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Technical Briefs |
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1 Division of Clinical Biochemistry and Immunology,
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Section of Biostatistics,
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Division of Nephrology, and
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Division of Hematology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905;
aauthor for correspondence: fax 507-266-4088, e-mail katzmann.jerry{at}mayo.edu)
Multiple myeloma is a malignant plasma cell dyscrasia characterized by bone marrow plasmacytosis (1). Malignant plasma cells produce an abnormal monoclonal immunoglobulin, the laboratory hallmark of the disease process, as well as cytokines, which stimulate cells of the bone marrow microenvironment (2)(3). The neoplastic clone and its products cause the dysfunction of several organs, including bone pain or fractures, renal failure, anemia, susceptibility to infection, hyperviscosity, and hypercalcemia (1). However, the most characteristic feature of multiple myeloma and other monoclonal gammopathies is the presence of a serum and/or urinary monoclonal (M) component on immunofixation (4). Approximately two-thirds of patients with a serum M component also have Bence Jones proteins (BJPs) in the urine. In almost 20% of myelomas, only immunoglobulin light chains are present in the serum and/or urine and are often designated as light chain multiple myeloma (LCMM).
Renal failure occurs in 
25% of myeloma patients, and there is some renal pathology in more than one-half (1)(5)(6). The number of patients with renal disease varies considerably depending on the criteria used to define renal impairment. Serum creatinine concentrations remain in the reference interval until the glomerular filtration rate is reduced by almost 50%; therefore, the data obtained with blood creatinine concentrations most likely underestimate the incidence of renal involvement in myeloma. Data using the estimated creatinine clearance rate (7), which takes into account various variables, including patient age, weight, and gender, indicate that approximately one-half of patients have renal insufficiency at the time of diagnosis (5). The nature of the M component is also associated with the prevalence of renal disease (5)(8)(9). In light chain myeloma, 65% of patients have impaired renal function at the time of diagnosis when estimated creatinine clearance is used as the variable (5). The incidence of renal dysfunction is greater in patients with compounding factors, such as hypercalcemia and advanced disease (5)(8)(9). Although there are numerous contributing factors for renal dysfunction in myeloma, the primary among them is the filtration of large quantities of light chains by the glomeruli (10)(11), which produces a huge reabsorptive load on the proximal tubules.
Tubular dysfunction is seen in >98% of patients with Bence Jones proteinuria >1 g/24 h (9). However, tubular damage associated with the excretion of light chains is almost always present (10). Usually, because light chains are of low molecular weight (25 000), they are readily filtered by the glomeruli, reabsorbed in the renal tubules, and catabolized. If the filtered load is excessive, as occurs in LCMM, this reabsorptive capacity is exceeded and free light chains appear in the urine, where they have also been concentrated by physiologic renal tubular water reabsorption. Tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes (10). The proteinuria that involves essentially only light chains does not cause hyperalbuminuria. Usually, there is very little albumin in the urine because glomerular function is intact. Patients with myeloma may present with acute renal failure at the time of diagnosis, or acute renal failure may manifest itself during the course of disease. In a study done at Oxford, it was noted that among patients admitted for acute renal failure, there was an excess of LCMMs and IgD myelomas (10)(12).
Various laboratory markers are used for the diagnosis and monitoring of patients with multiple myeloma. Among the protein components, serum M peaks and/or BJPs are identifiable in virtually all patients with the disease (13)(14)(15)(16).
A major pitfall in the measurement of urinary light chains is that dipsticks for detecting proteinuria are unreliable in recognizing free light chains. Additionally, the conventional tests used for detecting BJPs are falsely negative in approximately one-half of patients with LCMM. Because of the high urinary concentration of light chains, 24-h urine collections have traditionally been used for the detection of light chains in patients with suspected multiple myeloma. Moreover, the amount of light chain excreted in the urine often correlates with disease progression. However, 24-h urine collections are cumbersome and are prone to inaccuracies because of incorrect collection, and measurement of urinary light chains by electrophoresis is difficult. It is therefore clinically relevant to develop a modality to measure free light chains in the serum as a viable alternative to measuring BJPs to follow the course of disease in this group of patients.
