearence of PAH = volume of plasma that flows through (RPF)
RPF = Upah x V*/Ppah
What carriers transport PAH?
Active transport of PAH occurs on the basolateral membrane with a Na+ symporter. While, on the apical membrane there is passive transport into the tubule via an antiporter.
What substances determine GFR and RPF?
GFR is determined by inulin clearance
RPF is determined by PAH clearance
What is renal filtration fraction?
GFR/RPF x 100
It is the fraction of plasma that is filtered through the glomeruli
