RCPA / AACB 2007 - GFR GFR estimation: the key to assessment of kidney disease Dr Graham Jones Department of Chemical Pathology St Vincent’s Hospital,

RCPA / AACB 2007 - GFR

GFR estimation: the key to assessment of kidney disease

Dr Graham Jones

Department of Chemical Pathology

St Vincent’s Hospital, Sydney


Functions of the Kidney

• Homeostatic / waste removal– water– hydrogen ions (pH)– sodium– potassium– calcium– phosphate– magnesium– nitrogen

Kidney damage: abnormalities of these factors


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


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 removalPlus: acute phase changes


CKD Symptoms

Tietz Textbook of Clinical Chemistry: Renal Function and Nitrogen Metabolites


“Renal Failure”

• Chronic– CKD: Chronic Kidney Disease

• Acute– ARF: Acute Renal Failure– AKI: Acute Kidney Injury

• Acute Classification– Pre-renal– Renal– Post-renal


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


Diseases of the Kidney

• 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 - GFRK/DOQI (USA)

http://www.kidney.org/professionals/kdoqi/guidelines_ckd/Gif_File/kck_t10.gif


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, post-glomerular 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


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


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


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


Estimate of GFR

• Measured GFR

• Serum creatinine

• Creatinine clearance

• Formulae based on serum creatinine– Cockcroft and Gault– MDRD

• Other– Eg Cystatin C

All based on measurements of serum creatinine


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


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


S.creatinine approx. = 1/GFR

GFR

Ser

um C

reat

inin

e (m

g/dL

)


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%)


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


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


GFR Assessment

• Measured GFR

• Serum creatinine

• Creatinine Clearance

• Cockcroft and Gault

• or one of over 40 other formulae using serum creatinine


MDRD* Formula

• 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


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)


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

• Accuracy approximately +/- 30%

• Recommended in USA (www.nkdep.nih.gov)

• Recommended in UK (MDRD or C&G)

• Law in France (C&G)


www.nkdep.nih.gov

www.kidney.org/PROFESSIONALS/kdoqi

www.kdigo.org

www.kidney.org.au

http://www.nkdep.nih.gov/


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


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


Meeting 2

• 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


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


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 GFR estimation: the key to assessment of kidney disease Dr Graham Jones Department of Chemical Pathology St Vincent’s Hospital,

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