eGFRand CystatinC as Predictors of Mortality & Morbidity · Serum Cr GFR 1 3 5 10 Cr = 1.0 mg/dl Cr...
Transcript of eGFRand CystatinC as Predictors of Mortality & Morbidity · Serum Cr GFR 1 3 5 10 Cr = 1.0 mg/dl Cr...
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Dan Negoianu, M.D.
Assistant Professor of Clinical Medicine
Medical Director, Inpatient Dialysis and Ultrafiltration
Hospital of the University of Pennsylvania
eGFR and Cystatin C as
Predictors of Mortality & Morbidity
Goals
• Describe the function of the kidney
• Identify glomerular filtration rate (GFR) as
the key metric of kidney function
• Explain how GFR is measured
• Discuss GFR estimation equations
• Describe how GFR is related to patient
outcomes
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Goals
• Describe the function of the kidney
• Identify glomerular filtration rate (GFR) as
the key metric of kidney function
• Explain how GFR is measured
• Discuss GFR estimation equations
• Describe how GFR is related to patient
outcomes
The Kidney is A Filter
• What kind of filter that gets rid of poisons
you did not know about when you built it?
• A filter that throws everything away and
then takes back the stuff you want
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The Kidney is A Filter Like That
• Each kidney is made up of about one
million tiny filters
• Each filter is called a nephron
• Each nephron has two parts:
– A tuft of capillaries that “throws away” about a fifth of the plasma flowing through it
– A long tubule that reabsorbs about 99% of the fluid that was thrown away
The Nephron
http://home.comcast.net/~llpellegrini/urinarysystem.htm
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The Glomerulus
http://en.wikipedia.org/wiki/File:Gray1130.svg
The Tubule
http://en.wikipedia.org/wiki/File:2618_Nephron_Secretion_Reabsorption.jpg
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Summary Schematic
http://en.wikipedia.org/wiki/File:Physiology_of_Nephron.png
Glomerular Filtration
http://en.wikipedia.org/wiki/File:Physiology_of_Nephron.png
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Reabsorption
http://en.wikipedia.org/wiki/File:Physiology_of_Nephron.png
Secretion
http://en.wikipedia.org/wiki/File:Physiology_of_Nephron.png
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Net Excretion
http://en.wikipedia.org/wiki/File:Physiology_of_Nephron.png
GFR is the Major Measure of
Kidney Function• Glomerular Filtration
Rate (GFR):
– Volume squeezed through the glomerulus per minute
– About 100ml/min in a “normal-sized” adult
– 144 liters per day
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GFR is the Major Measure of
Kidney Function• Decreased GFR is
evidence of kidney
disease
Other Evidence of Kidney Disease
• Remember when I
said that the
glomerulus throws
“everything” away?
• Not quite true
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• Healthy glomeruli
prevent certain things
from being filtered
– Red Blood Cells
– Protein (albumin)
– If these are in the urine, then kidney disease may be present even with normal GFR
Other Evidence of Kidney Disease
GFR is the Major Measure of
Kidney Function
http://en.wikipedia.org/wiki/File:Physiology_of_Nephron.png
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Goals
• Describe the function of the kidney
• Identify glomerular filtration rate (GFR) as
the key metric of kidney function
• Explain how GFR is measured
• Discuss GFR estimation equations
• Describe how GFR is related to patient
outcomes
How To Measure GFR?
• Substance that:
– Is filtered
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How To Measure GFR?
• Substance that:
– Is filtered
– Not reabsorbed
How To Measure GFR?
• Substance that:
– Is filtered
– Not reabsorbed
– Not secreted
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How To Measure GFR?
• Then measure:
– Concentration in the blood
How To Measure GFR?
• Then measure:
– Concentration in the blood
– The rate it is excreted
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How To Measure GFR?
• Substances that are:
– Filtered
– Not reabsorbed
– Not secreted
• No substances
produced by the
body have these
perfect qualities
How To Measure GFR?
• Artificial
Substances:
– Inulin
– Iothalamate
– Iohexol
• Need to be injected
• Not practical
• Only used in
research
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How To Measure GFR?
