Determinant of Glomerular Filtration

Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai

Moderators:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D. Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

 The most important function of the kidney is the
process of glomerular filtration.
 Through the passive ultrafiltration of plasma
across the glomerular membrane,
 the kidney is able to regulate total body salt and water
content, electrolyte composition, and eliminate waste
products of protein metabolism
 The process of filtration is analogous to fluid
movement across any capillary wall, governed by
Starling forces
3
Dept of Urology, GRH and KMC, Chennai.

 The glomerular filtration rate (GFR) is determined by
both hydraulic and oncotic pressure differences
between the glomerular capillary and the Bowman
space, as well as by the permeability of glomerular
membrane
 GFR = LpS × (hydrostatic pressure − oncotic
pressure)
where Lp = glomerular permeability and
S = glomerular surface area
4

 expressed in milliliters per minute.
 GFR is reflection of overall renal function.
 Average GFR - 125 ML/min
- 7.5 L/hr
-180 L /day
:
5

➢ Trans glomerular pressure
➢Renal plasma flow
➢Glomerular permeability
➢Oncotic pressure
6

Transglomerular (hydraulic)
pressure (TGP)
 the most significant determinant of GFR is the TGP
 glomerular capillary is interposed between two
arterioles , can regulate intraglomerular capillary
pressure
 IGP- independent of systemic pressures through
changes in afferent and efferent arteriolar tone.
 normally the pressure within the Bowman space is
essentially zero
 conditions of urinary obstruction pressure increase to
clinically significant levels. Thus the TGP = IGP.
7

Renal plasma flow
 increases in RPF lead to increases in GFR.
8

GLOMERULAR PERMEABILITY
 Increase in permeability doesn’t leads to increase in
GFR
 increased filtration of larger molecules not normally
filtered, such as albumin.
 Reductions in permeability, or in glomerular
surface area, can lead to reductions in GFR.
9

Oncotic pressure
 least relevant of all the variables.
 normally , plasma proteins are not filtered
across the glomerular membrane and so oncotic
pressure within the Bowman space is essentially zero.
10

Regulation of Glomerular
Filtration Rate
 GFR is maintained at a relatively constant level,
despite large fluctuations in systemic arterial
pressures and renal blood flow
 accomplished through the processes
Autoregulation
Tubuloglomerular feedback (TGF)
11

Autoregulation
 increases in mean arterial pressure(MAP), afferent
arteriolar tone increases to minimize increases in IGP.
 Autoregulation IGP - effective MAP of about 70 mm
Hg
below 70mmHg reductions in MAP lead to
reductions in GFR,
below MAP of 40 mm Hg, filtration ceases.
 mediated through myogenic stretch receptors in the
afferent arteriole wall, possibly mediated by ATP &
angiotensin II
12

Tubuloglomerular feedback (TGF)
 tubular ultrafiltrate flow rates are monitored by cells
in the macula densa.
 If SN-GFR increases, delivery of sodium cations
(Na+) and chloride anions (Cl−) to the distal tubule
also increases.
 increased Cl− delivery triggers a response by the
macula densa, leads to an increase in afferent
arteriolar tone and decrease in RPF, thus returning
SN-GFR back to baseline.
13

 TGF can be thought of as a mechanism to minimize
salt and water losses through regulation of GFR.
 mediators of this response are angiotensin II,
adenosine and thromboxane
14

FACTORS AFFECT GFR
 Changes in renal blood flow
 Changes in glomerular capillary hydrostatic pressure
 Changes in systemic BP
 Afferent or efferent arteriolar constriction
 Changes in hydrostatic pressure in bowmans capsule
 Ureteral obstruction
 Edema of kidney changes in conc of plasma proteins
 Changes in kf
 Changes in glomerular permeability
15

Clinical Assessment of Glomerular
Filtration Rate
 best estimate of GFR can be obtained by
measuring the rate of clearance of a given
substance from the plasma
 substance to be measured must meet certain criteria
➢ Be able to achieve a stable plasma concentration,
➢ Be freely filtered across the glomerulus,
➢ Not be secreted, reabsorbed, synthesized,
metabolized by the renal tubules,
➢ Not be impacted by any other means of removal
from the plasma
16

 GFR = U[X]× urine volume/P[X]
U –conc of substance in urine
V – ml of urine excreted per min
P - conc of substance in plasma
clearance of a substance and reflects the amount of
plasma that is completely cleared of the substance per
unit time.
 number of substances that have been used clinically
to estimate GFR.
17

