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Plasma creatinine and the estimation of glomerular filtration rate (GFR)

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. Glomerular Filtration Rate.

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Plasma creatinine and the estimation of glomerular filtration rate (GFR)

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  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, 4th July 2006

  2. Glomerular Filtration Rate Why the sudden interest in estimating GFR from plasma creatinine? Final realisation that a plasma creatinine normal range is meaningless Conceptual difficulty relating plasma creatinine to GFR Formulae attempting to fix the problem - eGFR eGFR routine in paediatric nephrology for nearly 30y

  3. The Glomerulus

  4. Glomerular Filtration Rate fundamental to: diagnosis of kidney disease early detection stratification monitoring the progression of kidney disease prognosis efficacy of treatment facilitate timing of therapeutic interventions drug dosage elimination of drugs/drug metabolites by the kidney

  5. Glomerular Filtration Rate 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 UV ml/min P . Requires accurately timed urine collection!

  6. Glomerular Filtration Rate The ideal marker is endogenous, freely filtered by the glomerulus, neither reabsorbed nor secreted by the kidney tubule, and eliminated only by the kidney No ideal marker described! Defined using exogenous markers, primarily inulin

  7. Glomerular Filtration Rate Hence, formal measurement of GFR rarely performed Difficult! Reliable? Logistics of test performance Radiochemical/biochemical tracer analysis Failure to appreciate the clinical importance

  8. Glomerular Filtration Rate Clinical importance Detection of kidney disease Cardiovascular risk

  9. Glomerular Filtration Rate Compromise: 24h creatinine clearance Ucr * V Pcr All the hassle and responsibility on the patient As a result unreliable Problem of tubular secretion of creatinine

  10. Glomerular Filtration Rate Measurement of GFR in children with type 1 diabetes Clearance Diabetics (n=11) Controls (n=12) ml/min/1.73m2 ml/min/1.73m2 Inulin 126 + 34 112 + 13 Creatinine 172 + 45 (137%) 145 + 16 (129%) 51Cr-EDTA 116 + 30 (92%) 104 + 13 (93%) Diabetics, median age 13.9y (5.5-19.3) Controls, median age 21.0y (16.2-34.0)

  11. Glomerular Filtration Rate Further compromise: 24h creatinine clearance Ucr * V Pcr Therefore, creatinine clearance µ 1/Pcr Only need to measure plasma creatinine!

  12. Glomerular Filtration Rate Basics 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

  13. Glomerular Filtration Rate As kidney function declines urine creatinine excretion remains the same i.e. creatinine excretion is independent of kidney function creatinine clearance = (Ucr x V)/Pcr ml/min Implies: creatinine clearance x Pcr = Uc rx V Ccr Pcr Ucr x V ml/min µmol/l µmol/min Subject A 120 70 8.4 Subject B 60 140 8.4 Subject C 30 280 8.4

  14. Serum creatinine v inulin clearanceShemesh O et al, Kidney International, 1985 predicted creatinine

  15. Glomerular Filtration Rate Plasma creatinine determined by: GFR secretion by kidney tubules production rate children the worst case – increasing production rate with age and anabolic growth spurts Valuable demonstration of estimating GFR from plasma creatinine

  16. Glomerular Filtration RatePlasma creatinine v Inutest GFR in children

  17. Glomerular Filtration Rate creatinine clearance µ 1/Pcr

  18. Glomerular Filtration Rate1/Pcr v Inutest GFR in children

  19. Glomerular Filtration Rate creatinine clearance µ 1/Pcr creatinine clearance = k/Pcr

  20. Glomerular Filtration Rate creatinine clearance µ 1/Pcr creatinine clearance = k/Pcr Schwartz et al, 1976 analysis of 1/Pcr, ht/PCr, & SA/Pcr v CrCl best fit with height (length)

  21. Glomerular Filtration Ratecreatinine clearance v 0.55*ht(cm)/Pcr(mg/dl) in children (Schwartz et al, 1976)

  22. Glomerular Filtration Rate k Schwartz et al,1976 0.55 (Pcr mg/dl) 48.6 (Pcr µmol/l) creatinine clearance ml/min/1.73m2 Method: end-point Jaffe

