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Meeting Minutes – Manufacturers' Forum July 31, 2014

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

National Kidney Disease Education Program (NKDEP)
Laboratory Working Group (LWG) Meeting

AACC 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, 2014
11:00 a.m. to 12:00 p.m.

Participants:

Greg Miller, Flavio Alcantara, Lorin Bachmann, Jian Dai, David Bunk (phone), Johanna Camara, Cristine Canada-Vilalta, Matthew Carlay, Mekashia Chenault, Anchalee Chittamma, John Eckfeldt, Neil Greenberg, Lars-Olaf Hansson, Glen Hortin, Graham Jones, John Leiske (phone), Andrew Narva, Tetsuya Nejime, Evan Ntrivalas, Mauro Panteghini, Karen Phinney (phone), Claus Pruemper, Heinz Schimmel, David Seccombe, Sarah Steinberg, Nickolas Voskoboev

Meeting Minutes

Standardization of Urine Albumin Measurements


Commutability of Current Reference Materials for Urine Albumin

Lorin Bachmann, Virginia Commonwealth University

  • The recently published report on the current state of agreement among 16 routine quantitative methods for urine albumin was based on results for 332 fresh native human urine samples from patients with chronic kidney disease (Clin Chem 2014, 60: 471–80).  The study included candidate reference materials from the Institute for Reference Materials and Measurements (IRMM) and the Japanese Society of Clinical Chemistry (JSCC).
  • There was lack of agreement among the methods particularly in lower concentration ranges suggesting that standardization efforts are warranted for urine albumin methods.
  • Bias was the predominant source of lack of agreement. The majority of methods had non-constant bias particularly at low concentrations. Non-constant bias will be a difficult problem for commutability assessment/standardization and affected manufacturers may want to investigate the cause of the bias at different concentration intervals.
  • The commutability characteristics of a JSCC urine albumin reference material and a diluted IRMM serum albumin reference material are being investigated.  For some UA methods, the results for IRMM reference materials were clustered among the patient sample results when compared to the IDMS procedure used as a candidate reference method.  For other UA methods, there was lack of agreement between IRMM reference materials and patient samples, especially at lower concentrations.
  • Next steps for commutability assessment are to assess the ability of mathematical recalibration of the patient results based on the reference materials responses to improve agreement among the methods.
NIST Reference Materials Update

Greg Miller, Virginia Commonwealth University, for David Bunk, NIST

  • SRM 3667 frozen human urine creatinine reference material has been available for sale for about 1 year.
  • SRM 3666 frozen human urine albumin reference material is in the development process and may be available in 2015.

Commutability Assessment of the NIST SRMs

  • The commutability study is planned for next year depending on when the urine albumin reference material becomes available.
  • We will be contacting manufacturers to participate in the commutability study. The CAP accuracy based urine proficiency testing materials will likely be included in the study since this survey provides a surveillance mechanism.
  • The commutability assessment will include 100 – 120 urine samples replicated in triplicate or quadruplicate.
Urine Albumin Reference Measurement Procedures Validation: NIST and Mayo Clinics

Greg Miller for David Bunk and John Lieske, Mayo Clinic

  • An IDMS candidate reference measurement procedure was developed at Mayo Clinic and a similar method is in development at NIST.
  • A validation study between the two reference methods is in process now and will be submitted for publication.
  • JCTLM submission is planned for either 2015 or 2016.
  • It is anticipated that in 2-3 years a complete reference system will be available for recalibration of urine albumin measurement procedures.
Engaging Manufacturer's in the Standardization Process

Greg Miller

  • Urine albumin method non-linearity and imprecision should be addressed in advance of the commutability study of NIST SRMs and recalibration to achieve standardized results.
  •  It is planned to organize a conference call or a meeting with manufacturers to address approaches to method improvements needed to support commutability assessment of the NIST reference materials and to accomplish standardization for urine albumin methods once the reference materials are available.
  • Literature data suggests that the urine albumin values useful for risk assessment in cardiovascular and kidney diseases are likely to be in the 5-10 mg/L range. Establishing decision values in this concentration range is not practical until the urine albumin methods are standardized over the next several years.  However, planning to improve measurement procedure performance at these lower concentrations should begin.

Creatinine and Cystatin C Topics


Creatinine Performance Recommendations Outside the 1.0-1.5 mg/dL Interval; especially lower values seen in pediatric patients

Greg Miller

  • Volunteers were identified for this task force last year; however, a chair to lead the effort is being recruited.
Recommendations Regarding MDRD vs. CKD-EPI Equations for eGFR from Creatinine; see attached CAP Survey information

Andrew Narva, NKDEP

  • The NKDEP website will be updated to emphasis the following points:
    • The importance of using eGFR,
    • The importance of using a standardized creatinine assay,
    • The need to use an equation that incorporates IDMS creatinine values
    • If eGFR numeric results greater than 60 are to be reported, the CKD-EPI equation should be used
    • If using the MDRD equation, numeric values greater than 60 should not be reported.
Report on current implementation of standardization of cystatin C assays based on traceability to ERM DA471/IFCC

John Eckfeldt, MD, PhD, University of Minnesota

  • Two regular"processed human plasma" (CYS-01 and CYS-02) and two "wildcard" off-the-clot, fresh frozen serum pools were prepared for the CAP cystain C proficiency challenge. Results were reported by 132 laboratories.
  • One wildcard was from normal volunteers (CYS-WC1) and one from CKD patients (CYS-WC2).
  • Questions were asked about reagent, instrument platform and calibration.
  • International certified reference material ERM-DA471/IFCC was used to establish target values of the fresh frozen serum pools using a 2-point calibration curve: Normal pool target = 0.97 mg/L, CKD pool target = 2.37 mg/L
  • There was a nearly two-fold variation in the concentration of cystatin C that the labs reported for each of the fresh frozen CAP samples.
  • For the normal CYS-WC1 sample the central 95% of the results would yield an eGFR ranging from 116 to 65 mL/min/1.73 m2.
  • For the CYS-WC2 CKD pool the central 95% of the results would yield an eGFR ranging from 35 to 19 mL/min/1.73 m2.
  • Conclusion: Manufacturers of IVD's for measurement of cystatin C concentrations and clinical laboratories using them need to improve the accuracy of their measurements if eGFR based on cystatin C is to be useful clinically.
eGFR reporting based on creatinine and cystatin C equations for various categories of diseases

Lars-Olof Hansson, MD, PhD, Karolinska Hospital, Sweden

  • Regression plots for cystatin C and creatinine measured for a series of pooled samples suggested that two linear segments could be identified that changed slope at about cystatin C of 2.0-2.5 mg/L.  This data suggested that there may be a change in physiology of filtration that affects the two molecules differently.
  • Data from eGFR calculated using a cystatin C based equation was compared to a creatinine based equation in several patient groups: primary care, cardiac clinic, neuro-ICU and oncology clinics.
  • The relationship between eGFRcyst and eGFRcreat in a regression plot was different depending on the clinical group examined with a more abrupt change in the slope of the relationship occurring at about 50 mL/min/1.73m^2 observed for the neuro-ICU and oncology groups and less change in eGFRcreat than in the eGFRcyst. 
  • In Sweden, they will start to report eGFR based on both equations and there will be a bigger difference between estimates in sicker patients. The physician will have to interpret results based on the patient cohort.

Closing remarks

Greg Miller

The Lab Working Group will follow-up with manufacturers to schedule a focus meeting to address urine albumin standardization. We look forward to working collaboratively with everyone over the next several years.

September 17, 2014

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