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Meeting Minutes – Manufacturers' Forum July 31, 2013

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

National Kidney Disease Education Program (NKDEP)
Laboratory Working Group (LWG) Meeting
A​ACC Annual Meeting – Houston, TX
A joint meeting with the International Federation of Clinical Chemistry (IFCC) Working Group for Standardization of Albumin in Urine (WG-SAU)
July 31, 2013
11:30 a.m. to 12:30 p.m.


Greg Miller, Lori Bachmann, Diana Blanco, Steven Breeze, David Bunk, Joanna Camara, Jian Dai, Joris Delanghe, John Eckfeldt, James Fleming, Wolfgang Gentzer, Lars-Olaf Hansson, Desiree Hiraman, Glen Hortin, Hiromi Ito, Anthony Killeen, Hans-Joachim Kytzia, Bill Manchester, Andrew Narva, Prasad Pamidi, Mauro Panteghini, Linda Parisi, Karen Phinney, Claus Prümper, Heinz Schimmel, David Seccombe, Jill Tate, Linda Thienpont, David Torrens, Clarke Xu, Dror Yahalom, Jack Zakowski

Meeting Minutes

Creatinine Performance Recommendations Outside the 1.0-1.5 mg/dL Interval (especially lower values seen in pediatric patients)
Greg Miller, PhD, Lab Working Group Chair

  • A task force will be created to investigate the clinical requirements for pediatric care based on creatinine measurement in the lower range of 0.3-1.0 mg/dL. The task force will make recommendations for assay performance at these lower concentrations.
  • The task force will try to have recommendations by the Laboratory Working Group (LWG) meeting in 2014. The recommendations will be posted to the NKDEP website and published.

Derived Formulas Based on Creatinine in Various Medical Specialties and Impact of Standardization
Joris Delanghe MD, PhD, Ghent University Hospital, Belgium

  • Despite significant progress in creatinine standardization, some problems remain.
  • Most drug dosing recommendations for existing drugs are based on Cockcroft Gault estimates of kidney function using non-standardized creatinine determinations. It is impossible to re-express all current drug dosing recommendations for use with standardized creatinine values.
  • Assessing kidney function using alternative methods (e.g., measured CrCl or measured GFR using exogenous markers) should be considered for drugs with narrow therapeutic indices, for individuals in whom eGFR and eCrCl provide different estimates, or for patients in whom estimates based on creatinine are likely to be inaccurate.
  • Vigilance is required to tackle the side effects of creatinine restandardization on drug dosing and other guidelines based on GFR.
  • In children, Cystatin C determination might offer an interesting alternative for GFR estimation. The recent availability of the IFCC Cystatin C standard will contribute to the popularization of Cystatin C as a renal function marker.
  • J. Delanghe will conduct a literature search and develop a list of issues that need to be addressed by the LWG.
  • NKDEP has no recommendation about whether to use Jaffe or enzymatic methods.
  • J. Tate inquired about age-related reference intervals for creatinine above 70 years of age. G. Miller responded that currently NKDEP has no position on reference intervals.

Update on NKDEP Pharmacy Working Group and HIT Working Group
Andrew Narva, MD, FACP, NKDEP Director

  • NKDEP has created two new working groups using the LWG as the model.
  • The Pharmacy Working Group (PhWG), led by Amy Pai at Albany College of Pharmacy and Health Sciences, will focus on the community pharmacists from who most people get their prescriptions. The overall objective is to support community pharmacists to improve outcomes in people with CKD. One area of focus is to include eGFR in electronic prescriptions.
  • The Health Information Technology (HIT) Working Group, led by Uptal Patel at Duke University, will focus on facilitating the interoperability of data related to kidney health among healthcare software applications to optimize CKD detection and management. Electronic records need to be searchable in a way that allows identification of people with CKD.

Standardization of Cystatin C Measurements and eGFR Equations Based on Cystatin C

  • Report on Lund Conference, February 2013
    John Eckfeldt, MD, PhD, University of Minnesota
    • The meeting was hosted by Anders Grubb. The goals were to discuss clinical use of Cystatin C measurements, standardization of measurement of Cystatin C, and equations to estimate eGFR using Cystatin C. Attendees were from the U.S., Asia, and Europe and were from research labs, clinical medicine, nephrology, and IVD industry.
    • Data from pooled samples collected from patients with kidney disease that were assayed by several labs in preparation for this meeting showed that it is possible to standardize Cystatin C and manufacturers need to be sure they are traceable to ERM/IFCC DA471. At present, some assays appear not to be traceable.
    • For now, there are likely to be multiple eGFR equations recommended by different research groups and organizations.
  • IFCC Working Group for Standardization of Cystatin C Update
    Lars-Olof Hansson, MD, PhD, Karolinska Hospital, Sweden
    • Ten pools were run in duplicate using six different manufacturer’s assays in four laboratories over five days. If data from one manufacturer’s assay is excluded, the range of results for the other five assays is very tight. Precision of Cystatin C results is especially important in the GFR range of 60–120 mL/min/1.73m2.
    • These pools have now been sent to Siemens in the U.S., Marburg, Roche in Pensberg, Germany, and Amanda Anderson at the University of Pennsylvania. It is possible for other manufacturers to receive these pools as well.
  • Cystatin C Education Recommendations
    Greg Miller, PhD, Lab Working Group Chair
    • The LWG website will be updated to summarize the Cystatin C findings described by J. Eckfeldt and L-O. Hansson. It has been demonstrated that the ERM/IFCC DA471 reference material is commutable for a large number of methods (data to be published by IFCC/IRMM WG) and is suitable for standardization of most methods.
    • The LWG website will continue to recommend that laboratories do not report eGFR using equations based on Cystatin C until their assay is standardized.

