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Creatinine, cystatin C and urine albumin – Analytical update

Creatinine, cystatin C and urine albumin – Analytical update . Joris Delanghe , MD, PhD Ghent University , Belgium. creatinine, cystatin C (cys C), and micro-albumine are key parameters for assessing renal function.

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Creatinine, cystatin C and urine albumin – Analytical update

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  1. Creatinine, cystatin C and urine albumin – Analytical update Joris Delanghe, MD, PhD GhentUniversity, Belgium

  2. creatinine, cystatin C (cys C), and micro-albumine are key parameters for assessing renal function. In order to improve their clinical utility, standardisation efforts are ungoing

  3. The protein error got into the determination! 1970 - 2000: “Jaffe” rules the creatinine market in Europe and VS Protein error leads to underestimation of GFR! (CrCl << GFR) some enzymatical determinations recalculated to Jaffe-equivalence! Only ref. values were adapted!!!! Physiology books, derived formulas, pharmacokinetics??????

  4. 7.12.2003CE GUIDELINES CE Guideline 98/79/EG on in-vitro diagnostics Calibration using standard of “higher order” INTRODUCTION OF THE TERM CKD→ NECESSITY FOR STANDARDISATION

  5. NIST 967 reference material • Demonstrated commutability with native clincal specimens • All methods are now expected to have calibration traceable to an IDMS reference measurement procedure • 2006-2009:Adaptation by IVD industry • Enzymatic methods recommended • Problem solved?

  6. Creatinine in urine • NIST has issued SRM 3667 creatinine urine reference material which provides an initial step for a urine creatinine reference system. • SRM 3667 is a human urine pool colected from healthy individuals

  7. The situation now in the EU…

  8. LEVEL 1 target 75.9 µmol/l (TAE :5.27)

  9. LEVEL 3 target 304.9 µmol/l (TAE :21.18)

  10. French and Italian multicentric evaluations

  11. The end of the Jaffe era for creatinine ?

  12. 1905…. … 2014

  13. REAL LIFE vs. RESEARCH… • Using concentrated reagents (near saturation concn) in automated platforms increase the evaporation effects (crystallisation) • Important lot-to lot variation • Low profits are not encouraging for R&D

  14. DOES A PERFECT CREATININE DETERMINATION SOLVE THE PROBLEM? • When Not to Use the MDRD Equation: • Nonadults. This includes all individuals under the age of 18. The Schwartz equation should be used to estimate GFR for infants, toddlers, children, and teens under age 18. • Individuals with unstable creatinine concentrations: pregnant women; patients with serious co-morbid conditions; and hospitalized patients, particularly those with acute renal failure. The MDRD equation should be used only for pts with stable creatinine concentrations. • Persons with extremes in muscle mass and diet: this includes, but is not limited to amputees, paraplegics, bodybuilders, or obese; pts who have a muscle-wasting disease or a neuromuscular disorder; and those suffering from malnutrition, eating a vegetarian or low-meat diet, or taking creatine dietary supplements.

  15. How to establish eGFR in children? Updated formula: Schwartz GJ, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009; 20: 629-637 GFR (ml/min/1.73 m2) = k’ x L (cm)/P (mg/dl) only valid for enzymatic method

  16. CONFUSION…… Cockroft|Gault equation CrCl (ml/min) = (140-age) * weight * 0.85 if female 72 * Creat (serum) IDMS-Traceable MDRD Equation should be used only with creatinine methods that have been recalibrated to be traceable to IDMS. GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American) (conventional units) CKD-EPI formula

  17. CONFUSION! SRM 967 CKD-EPI

  18. 2014… • Although substantial improvement with compensated Jaffe method • has been made regarding traceability to the IDMS reference method, enzymatic methods should be used for classification of chronic kidney disease specially at early stages. • at levels < 70 μmol/L only enzymatic creatinine reaches the desirable 7.6% TE specified by the NKDEP. • Due to protein-related pseudo-chromogens, enzymatic creatinine assay should be preferred over the compensated IDMS traceable assay in everyday practice because compensation of Jaffe methods can lead to overcorrection in children, elderly, cancer or cirrhotic patients, causing huge overestimation of renal function by eGFR. • Important cost issues!