Inulin
 fructose polysaccharide that meets the necessary
requirements
 inulin clearance is felt to be the best measure of GFR.
 However, it is not clinically useful because it is
difficult to administer, measure & expensive.
18

Radiolabelled compounds
 iothalamate or diethylenetriaminepentaacetic
acid (DTPA).
 very accurate, but are again limited in clinical use by
their cost and availability
19

Creatinine
 the most widely used estimate of GFR is the 24-
hour creatinine clearance (CrCl)
 It uses endogenous creatinine, which is produced at a
constant rate. The rate of production varies from
individual to Individual
 advantage of being easy to perform , is relatively
cheap, and readily available.
20

 less accurate than inulin clearance, because some
creatinine is cleared from plasma through proximal
tubular secretion
 CrCl overestimates true GFR, on average, by 10% to
20% becomes even more important as GFR declines,
because tubular secretion increases in response to
increasing serum creatinine level
 CrCl should be considered the “upper limit” of
the true GFR.
21

Plasma Markers
 simpler method to estimate GFR is
 use of plasma levels of substances that can be used as
surrogate markers of GFR.
 Three such substances have been used
Plasma creatinine (PCr)
Plasma urea
Plasma cystatin C
22

Plasma creatinine (PCr)
 most widely used plasma marker of GFR.
 rate depends upon muscle mass, influenced by age,
sex, and body mass.
 there is no single “normal” PCr that reflects a
“normal” GFR; it must be individualized for every
person.
 Reference values Males – 0.7 – 1.4 mg/dl
Female - 0.6 -1.3 mg/dl
23

 However, the relationship of PCr to GFR is relatively
constant
 changes in PCr can be used to predict corresponding
changes in GFR.
 As a rule of thumb, every 50% reduction in GFR
results in a doubling of PCr.
24

LIMITATIONS;
➢ GFR falls, tubular secretion of creatinine increases;
PCr may not change noticeably until there has been a
significant drop in GFR
➢ Creatinine production may increase in states of
increased muscle breakdown (e.g., rhabdomyolysis) or
with increased dietary protein intake or supplementation,
leading to an underestimation of true GFR.
➢ Creatinine production may decrease with liver
cirrhosis, leading to an overestimation of true GFR
25

Plasma urea
 another widely used plasma marker.
 Urea production and excretion is highly variable,
instance by dehydration, high-protein diets, and
increased tissue breakdown
 less reliable marker of GFR than is the PCr
 should not be used as the sole determinant.
26

Plasma cystatin C
 An endogenous protein found in all nucleated cells
 Potent inhibitor of lysosomal proteinease
 Constant rate of production unaffected by diet &
muscle mass,
 Not widely available at present, but likely will replace
PCr as the standard test in GFR assessment.
 Clinical uses in early kidney disease, kidney
transplant, AKI, role in CVD , Alzheimer’s disease
 Normal values - 0.8 to 1.2mg/dl
27

Mathematical Correction
 number of mathematical formulas to improve
the accuracy of the PCr estimation of GFR
 The two most widely used
➢ Cockcroft-Gault and
➢ “modification of diet in renal disease”(MDRD)
formulas.
28

Cockcroft-Gault
 simple formula to estimate CrCl (not GFR) that
corrects for age, sex,and body mass
 Crcl ={ ( 140- age) x IBW in kg / Pcr x 72 }
x 0.85 [ female]
 advantage of being very simple, but is not as
accurate as other methods when renal function is
impaired
29

MDRD formula
 simplest estimate of GFR is the four-variable equation
( Pcr, age, sex & ethinicity)
 GFR =I86 x [Pcr(mg/dl)]-1.154 x (age) -0.203 x
0.742[female] x 1.210[ african american]
 summary, - GFR is analogous to renal function.
approximated by creatinine clearance
formula based on age, weight, & serum
creatine
30

 Estimated GFR (eGFR) using Mayo Quadratic formula
e GFR = exp( 1.911+5.249/sr.creatine-2.114/ sr.creatine
- 0.00686 x age –(o.205 if female)
 Estimated GFR for children using Schwartz formula
e GFR= K x height/ sr.creatine
 Estimated GFR (eGFR) using the CKD-EPI formula
e GFR = 141 x min(sr. cr/k,1)9 x max ( sr.cr/ k,1)-1.209
x 0.993 age x (1.018 if female) x( 1.159 if black)
31

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Determinant of Glomerular Filtration

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