National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Kidney Disease Education Program (NKDEP) Manufacturers Forum
AACC Annual Meeting — Los Angeles, CA
July 19, 2012
11:00 a.m. to 12:20 p.m.
The NKDEP Laboratory Working Group (LWG) met in conjunction with the International Federation of Clinical Chemistry and Laboratory Medicine's Working Groups for Glomerular Filtration Rate Assessment (WG-GFRA) and for Standardization of Albumin in Urine (WG-SAU), as the membership and goals overlap, and many of the scientific activities are conducted as joint efforts.
Participants: Greg Miller, Flavio Alcantera, Harald Althaus, Dave Armbruster, Lori Bachmann, Diana Blanco, David Bunk, Christa Cobbaert, Joris Delanghe, John Eckfeldt, James Fleming, Neil Greenberg, Susan Hahn, Lars-Olaf Hansson, Glen Hortin, Yoshihisa Itoh, Ron Jamison, Graham Jones, Dave Koch, Hans-Joachim Kytzia, David Lacher, Jack Levine, John Lieske, Gary Myers, Andrew Narva, Ron Newby, Mauro Panteghini, Karen Phinney, Sirpa Riistama-Laari, James Ritchie, Heinz Schimmel, David Seccombe, David Torrens, Jack Zakowski
Uncertainty in Laboratory Assessment of Kidney Disease
Andrew Narva, MD, FACP; NKDEP Director
Cystatin C-based eGFR Equations
- NKDEP should collaborate with laboratorians to educate clinicians about how to understand and express the uncertainty of the eGFR result in an individual patient.
- P30 is the percent chance that the eGFR is within 30% of the measured GFR.
- Emphasis will be made on the fact that the eGFR is an estimate.
Greg Miller, PhD; LWG Chair; Virginia Commonwealth University
Creatinine Specificity Study Education Recommendations (from NKDEP/IFCC)
- IFCC reported that they are still working on the estimating equation using cystatin C. More children need to be added to the data set to determine if a single equation can be used for both adults and children.
- CKD-EPI working group published a report evaluating a new equation using standardized cystatin C and a second equation using both cystatin C and creatinine. This large data set represented an aggregation from a number of cohorts around the world.
- LWG plans to create a task force between the IFCC and CKD-EPI working groups with the goal of arriving at an appropriate cystatin C equation that can be promoted worldwide.
- LWG plans to work with the FDA to discuss the issues surrounding recalibrating cystatin C assays using the international reference material.
- LWG plans to develop educational materials on the status of recalibration of cystatin C and best practices for using cystatin C- and creatinine-based equations.
Neil Greenberg, PhD; Chair, former IFCC WG-GFRA
IFCC/WASPaLM Task Force Update
- Conclusions about the creatinine method specificity study included:
- There are differences in magnitude and direction of bias for both enzymatic and Jaffe methods when interfering conditions were present;
- Influence of interfering substances was less frequent with enzymatic assays; and
- Details of implementation of a method principle influenced its susceptibility to interfering substances.
- Recommendations for Clinical Labs:
- Each lab should review and understand interference claims published in product labeling.
- Users should review other literature explaining strengths and limitations of their creatinine assay (A list of selected references will be included in the recommendations).
- Each lab should take into account characteristics of the population it serves and understand potential for interference and non-specificity to affect the creatinine results (Examples will be provided in the recommendations).
- When creatinine results are not consistent with the clinical situation, labs should consider using a different procedure or another biomarker for kidney function, e.g. cystatin C or a measured GFR.
- Recommendations for Manufacturers:
- Add an explanatory statement to product instructions for use (IFU) clarifying that non-specificity with individual patient samples may still be an important limitation.
- Acknowledge that calibration traceability to higher order reference materials and reference measurement procedures do not alter the influence of potential interfering substances on a result for individual patient samples.
- In the IFU, state the criteria used to determine “bias” or “no bias” from potentially interfering substances.
- Include the concentrations of interfering substances and creatinine levels that were tested.
- Concentrations of interfering substances tested should be at least what is typically encountered in diseased patient populations.
- A minimum list of substances that should be evaluated will be provided in the recommendations.
