Plasma Creatine estimation of GFR

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Plasma Creatine estimation of GFR

  1. 1. Plasma creatinine and the estimation of glomerular filtration rate (GFR) R Neil Dalton WellChild Laboratory King’s College London/ Guy’s Hospital ACB South West & Wessex Region Scientific Meeting Salisbury, 4 th July 2006
  2. 2. Glomerular Filtration Rate <ul><li>Why the sudden interest in estimating GFR from plasma creatinine? </li></ul><ul><li>Final realisation that a plasma creatinine normal range is meaningless </li></ul><ul><li>Conceptual difficulty relating plasma creatinine to GFR </li></ul><ul><li>Formulae attempting to fix the problem - eGFR </li></ul><ul><li>eGFR routine in paediatric nephrology for nearly 30y </li></ul>
  3. 3. The Glomerulus
  4. 4. Glomerular Filtration Rate <ul><li>fundamental to: </li></ul><ul><li>diagnosis of kidney disease </li></ul><ul><li>early detection </li></ul><ul><li>stratification </li></ul><ul><li>monitoring the progression of kidney disease </li></ul><ul><li>prognosis </li></ul><ul><li>efficacy of treatment </li></ul><ul><li>facilitate timing of therapeutic interventions </li></ul><ul><li>drug dosage </li></ul><ul><li>elimination of drugs/drug metabolites by the kidney </li></ul>
  5. 5. Glomerular Filtration Rate <ul><li>Glomerular filtration rate (GFR) is the clearance, by the kidney, of a marker in plasma, expressed as the volume of plasma completely cleared of the marker per unit time </li></ul><ul><li>UV ml/min </li></ul><ul><li>P . </li></ul><ul><li>Requires accurately timed urine collection! </li></ul>
  6. 6. Glomerular Filtration Rate <ul><li>The ideal marker is endogenous, freely filtered by the glomerulus, neither reabsorbed nor secreted by the kidney tubule, and eliminated only by the kidney </li></ul><ul><li>No ideal marker described! </li></ul><ul><li>Defined using exogenous markers, </li></ul><ul><li>primarily inulin </li></ul>
  7. 7. Glomerular Filtration Rate <ul><li>Hence, formal measurement of GFR rarely performed </li></ul><ul><li>Difficult! </li></ul><ul><li>Reliable? </li></ul><ul><li>Logistics of test performance </li></ul><ul><li>Radiochemical/biochemical tracer analysis </li></ul><ul><li>Failure to appreciate the clinical importance </li></ul>
  8. 8. Glomerular Filtration Rate <ul><li>Clinical importance </li></ul><ul><li>Detection of kidney disease </li></ul><ul><li>Cardiovascular risk </li></ul>
  9. 9. Glomerular Filtration Rate <ul><li>Compromise: </li></ul><ul><li>24h creatinine clearance </li></ul><ul><li>Ucr * V </li></ul><ul><li>Pcr </li></ul><ul><li>All the hassle and responsibility on the patient </li></ul><ul><li>As a result unreliable </li></ul><ul><li>Problem of tubular secretion of creatinine </li></ul>
  10. 10. Glomerular Filtration Rate <ul><li>Measurement of GFR in children with type 1 diabetes </li></ul><ul><li>Clearance Diabetics (n=11) Controls (n=12) </li></ul><ul><li>ml/min/1.73m 2 ml/min/1.73m 2 </li></ul><ul><li>Inulin 126 + 34 112 + 13 </li></ul><ul><li>Creatinine 172 + 45 (137%) 145 + 16 (129%) </li></ul><ul><li>51 Cr-EDTA 116 + 30 (92%) 104 + 13 (93%) </li></ul><ul><li>Diabetics, median age 13.9y (5.5-19.3) </li></ul><ul><li>Controls, median age 21.0y (16.2-34.0) </li></ul>
  11. 11. Glomerular Filtration Rate <ul><li>Further compromise: </li></ul><ul><li>24h creatinine clearance </li></ul><ul><li>Ucr * V </li></ul><ul><li>Pcr </li></ul><ul><li>Therefore, </li></ul><ul><li>creatinine clearance  1/Pcr </li></ul><ul><li>Only need to measure plasma creatinine! </li></ul>
