GFR estimation: the key to
assessment of kidney disease
Dr Graham Jones
Department of Chemical Pathology
St Vincent’s Hospital, Sydney
RCPA / AACB 2007 - GFR
Functions of the Kidney
• Homeostatic / waste removal
– water
– hydrogen ions (pH)
– sodium
– potassium
– calcium
– phosphate
– magnesium
– nitrogen
Kidney damage: abnormalities of these factors
RCPA / AACB 2007 - GFR
Homeostasis
• For a person in steady state: input = output
• Urine volume = water intake (food + drink)
- fecal, sweat, respiratory
losses
• Sodium excretion = sodium intake – fecal and
sweat losses
RCPA / AACB 2007 - GFR
Other Functions of the Kidney
• Endocrine
– 1-Hydroxylation of vitamin D
– Erythropoietin production
– Renin production
• Metabolic
– Glycogen storage (minor role)
• Drug removal
Kidney Damage: hypocalcaemia, anaemia
Impaired drug removal
Plus: acute phase changes
RCPA / AACB 2007 - GFR
CKD Symptoms
Tietz Textbook of Clinical Chemistry: Renal Function and Nitrogen Metabolites
RCPA / AACB 2007 - GFR
“Renal Failure”
• Chronic
– CKD: Chronic Kidney Disease
• Acute
– ARF: Acute Renal Failure
– AKI: Acute Kidney Injury
• Acute Classification
– Pre-renal
– Renal
– Post-renal
RCPA / AACB 2007 - GFR
The CKD problem
• Clinically silent in the early stages
• Cost of renal disease can be extreme to health
care service
• Effects of renal disease can be extreme on patient
• Treatments now available to slow progression
• Need an “early warning” system for CKD
RCPA / AACB 2007 - GFR
Diseases of the Kidney
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Diabetes
Hypertension
Atherosclerosis
Glomerular diseases
Toxins
– Gentamicin
– NSAIDS
– Compound analgesics
• Inherited diseases
• Tubular disorders
All global renal
diseases affect
glomerular filtration
rate (GFR)
RCPA / AACB 2007 - GFR
K/DOQI (USA)
RCPA / AACB 2007 - GFR
What is GFR?
• Glomerular Filtration Rate is the volume of fluid
passing through the glomerulus in a given period of
time.
• Influenced by renal perfusion pressure, renal
vascular resistance, glomerular damage, postglomerular resistance.
• “Normal Range” approx 90 - 150 mL/min
– Approx 170 L per day
• A larger healthy person has a higher GFR
– Can be reported as 90 - 150 mL/min/1.73m2
• Values fall with increasing age
RCPA / AACB 2007 - GFR
Other reasons for estimating the
GFR
• Monitoring progression of CKD
• GFR estimates are used for drug dosing decisions
– Dosing of renally excreted drugs
– Avoiding nephrotoxic drugs
• Risk factor for cardiovascular disease mortality
• Renal involvement in systemic diseases, such as
diabetes mellitus or SLE
RCPA / AACB 2007 - GFR
How do we measure GFR?
• Ideal marker of GFR:
– Constantly produced
– Freely filtered at the glomerulus
– Neither resorbed or secreted in the tubules
– Not lost to the body in any other way
• Inulin is the prototype GFR marker
– Sugar of MW 5,000
– Requires constant inulin infusion
– Not used in practice
RCPA / AACB 2007 - GFR
Measurement of GFR
• Cr51-EDTA, I125-iothalamate, Tc99-DTPA, iohexol
• Intravenous injection of substrate
• Measure concentrations in blood and or urine at
various time points
• Calculate clearance as estimate of GFR
• Time consuming
• Expensive
• Radioactive material
• Significant Between-laboratory variation (5-20%)
• “Gold standard” not very golden
RCPA / AACB 2007 - GFR
Estimate of GFR
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Measured GFR
Serum creatinine
Creatinine clearance
Formulae based on serum creatinine
– Cockcroft and Gault
– MDRD
All based on measurements
• Other
of serum creatinine
– Eg Cystatin C
RCPA / AACB 2007 - GFR
Marker of GFR (creatinine)
• Constant production 
• Freely filtered at the glomerulus 
• No tubular secretion or resorption
– Some tubular secretion X
• No extra-renal metabolism 
• No extra-renal loss
– Some GIT loss X
• Loss of creatinine through avenues other than
glomerular filtration means Creatinine Clearance
is slightly higher than the GFR
RCPA / AACB 2007 - GFR
Serum Creatinine Alone
• Default / Historical position
• Only marker universally available
– Only marker for screening (case finding)
• Concentration reflects rate of production as well as
rate of removal
• Relationship to rate of removal is not linear
– “rectangular hyperbola”
• Requires doctor to take multiple (non-linear)
factors into account
RCPA / AACB 2007 - GFR
Serum Creatinine (mg/dL)
S.creatinine approx. = 1/GFR
GFR
RCPA / AACB 2007 - GFR
Cockroft and Gault
• Developed in 1976 from 249 people (96%
male)
– Subsequently validated in at least 58 studies
• A measure of creatinine clearance
• Estimate urine creatinine based on age, weight
and sex of patient.