• Endogenous
Substance: Creatinine
– Made by muscle
– Filtered
– Not reabsorbed
– BUT, does have some secretion
• About 20%
• (This is variable)
How To Measure GFR?
• In the past, kidney function was often
estimated just by looking at serum levels
of creatinine
• Serum level of creatinine will rise if GFR
drops
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0
20
40
60
80
100
120
0 2 4 6 8 10 12
Serum Cr
GF
R
1 3 5
10
Cr = 1.0 mg/dl
Cr = 1.5 mg/dl
Cr = 2.0 mg/dl
Theoretical Curve
Issues with Creatinine
• It’s Made By Muscle
• People with more
muscle produce more
creatinine in day
• Creatinine of 1.5 mg/dl
may be normal for some
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Issues with Creatinine
• But not others
Issues with Creatinine
• This problem can be solved by collecting
urine for 24 hours
• This allows the amount of creatinine
produced to be measured
• Plasma creatinine concentration is also
measured
• Volume of plasma that has been “cleared”
of creatinine can then be calculated
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Creatinine Clearance Equation
• Assume that all creatinine is removed by
GFR, then:
– GFR = [UCr x V]/SCr
– This assumption is imperfect, since some creatinine is removed by excretion
• 24-hour urine collection is impractical
– It is used clinicaly, but rarely
Next Step
• Can kidney function be estimated from
blood tests alone?
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Goals
• Describe the function of the kidney
• Identify glomerular filtration rate (GFR) as
the key metric of kidney function
• Explain how GFR is measured
• Discuss GFR estimation equations
• Describe how GFR is related to patient
outcomes
Cockcroft-Gault Equation
• Oldest equation
• In 249 patients, measured:
1. 24-hour urine creatinine excretion
2. Serum creatinine level
• Used linear regression to derive:
(140 - age) x weight [kg]
CCr (mL/min) = ———————————
Cr [mg/dL] x 72
Cockcroft DW, Gault MH. Nephron. 1976;16(1):31-41.
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Cockcroft-Gault Equation
(140 - age) x weight [kg]
CCr (mL/min) = ———————————
Cr [mg/dL] x 72
• Multiple the above by 0.85 for women
Cockcroft DW, Gault MH. Nephron. 1976;16(1):31-41.
Cockcroft-Gault Equation
(140 - age) x weight [kg]
CCr (mL/min) = ———————————
Cr [mg/dL] x 72
• Multiple the above by 0.85 for women
• In essence, Cockroft-Gault attempts to
account for muscle mass
Cockcroft DW, Gault MH. Nephron. 1976;16(1):31-41.
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Cockcroft-Gault Equation
• Because it’s the oldest equation, is used
for many drug dosing guidelines
• RARELY used clinically because of many
limitations:
Cockcroft DW, Gault MH. Nephron. 1976;16(1):31-41.
Cockcroft-Gault Equation
• Because it’s the oldest equation, is used
for many drug dosing guidelines
• RARELY used clinically because of many
limitations:
– It’s not 1976
Cockcroft DW, Gault MH. Nephron. 1976;16(1):31-41.
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Cockcroft-Gault Equation
• Because it’s the oldest equation, is used
for many drug dosing guidelines
• RARELY used clinically because of many
limitations:
– It’s not 1976
• Body weight today is more likely to come from fat
• Laboratory creatinine assays have changed
• Because of this it tends to over-estimate creatinine
clearance
Cockcroft DW, Gault MH. Nephron. 1976;16(1):31-41.
Cockcroft-Gault Equation
• Because it’s the oldest equation, is used
for many drug dosing guidelines
• Otherwise is RARELY used clinically
because of many limitations:
– It’s not 1976
• Body weight today is more likely to come from fat
• Laboratory creatinine assays have changed
• Because of this it tends to over-estimate creatinine
clearance
– Weight can be surprisingly difficult to getCockcroft DW, Gault MH. Nephron. 1976;16(1):31-41.
