U.S. Department of Health and Human Services

Meeting Minutes – Manufacturers' Forum July 30, 2008

​National Institute Of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Kidney Disease Education Program (NKDEP) Manufacturers' Forum
AAAC Annual Meeting – Washington, DC

Participants: Greg Miller (Chair), George Schwartz, Mauro Panteghini, Chandra Jain, Neil Greenberg, John Lieske, Glen Hortin, Graham Jones, Joris Delanghe, Eileen Newman, David Seccombe, Karen Phinney, Matthew McQueen, Mary Robinson, John Eckfeldt, Yoshihisa Itoh, Andrew Narva, David Bruns, Gary Myers, HaraldAlthaus, Dave Armbruster, Mara Belville, Cindy Coady, Christa Cobbaert, Kelley Cooper (Carville), Jian Dai, Patrick Daley, Joseph De Giorgio, Howard Deahr, Mary Lou Gantzer, Matthew Gnezda, George Koumantaris, Jack Levine, Nicole Magrini, Andrei Malic, David McDiarmid, Murray Rosenthal, Fabio Rota, Charlene Soley, Jill Tate, Dave Torrens, Bill Walters, Jr., Steve Wolf, Reba Wright, Esther Yang, Nancy Accetta, Christen Horn

Summary of Action Items:

  • Manufacturers agreed to send an email to Nancy Accetta as to status of their creatinine standardization and introduction of enzymatic methods, both inside and outside US.
  • Follow-up comments should be submitted to Greg Miller within the next week.

Meeting Minutes

1. Update on Creatinine Standardization, Greg Miller, LWG Chair

  • Based on CAP Survey:
    • 70% of labs report eGFR along with serum creatinine; of those, 77% report with all creatinine values reported and lesser percentages report only when requested, with specific panels, or only on outpatients
    • 80% use MDRD 4-parameter equation
    • 4% used Cockcroft-Gault (C-G); 2% used MDRD 6-parameter
    • 71% reported as >60 mL/min/1.73m2
  • 43% used methods with calibration traceable to IDMS reference system
  • Issues with IDMS-traceable calibration: it produces 10-20% lower creatinine values; MDRD 4-parameter equation is available for use with IDMS-traceable methods; there is no IDMS-traceable version of the MDRD 6-parameter or C-G equations; use of C-G or MDRD 6-parameter equation will over-estimate GFR and under-estimate extent of kidney damage
  • Pharmacy impact of IDMS-traceable creatinine methods: drug dose adjustment is based on kidney function; drug labeling has used the C-G equation; C-G will give an erroneously high estimate of GFR with an IDMS-traceable creatinine result (whether from Jaffe or enzymatic methods); this is important for drugs with narrow therapeutic or toxic ranges; MDRD will give a more accurate estimate of GFR and kidney function, but has not been used in the drug labeling; physicians and pharmacists need to be aware of decreased creatinine results to avoid inappropriate decisions on drug dosages; laboratory should provide the percent change in creatinine when introducing an IDMS-traceable method and the lab is dependent on the manufacturer for this information
  • NKDEP is developing educational tools to help physicians and pharmacists understand how to look at drug dosing and kidney function during this time of transition; guidelines for drug manufacturers will come from FDA, but generally new drug labeling will give information with MDRD and C-G equations
  • Manufacturers were polled as to which have IDMS-traceable methods: those that have not yet changed, plan to do so by end of year; all plan to change soon (Note: The Jaffe will not be traceable to IMDS on the Dimension series, but the enzymatic procedure is IDMS traceable.)
  • All manufacturers agreed to send an email to Nancy Accetta as to status of their creatinine standardization and introduction of enzymatic methods, both inside and outside US.
  • A question was asked about the status of whole blood creatinine calibration: a suggested protocol/guideline is published on the NKDEP website; essentially the methods should be calibrated to produce results comparable to plasma/serum creatinine; there are no plans for commutability studies for whole blood devices

2. Update on Creatinine Specificity Study, Neil Greenberg (Chair IFCC WG-GFRA), Ortho Clinical Diagnostics

  • Background:
    • Gerard et al, 1985: observed that the alkaline picrate method is more sensitive than enzymatic methods in ketotic patients
    • Weber et al, 1991: showed that carbonyl compounds such as dopamine, cephalosporines, and bilirubin interfere with Jaffe reaction; while bilirubin, creatine, dopamine, ascorbic acid, and sarcosine interfere with enzymatic methods, concluding that the elimination of interferences had not been achieved
    • Franzini et al, 1991: observed no sign of interference from conjugated or unconjugated bilirubin for methods that remove proteins or enzymatic methods with NADH oxidation, but observed negative interference with alkaline picrate and direct enzymatic methods based on hydrogen peroxide measurement
    • Peake et al 2006: concluded that Roche Modular Jaffe method was suitable for routine adult measurements, but unacceptable for use in neonates due to hemoglobin F interference
  • Study group members are Neil Greenberg, Greg Miller, Jack Zakowski, and Bill Roberts
  • Study Approach:
    • Focus on evaluation of unaltered patient samples from selected patient populations
    • Examine more than 400 native, non-pooled patient samples from selected pathological groups (e.g., diabetics, CKD, liver disease, high and low protein syndromes, such asmonoclonal gammopathies and nephrotic syndrome), and selected therapeutic drug users
    • Include supplemental spiked samples for certain important potential interferents that are more volatile (e.g., ascorbate)
    • All samples tested with four different manufacturer's methods (including alkaline picrate and enzymatic methods); testing to be performed by manufacturers (Ortho, Beckman, Siemans, Roche); available volumes from residual lab samples prevent including more methods
  • Targeted Patient Groups:
    • Cephalosporins; Dobutamine; Dopamine
    • Hemolyzed samples; high bilirubin samples
    • High beta-hydroxybutyrate samples; high glucose samples
    • Diabetes patients; Pyruvate; Lidocaine samples
    • Lipemic samples; low serum protein samples
    • Myeloma patients (high protein)
    • Cardiovascular patients (high blood pressure medications)
    • Chronic kidney disease patients; dialysis patients
    • Nephrotic syndrome patients; kidney transplant patients
  • ID-LC MS/MS reference measurements will be performed in the laboratory of Neil Dalton, Evelina Childrens Hospital, London, UK, using a method published by Preiss DJ, et al, 2007 in Ann Clin Biochem
  • Project status:
    • Draft proposal has been developed and circulated for review and comment
    • Funding request has been made for NKDEP funds
    • Study protocol has been submitted for IRB review at University of Utah and Medical College of Virginia
    • Sample collection should be completed by early 2009; distribution and testing will follow in 2009

