1. DR RANJIT SINGH
DNB TRAINEE
DR RMLIMS

2. Definition:
Rate at which a substance is cleared from the plasma in unit time by the glomeruli (in
ml/min)
i. Best for assessing excretory renal function
ii. Varies according to age/sex/body surface area (BSA)
iii. Also depends on renal blood flow and pressure
iv. Normal GFR = 125ml/min/1.73m2.
GLOMERULAR FILTERATION RATE:
GLOMERULAR FILTERATION RATE:
GFR declines with age after 40 years at 1ml/min/year due to progressive glomerular
sclerosis.

3.  Amount of plasma ultrafiltrate formed each minute
 Normal GFR : 125 ml/min ( in a healthy adult of average size)
 Or 7.5 L/hr or 180 L/day
 But urine output : about 1 L/day ( 99 % or more of the filtrate is normally
reabsorbed)
 10% lower in females
Plasma volume (70-kg young adult man) = about 3L
kidneys filter amount of fluid equal to 4 times of TBW, 15 times of ECF volume and
60 times theplasma volume in a day

4. Direct assessment
(Clearance Tests)
Indirect assessment
from
Substances

5.  Volume of plasma from which a substance is completely removed by the kidney in a given
amount of time ( usually minutes)
C = UV/P
C = clearance of substance (ml/min)
U=Concentration of substance in urine (mg/dl)
V=Volume of urine per min (ml/min)
P=concentration of substance in plasma (mg/dl)

6. Ideal agent for clearance studies:
No ideal agent has been found, however the agent used should fulfill most
of the following criteria :
• Distributed freely and instantaneously throughout the extracellular space
• Not bound to plasma proteins
• Freely filtered at the glomerulus
• Not secreted or absorbed at the tubules
• Eliminated wholly by the kidney
• Resistant to degradation
• Easy and inexpansive to measure

7. Agents used to estimate
GFR
EXOGENOUS COMPOUNDS
1. Inulin
2. 51Cr EDTA
3. DTPA
4. Iohexol
5. Iothalamate
ENOGENOUS COMPOUNDS
1. Creatinine
2. Cystatin C
3. Urea
4. Beta trace protein
5. Beta 2 microglobulin
6. Symmetrical
dimethylarginine

8.  Gold Standard filtration marker
 Polymer of fructose
 Distribute in ECF, does not bound to plasma proteins, freely filtered at
glomerulus
 Neither reabsorbed nor secreted by renal tubules
Method:
 Bolus dose is administered followed by constant i.v. infusion for maintaining
constant plasma levels
 Timed urine samples are collected and blood samples are obtained at mid
points of urine collection.

9. Disadvantage:
Rarely used in practice because
1. Time consuming
2. Expensive
3. Difficult to dissolve and maintain into solution
4. Need to maintain steady plasma levels
Normal Values of Inulin clearance:
Males : 125 ml/min/1.73 m2
Females: 110 ml/min/1.73 m2

11.  Most commonly used endogenous marker for measuring GFR
 Produced constantly from creatine in muscles
 completely filtered by glomeruli, not bound to plasma proteins, not reabsorbed
 But secreted by tubules
 Does not measure GFR but varies inversely with GFR and so is an indirect
marker of GFR
 Serum creatinine – used in estimation equations
 Urinary creatinine clearance- used to approximate GFR

12. factors affecting creatinine level
Muscle mass
age, sex, race and physical activity
Injury
rhabdomyolysis
Consumption of non vegetarian ( meat ) diet
factors affecting secretion of creatinine from renal tubules
(a) drugs : pyrimethamine, cimetidine, trimethoprim, dapsone
(b)decreased renal function: secretory procss is saturate when
S creat level exceeds 1.5 to 2 mg/dl

13. Creatinine clearance:
• 24 hour urine sample is preferred
• First voided sample is discarded, Subsequently all urine
passed is collected in containers. Next morning voided
sample is collected and all containers are sent to laboratory
• A blood sample is obtained at midpoint of urine collection
• Cimetidine which blocks renal secretion can be used to
prevent overestimation
• Final calculation is by the formula UV/P, (with adjustment
of 10% for secretion)

14. Disadvantages:
• Small amounts of creatinine secreted by renal tubules can
increase further in advanced renal failure
• Affected by intake of meat and muscle mass
• Collection of urine is incomplete/ inaccurate timed urine
collection
• Creatinine levels are affected by drugs such as cimetidine,
probenecid and trimethoprim that block tubular secretion.
• Nonlinear relationship between creatinine and GFR
- Compensatory hyperfiltration of remaining nephrons
- Secretion of creatinine
- Extrarenal elimination of creatinine as GFR declines