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MDRD Equation
• Modification of Diet in Renal Disease
Study was an RCT in which subjects had:
– GFR measured by iothalamate clearance
– Serum creatinine measured
– Many other lab data as well
• Used to derive the “MDRD equation”
– Simplified form of this equation is the dominant clinical tool for estimated GFR today
Levey et al. Ann Intern Med. 2006;145:247-254
Levey et al. Ann Intern Med. 1999; 130:461-470.
GFR = 175 x Screat-1.154 x age-0.203 x
1.212 [if black] x 0.742 [if female]
• Needs a calculator/computer
• Data easy to obtain
• What happened to body weight though?
• Output of the equation is ml/min/1.73m2
Body Surface Area
• Body Surface Area (BSA) is calculated by
weight and height
Levey et al. Ann Intern Med. 2006;145:247-254
Levey et al. Ann Intern Med. 1999; 130:461-470.
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MDRD eGFR Co-incided with
New Definition of
Chronic Kidney Disease (CKD)
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm
Limitations of MDRD
• Derived from a population with average
GFR 40 ml/min/1.73m2
– Few patients with normal/near normal GFR
• Tends to under-estimate GFR in patients
with true GFR>60 ml/min/1.73m2
Poggio et al. J Am Soc Nephrol. 2005;16(2):459
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eGFR Alone Can Only Define
CKD if < 60 ml/min/1.73m2
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm
For Stage 1 or 2, Additional
Evidence of CKD is needed
http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm
• Proteinuria
• Hematuria
• Abnormal Kidneys
on Imaging
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• Proteinuria
• Hematuria
• Abnormal Kidneys on Imaging
Significant Imprecision
Stevens et al. J Am Soc Nephrol 18: 2749–2757, 2007
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CKD-EPI Equation Attempts to
Do Better at High GFR
Stevens et al. Ann Intern
Med. 2009; 150:604-612
Benefits Modest for GFR<60
Stevens et al. Ann Intern
Med. 2009; 150:604-612
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Major Variability Still Present
• Creatinine is produced by muscle
• Non-GFR variability of creatinine
essentially unavoidable
• Is there a molecule that is not produced by
muscle that could be used?
Cystatin C
• Protein that is produced by all cells
• Freely filtered
• Broken down by tubular cells, but not
reabsorbed
• Much less clinical experience with this
metric
Filler et al Clinical Biochemistry 38 (2005) 1 – 8
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How to Demonstrate Utility?
Goals
• Describe the function of the kidney
• Identify glomerular filtration rate (GFR) as
the key metric of kidney function
• Explain how GFR is measured
• Discuss GFR estimation equations
• Describe how estimated GFR is related to
patient outcomes
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• Meta-analysis of 16 cohorts with total of
93,710 patients
• Attempted to look at associated of death
and other outcomes with different eGFR
estimates
Shilpak et al. N Engl J Med 2013;369:932-43.
Shilpak et al. N Engl J Med 2013;369:932-43.
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Shilpak et al. N Engl J
Med 2013;369:932-43.
Reclassification with Cystatin
Shilpak et al. N Engl J Med 2013;369:932-43.
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Reclassification with Cystatin
Shilpak et al. N Engl J Med 2013;369:932-43.
Shilpak et al. N Engl J Med 2013;369:932-43.
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Shilpak et al. N Engl J Med 2013;369:932-43.
Shilpak et al. N Engl J Med 2013;369:932-43.
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Shilpak et al. N Engl J Med 2013;369:932-43.
One Would Expect These
Findings• Low Creatinine is both “good” and “bad”
• “Good” because associated with high GFR
• “Bad” because associated with low muscle
mass/malnutrition
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So we should all be using
Cystatin C, right?
Not So Fast
• It is very rarely checked
• More expensive and less available than
creatinine
• Less clinical experience
• Clinicians often care more about trends of
eGFR than the absolute value, since
precision is poor for all methods
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Summary
• GFR is the major metric of kidney function
• It is difficult to measure with precision in
clinical practice
• In the research setting, Cystatin C may
offer advantages in predicting outcomes
• It’s real-world utility is currently limited,
since it is not routinely ordered by
clinicians