3. Review of Revised Pediatric Content for Website (Equation and Calculator), Greg Miller, George Schwartz, Joris Delanghe

The following documents were reviewed; they will be added to the website in the coming weeks:

  • Document #3: Guidelines for laboratories
  • Document #2: For Laboratory Professionals Section of NKDEP site
  • Document #1: For Health Professionals section of NKDEP site
  • Follow-up comments should be submitted to Greg Miller within the next week

4. Update: Cystatin C Standardization by IFCC-EU Working Group, Harald Althaus, Siemens Medical Solutions Diagnostics

  • Working Group was formed in 2004; members are Søren Blirup-Jensen, Camilla Schmidt, Veronica Lindström, Anders Grubb, Ingrid Zegers, Yoshi Itoh, Harald Althaus
  • Goal: to produce and characterize primary and secondary reference preparation for cystatin
  • Primary Reference Preparation: recombinant human cystatin C was produced in E.coli; purified product was placed in vials and lyophilized; characterization shows that the recombinant Cystatin C primary reference preparation is monomeric, highly pure, has the expected mobility, has the expected molecular mass, shows high homogeneity, is identical to native intact human Cystatin C
  • Secondary Reference Preparation (SRP): a human serum pool was collected and stabilized in the same way used for the production of CRM 470; serum from healthy donors was collected in Lund, Sweden and Marburg, Germany using the same protocol; recombinant Cystatin C (PRP) was added to get a final Cystatin C concentration between 5 and 6 mg/L and about 4,400 vials were produced; these are stored at -80o C at IRMM
  • Next steps: value assignment, stability studies, homogeneity studies, commutability study, further characterization
  • Question: George Schwartz asked if there are secondary characteristics of the human protein that differ from the E.coli synthesized protein that may affect antibody binding. Answer: An investigation published previously shows that this material is comparable with native material.
  • Question: Neil Greenberg asked if there is any idea why there is a difference between the Dako and Dade Behring assays. Answer: Dade Behring uses cystatin C from human serum and Dako calibration is based on recombinant cystatin C.
  • Question: When will a certificate of analysis be available? Answer: Only IRMM can answer that; plan to make value assignment in August or September, so maybe by the end of the year.
  • Question: John Eckfeldt asked how the commutability studies will be performed. Answer: Optimized turbidimitry and nephelometry methods are published as reference methods by JCTLM, but nothing is final so recommendations are welcome.

5. Update: Urine Albumin Group Activities, Greg Miller, LWG Chair

  • In 2007 a joint NKDEP/IFCC conference on current issues and reporting of urine albumin excretion: a manuscript on that conference will be published in Clinical Chemistry soon; in 2008 a joint NKDEP-IFCC work group for standardization of albumin in urine was formed with Greg Miller as the chair
  • Recommendations:
    • "Urine albumin" should replace "microalbumin"
    • 1st-morning void provides lower CVi than a random collection
    • 2nd-morning void may be acceptable but no evidence for superior to a 1st-morning void
    • Urine albumin should be measured in non-frozen urine within 7 days
    • Refrigerated samples should be warmed to RT, examined for precipitate, and centrifuged if necessary
    • Long-term storage of samples should be at less than -70o C
    • Albumin creatinine ratio (ACR) should be reported with all urine albumin measurements
    • Reporting units for ACR should be uniform in a country or geographic region (mg/g or mg/mmol)
    • Reporting urine albumin as mg/L is difficult to interpret and should not be reported alone
  • Next steps:
    • Clarification of pre-analytical requirements: influence of container type (adsorption); influence of timing of collection (first morning, second morning, random, 24 hour) related to CVi
    • Clarification of the degree of urine albumin degradation under various conditions of storage
    • Clarification of the molecular forms of albumin in freshly voided urine, and the definition of the measurand
    • Clarification regarding the variation in urinary matrix composition over which urine albumin measurement procedures must operate: influence of blood, seminal fluid and other physiologic contaminants of urine
    • Clarification of the clinical requirements for total error in measurement of urine albumin; dependent on good estimate of CVi
    • Reference measurement procedure; reference material for urine albumin, both primary (pure substance) and secondary (matrix based); reference material for urine creatinine has not yet been prepared; NIST SRM 914 crystalline creatinine is available, but there is not a secondary (matrix based) material in urine
    • Interpretive criteria: decision thresholds for ACR and AER; ACR varies with age, gender, ethnicity; risk for CKD and CVD are continuous functions of urine albumin concentration, and fixed thresholds may not be appropriate; usefulness of age- and gender-specific equations to convert ACR to an estimated AER for which a single reference limit may be appropriate

Meeting adjourned at 4:45 p.m.


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