  12. 12. Glomerular Filtration Rate <ul><li>Basics </li></ul><ul><li>As GFR declines, the elimination of a metabolite that relies on clearance by the kidney, e.g. creatinine, is maintained by increases in its plasma concentration </li></ul>
  13. 13. Glomerular Filtration Rate <ul><li>As kidney function declines urine creatinine excretion remains the same </li></ul><ul><li>i.e. creatinine excretion is independent of kidney function </li></ul><ul><li>creatinine clearance = (U cr x V)/P cr ml/min </li></ul><ul><li>Implies: creatinine clearance x P cr = U c r x V </li></ul><ul><li>C cr P cr U cr x V </li></ul><ul><li>ml/min µmol/l µmol/min </li></ul><ul><li>Subject A 120 70 8.4 </li></ul><ul><li>Subject B 60 140 8.4 </li></ul><ul><li>Subject C 30 280 8.4 </li></ul>
  14. 14. Serum creatinine v inulin clearance Shemesh O et al, Kidney International, 1985 predicted creatinine
  15. 15. Glomerular Filtration Rate <ul><li>Plasma creatinine determined by: </li></ul><ul><ul><li>GFR </li></ul></ul><ul><ul><li>secretion by kidney tubules </li></ul></ul><ul><ul><li>production rate </li></ul></ul><ul><li>children the worst case </li></ul><ul><li>– increasing production rate with age and anabolic growth spurts </li></ul><ul><li>Valuable demonstration of estimating GFR from plasma creatinine </li></ul>
  16. 16. Glomerular Filtration Rate Plasma creatinine v Inutest GFR in children
  17. 17. Glomerular Filtration Rate <ul><li>creatinine clearance  1/Pcr </li></ul>
  18. 18. Glomerular Filtration Rate 1/Pcr v Inutest GFR in children
  19. 19. Glomerular Filtration Rate <ul><li>creatinine clearance  1/Pcr </li></ul><ul><li>creatinine clearance = k/Pcr </li></ul>
  20. 20. Glomerular Filtration Rate <ul><li>creatinine clearance  1/Pcr </li></ul><ul><li>creatinine clearance = k/Pcr </li></ul><ul><li>Schwartz et al, 1976 </li></ul><ul><li>analysis of 1/Pcr, ht/PCr, & SA/Pcr v CrCl </li></ul><ul><li>best fit with height (length) </li></ul>
  21. 21. Glomerular Filtration Rate creatinine clearance v 0.55*ht(cm)/Pcr(mg/dl) in children (Schwartz et al, 1976)
  22. 22. Glomerular Filtration Rate <ul><li>k </li></ul><ul><li>Schwartz et al,1976 </li></ul><ul><li>0.55 (Pcr mg/dl) </li></ul><ul><li>48.6 (Pcr µmol/l) </li></ul><ul><li>creatinine clearance ml/min/1.73m 2 </li></ul><ul><li>Method: end-point Jaffe </li></ul>
  23. 23. Glomerular Filtration Rate <ul><li>k </li></ul><ul><li>Counahan et al, 1976 </li></ul><ul><li>0.43 (Pcr mg/dl) </li></ul><ul><li>38.0 (Pcr µmol/l) </li></ul><ul><li>51 Cr-EDTA plasma clearance ml/min/1.73m 2 </li></ul><ul><li>Method: ion exchange absorption, end-point Jaffe </li></ul>
  24. 24. Glomerular Filtration Rate <ul><li>k </li></ul><ul><li>Morris et al, 1982 </li></ul><ul><li>40.0 (Pcr µmol/l) </li></ul><ul><li>51 Cr-EDTA plasma clearance ml/min/1.73m 2 </li></ul><ul><li>Method: automated kinetic Jaffe </li></ul>
  25. 25. Glomerular Filtration Rate 35*ht/Pcr (MSMS) v Inutest plasma clearance ml/min/1.73m 2 in children
  26. 26. Glomerular Filtration Rate Difference plot 35*ht/Pcr (MSMS) – Inutest plasma clearance v Inutest plasma clearance ml/min/1.73m 2 in children
  27. 27. Glomerular Filtration Rate Lessons learned from paediatrics <ul><li>Can apply a simple formula to estimate a GFR from plasma creatinine, even in children, where creatinine production rate is increasing </li></ul><ul><li>Accuracy totally dependent on method for measuring plasma creatinine </li></ul><ul><li>Need to understand the measure of GFR any formula derived from </li></ul><ul><li>Does the formula correct for BSA, i.e. ml/min or ml/min/1.73m 2 ? </li></ul><ul><li>Despite good correlation for a population it is important to appreciate that there are wide limits of agreement </li></ul>
