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Meeting Minutes – Manufacturers' Forum July 22, 2009

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Kidney Disease Education Program (NKDEP) Manufacturers Forum
AACC Annual Meeting — Chicago, IL

Participants: Greg Miller (Chair), Lorin Bachmann, David Bunk, Johanna Camara, Christa Colbbaert, Paul D'Orazio, John Eckfeldt, James Fleming, Mary Lou Gantzer, Matthew Gnezda, Neil Greenberg, J. Mark Herlan, Yoshihisa Itoh, Chandra Jain, Graham Jones, Hans-Joachim Kytzia, Yemmi Lemma, Jack Levine, Bob Maher, Andrei Malic, Ezio Marelli, Leigh Ann Milburn, Andrew Narva, Eileen Newman, Mauro Panteghini, Thomas Pisani, Max Robinowitz, Mary Robinson, Fabio Rota, Kazuhiko Sameshima, Heinz Schimmel, George Schwartz, Sari Tikanoja, Dave Torrens, Reba Wright, Fawn Xie, Esther Yang, Ichimaru Yasuyuki, Ingrid Zegers

Meeting Minutes

Status of Creatinine Standardization from IVD Manufacturer Survey

Greg Miller

Status of Creatinine Standardization from IVD Manufacturer Survey — Greg Miller

  • By the end of 2009 all methods for sale by the participating respondents (all major global IVD manufacturers) will use calibrators traceable to IDMS standards with two exceptions:
    • Nova whole blood methods will not be traceable to IDMS, but they will provide an option for individual user adjustment of calibration.
    • Siemens Dimension/Vista — Jaffe methods will not be traceable to IDMS, but an enzymatic method that has calibration traceable to IDMS will be introduced soon.
  • For all practical purposes, all creatinine methods will be IDMS traceable by early 2010 when the last lots of older calibration products will be used up by customers.
  • A poll of manufacturers present indicates that this will be effective worldwide. Review of survey responses confirmed that only an IDMS-traceable calibration will be sold in all markets.
Status of eGFR Reporting from the College of American Pathologists Survey

Greg Miller

  • Approximately 77% of labs are reporting eGFR
  • Approximately 74% of labs reporting eGFR do so with every creatinine result
  • Approximately 63% of labs do not report numeric values for eGFR when the result is greater than 60; 10% of labs report numeric values if the result is < 90, and 27% report any value. The MDRD equation values have significant error at these higher ranges, but there is pressure to know the values above 60.
  • Approximately 81% use MDRD 4-parameter; a few use MDRD 6-parameter and Cockcroft-Gault equations, neither of which are available with coefficients suitable for IDMS traceable creatinine methods
NKDEP Drug Dosing Educational Statement for Providers

Lesley Stevens

  • FDA labels guide adjustment of drug dosage using the Cockcroft-Gault (C-G) equation to estimate creatinine clearance (eCrCl). Consequently, there was resistance to labs changing to the MDRD equation to estimate GFR.
  • A large oncology group published a single formula for all creatinine methods to adjust standardized creatinine results to older non-standardized results so they could be used in the C-G equation. It is not possible to have a single equation that would be applicable to all creatinine methods because the amount of bias that was removed in the standardization traceability process was different for different methods. A single factor cannot be used.
  • An educational advisory was developed by NKDEP to help providers use eGFR in drug dosing applications.
  • The revised NKDEP recommendations for drug dosing that were approved at this meeting and will be posted to the NKDEP website make the following summary recommendations (see website for details and additional information):
    • Utilize eGFR or eCrCl for dosing drugs.
    • If using eGFR in very large or very small patients, multiply the reported eGFR by the body surface area in order to obtain eGFR in units of mL/min.
    • Perform confirmatory test (measured CrCl or measured GFR using exogenous filtration markers) for:
      • Drugs with a narrow therapeutic index.
      • Individuals in whom eGFR and eCrCl provide different estimates of kidney function.
      • Individuals where any estimates based on creatinine are likely to be inaccurate.
CKD-EPI eGFR Equation and Adoption Considerations

Lesley Steven

There are limitations with the MDRD equation if the eGFR is > 60. The CKD-EPI study developed a better equation to estimate GFR using data from studies in which there was a measured GFR and included patients with and without CKD. The new equation shows greater accuracy across the GFR range; and in particular, it has improved agreement with measured GFRs > 60. This equation was applied to the NHANES population to evaluate the effect of the new equation on the burden of CKD in the US. Using the new equation, the burden of CKD was reduced from 26 to 23 million. The CKD-EPI results were just published and NKDEP is not making a recommendation regarding the equation at this time; rather there will be a period of validation to determine its impact on the field. In the interim, the LWG intends to develop information on this equation to be posted to the NKDEP website in the next few months.

