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and Free 
Immunoglobulin Light Chains: Relative Sensitivity for Detection of Monoclonal Light Chains
1 Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
2 The Binding Site Ltd and The Medical School, University of Birmingham, Birmingham B15 2TT, England.
aAddress correspondence to this author at: Mayo Clinic, Hilton Bldg., Room 920, 200 First St. SW, Rochester, MN 55905. Fax 507-266-4088; e-mail katzmann{at}mayo.edu.
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Abstract |
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 Top Abstract IntroductionParticipants and MethodsResultsDiscussionReferences |
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Methods: We used an automated immunoassay for FLCs and sera from a population 21–90 years of age. We used the calculated reference and diagnostic intervals to compare FLC results with those obtained by immunofixation (IFE) to detect low concentrations of monoclonal 
and 
FLCs in the sera of patients with monoclonal gammopathies.
Results: Serum and FLCs increased with population age, with an apparent change for those >80 years. This trend was lost when the FLC concentration was normalized to cystatin C concentration. The ratio of FLC to FLC (FLC K/L) did not exhibit an age-dependent trend. The diagnostic interval for FLC K/L was 0.26–1.65. The 95% reference interval for FLC was 3.3–19.4 mg/L, and that for FLC was 5.7–26.3 mg/L. Detection and quantification of monoclonal FLCs by nephelometry were more sensitive than IFE in serum samples from patients with primary systemic amyloidosis and light-chain-deposition disease.
Conclusions: Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal FLCs easier and more sensitive than with current methods. The serum FLC assay complements IFE and allows quantification of FLCs in light-chain-disease patients who have no detectable serum or urine M-spike.
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Introduction |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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Sensitive nephelometric assays that are specific for and free light chains (FLCs) but that do not recognize light chains bound to immunoglobulin heavy chains have recently been described (4). These automated assays are reported to be more sensitive than IFE for the detection of monoclonal FLCs. The nephelometric assays were used to evaluate serum samples from NSMM patients whose serum and urine samples were negative for FLCs by IFE, and these assays detected excess serum or FLCs in 19 of 28 patients (5). In a subset of NSMM patients, serial serum samples were analyzed for FLCs, whose quantities were correlated with disease activity.
Because IFE does not quantify FLCs and is not sufficiently sensitive to detect small amounts of monoclonal FLCs in all patients with light-chain plasma-cell dyscrasias, it is important to evaluate the utility of FLC assays to diagnose and monitor the light-chain diseases. These diseases affect mainly the elderly, and we designed this study to determine the 95% reference intervals of and FLCs, as well as the diagnostic interval for the ratio of FLC to FLC (FLC K/L) in a population 21–90 years of age. In addition, we applied these intervals to a group of patients with light-chain diseases and compared the ability of the nephelometric assay with that of the IFE assay to detect abnormal light chains.
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Participants and Methods |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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FLC content, FLC content, or FLC K/L were found between the 25 fresh and 47 frozen samples in this overlapping age group. All sera were assessed by SPEP and IFE for an M-spike or a restricted migration pattern that would suggest the presence of a monoclonal protein. No abnormalities were detected.
Twenty-five polyclonal hypergammaglobulinemia serum samples were obtained from the clinical electrophoresis laboratory. As determined by SPEP, all 25 sera had increased 
-globulin concentrations of 18–39 g/L. None of these sera contained a monoclonal protein as determined by IFE.
The clinical laboratory also identified 47 serum samples that had given equivocal IFE results. These samples were either determined to have a monoclonal light chain after multiple IFE assays at different sample dilutions or were from patients who were serum negative but urine positive for a monoclonal light chain. These 47 frozen sera had been collected from AL, LCDD, or MM patients: 24 samples were from patients with a monoclonal light chain and 23 from patients with a monoclonal light chain.
Sera from 19 patients with LCDD were obtained from the Dysproteinemia Clinic frozen serum bank. These LCDD serum samples were selected to represent patients with (a) monoclonal light chains detected by IFE in the serum, (b) monoclonal light chains detected by IFE in the urine but not the serum, or (c) a monoclonal population of bone marrow plasma cells but no IFE-detectable light chains in either serum or urine.
analytic methods
SPEP was performed on agarose gels with the Helena REP system (Helena Laboratories). Ponceau S stain was used to visualize the proteins, and the stained gels were scanned with a Helena Cliniscan 3 scanner. Serum total protein was determined with biuret reagent on a Hitachi 747 analyzer (Boehringer-Mannheim Corp.). The serum total protein value multiplied by the percentage of protein migrating in the gamma region was used to quantify the gamma fraction.