15.  LMW basic protein, produced at constant rate
 Freely filtered by kidney and is not secreted
 reabsorbed at PCT, catabolized and filtered, so can not be used
as a conventional urinary excretory marker for GFR
 Considered as one of the markers of kidney injury
Advantages
1. Independent of sex, muscle mass and age after 12 months of
age
2. Highest in the 1st days of life and stabilize after 1 yr of age

16. Disadvantages
1.Affected by factors independent of renal function:
corticosteroids use, thyroid dysfunction, obesity,
Smoking, Diabetes, high C reactive protein values.
2.Not suitable for transplant patients
subclinical inflammation and long use of steroids
3. Variation in production
4. Absence of universal assay standardization
5. Not shown superior to estimated eGFR using
Creatinine.

17. 1. Cockcroft-Gault : 1976
2. MDRD equation : 1999
MDRD equation without ethnicity factor
3. CKD-EPI equation : 2009
CKD-EPI cystatin C : 2012
CKD-EPI creatinine- cystatin C : 2012

18.  Cockcroft – Gault equation:
In 1969, 249 men
estimates creatinine clearance rather than GFR
Overestimates the GFR and should not be used
CrCl ( ml/min) =(140-age)x lean body weight (Kg)/Cr (mg.dl)x 72

19.  MDRD equation, 1999, 1628 subjects
 S creatinine ( jaffe method)
 Updated MDRD , 2004 ( IDMS
method)
 Compared against a gold standard,
urinary clearance of iothalamate
 Ideal between age group 18- 70 yrs
 Good for estimation if GFR <
60ml/min
 Limitations
Tendency to underestimate GFR
Low accuracy at higher GFR value
 CKD-EPI, 2009, 8254 subject
 Compared against a gold std, urinary
clearance of iothalamate
 Less biased and has greater accuracy
than MDRD equation especialy at higher
GFR
 Good for all age groups
 Updated CKD-EPI : 2012
(i)cystatin C ( not superior to creatinine)
(ii)cystatin C + serum creatinine ( more
accurate than either marker alone)

20. (A) CHILDREN- Adult GFR equations are inappropriate to asses GFR in children < 9 yrs
Schwartz equation : e GFR = k X L/S creat ( K depends upon age of child)
systematically overestimates GFR
cystatin C : more accurate than creatinine as an indirect marker of renal function in children
(C ) ACUTE KIDNEY INJURY- No steady creatinine state
Creatinine is insensitive to substantial decrease in GFR
needs kinetic estimation of GFR
best to asses for others new biomarkers ( more sensitive and early recognized)

21.  The current staging system for CKD is largely based on the notion that a
GFR >90 ml/min/1.73 m2 is normal;
60–89 ml/min/1.73 m2 is reduced
<60 ml/min/ 1.73 m2 is always abnormal
 This is a rigid approach which ignores biological variability and renal reserve
sufficient enough to meet homeostatic needs.
 The objective evidence for insufficiency of GFR or abnormal kidney function would
hypertension, a blunted erythropoietin axis causing anaemia, disturbed calcium and
phosphate balance causing secondary hyperparathyroidism.
 Homeostatic failure seems to occur with increasing frequency at a GFR < 60
ml/min/1.73 m2 and most obviously at <45 ml/min/ 1.73 m2 [5].
 A low GFR implies a reduced reserve and vulnerability to drug overdosing (especially
with water-soluble drugs that depend on GFR for excretion), and the insults which can
precipitate AKI.

22.  Structural changes: Increase in sclerotic glomeruli, less glomerular lobulation
 Increase in aglomerular arterioles- shunt from afferent to efferent side
 Thickening of basement membrane
 Hyalinosis of arterioles
 Decrease in glomeruli : Number of glomeruli decrease with age
 More sclerotic glomeruli- compensatory hyperfilteration which cause HTN and further
glomerular injury.
 Reduced permeability, reduced total surface area (fewer intact glomeruli)
 Sporodic Insults: Chronic systemic disease Accelerate renal aeging
 Scarring dur to AKI, Pyelonephritis, Hypotension
 Advanced Glycation End products
 Molecular Mechanisms: Telomere Shortening
 Oxidative Stress
 Impaired vasodilation: more dependent on prostaglandin and NO production for Vasodialation

23.  Lower creatinine production- decreased
muscle mass.
 Reduced dietary protein intake,
malnourishment reduce creatinine
Levels.
 Plasma creatinine may remain stable
despite loss of GFR in elderly.
 Non linear relationship between serum
creatinine and GFR.
 A numerically similar change in
creatinine indicate far greater
deterioration in kidney function for
patients with better preserved renal
function at baseline.

