renal plasma clearance Flashcards
Glomerular Filtration Rate (GFR)
how much filtrate is removed from the blood each minute
pressure that favours filtration
hydrostatic pressure in the glomerular capillaries
pressures that don’t favour filtration
- oncotic pressure/colloid osmotic pressure generated by the plasma proteins (mainly albumin) in the blood
- hydrostatic pressure of the Bowman’s space
Urinary excretion rate
GFR - reabsorption + secretion
how much of the plasma that flows through the glomerular capillaries is filtered?
20% (other capillary beds = 1%)
means that 80% doesn’t go through the nephron, just remains in the CVS
why is GFR important:
- contributes to rapid removal of waste products
- important clinical indicator of renal function, as it is affected by the pressures mentioned above, surface area and capillary permeability - if any of these change the GFR will also change
2 substances which have been used to measure GFR, and why are they used?
inulin and creatinine
used because because nothing is secreted, reabsorbed or metabolised so the concentration of the substances in the plasma will equal the concentration of these substances in the urine
Rate of filtration through glomerular membrane per minute = Rate of entry into bladder per minute
what is inulin?
an inert polysaccharide that filters freely through the glomerular membrane and is not absorbed, secreted or metabolised
(for inulin and creatinine) the rate of filtration through glomerular membrane per minute equals….
the rate of entry into bladder per minute
since we do not make inulin how does it get into the body?
have to infuse it in steady iv until its plasma level becomes stable
when does the inulin plasma level become stable?
when the inulin infusion rate equals the inulin excretion rate
when plasma inulin concentration has become stable what happens?
1) at timed intervals, plasma and urine inulin concentrations and the urine volume is collected and measured using a micropipette
2) a blood sample is obtained at the mid-point of each urine collection period
GFR equation
Pin
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
what is V* and how is it calculated?
the urine flow rate
calculated by dividing the urine volume collected by the duration in minutes of the collection period
renal clearance
the volume of plasma that is completely cleared of the substance by the kidney per unit of time, ml/min (ie. excreted in urine)
where does all the inulin that is filtered into the bowman’s capsule end up?
ends up in urine
formula of renal clearance
Cs x Ps = Us x V*
where Cs = clearance rate of substance (s) Ps = plasma concentration of s Us = urinary concentration of s V* = urine flow rate
drawbacks to the inulin method?
- prolonged infusion
- repeated plasma samples
- difficult routine clinical use
advantages of the creatinine method?
- inert substance
- Released at a steady level in plasma from skeletal muscle
- No infusion needed (because it is intrinsic ie. made by the body in the skeletal muscle)
disadvantages of the creatinine method?
some secreted into the tubule so more goes into urine
where is the majority of creatine found?
95% found in muscular tissues
how does Creatine (Cr) get into the muscle?
-muscle has virtually no Cr-synthesizing capacity so Cr has to be taken up from the blood against a large concentration gradient by a saturable, Na+- and Cl−-dependent Cr transporter that spans the plasma membrane
how is the daily demand for Cr met?
by intestinal absorption of dietary Cr or by de novo Cr biosynthesis
how is creatine converted to creatinine?
creatine (Cr) is metabolised to phosphocreatine (PCr) in the skeletal muscle by creatine kinase - this process generates a lot of energy, and it’s a reversible reaction
creatine and phosphocreatine can be non-enzymatically converted to creatinine which is released from the muscle (diffuses out of the cells) and is excreted by the kidneys into urine.
Trimethoprim
competitive inhibitor of creatinine
competes with Crn for same transporters that secrete Crn from tubular blood into urine, leads to an increase in serum levels of Crn
how does GFR affect age and gender?
