IVD Manufacturers

Sample Customer Letter

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Creatinine Standardization Recommendations

In vitro diagnostic (IVD) manufacturers are crucial partners in the successful implementation of the Creatinine Standardization Program. For IVD manufacturers, the following steps are necessary:

1. Continue using or recommending the Original Modification of Diet in Renal Disease (MDRD) Study equation for routine methods that have not been calibrated to be traceable to IDMS.
2. Calibrate serum creatinine methods to be traceable to an isotope dilution mass spectrometry (IDMS) reference measurement procedure. Standardization of method calibration will reduce the interlaboratory bias in results and yield more accurate estimated GFR (eGFR) when using the IDMS-traceable MDRD Study equation. 
• A new reference material with IDMS-traceable creatinine values (NIST SRM 967) is now available for calibrating routine methods (see information on SRM 967).
• Alternatively, routine methods can be calibrated with the assistance of an existing IDMS reference measurement laboratory. The Joint Committee for Traceability in Laboratory Medicine (JCTLM) lists approved reference measurement procedures and the submitting laboratories at www.bipm.fr/utils/en/xls/jctlm_listI.xls. JCTLM also provides a list of laboratories that can provide reference measurement services.
3. Coordinate with customer laboratories so that, upon using a method with IDMS-traceable calibration, they immediately begin using the IDMS-traceable MDRD Study equation. During the transition to IDMS-traceable calibration, methods that produce results that have acceptable bias [as defined in Clinical Chemistry 2006;52(1):5-18] when compared to an IDMS-traceable method should use the IDMS-traceable MDRD Study equation.
4. Communicate to customers the clinical issues associated with introducing a serum creatinine method that is calibrated to be traceable to IDMS. IVD manufacturers should:
• Provide a serum creatinine reference interval appropriate for the method.
  • The effect on measured creatinine clearance will vary depending on the procedure used to calibrate serum and urine measurements. Creatinine clearance values based on measured serum and urine creatinine results may increase and a new reference interval and interpretive criteria may need to be established. Read NKDEP’s recommendations for clinical laboratories for more information on using creatinine clearance to assess kidney function.
• Describe the relationship between creatinine results when measured by methods that have IDMS-traceable calibration compared to the results obtained using methods with traditional calibration. Include detailed descriptions (including mathematical conversion factors, equations, or functions) of the impact of a calibration change for both serum and urine creatinine values, with emphasis on the 0.5 to 2.5 mg/dL (45 to 220 µmol/L) range of interest. This information will ensure that customers or laboratories using any of the pharmacy drug-dosing approaches can adjust IDMS-traceable creatinine values for use with appropriate legacy dosing reference tables and algorithms (such as serum creatinine value; GFR or creatinine clearance based on estimating equations other than the MDRD Study equation; or traditionally measured creatinine clearance from serum and urine values). Read NKDEP’s recommendations for clinical laboratories and for pharmacists and authorized drug prescribers for more information on implications for drug dosing.
• Communicate that equations, other than the IDMS-traceable MDRD Study equation, used to estimate kidney function, such as Cockcroft-Gault, Schwartz, or Counahan-Barratt, will give values that, in most cases, are higher than the values obtained using traditionally calibrated creatinine methods. This change in calibration will affect interpretive criteria based on these estimates of kidney function.
• Emphasize that creatinine measurements at the low values usually observed in pediatric patients have greater measurement variability than for values seen in adults. Estimates of kidney function based on these values also will have greater variability than for adults.
  
5. Improve the precision of creatinine methods to meet the total error goal for serum creatinine measurement described in Figure 3 in the paper published in Clinical Chemistry 2006;52(1):5-18 (reproduced below). This figure provides an error budget for creatinine measurement in the range 1.00-1.50 mg/dL (88.4-133 µmol/L) that will ensure less than 10 percent increase in the relative error of the eGFR. An example of method performance, in the absence of any interfering substances in the serum sample, that would achieve this total error goal is analytical imprecision (including interlaboratory calibration variability) SD <0.08 mg/dL (7.1 µmol/L) and analytical bias (compared to an IDMS reference measurement procedure) <0.05 mg/dL (4.4 µmol/L) at a serum creatinine concentration of 1.00 mg/dL (88.4 µmol/L).

6. Ensure optimal method performance at 1.00 mg/dL (88.4 µmol/L) for existing and new methods, and ensure that comparable trueness and imprecision extend throughout the analytical measurement range. Method imprecision at concentrations <1.00 mg/dL (88.4 µmol/L) should be addressed to reduce the uncertainty in eGFR for pediatric populations, and possibly to allow extension of eGFR to values ≥60 mL/min/1.73 m².
   
   
7. Design instruments that report serum creatinine values as mg/dL to two decimal places, or as µmol/L to the nearest whole number. This will reduce the contribution of a rounding error when using the MDRD Study equation.
   
   
8. Address analytical nonspecificity issues in routine serum creatinine methods. The NKDEP Laboratory Working Group is currently developing recommendations for creatinine method specificity requirements.
   
   
9. Communicate with Proficiency Testing and External Quality Assessment Scheme (PT/EQA) providers to inform them when a revised creatinine calibration will become effective, and work with the PT/EQA provider to develop appropriate instrument/method peer groups for participants to be evaluated appropriately. Read NKDEP’s recommendations for PT/EQA providers.