• False elevation of serum creatinine assays (in
1976) gave lower results, serendipitously
approximating the GFR
• Newer (better) creatinine assays give falsely
elevated GFR estimates (approx 15%)
RCPA / AACB 2007 - GFR
Cockcroft and Gault - questions
• Should we correct for “new” creatinine
measurements (decrease results by 15%)
• Should we use ideal body weight (estimated from
height)
– If so, when
RCPA / AACB 2007 - GFR
Creatinine Clearance
• Measurement of clearance of creatinine using:
– Serum creatinine concentration
– Timed urine collection (often 24 hours)
– Urine creatinine concentration
– Urine Volume
– Clearance = Ucreat x Uvol / Screat x 24 hours
• Timed urine samples notoriously difficult
RCPA / AACB 2007 - GFR
GFR Assessment
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Measured GFR
Serum creatinine
Creatinine Clearance
Cockcroft and Gault
• or one of over 40 other formulae using serum
creatinine
RCPA / AACB 2007 - GFR
MDRD* Formula
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Levey et al Ann Intern Med 130:461-470, 1999
Approx 1070 in training set and 558 validation set
New formula developed for GFR
More accurate and precise than other formulae
• *Modification of Diet in Renal Disease
RCPA / AACB 2007 - GFR
MDRD – Notes:
• Not good for people with normal renal function
– Few normals in training set
– Low creatinine measurement less good
• Results reported as mL/min/1.73 m2 BSA
– Good for grading renal failure
– Effect on drug dosing?
• “Abbreviated” MDRD only requires age, sex and
race (African-American or not)
RCPA / AACB 2007 - GFR
KHA, RCPA, AACB Proposal:
• Report estimated GFR with MDRD with all
creatinine requests for patients over 18
• Results >60 mL/min/1.73m2 reported as “>60
mL/min/1.73m2”
– to be extended to 90 mL/min/1.73m2
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Accuracy approximately +/- 30%
Recommended in USA (www.nkdep.nih.gov)
Recommended in UK (MDRD or C&G)
Law in France (C&G)
RCPA / AACB 2007 - GFR
www.nkdep.nih.gov
www.kidney.org/
PROFESSIONALS/kdoqi
www.kdigo.org
www.kidney.org.au
RCPA / AACB 2007 - GFR
Limitations
• Not a sensitive test for renal failure
– Serum creatinine best for early detection
and monitoring patients
• Delayed response in severe acute renal failure
(as with serum creatinine)
• Wrong in dialysis patients
• Drug dosing issues not well addressed
• Interpretation in the elderly
• Interpretation in different racial groups
RCPA / AACB 2007 - GFR
Actual Outcomes
• Almost universal uptake of eGFR reporting
• Near complete standardisation of units
– umol/L and mL/min
• Increase in referrals to nephrologists
– Initial spike
– Settled to approx. 30% increase
– 85% of referrals were appropriate
– Referrals were undertreated
• Professor David Johnston (Queensland)
• Awareness of reduced GFR increased
RCPA / AACB 2007 - GFR
Meeting 2
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December 2006
Issues
The “175” equation for IDMS-aligned assays
Reporting up to 90 mL/min/1.73m2
Age-related decision points
Drug Dosing
Racial differences
RCPA / AACB 2007 - GFR
The Future
• Better detection and management of CKD
• Better relationship with clinical colleagues
– Started on urine albumin and protein
– Starting on LFT and uric acid
• Recognition of role of laboratory
– Recognising and solving metrological issues
– Effector organ for clinical guidelines
• Better co-operation between laboratories for the
benefit of doctors and patients
RCPA / AACB 2007 - GFR
References
• Assessing Kidney Function - Measured and Estimated
Glomerular Filtration Rate
– Stevens LA et al. NEJM 2006;354:2473-83.
• Automated Reporting of Glomerular Filtration Rate - Just
what the doctor ordered.
– Levey AS et al. Clin Chem 2006;52:2188-93
• Australasian Creatinine Consensus Working Group.
Chronic Kidney Disease and Automatic Reporting of
eGFR. A position statement.
– Med J Aust. 2005;183:138-141
RCPA / AACB 2007 - GFR