Report on AACC/AdvaMedDx/FDA Forum; The road to harmonization: regulatory considerations for recalibrating IVD devices, June 2013
Greg Miller, PhD, Lab Working Group Chair

  • AACC and AdvaMedDx organized a conference for manufacturers and the FDA to discuss problems with recalibration applications.
  • A summary of this conference will be published on the www.hamonization.net.
  • It is preferable that calibrations be traceable to accepted reference systems whenever one exits.
  • It is acceptable to use calculations based on a relationship between an old calibration and the new one.
  • The FDA has a triage program that simplifies the 510K process and the FDA strongly recommends that manufacturers contact them when a recalibration is necessary to determine exactly what data is needed.
  • Manufacturers can collaborate and come to the FDA as a group to discuss recalibration issues.
  • AdvaMedDx has offered to assist manufacturers with this collaboration.
  • The FDA prefers that manufacturers contact them when international reference systems are being established rather than waiting until the end.
  • The next step is to develop, in cooperation with the FDA, a guidance document for recalibration to conform to international recommendations.

Urine Albumin Harmonization Status Investigation
Lori Bachmann, PhD, Virginia Commonwealth Universit

  • The objectives of the harmonization study were to assess the current state of agreement among routine urine albumin procedures using native patient samples, evaluate analytical performance characteristics of the methods, evaluate commutability characteristics of JSCC and diluted IRMM ERM-DA470k/IFCC reference materials, and assess the utility of candidate reference materials for use in standardization of routine methods.
  • The bias was greater than ± 10% for 13 of 16 quantitative methods indicating that standardization is needed.
  • Several methods had non-constant bias with concentration suggesting that calibration technique needs investigation.
  • Dilution caused changes in bias for some methods.
  • CVt was greater than 10%for five methods showing that improvement in precision is needed for those assays.
  • In general, sample-specific effects were not clinically significant.
  • Recommendations for manufacturers include: 1) method imprecision should be reduced for those methods with higher CVs; especially at low urine albumin concentrations that may influence CKD risk assessment; 2) methods that showed a non-constant calibration bias over the method measuring interval should be investigated and this problem corrected; and 3) methods with poor dilution protocols should improve their user information to include specified dilution buffers and validate their protocols for matrix bias.
  • The harmonization assessment manuscript has been submitted to Clinical Chemistry.
  • Next steps include assessing the commutability characteristics of IRMM and JSCC candidate reference materials and evaluating the improvement in agreement that may be possible based on mathematical recalibration using these reference materials

NIST Reference Materials Update
Karen Phinney, PhD and David Bunk, PhD, National Institute of Standards and Technology

  • NIST SRM 3667 is creatinine in frozen human urine and was issued one year ago. It is a single level.
  • NIST SRM 2925 Human Serum Albumin is a primary reference material intended for calibration of the candidate reference method procedure and is not for routine assays because a commutability study has not been done. It is a frozen recombinant human albumin and should be available in four to six months.
  • NIST SRM 3666 is a matrix certified reference material that is in the preparation stage. It will be albumin in frozen human urine that has four levels in 1 mL aliquots and should be available in 10-12 months. 40-50 aliquots will be held for commutability studies and for new methods.

Urine Albumin Reference Measurement Procedures Validation: NIST and Mayo Clinics
Karen Phinney, PhD and David Bunk, PhD, National Institute of Standards and Technology and John Leiske, MD, Mayo Clinic

  • Now that SRM 2925 is available, a validation study between NIST and Mayo will be conducted. In addition, a certification and commutability study of SRM 3666 will need to be performed. This will involve participation of the assay manufacturers to test SRM 3666 and 80 patient samples.

Update on Other Urine Albumin Standardization Activities

  • Establishing Reporting Cut-offs for Urine Albumin
    Andrew Narva, MD, FACP, NKDEP Director
    • Based on a literature review, it is possible that the cut-off will be set lower than the currently accepted level of 30 mg/g Cr. There is evidence that the risk of cardiovascular disease occurs at levels lower than 30mg/g Cr. Also, it is possible that the LWG will recommend a cut-off that is stratified by gender since women excrete less creatinine which could result in over reporting of women with kidney disease. Efforts to standardize urine albumin need to be completed before lower concentration cut-off levels can be established.
  • Lieske et al. A reference system for urinary albumin: current status. Clin Chem Lab Med. 2013 May;51(5):981-9. doi:10.1515/cclm-2012-0768.
    • This paper describing the status of a reference system for urinary albumin has been published and is available online.

November 20, 2013


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