GFR will decline with age
difference between men and women is due to different muscle mass and surface area
The serum creatinine concentration is inversely proportional to….
the creatinine clearance
eGFR
estimated Glomerular Filtration Rate
using blood tests, age, sex, and sometimes other information to estimate the GFR from the MDRD equation
isn’t as good as measuring it (i.e. 24h urine collection), but is much simpler as it requires just one blood test
used to spot kidney disease earlier than would be possible using just creatinine measurements
however it was modified due to overestimating impaired kidney function in older people
CKD-EPI (over 18’s)
The equation does not require weight, as the results are normalised to 1.73m2 body surface area
CKD-EPI is more accurate than MDRD, less biased at GFR and performs better in people >75years
what are the stages of CKD based on?
measured or estimated GFR
5 stages - look at table in notes
problems with eGFR
It is only an estimate so a significant error is possible
most likely to be inaccurate in people with extreme body types - malnourished, amputees, etc.
not valid in pregnant women, patients older than 70yrs or in children
Race: Some racial groups may not fit the MDRD equation well. It was originally validated for US white and black patients.
A Chinese coefficient for MDRD equation has been determined - they make their own because they have their own population biases
what does it mean when a substance has a clearance less than inulin/less than GFR?
Not filtered freely
E.g. Albumin clearance = 0ml/min
Similarly for drugs bound to albumin e.g. digoxin, warfarin
(or) Reabsorbed from tubule
- Filters freely but is usually absent from urine - completely reabsorbed actively or passively
e. g. Glucose clearance = 0ml/min
what does it mean when a substance has a clearance more than inulin/more than GFR?
Secreted into tubule
Filters freely
Secreted actively against electrochemical gradient
Endogenous substances e.g. weak organic acids & bases, adrenaline, dopamine, steroids
Exogenous substances e.g. penicillin, probenecid,
para-amino hippuric acid (PAH)
penicillin
If you inject penicillin levels fall rapidly in patient’s body fluids because renal tubular cells actively secrete it into urine
Counteract this by giving probenecid - will compete with penicillin for the same transporters, but the transporters have a slightly higher preference for probenicid so plasma penicillin levels are maintained for a bit longer
Glucose handling by the kidney
Rate of glucose filtration increases hand in hand with plasma [glucose], NO glucose in urine (PCT has reabsorbed all of it)
renal threshold of 15mM is reached - glucose starts appearing in the urine, glycosuria
above 22mM the reabsorption line plateaus - known as the Tm, transport maximum - when all the - all the transporters in each of the 2 million nephrons get completely saturated
diabetic patients whose plasma [gluc] lie above the renal threshold have glycosuria
why does glucose appear in urine (15mM) before the Tm (22mM) is reached?
because different nephrons have different Tm so some will start excreting glucose in urine before others
once glucose starts appearing in urine, will it ever reach the levels of inulin?
it would never get up to the level of inulin, because the transporters are still working away
the only way glucose would get up to inulin urine levels would be if all the transporters were blocked
Clearance of other substances
Actively Reabsorbed -all amino acids clearance = 0ml.min-1 unless excess filtered or pathological conditions (e.g. myeloma and production of Bence-Jones protein in plasma which block filtration system in the kidneys) -Ca2+, Na+, PO42-, Mg2+ -water-soluble vitamins
Passively Reabsorbed
Cl– and urea
do active and passive transport both have a Tm value?
just active
substances that are passively reabsorbed DO NOT display Tm because their rate of transport is determined by other factors (electrochemical gradient, permeability etc.)
all the molecules which are actively reabsorbed will therefore need a transporter, and so will display a Tm value
which drugs return to the blood?
only lipid soluble substances can cross the tubular wall so lipophilic drugs tend to return to blood stream whilst hydrophilic drugs are lost in urine
Renal Plasma Flow (RPF)
RPF is the rate at which plasma flows through the kidney
-can use this to work out the renal blood flow: if you know RPF and the haemaotcrit, you can subtract the 2 and work out RBF
Paramminohippuric Acid (PAH)
- weak acid metabolite found in horse’s urine
- used to measure RPF
-virtually completely cleared in single pass through kidney:
filtered freely & enters glomerular filtrate, but a large amount is still in the plasma- the majority is secreted back into proximal convoluted tubule and excreted in urine
- active transport of PAH occurs in basolateral membrane (blood into cell)
- passive transport across luminal membrane into tubule (cell into tubular lumen)
RPF is equal to…
PAH clearance
Renal Filtration Fraction
GFR & RPF can be used to calculate the filtration fraction
i.e. fraction of plasma that is filtered through the glomeruli
GFR/RPF
GFR determined from Inulin clearance
RPF determined from PAH clearance