IFE was performed with a Sebia HYDRAGEL 4IF reagent set on a Sebia HYDRASYS electrophoresis system and agarose gels. The IFE assay used antisera against , 
, µ, , and to fix specific proteins after electrophoretic separation, and precipitated protein was visualized with acid-violet stain. The detection limits of the IFE assay for monoclonal proteins are 25–50 mg/L, depending on the position of the monoclonal protein band and the content of polyclonal immunoglobulin. Any samples that exhibited monoclonal light-chain staining but no corresponding monoclonal heavy-chain staining were also analyzed by the Ouchterlony method for 
and 
reactivity. This assay has a detection limit of 40 mg/L for IgD and IgE. When either or was detected, the IFE was repeated with antisera to , , , and to detect a monoclonal IgD or IgE protein.
Nephelometry was performed on a Dade-Behring BNII. Quantification of total , total , and cystatin C used antibodies from Dade-Behring. FLCs were quantified with FREELITETM reagent sets from The Binding Site Ltd. These FLC assays use sheep antisera coated on polystyrene latex particles and are enhanced by the addition of polyethylene glycol to the reaction. Saline-diluted serum samples that contained either a monoclonal or a light chain were used to test assay linearity. We performed 20 replicate tests on polyclonal sera with typical FLC values to determine the CV of the assay. The FLC assay was linear to a minimum value of 0.5 mg/L; at 0.7 mg/L, the intraassay CV was 7.9%; and at 14 mg/L, the interassay CV was 8.7%. The FLC assay was linear to a minimum value of 0.6 mg/L; at 0.9 mg/L, the intraassay CV was 10%; and at 32 mg/L, the interassay CV was 7%.
statistical analysis
The SAS and S-PLUS statistical software packages were used to perform the analyses and create graphs. Reference intervals were determined with a method suggested by O’Brien and Dyck (6). This method accounts for differences in means and the variability across age and sex groups. Linear regression analysis was used to adjust for significant differences in means across age or sex groups (6). Significance was defined as both P <0.05 and R2 >0.10. For variables with a means adjustment, variability was adjusted separately for positive and negative residuals from the first regression, again only when significant. Z-scores were then created for each datum by subtracting the fitted value from the first regression and dividing the fitted value (corresponding to the appropriate second regression), depending on whether the residual from the first regression was positive or negative. The 2.5 and 97.5 percentiles were then determined from the Z-scores. These percentiles were back-transformed to the units of measure by reversing the process that had created the Z-scores, which produced reference intervals stratified by age and/or sex when significant.
Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were estimated for the FLC K/L on the basis of both the central 95% interval and a diagnostic range that captured 100% of the test data. Accuracy was calculated as the proportion of individuals classified correctly. Confidence intervals were calculated according to the exact binomial distribution for sensitivity, specificity, and accuracy and by bootstrap for PPV and NPV. We calculated both PPV and NPV after assuming a 15% prevalence of monoclonal proteins in the samples submitted for monoclonal protein studies.
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Results |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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fraction, total , and total were quantified for the 282 reference serum samples (data not shown). There was no age or sex dependence in samples from donors between the ages of 21 and 90 years. The median and central 95% interval for the fraction were 13.1 and 7.9–19.3 g/L, respectively. The fraction should be mostly IgG, and approximately one-third of its mass should be immunoglobulin light chain (two-thirds and one-third ) bound to the heavy chain. The total content was 2.52 g/L (1.55–3.78 g/L), and the total content was 1.43 g/L (0.89–2.03 g/L). The ratio of total to total (K/L) had a median value of 1.78 and a central 95% interval of 1.30–2.52.
Quantification of and FLCs showed a trend of increasing values with increasing age (Fig. 1, A and B
). There was no relationship between FLC and sex. The and FLC values showed an increase that was most apparent for those >80 years of age (Table 1
). Although the data for the FLCs tended to increase with increasing age, this increase was not significant. The P value and R2 result for FLC vs age were 0.004 and 0.06, respectively, whereas for FLC, the respective values were 0.06 and 0.03. A central 95% reference interval was defined without regard to age or sex (Table 2
). FLC K/L did not vary with age (Fig. 1C
). Cystatin C concentrations showed a relationship with age similar to that between and FLC concentrations and age (Fig. 2A
). When the FLC results were expressed as a ratio of FLC to cystatin C, the trend with age was no longer apparent (Fig. 2, B and C
). When the FLC results were expressed as a ratio of FLC to creatinine, the age dependence was reduced but not eliminated (data not shown).
