Serum Free Light Chain Measurement Aids the Diagnosis of Myeloma in Patients With Severe Renal Failure

Colin A Hutchison; Tim Plant; Mark Drayson; Paul Cockwell; Melpomeni Kountouri; Kolitha Basnayake; Stephen Harding; Arthur R Bradwell; Graham Mead


BMC Nephrology 

In This Article

Abstract and Background

Background: Monoclonal free light chains (FLCs) frequently cause rapidly progressive renal failure in patients with multiple myeloma. Immunoassays which provide quantitative measurement of FLCs in serum, have now been adopted into screening algorithms for multiple myeloma and other lymphoproliferative disorders. The assays indicate monoclonal FLC production by the presence of an abnormal κ to λ FLC ratio (reference range 0.26-1.65). Previous work, however, has demonstrated that in patients with renal failure the FLC ratio can be increased above normal with no other evidence of monoclonal proteins suggesting that in this population the range should be extended (reference range 0.37-3.1). This study evaluated the diagnostic sensitivity and specificity of the immunoassays in patients with severe renal failure.
Methods: Sera from 142 patients with new dialysis-dependent renal failure were assessed by serum protein electrophoresis (SPE), FLC immunoassays and immunofixation electrophoresis. The sensitivity and specificity of the FLC ratio's published reference range was compared with the modified renal reference range for identifying patients with multiple myeloma; by receiver operating characteristic curve analysis.
Results: Forty one patients had a clinical diagnosis of multiple myeloma; all of these patients had abnormal serum FLC ratios. The modified FLC ratio range increased the specificity of the assays (from 93% to 99%), with no loss of sensitivity. Monoclonal FLCs were identified in the urine from 23 of 24 patients assessed.
Conclusion: Measurement of serum FLC concentrations and calculation of the serum κ/λ ratio is a convenient, sensitive and specific method for identifying monoclonal FLC production in patients with multiple myeloma and acute renal failure. Rapid diagnosis in these patients will allow early initiation of disease specific treatment, such as chemotherapy plus or minus therapies for direct removal of FLCs.

Immunoglobulin free light chains (FLCs) are by-products of immunoglobulin synthesis and in normal subjects are released into the circulation in small quantities.[1] The FLCs are then rapidly removed by renal clearance.[2] In patients with multiple myeloma, however, the clonal proliferation of plasma cells can produce FLCs in quantities thousands of times higher than normal.[3] These monoclonal FLCs often result in renal pathologies, most importantly cast nephropathy.[4,5,6] Indeed, multiple myeloma is the haematological malignancy most commonly associated with acute kidney injury (AKI).[7] It has been proposed that the combination of multiple myeloma and AKI should be treated as a medical emergency with prompt diagnosis and intervention to avoid irreversible renal failure.[8] However, the standard screening tests for myeloma, serum protein electrophoresis (SPE) and urine Bence Jones protein analysis are not always requested or reported promptly.

Recently, immunoassays which measure the concentration of FLCs in serum have been incorporated into haematological screening algorithms for myeloma.[9,10,11] These FLC assays are automated and allow same-day analysis and reporting of results. With these assays, the presence of monoclonal FLC production is indicated when the ratio of kappa (κ) to lambda (λ) serum FLCs is outside the reference range of 0.26-1.65.[12] The presence of an abnormal FLC ratio, suggestive of monoclonal FLCs production can occur in the settings of both intact immunoglobulin multiple myeloma and light chain only multiple myeloma. The identification of monoclonal protein production is not proof of multiple myeloma, but indicates that further investigations are required (principally a bone marrow biopsy and skeletal survey).

For patients presenting with AKI, more rapid identification of multiple myeloma may lead to earlier interventions and improved patient outcome. However, there are no reported evaluations of the diagnostic utility of FLC assays in this setting. One complicating factor is that patients with renal impairment can have κ/λ FLC ratios slightly above the reference range with no other evidence of monoclonal proteins.[13,14] This reflects a change in the dynamics of serum FLC clearance in renal failure. In normal subjects, the clearance of FLC from the serum is dominated by renal removal of FLCs which is preferential to the smaller, monomeric, κ molecules. This gives a shorter serum half-life for κ and a median κ/λ FLC ratio of approximately 0.6. As the kidneys fail, however, the non-preferential reticulo-endothial route forms an increasing proportion of the FLC clearance.[15] This results in a more similar serum half-life for the two FLCs and the FLC ratio therefore becomes increasingly influenced by the underlying production rates, by the plasma cells. There are approximately twice as many κ producing cells as there are λ cells[16] and this results in a ratio of total κ to total λ in the serum of approximately 1.8.[12]

As expected, FLC analysis of sera from 688 patients with pre-dialysis, chronic kidney disease but no evidence of monoclonal immunoglobulin production (by serum immunofixation electrophoresis) demonstrated the serum κ and λ FLC concentrations increased with decreasing renal function, FLC ranges: 3-251 mg/L and 1-251 mg/L, respectively. The κ/λ FLC ratio increased with each increasing chronic kidney disease stage, through stages: 1-5 (population's serum creatinine: 56-875 μmol/L; estimated GFR: 6-128 mL/min/1.73 m2). The median κ/λ FLC ratio of the population was 1.1 with a 100% range of 0.37-3.1.[17] This change in the ratio could reduce the diagnostic utility of FLC analysis in renal impairment. We propose that modifying the κ/λ reference range to 0.37-3.1 may improve the diagnostic specificity when investigating patients with renal failure.

The aim of this study was to evaluate serum FLC measurement as a diagnostic tool for detecting monoclonal FLCs and underlying multiple myeloma, in patients with dialysis-dependent AKI. The sensitivity and specificity of the published reference range was compared with the proposed renal failure reference range.


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