Graham Jones, MBBS, BSc, DPhil, FRCPA, FAACB; St. Vincent’s Hospital
- K/DOQI 2002 guidelines have been influential around the world. Estimated eGFR has been incorporated into routine practice and has led to collaborative work between laboratory medicine and clinical groups. The third edition of Australian eGFR guidelines will come out later this year.
- Some countries are still using assays that are not IDMS-traceable. Help is needed from manufacturers to determine how widespread their IDMS-traceable assays are so that CKD Programs can suggest using those assays in areas that may be using non-IDMS traceable assays.
- Manufacturers can help identify people and resources that can be used to assist the national CKD programs.
Update on Other Urine Albumin Standardization Activities
Urine Albumin and Creatinine Reference Materials
Karen Phinney, PhD; National Institute of Standards and Technology
Urine Albumin Reference Materials
- SRM 2925 Human Serum Albumin Solution is a primary certified reference material for use with higher order reference measurement procedures for albumin in urine. It is an aqueous solution (1 g/L) that will be characterized over the next several months and will be available early next year.
- SRM 3667 Creatinine in Frozen Human Urine is a pool from a minimum of 10 male and female donors. The concentration is ~61 mg/dL and it will be released at the end of 2012.
- A frozen human urine based albumin and creatinine reference material is planned for development in 2013.
Y. Itoh, MD, DrSci; Asahikawa Medical College
Urine Albumin Reference Measurement Procedures
- The JSCC has developed a secondary reference material for urine albumin. The assigned value is 225.1+/- 9.11 mg/L based on value transfer from ERM-DA470. This is a monomeric human serum albumin that can be used for standardization of urinary albumin and total protein assays, and protein in dipstick tests.
David Bunk, PhD; National Institute of Standards and Technology
Adsorption to Containers
- Albumin in urine is digested by trypsin to release peptides that are quantified by LC-MS/ MS.
- The urine albumin reference measurement procedure under development at Mayo quantitatively measures 3 peptides. The inter-assay CV is 3 - 4% and the intra-assay CV is 2 - 4%. Adding peptides and/or transitions can increase precision.
- NIST has developed a similar procedure and a comparison between the two methods is planned.
- Submission to JCTLM is planned for the spring of 2013.
Physiologic Variability Investigation
- Work is completed and the manuscript is almost ready to submit. In summary, there is less than 1% influence of adsorption of albumin to containers.
Urine Albumin Harmonization Status Investigation
- Project is still in the planning stage. The patients will come from Emory University Hospital.
Lori Bachmann; Virginia Commonwealth University
- The project objectives were to:
- Assess current status of harmonization of routine measurement procedures versus ID-LCMS candidate reference measurement procedure using native patient samples;
- Evaluate analytical performance characteristics of urine albumin measurement procedures;
- Evaluate commutability characteristics of JSCC and diluted IRMM ERM-DA470k/ IFCC reference materials; and
- Assess utility of candidate reference materials for use in standardization of routine measurement procedures. The agreement among medians of 330 urine samples was ~40%.
- Bias of routine measurement procedures vs. a candidate reference measurement procedure expressed as slope in a regression analysis was 0.82 – 1.34.
- Dilution introduced bias in some routine measurement procedures and many manufacturers do not suggest a dilution protocol or dilution solution in their instructions.
- Freeze/thaw effect was minimal.
- Imprecision study: 9 assays had CV less than 5%, 2 assays plus LCMS had CV between 6 - 10%, and 5 assays had CV greater than 10%.
- Sample specific effects were found to be 4 - 8% of the total imprecision for the different measurement procedures.
- Next Steps:
- Harmonization manuscript will be submitted in the fall of 2012.
- Assess commutability characteristics of IRMM and JSCC candidate reference materials.
- Evaluate the ability of mathematical recalibration (based on reference materials) to achieve method standardization.
- Based on comments at the LWG meeting, there is a plan to look at the correlation between routine methods.
- There is a plan to notify manufacturers of the data prior to publication.
- G. Miller asked the manufacturers if this meeting is useful to them and they agreed that it was. Consequently, we will continue to offer this meeting to summarize progress in measurements for CKD.
November 7, 2012