9/24/2014

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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

9/24/2014

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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