As part of another research project, a registry of 29 500 dysproteinemic patients identified at the Mayo Clinic from 1960 to the present is maintained. From this registry, 28 patients with LCMM were selected for this analysis. This study was conducted with approval from the Institutional Review Board. A previously described nephelometric assay, performed using a Dade Behring BNII nephelometer [Ref. (17) and Katzmann JA, Clark RJ, Abraham RS, Bryant SC, Lymp JF, Bradwell AR, et al. Serum diagnostic and reference ranges for free 
and free 
immunoglobulin light chains: age dependence and relative sensitivity for detection of monoclonal light chains, submitted for publication], was used to quantify free immunoglobulin light chains (FLCs) in the sera of these patients. This method uses antibodies (Freelite®; The Binding Site, Ltd.) specific for and light chains in free form, not bound to the heavy chain (17).
For most patients, data from at least two to three different time intervals were analyzed. Of the 28 LCMM patients in the study, 9 were positive for light chain and 19 for light chain. All of these patients had a monoclonal light chain detected by immunofixation in the serum and urine. Although all the patients had a M peak in the urine, only 3 of 9 patients and 13 of 19 patients had a M peak in the serum. We wished to determine whether serum FLC quantification could serve as a surrogate for urinary M-protein measurements in this group of patients. In the subgroup, of the nine patients, eight (89%) had increased FLCs in the serum. The median FLC was 699 mg/L (reference interval, 2–11.2 mg/L). All nine patients had abnormally increased free light chain / (FLC K/L) ratios, with a median value of 248 (reference interval, 0.09–0.89). In the group, all 19 (100%) patients had both increased FLCs and abnormally decreased FLC K/L ratios in the serum, with median values of 1390 mg/L (reference interval, 6.8–25.2 mg/L) and 0.005 (reference interval, 0.09–0.89), respectively. The utility of the serum FLC K/L ratio for detecting monoclonality was evaluated by measuring FLC concentrations in the sera of seven patients who had increased urinary protein unrelated to a monoclonal gammopathy. These patients had renal disease secondary to systemic lupus erythematosus, glomerulonephritis, or renal disease of unknown etiology. Six of seven patients had serum and FLC concentrations within the respective reference intervals. The single abnormal result was an increased serum FLC. The FLC K/L ratios, however, were within the reference interval for all seven patients, suggesting that excess or serum FLC is a marker in the context of monoclonal gammopathies.
Results for sequential serum FLCs and 24-h urinary monoclonal protein were compared for a representative and a representative LCMM patient (Fig. 1
). These two patients illustrate that the serum FLC and the 24-h urinary M-protein concentrations behave in a coordinated fashion. However, the absolute value for urinary M protein could not be correlated with the absolute value for serum FLC, as evidenced by the initial measurements for 24-h urinary M protein and serum FLC (Table 1
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In light of this information, we were interested in evaluating whether changes in urinary M-protein concentrations could be predicted by serum FLC. A random-effects model was fit to these data to estimate the correlation between changes in urinary M protein and serum FLC and to test whether the correlation was significantly different from zero (18). The dependent variable was log10(urinary M protein), whereas the independent variable was log10(serum FLC). Log transformations were made to both the dependent and independent variables to improve the model fit.
Changes in urinary M protein correlated strongly with changes in serum FLC concentrations when we used the random-effects model (P = 0.0001). In other words, although serum FLC does not quantitatively match urinary M-protein concentrations, changes in serum FLC over a period of time correlate with changes in the amounts of 24-h urinary M protein for an individual patient.
It appears, therefore, that the quantification of FLCs in serum by nephelometry correlates linearly on a log-log scale with changes in urinary FLC excretion. This correlation suggests that serum measurements may provide a logical and feasible alternative to 24-h urine collections in monitoring patients with LCMM.
Acknowledgments
This study was supported in part by Grant CA 62242 from the National Cancer Institute. We also wish to acknowledge Dr. A. R. Bradwell and The Binding Site, Ltd (Birmingham, United Kingdom) for providing the FLC reagents for analysis.
References
The following articles in journals at HighWire Press have cited this article:
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  C. A. Hutchison, S. Harding, P. Hewins, G. P. Mead, J. Townsend, A. R. Bradwell, and P. Cockwell Quantitative Assessment of Serum and Urinary Polyclonal Free Light Chains in Patients with Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., November 1, 2008; 3(6): 1684 - 1690. [Abstract] [Full Text] [PDF]
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