  23. Glomerular Filtration Rate k Counahan et al, 1976 0.43 (Pcr mg/dl) 38.0 (Pcr µmol/l) 51Cr-EDTA plasma clearance ml/min/1.73m2 Method: ion exchange absorption, end-point Jaffe

  24. Glomerular Filtration Rate k Morris et al, 1982 40.0 (Pcr µmol/l) 51Cr-EDTA plasma clearance ml/min/1.73m2 Method: automated kinetic Jaffe

  25. Glomerular Filtration Rate35*ht/Pcr (MSMS) v Inutest plasma clearance ml/min/1.73m2 in children

  26. Glomerular Filtration RateDifference plot35*ht/Pcr (MSMS) – Inutest plasma clearance v Inutest plasma clearance ml/min/1.73m2 in children

  27. Glomerular Filtration RateLessons learned from paediatrics • Can apply a simple formula to estimate a GFR from plasma creatinine, even in children, where creatinine production rate is increasing • Accuracy totally dependent on method for measuring plasma creatinine • Need to understand the measure of GFR any formula derived from • Does the formula correct for BSA, i.e. ml/min or ml/min/1.73m2? • Despite good correlation for a population it is important to appreciate that there are wide limits of agreement

  28. Glomerular Filtration Rate Application of a formula to estimate GFR from plasma creatinine in adults We know plasma creatinine is a poor marker of glomerular filtration rate

  29. Glomerular Filtration RateSerum creatinine (MSMS) v formal GFR

  30. Serum creatinine v inulin clearanceShemesh O et al, Kidney International, 1985 predicted creatinine

  31. Glomerular Filtration Rate The early decline in GFR results in a relatively small increase in plasma creatinine A population normal range is inappropriate

  32. Biological Variation of Serum CreatinineGowans & Fraser 1988, Ann. Clin. Biochem. 25:259-263

  33. Glomerular Filtration Rate

  34. Glomerular Filtration Rate

  35. Glomerular Filtration Rate Application of a formula to estimate GFR from plasma creatinine in adults Assumes individual production rates are predictable from demographics Some reasonable measure of GFR essential for rationalisation of services for kidney disease

  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. Glomerular Filtration RateNational Kidney Foundation (NKF)Kidney Disease Outcomes Quality Initiative (K/DOQI)

  38. Glomerular Filtration RateNKF-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. Glomerular Filtration RateNKF-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. Glomerular Filtration RateNKF-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. Glomerular Filtration RateNational 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. Glomerular Filtration RateNational 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. Glomerular Filtration RateLessons learned from paediatrics • Can apply a formula to estimate a GFR from plasma creatinine even in children where creatinine production rate is increasing • Accuracy totally dependent on method for measuring plasma creatinine • Need to understand the measure of GFR any formula derived from • Does the formula correct for BSA, i.e. ml/min or ml/min/1.73m2? • Despite good correlation for a population it is important to appreciate that there are wide limits of agreement

  44. Glomerular Filtration Rate Use of plasma creatinine for the estimation of GFR Need to understand the factors on which a plasma creatinine depends Need to appreciate the importance of the creatinine measurement Need to understand the limitations of any formula derived eGFR

  45. Glomerular Filtration Rate Factors affecting plasma creatinine GFR, tubular secretion, production rate Calculation of eGFR assumes that the rate of production is related to a series of demographics, e.g. height, weight, sex, ethnic origin, age Statistically may be true for a population but not necessarily for the individual

  46. Limitations of plasma creatinine determination and eGFR Age Wt Pcr GFR C&G GFR inulin y kg µmol/l ml/min/1.73m2 Subject1 40 80 68 144 116 Subject2 40 80 120 82 118 Effect of 50% loss of renal function Subject1 40 80 136 73 58 Subject2 40 80 240 41 59 Normal range for creatinine 55-120µmol/l

  47. Glomerular Filtration Rate Plasma creatinine measurement is critical Accuracy very poor Assays vary in standardisation, linearity, and relative interferences between and within supplier

  48. Glomerular Filtration Rate Measurement of plasma creatinine Comparison of various routine methods with isotope-dilution electrospray mass spectrometry-mass spectrometry Fully validated method using a NIST traceable standard and EC certified reference materials Between assay CV 2%

  49. Plasma creatinine - isotope-dilution MSMSmethod comparison

  50. Plasma creatinine - isotope-dilution MSMSmethod comparison

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