Measuring GFR

Dr Jen Holness

Nuclear Medicine Division, Tygerberg Hospital and Stellenbosch University

23/09/2016

jen@sun.ac.za
 Aims

Understanding of
the principles of GFR

GFR-phobia
 Why?
• GFR is the best measure of kidney function

• GFR decreases before symptoms of kidney

failure develop
 Who?
• Kidney donors

• Patients on nephrotoxic drugs (e.g. chemotherapy)

• Patients with a single kidney

• Pre-surgery

• Patients with bilateral renal pathology (e.g. children with bilateral

PUJ obstruction)

• Anyone in whom an accurate measure of renal function is required

 How?
• GFR cannot be measured directly

• Rely on measurement of the clearance of an

endogenous/exogenous substance
 Measuring GFR
Inulin clearance
Increasing Increasing availability
complexity Clearance of other
exogenous substances Increasing use
Increasing cost (51Cr-EDTA, 99mTc-DTPA,
125I-iothalamate, iohexol)

Gamma-camera based methods

Creatinine Clearance

Estimated GFR

Serum creatinine
 Inulin clearance
Carbohydrate in the
A perfect GFR tracer… roots of certain plants

SHOULD :
– be freely filtered (low MW)
– have a stable plasma concentration
– be physiologically inert

SHOULD NOT :
– be reabsorbed
– be secreted
– be bound to proteins in the plasma
– be metabolised
– be excreted through other routes
 Inulin clearance
• Renal inulin clearance is the gold standard measure of
GFR

• Requires a constant plasma concentration – continuous

infusion is necessary

• Difficult to perform accurately

• Inconvenient for the patient

• Not feasible for everyday use

 Inulin clearance

Clearance of other
exogenous substances
(51Cr-EDTA, 99mTc-DTPA,
125I-iothalamate, iohexol)

Gamma-camera based methods

Creatinine Clearance

Estimated GFR

Serum creatinine
 Creatinine
For: Against:
• Cheap (~R30) • ~ 50% of nephron function
• Widely available is lost before creatinine
• 1 blood sample starts to rise
• Influenced by many factors:
– Diet
– Muscle mass
– Variable tubular secretion
884 μmol/L = 10 mg/dl

442 μmol/L = 5 mg/dl – Drugs (cimetidine,

176 μmol/L = 2 mg/dl trimethoprim)
88 μmol/L = 1 mg/dl
– Extra-renal excretion
 Inulin clearance

Clearance of other
exogenous substances
(51Cr-EDTA, 99mTc-DTPA,
125I-iothalamate, iohexol)

Gamma-camera based methods

Creatinine Clearance

Estimated GFR

Serum creatinine
 Estimated GFR (eGFR)
• Improve on sCr by correcting for a number of factors:
– Age
– Weight
– Gender
– Ethnicity
– Kidney function

• Commonly-used equations:
– Cockgroft-Gault
– MDRD NHLS gives an MDRD estimate
– CKD-EPI alongside every sCr value
Estimated GFR (eGFR)
The equations have all been
P30 shown to be inaccurate in South
• CG = 58 % Africans
• MDRD = 74 %

P30
• CG = 35-70 %
• MDRD = 36-69 %

P30 definition:
• Proportion of estimates within 30% of the true GFR
• E.g. if true GFR = 100 ml/min/1.73m2, what % of
estimates fall between 70 and 130 ml/min/1.73m2

P30
• CKD-EPI = 56 %
 Case 1
• JN, 55 yo female
• Stage IIIB cervix cancer for chemoradiation (Cisplatin)

• Baseline sCr = 77 μmol/L

• MDRD GFR = 68 ml/min/1.73m2 Cisplatin 

• mGFR = 41 ml/min/1.73m2 Cisplatin X

(contra-indicated)
 Case 2
• RS, 59 yo female
• High-grade NET – for chemotherapy

• sCr = 27 μmol/L
• MDRD GFR = > 200 ml/min/1.73m2

• mGFR = 97 ml/min/1.73m2
 Case 3
• JN, 22 yo male
• Testicular cancer for chemotherapy

• MDRD eGFR = 108 ml/min/1.73m2

• mGFR = 59 ml/min/1.73m2 Cisplatin
contra-indicated
• Repeat: MDRD = 131 ml/min/1.73m2
• Repeat: mGFR = 59 ml/min/1.73m2
 Inulin clearance