24.  Estimated GFR from serum creatinine:
- GFR can be calculated by equations that use age, weight, gender, race as surrogate markers for
creatinine generation.
- Despite ongoing refinements GFR estimates remain imprecise and none of the equations
expected to work well in patients with extreme levels of creatinine generation- ammputees, large
or small individuals, patients with muscle wasting, elderly patients .
- Equation Currently recommended for use:
- CKD EPI 2009- developed in large database including with and without kidney disease, diabetes
and history of organ transplantation. It includes age, race, sex and std creatinine and is accurate
across full range of GFR. 2012 KDIGO guidelines recommend that clinical laboratories use CKD-
EPI to report eGFR for all adults.
- Equations previously recommended for use:
- Cockcroft gault equation estimates CrCl from age, gender, body weight, serum creatinine.
- CG formula has several limitations- it is not precise if GFR is below 60.
- It estimates creatinine clearence rather than GFR therefore expected to over estimate GFR.
- It overestimates CrCl in edematous and obese individuals. In older indviduals will have lower
levels of eGFR according to CG formula.
- MDRD equation- Underestimates the measured GFR in populations with higher levels of GFR

25.  Estimated eGFR from Serum Cystatin C.
 Cystatin C is less affected by muscle mass than creatinine, but eGFR based on
Serum Cystatin C is not more accurate than eGFR by s.creatinine.. Equations
combining both these filtration markers appear to be more precise than equations
using either marker alone.
 The 2012 CKD – EPI cystatin c and Creatinine- cystatin c equations are
recommended by 2012 KDIGO guidelines.
 Drawbacks- Full implementation will require standardization, greater availability
and cost reduction of cystatin based assays.

26.  Neither the Cockcroft–Gault nor the 2 most frequently used estimating equations, the MDRD
study equation and the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation
were developed in older adults.
 Although the CKD-EPI incorporated approximately 650 participants in this age group .
 These equations are based on serum creatinine levels, which are influenced by alterations in
muscle mass and dietary protein intake as well as by chronic disease (common conditions in older
adults).
 Equations based on cystatin C, an alternative marker of GFR, may be advantageous at older ages.
However, validation studies using a reference method against a gold standard to measure GFR
are scarce.
 Elderly persons have generally been under represented— even in large cross-sectional data sets of
equation development for GFR.

27.  Berlin Initiative Study (BIS) – to assess kidney function in an elderly population-
based cohort by comparing existing equations with a gold standard measurement
and to derive a novel estimating equation that would estimate GFR more correctly
in persons aged 70 years or older.
 This is clinically relevant because it would lead to less misclassification of persons
 The final BIS2 equation for estimating GFR includes serum creatinine, serum
cystatin C, sex, and age:
 BIS2 = 767 x Cystatin C-0.61 x Creatinine-0.40 x age-0.57 x 0.87(if female)
 For practicability, developed a creatinine-based equation that did not include
cystatin C
 BIS1= 3736 x creatinine-0.87 x age-0.95 x 0.82 (if female).
 BIS includes only white participants with mild to moderately reduced kidney
function; thus, we can- not necessarily extend these results to other ethnicities or to
patients with more severe kidney function
 Iohexol measurements revealed lower GFRs than predicted by BIS equations used
to estimate GFR in participants aged 70 years or older who have normal or mild to
moderately reduced kidney function.
 The newly developed BIS equations may provide more precise and accurate tools for
estimating GFR in elderly age group.

28. Conclusions
• Serum creatinine concentration is an insensitive measure for evaluating renal function in the elderly
because it correlated poorly with the gold stand.
• Estimating the GFR based on serum cystatin C concentration has not been studied extensively in the
elderly.
• Based on the available studies, it is not possible to say which of these two formulas is better for
evaluating renal function in people aged 65 years and older.
• Guideline made no specific suggestions or recommendations for use of any markers in the elderly.
• However, because serum cystatin C is less dependent on muscle mass than serum creatinine and is
virtually completely cleared from the circulation by glomerular filtration with subsequent proximal
tubular uptake and degradation, it is generally considered as an ideal alternate marker of kidney
function, particularly in older individuals.
• Cystatin C in combination with creatinine appears to be superior in estimating GFR and needs to be
considered in special circumstances.
• BIS equations appear to be the more accurate in estimating GFR in the elderly but there is not yet any
recommendation for an eGFR equation specific to this age group.