CKiD Updated Schwartz Equation Currently on the NKDEP Web Calculator Page for Standardized Creatinine Methods

George Schwartz

See below

New CKiD Study Equation Uses Creatinine, Urea, Cystatin

George Schwartz

  • Height/serum creatinine, BUN, and cystatin C are important markers for evaluating GFR.
  • The study used an enzymatic creatinine method that had calibration traceable to IDMS.
  • It is important to be able to distinguish between creatinine levels of 0.3 and 0.4 in order to screen for early kidney disease in children.
  • A new equation was developed using data from 349 children who had measured GFR values between 10-90 mL/min/1.75m2.
  • The new equation includes height/serum creatinine, cystatin C, BUN, gender, and height components.
  • Extension of the equation to GFR > 80 mL/min per 1.73 m2 will require precise, as well as accurate, measurements of serum creatinine and cystatin C at relatively low concentrations.
  • More recent work using a different cystatin method has resulted in a different equation in which BUN was not useful.
  • The new equation is intended for use in the CKiD study, and wider application will require standardization of assays for cystatin C.
  • Multivariate gender-based equations incorporating height/serum creatinine, cystatin C, gender, and height are significantly better than height/serum creatinine alone for estimating GFR.
  • A bedside formula was published as a modified Schwartz equation that uses only height/serum creatinine x 0.41. This equation works fairly well and is useful when eGFR > 80. This equation is now available on the NKDEP website.
Cystatin C Standardization Status

Greg Miller for Anders Grubb (Chair, IFCC WG-SCC)

The project has successfully prepared secondary reference material which is pooled human serum to which a recombinant cystatin product has been added. The value assignment is complete and they are beginning the commutability study. It is estimated that the product will be available in 2010. Also, a large study is planned to generate an equation using standardized cystatin C methods. There will be a notification through the IRMM website when the product is available, and the LWG will make an announcement when the product is available.

Status of Work in Progress

Greg Miller

a. Serum creatinine method specificity (IFCC WG-GFRA, LWG, Neil Greenberg)

  • Evaluate primarily unaltered patient samples from a variety of patient populations.
  • Samples are included from several pathological groups (e.g. diabetes, CKD, liver disease, high and low protein syndromes) and included samples spiked for volatile elements (e.g., ascorbate, acetoacetate).
  • Samples were sent to four manufacturers to be assayed by four alkaline picrate and four enzymatic methods.
  • The reference method was an ID-LC MS/MS method performed in Neil Dalton's laboratory at Evilina Children's Hospital in London.
  • Testing is complete and data analysis in being done; NIST SRM 967 was included in all runs; preliminary data shows that most methods recovered the NIST values well; significant and highly-variable biases were observed in both Jaffe and enzymatic methods among the patient samples; most of the data has not yet been analyzed in detail; more to come in approximately six to nine months; target publication is 2010.

Refer to written summary circulated with the agenda for the following:

b. Urine albumin reference material (Yoshi Itoh, JSCC)

Development of a urine albumin reference material is being sponsored by the Japanese government and estimated to be available in 2-3 years.

c. Urine creatinine and albumin reference materials (David Bunk, Karen Phinney, NIST)

NIST will develop a reference material for urine creatinine and albumin. A task force to determine parameters for this material was created today; it is estimated that a product will be developed in about 2 years.

d. Urine albumin IDMS candidate reference procedure (John Lieske, Mayo Clinic and David Bunk, NIST)

  • An IDMS method for quantitating urine albumin is being developed by John Lieske and his group at Mayo Clinic; they are planning to submit the method to JCTLM to be listed as a reference procedure method.
  • This project is being carried out in collaboration with NIST, which will set up this procedure to demonstrate transferability of the method to a second laboratory.
  • It is anticipated that it will be about 2 years before the method will have gone through all of the proper credentialing procedures.

e. Urine albumin biological variability study (Mary Robinson, CDC)

  • 3 centers will collect urine samples at various times to allow determination of biologic variability.
  • Anticipate starting to collect samples in September 2009.

f. Urine albumin adsorption study (Mary Robinson, CDC)

Want to investigate problems with adsorption of albumin to containers for collection and analysis.

g. Urine albumin method harmonization study (Lori Bachman, LWG)

  • 300 urine samples to be collected as residuals from lab submissions for urine albumin.
  • Samples will be sent to manufacturers as liquid urine (non-frozen).
  • Most manufacturers have expressed interest; hope to include all of them.
  • Plan to characterize the matrix of these samples.
  • Plan to begin in January 2010.

h. Urine albumin molecular forms study (Glen Hortin, LWG)

  • This study proposes to determine which fragments of albumin are present and if they can be measured by immunoassay methods.
  • Samples collected for method harmonization study will likely be used.


  • Jack Levine asked about options available to a manufacturer for obtaining comparisons with IDMS reference method for creatinine.
    • Greg Miller responded that JCTLM lists 2-3 labs that provide services and by next year up to 5 labs should be listed.
    • The concern for small companies is the cost for these services can be high.
  • Neil Greenberg commented that they have used a lab in the UK for the creatinine specificity study that has been less expensive than the ID-GC/MS methods. It is anticipated that they will submit their assay to JCTLM for listing. He added that availability of reference laboratories has been a challenge for manufacturers. An expanded network of reference labs for both creatinine and urine albumin is desirable, but not many labs are interested in going into that business. Ideas about how to promote that type of business would be appreciated.

March 1, 2012


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