Clearance of other
exogenous substances
(51Cr-EDTA, 99mTc-DTPA,
125I-iothalamate, iohexol)

Gamma-camera based methods

Creatinine Clearance

Estimated GFR

Serum creatinine
 Creatinine clearance
For: Against:
• Still relatively cheap • 24h urine collection

• Widely available
• 24h urine collection + 1
blood sample
• Slightly more accurate
than sCr
• Influenced by many factors:
– Diet
– Muscle mass
Over-estimation
– Variable tubular secretion
of GFR – Drugs (cimetidine, trimethoprim)
– Extra-renal excretion
 Inulin clearance

Clearance of other
exogenous substances
(51Cr-EDTA, 99mTc-DTPA,
125I-iothalamate, iohexol)

Gamma-camera based methods

Creatinine Clearance

Estimated GFR

Serum creatinine
 Camera-based methods
• Principle:
– The initial tracer accumulation by the kidneys is
proportional to the renal clearance
• Method:
– Counts in the kidney at time (t)/counts injected
– Use a validated nomogram to convert the %
injected dose to a renal clearance value
 Camera-based methods
Pros 
• Reproducible1
• Superior to creatinine
clearance1
• Avoid sources of error
inherent in plasma sampling
techniques2
– Timing of plasma samples
– Dilution of standards
– Pipetting volumes
Cons 
• Less accurate than plasma
sampling techniques3
• Have their own sources of
error2
– Background subtraction
– Estimation of renal depth

1Halkar et al. Urology 2007;69:426–430

2Taylor.J Nucl Med 2014; 55:608-615
3Blaufox et al. J Nucl Med; 996;37:1883–1890
 Camera-based methods
• Commercial camera-based techniques are
available
• Ensure appropriate QC features have been
incorporated
• Ensure the vendor can provide citable
validation studies to confirm the performance
of the software1
Recommendation: perform validation
studies in your department before
1Taylor.
implementing routinely
J Nucl Med 2014; 55:608-615
 Inulin clearance

Clearance of other
exogenous substances
(51Cr-EDTA, 99mTc-DTPA,
125I-iothalamate, iohexol)

Gamma-camera based methods

Creatinine Clearance

Estimated GFR

Serum creatinine
Measuring GFR using other exogenous
substances
• GFR can be measured from the plasma or renal
clearance of:
– 51Cr-EDTA
– 99mTc-DTPA
– 125I-Iothalamate
– Iohexal

• All validated as suitable agents comparable to

inulin
 51Cr-EDTA vs. 99mTc DTPA
51Cr-EDTA 99mTc-DTPA

Freely filtered?  
Reabsorbed?  
Secreted?  
Extra-renal clearance?  
Metabolised?  
Protein-bound?  Probably similar*1  ~ 10%1
*conflicting data ranging from 0.5 % to 12 %

Mean GFR approximately 10 %

1Rehling et al. Nucl Med Commun 2001; 22:617-623
lower than inulin clearance
 51Cr-EDTA
51Cr-EDTA……320 keV; T ½ = 28 d
• More widely used 
• More published reference data 
• Low doses  low counts  poor
counting statistics
• Cannot image 
• But can perform 99mTc-MAG3
renogram simultaneously 
• Can delay counting
• Low radiation dose
vs. 99mTc DTPA
99mTc-DTPA……140 keV; T ½ = 6 h
• More widely available
• Cheaper 
• Good counting statistics 
• Can image (useful for donors) 
• Counting must be completed on
the day of the study
• Low radiation dose 
 51Cr-EDTA vs. 99mTc DTPA

• median bias <1%

• P30 = 93%
• P10 = 72%4

• Comparable1-4
• Recommendation: Choose either one and stick to it

1Rehling et al. Clin Sci.. 1979 1984;66(5):613-619

2Biggiet al. Eur J Nucl Med. 1995;22(6):532-536
3Fleming et al. Eur J Nucl Med. 1991;18(6):391-395
4Holness et al. Am J Kidney Dis. 2015; 65(5):806
Guidelines
Bi-exponential model

Blood Interstitial fluid

(+transcellular fluid)

Kidneys
plasma  interstitial fluid
plasma  kidneys

plasma interstitial fluid

plasma  kidneys
GFR is estimated from the area under this curve (AUC)
 y-intercept (~Vd)

GFR = k x Vd Slope-intercept method

 **Neglected first, fast exponential**

Apply a correction for it – currently recommended is the Brochner-Mortensen method1-2

***But 1st correct for body surface area***

1Brochner-Mortensen J et al. Scand J Clin Lab Invest 1972; 30:271-274

2Brochner-Mortensen J et al. Scand J Clin Lab Invest 1974; 33:139-143
 Slope-intercept QC
1.