  28. 28. Glomerular Filtration Rate <ul><li>Application of a formula to estimate GFR from plasma creatinine in adults </li></ul><ul><li>We know plasma creatinine is a poor marker of glomerular filtration rate </li></ul>
  29. 29. Glomerular Filtration Rate Serum creatinine (MSMS) v formal GFR
  30. 30. Serum creatinine v inulin clearance Shemesh O et al, Kidney International, 1985 predicted creatinine
  31. 31. Glomerular Filtration Rate <ul><li>The early decline in GFR results in a relatively small increase in plasma creatinine </li></ul><ul><li>A population normal range is inappropriate </li></ul>
  32. 32. Biological Variation of Serum Creatinine Gowans & Fraser 1988, Ann. Clin. Biochem. 25:259-263
  33. 33. Glomerular Filtration Rate
  34. 34. Glomerular Filtration Rate
  35. 35. Glomerular Filtration Rate <ul><li>Application of a formula to estimate GFR from plasma creatinine in adults </li></ul><ul><li>Assumes individual production rates are predictable from demographics </li></ul><ul><li>Some reasonable measure of GFR essential for rationalisation of services for kidney disease </li></ul>
  36. 36. Glomerular Filtration Rate 16 March 1999 Volume 130 Number 6 Annals of Internal Medicine A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation Andrew S. Levey, MD; Juan P. Bosch, MD; Julia Breyer Lewis, MD; Tom Greene, PhD; Nancy Rogers, MS; and David Roth, MD, for the Modification of Diet in Renal Disease Study Group*
  37. 37. Glomerular Filtration Rate National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI)
  38. 38. Glomerular Filtration Rate NKF-K/DOQI guidelines GUIDELINE 4. ESTIMATION OF GFR Estimates of GFR are the best overall indices of the level of kidney function. The level of GFR should be estimated from prediction equations that take into account the serum creatinine concentration and some or all of the following variables: age, gender, race, and body size. The following equations provide useful estimates of GFR: In adults, the MDRD Study and Cockcroft-Gault equations. In children, the Schwartz and Counahan-Barratt equations.
  39. 39. Glomerular Filtration Rate NKF-K/DOQI guidelines The serum creatinine concentration alone should not be used to assess the level of kidney function. Clinical laboratories should report an estimate of GFR using a prediction equation, in addition to reporting the serum creatinine measurement. Autoanalyzer manufacturers and clinical laboratories should calibrate serum creatinine assays using an international standard. Measurement of creatinine clearance using timed (for example, 24-hour) urine collections does not improve the estimate of GFR over that provided by prediction equations.
  40. 40. Glomerular Filtration Rate NKF-K/DOQI guidelines A 24-hour urine sample provides useful information for: Estimation of GFR in individuals with exceptional dietary intake (vegetarian diet, creatine supplements) or muscle mass (amputation, malnutrition, muscle wasting); Assessment of diet and nutritional status; Need to start dialysis.
  41. 41. Glomerular Filtration Rate National Service Framework (NSF) for Renal Services Step three: Testing kidney function Local health organisations can work with pathology services and networks to develop protocols for measuring kidney function by serum creatinine concentration together with a formula-based estimation of glomerular filtration rate (estimated GFR), calculated and reported automatically by all clinical biochemistry laboratories.
