1. 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

2. 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

3. 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

4. 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

5. RCPA / AACB 2007 - GFR CKD Symptoms Tietz Textbook of Clinical Chemistry: Renal Function and Nitrogen Metabolites

6. 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

7. 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

8. RCPA / AACB 2007 - GFR 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)

9. RCPA / AACB 2007 - GFR K/DOQI (USA)

10. 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, 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/1.73m 2 Values fall with increasing age

11. 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

12. 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

13. RCPA / AACB 2007 - GFR Measurement of GFR Cr 51 -EDTA, I 125 -iothalamate, Tc 99 -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

14. RCPA / AACB 2007 - GFR 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

15. 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

16. 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

17. RCPA / AACB 2007 - GFR S.creatinine approx. = 1/GFR GFR Serum Creatinine (mg/dL)

18. 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%)

19. 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

20. 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

21. RCPA / AACB 2007 - GFR GFR Assessment Measured GFR Serum creatinine Creatinine Clearance Cockcroft and Gault or one of over 40 other formulae using serum creatinine

22. RCPA / AACB 2007 - GFR 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

23. 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 m 2 BSA –Good for grading renal failure –Effect on drug dosing? “Abbreviated” MDRD only requires age, sex and race (African-American or not)

24. 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/1.73m 2 reported as “>60 mL/min/1.73m 2” –to be extended to 90 mL/min/1.73m 2 Accuracy approximately +/- 30% Recommended in USA (www.nkdep.nih.gov) Recommended in UK (MDRD or C&G) Law in France (C&G)

25. RCPA / AACB 2007 - GFR www.nkdep.nih.gov www.kidney.org/ PROFESSIONALS/kdoqi www.kdigo.org www.kidney.org.au

26. 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

27. 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

28. RCPA / AACB 2007 - GFR Meeting 2 December 2006 Issues The “175” equation for IDMS-aligned assays Reporting up to 90 mL/min/1.73m 2 Age-related decision points Drug Dosing Racial differences

29. 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

30. 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