  19. Alternatives: • Cystatin C: well documented

  20. Cystatin C vs. creatinine Advantages: 1/[Cys C] ~ GFR independent from muscle mass, diet urinary determination not needed valuable in the “blind range” zone of creatinine No tubular secretion

  21. Creatinine-blind area

  22. Diagnostic performance of a creatinine-based GFR prediction equation (MDRD) (Grubb A. et al. Clin Chem 2005;51:1420-31)

  23. Diagnostic performance of a cystatin C-based GFR prediction equation (Grubb A. et al. Clin Chem 2005;51:1420-31)

  24. GFR-prediction equationsRelative GFR in mL/min/1.73m2 MDRDIDMS-traceable: GFR = 175 x (creatinine/88.4)-1.154 x age-0.203 x 0.742 (if female) x 1.212 (if African American) GFR(CC-estimate)= 84.69 x cystatin C-1.680 x 1.384 (if child<14years)

  25. Problems with creatinine- and cystatin C-based GFR-prediction equations METHOD-RELATED Differences in “Gold standard” methods for GFR-determination Different calibrators Different methods Different statistical models to generate the prediction equations PATIENT-RELATED Different patient cohorts

  26. A new cys C calibrator (ERM-DA 471/IFCC), was released in 2010, which enables an assay-independent, GFR-prediction equation.

  27. Consequence: new cys C based eGFR equations! Grubb et al. Generation of a New Cystatin C-Based Estimating Equation for Glomerular Filtration Rate by Use of 7 Assays Standardized to the International Calibrator. Clin Chem 2014 May 14. pii: clinchem.2013.220707. Many different cys C-based equations exist for estimating GFR. Major reasons for this are the previous lack of an international cys C calibrator and the nonequivalence of results from different cys C assays. Use of certified reference material ERM-DA471/IFCC and work to achieve high agreement and equivalence of 7 cys C assays allowed a substantial decrease of CV. By use of 2 assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasians, with their GFR determined by either inulin or iohexol clearance, a virtually assay-independent simple cys C-based equation for eGFR was produced. a simple cys C-based eGFR equation comprising only 2 variables, [cys C] and age. (no terms for race and sex). The equation is biologically oriented: 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cys C.

  28. It is desirable to develop a single cys C equation that can be promoted worldwide. CKD-EPI Cystatin C Equation group proposed a new equation using standardized cys C (variables: age, gender, cys C) and report a 2nd equation using both cys C and creatinine. The combined equation showed an improved performance. No real improvement vs. the creatinine equation was seen using the cys C equation alone. Cys C equation did not perform well at either very high or low eGFRs. The cys C only equation was not more accurate than the combined one, but may be useful when race cannot be specified.

  29. TWO MARKERS NEEDED GFR: Quantitativemeasurefor the number of nephrons (Micro)-albumine: quantitative marker for the quality of the glomerularmembrane.

  30. .Albuminuria: the long and winding road to standardisation. . SRM 2925 is a primarycertifiedreferencematerialforusewithhigher order referencemeasurement procedures foralbumin. It is a recombinant humanalbuminsolutionthatwillbecharacterized. A commutabilitystudy has not been done. NIST SRM 3666 is a matrix certifiedreferencematerialthat is in preparation. Itwillbealbumin in frozenhuman urine.The utility of candidatereferencematerialsforuse in standardization of albuminuriamethods is beingassessed. Bachmann’sharmonization paper provides compellingevidencethatstandardization is needed. Median differences between the largest pos. and neg. biases vs IDMS were 37-45%. Biases mostly exceeded ±10%. Mean biases ranged from -35% to 34% at 15 mg/L. Bias was the major source of disagreement among routine measurement procedures.

  31. Albumin adsorption onto surfaces of urine collection and analysis containers.Robinson M, Caudill S, Koch D, et al. ClinChimActa 2014;431:40-5. Adsorption of albumin onto urine collection and analysis containers may cause falsely low concentrations.125I-albumin was added to urine and to phosphate buffered solutions, incubated with 22 plastic container materials and measured adsorption measured.Adsorption of urine albumin at 5-6 mg/l was <0.9%; and at 90 mg/l was <0.4%. Adsorption from 11 unaltered urine samples (albumin 5-333 mg/l) was <0.8%. Albumin adsorption for the material with greatest binding was extrapolated to the surface areas of 100 ml and 2l collection containers, and to instrument sample cups and showed <1% change in concentration at 5 mg/l and <0.5% change at 20 mg/l or higher concns. Albumin adsorption differed among urine samples and plastics, but the total influence of adsorption was <1%. Adsorption of albumin from phosphate buffered solutions was larger than that from urine and could be a limitation for preparations used as calibrators.

  32. Screening recommendations • Creatinine: affordable • Albuminuria: expensive!

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