  42. 42. Glomerular Filtration Rate National Service Framework (NSF) for Renal Services • QUALITY REQUIREMENT ONE: People at increased risk of developing or having undiagnosed chronic kidney disease, especially people with diabetes or hypertension, are identified, assessed and their condition managed to preserve their kidney function. Markers of good practice • All people at increased risk of CKD are identified, and given appropriate advice, treatment and support (which is sensitive to the differing needs of culturally diverse groups) to preserve their kidney function. • People identified as having an increased risk of CKD have their kidney function assessed and appropriately monitored, using estimated GFR. • Implementation of the NICE clinical guideline on the management of Type 1 diabetes. • Implementation of the NICE clinical guidelines on the management of Type 2 diabetes: renal disease; blood glucose; blood pressure and blood lipids. • Implementation of the NICE clinical guideline on the management of hypertension in adults in primary care. • For children and young people with potential urinary tract infection, accurate diagnosis and prompt antibiotic treatment, and investigation sufficient to identify structural renal defects and to prevent renal scarring. • For children and young people with bladder dysfunction, planned investigation and follow-up, with access to urology services with paediatric expertise.
  43. 43. Glomerular Filtration Rate Lessons learned from paediatrics <ul><li>Can apply a formula to estimate a GFR from plasma creatinine even in children where creatinine production rate is increasing </li></ul><ul><li>Accuracy totally dependent on method for measuring plasma creatinine </li></ul><ul><li>Need to understand the measure of GFR any formula derived from </li></ul><ul><li>Does the formula correct for BSA, i.e. ml/min or ml/min/1.73m 2 ? </li></ul><ul><li>Despite good correlation for a population it is important to appreciate that there are wide limits of agreement </li></ul>
  44. 44. Glomerular Filtration Rate <ul><li>Use of plasma creatinine for the estimation of GFR </li></ul><ul><li>Need to understand the factors on which a plasma creatinine depends </li></ul><ul><li>Need to appreciate the importance of the creatinine measurement </li></ul><ul><li>Need to understand the limitations of any formula derived eGFR </li></ul>
  45. 45. Glomerular Filtration Rate <ul><li>Factors affecting plasma creatinine </li></ul><ul><li>GFR, tubular secretion, production rate </li></ul><ul><li>Calculation of eGFR assumes that the rate of production is related to a series of demographics, </li></ul><ul><li>e.g. height, weight, sex, ethnic origin, age </li></ul><ul><li>Statistically may be true for a population but not necessarily for the individual </li></ul>
  46. 46. Limitations of plasma creatinine determination and eGFR <ul><ul><li>Age Wt Pcr GFR C&G GFR inulin </li></ul></ul><ul><ul><li>y kg µmol/l ml/min/1.73m 2 </li></ul></ul><ul><ul><li>Subject1 40 80 68 144 116 </li></ul></ul><ul><ul><li>Subject2 40 80 120 82 118 </li></ul></ul><ul><ul><li>Effect of 50% loss of renal function </li></ul></ul><ul><ul><li>Subject1 40 80 136 73 58 </li></ul></ul><ul><ul><li>Subject2 40 80 240 41 59 </li></ul></ul><ul><ul><li>Normal range for creatinine 55-120µmol/l </li></ul></ul>
  47. 47. Glomerular Filtration Rate <ul><li>Plasma creatinine measurement is critical </li></ul><ul><li>Accuracy very poor </li></ul><ul><li>Assays vary in standardisation, linearity, and relative interferences between and within supplier </li></ul>
  48. 48. Glomerular Filtration Rate <ul><li>Measurement of plasma creatinine </li></ul><ul><li>Comparison of various routine methods with isotope-dilution electrospray mass spectrometry-mass spectrometry </li></ul><ul><li>Fully validated method using a NIST traceable standard and EC certified reference materials </li></ul><ul><li>Between assay CV 2% </li></ul>