Recommendation:
Wherever possible take
≥ 3 blood samples
 Slope-intercept QC
2.

plasma interstitial fluid

BNMS recommendation: The exact time to equilibration is

not known…do not take the 1st blood sample before 2 h
3. Slope-intercept QC
Interstitial fluid
Blood (+transcellular
fluid)

Kidneys

e.g. peritoneal cavity,

pleural cavity, eye, CSF

Large volume Increase volume Falsely high

ascites of distribution GFR

Recommendation: do not perform GFRs in patients

with ascites or pleural effusions (wait for it to resolve)
 Slope-intercept QC
4.
Recommendation: adhere to the BNMS guidelines1
 Example of errors
• 21-year-old man
• Kidney donor for his sibling
• True GFR = 105 ml/min/1.73m2
• Inexperienced radiographer does the pipetting of the 2h
samples
• He has had no training in pipetting technique
• (Pipetting is used because of its precision)
• Pipette volume should be 1 ml, but the volume pipetted for
one of the samples is 0.5 ml and the other 0.6 ml
• GFR calculated = 86 ml/min/1.73m2
• 18% difference
 Slope-intercept QC
5.
Recommendation: ensure adequate training of
radiographers/technologists performing the study

1Fleming JS et al. Nucl Med Commun 2004; 25:759-769

 Slope-intercept QC
6.
• However….had he incorrectly pipetted just
one of the 2 h samples (0.5 ml instead of 1 ml)
• GFR = 111 ml/min/1.73m2
• Only a 6% difference

Recommendation: always pipette duplicate samples

 Single-sample method
• Can GFR be calculated using just 1 blood
sample?
• Yes it can
• Principle: there is an inverse relationship
between GFR and plasma concentration at any
fixed time point
• Many equations published
• Recent systematic review1 found Fleming’s
method2 to be most accurate
1McMeekin H et al. Nucl Med Commun 2016; 37:743-755
2Fleming J et al. Nucl Med Commun 2005; 26:743-748
 Single-sample GFR
Advantages Disadvantages
• One blood sample from the • Cannot take blood sample
patient at 2 h (time depends on the
• Accuracy ≥ slope-intercept kidney function)
GFR • Loss of the majority of QC
checks
• Errors will go undetected

***Likely to become the recommended method in the updated

BNMS guidelines**
Recommendation: unless your department has the expertise and
years of practice, stick to the slope-intercept method
 Interpretation of results
• Refer to this paper for
reference data
• Largest of its kind using
51Cr-EDTA

• Also valid for 99mTc-

DTPA
 Interpretation of results
• A patient with a metastatic neuroendocrine tumour has a GFR
study
• Performed meticulously; no QC problems
• GFR = 100 ml/min/1.73m2
• Receives chemotherapy
• GFR is repeated after 3 cycles
• GFR now 88 ml/min/1.73m2

1. How do you interpret this result?

2. What will you say in your report?
 Interpretation of results
• Coefficients of variation for repeat
measurements are 8-10%

• A change of ≥ 20% is required before a

measured difference can be regarded as
significant1

1Fleming JS et al. Nucl Med Commun 2004; 25:759-769

 Interpretation of results
1. How do you interpret this result?
– Not statistically significant
– A drop from 100 to 88 ml/min/1.73m2 is a 12% decrease

2. What will you say in your report?

– There has been a decrease in the GFR
– Although this is not statistically significant (may be due to
normal day-to-day variation), a repeat study is suggested
after the next cycle of chemotherapy.
 Conclusion
1. Accurate measurement of GFR is essential in
certain patients
2. 99mTc-DTPA is as good as 51Cr-EDTA
3. Adhere strictly to the BNMS 2004 guidelines
4. Watch out for the updated guidelines
5. Ensure the radiographers/technologists
performing the studies are adequately trained
6. Perform all QC checks
7. Interpret the results wisely