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Letters to the Editor |
1 Division of Clinical Biochemistry and Immunology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN
2 Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN
3 Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN
aAddress reprint requests to this author at:, Mayo Clinic, 200 First St SW, Rochester, MN 55905, Fax 507-266-4088, E-mail Katzmann.Jerry{at}mayo.edu.
To the Editor:
Monoclonal gammopathies are usually monitored with serum and/or urine protein electrophoresis (PEL)(1). In addition, quantitative immunoglobulins are often ordered for patients with large serum M-spikes. For patients with monoclonal light-chain diseases, diagnosis and monitoring can be a challenge, and free light-chain (FLC) quantification in serum has become an important additional test(2). Although there have been some conflicting reports, serum FLC should not replace urine PEL for monitoring patients with a urine M-spikes(3)(4)(5). The purpose of this study was to determine if measuring urine FLCs or urine total light chains (TLCs) is useful in addition to measuring urine PEL for monitoring patients, in a manner analogous to measuring quantitative immunoglobulin as a complement to measuring serum PEL.
Sequential waste urines (n = 336) were obtained from excess samples in which a monoclonal protein was detected by urine immunofixation electrophoresis (IFE). We performed PEL assays with agarose gel electrophoresis (REP, Helena Laboratories) after we increased the protein concentration in urine samples up to 200-fold to achieve a protein concentration of 20–80 g/L. IFE assays were performed with Helena reagent sets. The FLCs and TLCs were quantified on a Dade Behring BN II nephelometer, with separate antisera for 
and 
FLCs (The Binding Site) and and TLCs (Dade Behring). The limits of quantification of the urine TLC and assays are 7 and 4 mg/L, respectively, and 1 mg/L for both and FLC. The reference range for the urine TLC : ratio was based on urine samples obtained from 54 healthy adult donors. These samples had total protein >100 mg/24 h, and we excluded 1 donor because of a highly increased TLC : ratio. The reference range for the urine FLC : ratio was based on urine samples from 91 healthy adult donors, and was the central 95% range.
Urine monoclonal protein was detected with IFE in all urine samples from the patient cohort; 64% of the samples had light chains and 36% had light chains. In the group, 132 patients (62%) had monoclonal protein quantifiable by urine PEL; an M-spike was observed in 74 (61%) of the patients with light chains. M-spike values were 10–8600 mg/L. To determine if quantification of the urinary FLC and TLC could aid in diagnosing monoclonal gammopathies, we determined the diagnostic sensitivities of the FLC and TLC : ratios (Table 1
). The diagnostic sensitivities of the urine FLC and TLC : ratios were 80% and 70%, respectively, with no differences between and isotypes. The diagnostic sensitivity was 93% to 100% in patients with an M-spike but decreased substantially in patients with no quantifiable M-spike. Although large M-spikes (>1 g/24 h) are usually associated with malignant disease, a small nonquantifiable M-spike in a patient with a monoclonal gammopathy does not rule out important clinical diseases such as multiple myeloma or primary amyloidosis. Therefore quantitative urine FLC and TLC assays do not have a role in diagnostic testing. The relatively low diagnostic sensitivity of the urine FLC assay is presumably due to the background of polyclonal FLC in the urine and the wide reference ranges for urine FLC assays. The serum FLC : ratio reference range, for example, is 0.26–1.65. The urine FLC : ratio reference range established in this study is 1–19, and the reference range has been reported elsewhere as 0.46–4.0(2). With the use of this narrower published reference range, the diagnostic sensitivity of the urine FLC : ratio increased from 80% to 90%, but the diagnostic specificity decreased to 27%.
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To determine if urine FLC or TLC may be useful to assist monitoring patients, we used linear regression to assess the relationships of light chain concentration with the quantitation of urine PEL M-spikes. The correlation coefficients for the urine TLC vs the M-spike were 0.95 and 0.98 for and , respectively, and 0.90 and 0.98 for the FLC assays (Table 1
). The slopes of the and TLC vs M-spike linear regression results were 0.40 and 0.60, and the slopes for and FLC were 0.07 and 0.15. These differences indicate that the standardization of these 3 assays is substantially different and reinforces the need for a traceable calibrator for the FLC assay.
Urine FLC and TLC are not sensitive diagnostic tests. Urine FLC and TLC, however, do correlate with the urine PEL M-spike, with the urine TLC being in closer agreement to the PEL M-spike. The quantification of urine TLC may therefore provide a useful quality check on measurements of patient urinary M-spike values. Like serum immunoglobulin quantification, the urine TLC assays may provide redundancy in disease monitoring by M-spike measurement.
Acknowledgments
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: Upon submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: None declared.
Expert Testimony: None declared.
Other: Study approved by the Mayo Clinic Institutional Review Board as a minimal risk protocol and required no informed consent.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
References
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