  49. 49. Plasma creatinine - isotope-dilution MSMS method comparison
  50. 50. Plasma creatinine - isotope-dilution MSMS method comparison
  51. 51. Plasma creatinine - isotope-dilution MSMS method comparison
  52. 52. Glomerular Filtration Rate
  53. 53. Glomerular Filtration Rate
  54. 54. Glomerular Filtration Rate
  55. 55. Glomerular Filtration Rate
  56. 56. Measurement of GFR
  57. 57. Glomerular Filtration Rate <ul><li>Plasma creatinine methods synonymous with lack of uniformity </li></ul><ul><li>Alignment with the MDRD formula laboratory would improve uniformity, but is wrong </li></ul><ul><li>Plasma creatinine: the importance of being consistently wrong </li></ul><ul><li>Finally, alignment with isotope dilution MS </li></ul>
  58. 58. Glomerular Filtration Rate <ul><li>Analytical variation in plasma creatinine will have a significant impact on estimated GFR (eGFR), e.g. Lamb et al. Susceptibility of glomerular filtration rate estimations to variations in creatinine methodology: a study in older patients. Ann Clin Biochem 2005 </li></ul>
  59. 59. Glomerular Filtration Rate <ul><li>Alignment of plasma creatinine standardisation and methodology, preferably to a true reference standard, could significantly improve the situation </li></ul><ul><li>However, interferences represent a major problem on a patient by patient basis, e.g. the impact of under-recognised renal failure in liver disease </li></ul><ul><li>Use eGFR in this patient group? </li></ul>
  60. 60. Glomerular Filtration Rate <ul><li>eGFR </li></ul><ul><li>The formulae </li></ul>
  61. 61. Glomerular Filtration Rate 16 March 1999 Volume 130 Number 6 Annals of Internal Medicine A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation Andrew S. Levey, MD; Juan P. Bosch, MD; Julia Breyer Lewis, MD; Tom Greene, PhD; Nancy Rogers, MS; and David Roth, MD, for the Modification of Diet in Renal Disease Study Group*
  62. 62. Glomerular Filtration Rate <ul><li>Levey et al, 1999 </li></ul><ul><li>Comparison of a range, 7 in total, of eGFR formulae </li></ul><ul><li>True GFR measure </li></ul><ul><li>radioactive iothalamate clearance </li></ul>
  63. 63. Glomerular Filtration Rate <ul><li>Equation 1: Serum creatinine </li></ul><ul><li>GFR (ml/min/1.73m 2 ) = 0.69 * [100/Pcr] </li></ul><ul><li>Equation 2: Cockcroft–Gault formula </li></ul><ul><li>GFR (ml/min) = 0.84 * [(140-age) * wt]/(Pcr * 72 ) note for females 85 </li></ul><ul><li>Equation 3: Creatinine clearance </li></ul><ul><li>GFR (ml/min) = 0.81 * [Ccr] </li></ul><ul><li>Equation 4: Average of creatinine and urea clearance </li></ul><ul><li>GFR (ml/min/1.73m 2 ) = 1.11 * [(Ccr + Curea)/2] </li></ul><ul><li>Equation 5: Creatinine clearance, urea clearance, and demographic variables </li></ul><ul><li>GFR (ml/min/1.73m 2 ) = 1.04 * [Ccr] 0.751 * [Curea] 0.226 * [1.109 if patient is black] </li></ul>
  64. 64. Glomerular Filtration Rate <ul><li>Equation 6: Demographic, serum, and urine variables </li></ul><ul><li>GFR (ml/min/1.73m 2 ) = 198 * [Pcr] -0.858 * [Age] -0.167 * [0.822 if patient is female] * [1.178 if patient is black] * [SUN] -0.293 * [UUN] 0.249 </li></ul><ul><li>Equation 7: Demographic and serum variables only </li></ul><ul><li>GFR (ml/min/1.73m 2 ) = 170 * [Pcr] -0.999 * [Age] -0.176 * [0.762 if patient is female] * [1.180 if patient is black] * [SUN] -0.170 * [Alb] 0.318 </li></ul><ul><li>Reduced/practical MDRD formula: </li></ul><ul><li>GFR (ml/min/1.73m 2 ) = 186 ( 175 ) * [Pcr /88.4 ] -1.154 * [Age] -0.203 * [0.742 if patient is female] * [1.121 if patient is black] </li></ul>
  65. 65. Glomerular Filtration Rate <ul><li>No bias </li></ul><ul><li>Equation 6 the most precise, R 2 =91.2% </li></ul><ul><li>Equation 7, R 2 =90.3% </li></ul><ul><li>Reduced formula only appeared in abstract form, performance equivalent to equation 7 </li></ul>