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The median FLC K/L was 0.59 and was substantially different from the median total K/L of 1.78. This difference has been attributed to the dimerization of light chains and the consequently slower clearance compared with that of light chains (5). The FLC K/L was not significantly related to age or sex. The FLC K/L central 95% reference interval was 0.3–1.2 (Table 2
). By definition, 5% of the general population will have a FLC K/L outside this 95% reference interval. If the FLC K/L is used as a diagnostic test for monoclonal FLCs and the FLC diseases, a 5% false-positive rate is unacceptable. We therefore defined a FLC K/L diagnostic range that included all 282 reference sera tested in this study. The FLC K/L had a 100% range of 0.26–1.65 (Table 2
).
The FLC results for 25 serum samples with polyclonal hypergammaglobulinemia are shown in Table 3
. Although a majority of the and FLCs were increased in this group of hypergammaglobulinemia sera, none of the FLC K/L values were abnormal.
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The and FLC values were determined for 47 patient serum samples that had been difficult to immunotype by IFE (Table 4
). Twenty-four samples came from patients for whom IFE had detected a monoclonal light chain in the urine or who had a history of a previous urine sample that contained a monoclonal light chain. The serum IFE assays identified 21 positive (monoclonal ) and 3 equivocal sera. Two of the patients with an equivocal IFE result for serum monoclonal protein had this protein detected in their urine by IFE. The third patient with an equivocal IFE result for serum monoclonal protein had no monoclonal in the concurrent urine sample. Interestingly, one of the patients with monoclonal serum protein, as detected by IFE, had no monoclonal protein detected in the concurrent urine by IFE. The FLC and the FLC K/L were abnormally increased in all 24 sera. The median FLC, median FLC, and median FLC K/L were 716 mg/L, 1.2 mg/L, and 539, respectively.
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There were also 23 serum samples from patients for whom IFE had detected monoclonal light chain protein in the urine or who had a history of monoclonal light chain protein detected in urine. The serum IFE assays identified 15 positive and 8 negative sera. Seven of the patients whose sera were protein negative by IFE had concurrent urine samples that were positive for monoclonal protein by IFE. One patient with a negative serum result by IFE had a concurrent urine sample that was also negative for monoclonal protein by IFE. The FLC concentration was abnormally increased in 22 sera, and the FLC K/L was abnormally low in 22 sera. The patient with negative FLC results also had negative serum and urine results by IFE. As in the group, there was one patient whose serum was positive for monoclonal by IFE and FLC, but whose urine was protein negative by IFE. The median FLC, median FLC, and median FLC K/L were 4.5 mg/L, 258 mg/L, and 0.019, respectively.
The results for 19 LCDD patients are listed in Table 5
. These four patient groups included (a) 9 patients whose sera were monoclonal positive by IFE; (b) 3 whose sera were monoclonal positive by IFE; (c) 4 whose sera were IFE negative but whose urine samples were positive for monoclonal by IFE; and (d) 3 whose sera and urine samples were both negative by IFE but whose bone marrow stains were restricted to . Among these 19 patients, 12 had a serum monoclonal protein detected by IFE (63%) and 17 had a serum monoclonal protein detected by FLC K/L (89%). Six patients with a negative serum IFE had a positive FLC K/L, and one patient with a positive serum IFE had a negative FLC K/L.
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The results from the 25 polyclonal hypergammaglobulinemia sera (Table 3
) and 282 reference sera were used to calculate the specificity of FLC K/L, and the results from the 66 patients with AL, MM, or LCDD (Tables 4
and 5
) were used to calculate the sensitivity in this selected patient group (Table 6
). As expected, use of the diagnostic range for FLC K/L significantly improved the specificity of the FLC assay.