  66. 66. Glomerular Filtration Rate
  67. 67. Glomerular Filtration Rate <ul><li>90 th centile %age absolute errors </li></ul><ul><li>19.1 ml/min/1.73m 2 (47.5%) for Cockcroft & Gault formula </li></ul><ul><li>12.9 ml/min/1.73m 2 (28.4%) for equation 7 </li></ul><ul><li>A more accurate method to estimate GFR </li></ul><ul><li>Good enough? </li></ul>
  68. 68. Glomerular Filtration Rate
  69. 69. Glomerular Filtration Rate <ul><li>Limits of agreement a problem </li></ul><ul><li>NB the study done in one laboratory with a particular creatinine method </li></ul><ul><li>In practice, without equivalence of creatinine methods eGFR not going to be clinically useful </li></ul><ul><li>MDRD with ECOS (evolving connectionist systems)? </li></ul>
  70. 70. Glomerular Filtration Rate <ul><li>Limits of agreement a problem </li></ul><ul><li>Even with equivalence of creatinine methods eGFR will not significantly improve early detection </li></ul><ul><li>eGFR of 80ml/min/1.73m 2 could be anywhere from 56 to 104ml/min/1.73m 2 – 90% of the time! </li></ul><ul><li>Only reporting values <60 ml/min/1.73m 2 while prudent does not improve early detection </li></ul>
  71. 71. Biological Variation of Serum Creatinine Gowans & Fraser 1988, Ann. Clin. Biochem. 25:259-263
  72. 72. Glomerular Filtration Rate <ul><li>The key to early detection of renal disease using plasma creatinine is to provide an assay with excellent between assay precision and monitor change </li></ul><ul><li>True primary care medicine </li></ul><ul><li>Urinary albumin/creatinine ratio? </li></ul>
  73. 73. Glomerular Filtration Rate <ul><li>Limits of agreement also a problem </li></ul><ul><li>for classification of disease stage </li></ul><ul><li>eGFR useful for monitoring progression of kidney disease once baseline established using formal GFR but so is plasma creatinine </li></ul><ul><li>Beware therapeutics affecting creatinine production, e.g. fibrates, and/or tubular secretion, e.g. cimetidine </li></ul>
  74. 74. Glomerular Filtration Rate <ul><li>Actions </li></ul><ul><li>Improve creatinine standardisation and methodology </li></ul><ul><li>Quote limits with every eGFR report </li></ul><ul><li>Develop a formula relevant to the UK demographic using a valid renal clearance technique (i.e. collect some urine!) </li></ul><ul><li>Early detection of kidney disease requires a better plasma marker </li></ul><ul><li>Cystatin C any better? </li></ul>
  75. 75. Measurement of GFR <ul><li>Early detection of kidney disease and appropriate staging remains a challenge </li></ul><ul><li>eGFR is a significant start, provided all associated professionals understand what it means </li></ul><ul><li>Kidney disease is a major public health problem and a significant determinant of cardiovascular risk that necessitates early detection and treatment </li></ul>
  76. 76. Measurement of GFR <ul><li>Beware: Deacon’s Challenge No:54 </li></ul><ul><li>Complexity of eGFR calculation </li></ul><ul><li>MDRD eGFR 41ml/min/1.73m 2 </li></ul><ul><li>Creatinine clearance 29ml/min </li></ul><ul><li>Comments: </li></ul><ul><li>inaccuracy of timed urine collection </li></ul><ul><li>failure to correct Ccr for BSA </li></ul><ul><li>Ccr should always be corrected for BSA </li></ul><ul><li>creatinine is secreted by tubules so Ccr is always higher than GFR </li></ul><ul><li>the 2 values are actually within the limits of agreement of the 2 methods – that is the problem! </li></ul>
  77. 77. Acknowledgements <ul><li>Charles Turner </li></ul><ul><li>Edmund Lamb and colleagues </li></ul><ul><li>Finlay McKenzie </li></ul><ul><li>Frederick van Lente </li></ul><ul><li>Carlo Donadio </li></ul><ul><li>The WellChild Trust </li></ul><ul><li>Guy’s & St Thomas’ Charity </li></ul><ul><li>Guy’s & St Thomas’ NHS Foundation Trust </li></ul>

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