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Discussion |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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The reference intervals reported herein are close to those described in the original report of this nephelometric FLC immunoassay (4). That study, however, did not include older healthy donors. The monoclonal gammopathies are more prevalent in older populations. Several epidemiologic studies have reported the incidence of monoclonal gammopathy of undetermined significance as 
1% in the population >50 years and 3% in the population >70 years of age (12). The and serum FLCs showed a trend for increased values with increasing age in our study, and there was a substantial increase in these values in individuals >80 years of age. The FLC K/L ratio, however, normalized the age-dependent increases in FLC. Because total and concentrations do not show an increase with age and because the FLC K/L normalizes the increase in and FLC values, the most likely explanation for the observed increase in serum FLC concentrations is a decrease in renal clearance with advancing age. Measures of renal clearance show an age-related decrease in renal function that begins in the third decade (13)(14). Cystatin C is a sensitive indicator of renal clearance, and the increase in FLC content with age is reflected by an increase in cystatin C. Dividing the FLC result by the cystatin C result eliminates the apparent dependence of FLC on age. The increase in FLC values is therefore likely attributable to reduced kidney function and not to age per se. Because many patients with monoclonal gammopathies also have decreased renal function and proteinuria, these could be confounding factors in interpreting FLC measurements. The FLC K/L, however, is not affected by renal function and is therefore the most straightforward representation of the data for diagnostic testing. In the group of 25 samples from patients with polyclonal hypergammaglobulinemia, the FLC values were also increased. The increment in this patient group was presumably not attributable to reduced kidney function but to increased immunoglobulin synthesis. The FLC K/L in this group of samples also normalized the and FLC increases, such that no samples had an abnormal FLC K/L.
Using the reference intervals and diagnostic ranges developed in this study, we assessed the relative sensitivity of the FLC assay for detecting monoclonal and FLC concentrations in sera of a cohort of patients who had a variety of monoclonal gammopathies. In this small, selected group of samples, the FLC measurements had a higher sensitivity than did IFE for detecting small concentrations of monoclonal light chains in serum. Interestingly, those serum samples that were negative by IFE had FLC concentrations that were similar to those in samples with positive IFE results. The lower sensitivity of the serum IFE assay in this group may be attributable to polyclonal immunoglobulins that obscure the small, monoclonal FLC band. The binding of the FLC assay is reported to be >10 000-fold higher for FLCs in comparison with the light chains bound to heavy chains in intact immunoglobulin (4). This binding preference may allow detection of a small increase in FLC concentration when polyclonal immunoglobulins are present. Alternatively, the serum IFE assay may not detect FLCs in some of these samples because of polymerization of monoclonal light chains. The polymerization of some light chains yields complexes that electrophorese in very broad patterns that are not recognized as monoclonal light chains (5). The increased sensitivity of the FLC K/L compared with serum IFE makes the FLC method a useful diagnostic assay. Primary systemic amyloidosis and LCDD are often difficult to diagnose, and the presence of a monoclonal FLC is an important differential diagnostic clue. The sensitivity of the IFE method in serum or urine is 70% for AL and 90% when both serum and urine assays are performed. The enhanced diagnostic sensitivity may be useful for disease detection and may be an additional laboratory assessment for patients suspected of having a light-chain disease.
The FLC data for the 19 LCDD serum samples demonstrate the differences between the FLC and IFE assays. Seven of these samples were negative for a serum monoclonal light chain by IFE, and 6 of these had an abnormal FLC K/L. Surprisingly, the FLC K/L was not increased in one of nine sera with a monoclonal light chain detected by IFE. This serum sample was retested, and the IFE and FLC results were reproducible. The FLC value in this sample was at the low end of the usual reference interval and was much lower than the other eight samples in this group. The assay selectivity for cryptic light-chain sites that are "hidden" when bound to heavy-chain proteins most likely depends on reactivity with very few sites on the light chain. We speculate that the lack of reactivity with the monoclonal light chain from this patient may have been attributable to truncation of the light chains and the consequent loss of antigenic sites. The increased sensitivity of the FLC assay compared with the serum IFE assay, coupled with the inability of the FLC assay to detect certain light chains, suggests that these two assays be used as complementary diagnostic tests.
In addition to the increased sensitivity and diagnostic potential of the FLC assays, the ability to quantify monoclonal FLCs may be useful to monitor the disease process in light-chain diseases. The disease course of AL can be difficult to assess and is currently monitored by evaluating organ function (e.g., kidney function by urine protein measurements). Changes in organ function, however, may take a long time to manifest, and therefore, direct measurements of the serum or urine M-spike provide a real-time marker for monitoring AL. Fewer than one-half of AL patients have a measurable M-spike, and the quantification of FLC may provide a more universal and timely assessment of disease activity. Studies correlating disease activity and FLC quantification remain to be done.
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Acknowledgments |
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Footnotes |
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FLC to FLC; PPV, positive predictive value; and NPV, negative predictive value. 
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References |
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TopAbstractIntroductionParticipants and MethodsResultsDiscussionReferences |
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, fresh sera. There is an apparent age dependence for FLC quantification but not for the FLC K/L.