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• W2023082867 abstract "Acute kidney injury (AKI) in plasma cell multiple myeloma (MM) is a medical emergency requiring a rapid, accurate diagnosis because prompt commencement of therapy and supportive care are essential. Most cases of AKI in MM are caused by cast nephropathy secondary to high levels of nephrotoxic serum free light chains (FLCs). This article reviews the role and relevance of FLC as an immunological biomarker for AKI and MM. We discuss the utility of FLC measurement as a screening tool in the cast nephropathy clinical setting. We present its analytical pitfalls and evolving evidence for the integration of an FLC assay into clinical algorithms. Acute kidney injury (AKI) in plasma cell multiple myeloma (MM) is a medical emergency requiring a rapid, accurate diagnosis because prompt commencement of therapy and supportive care are essential. Most cases of AKI in MM are caused by cast nephropathy secondary to high levels of nephrotoxic serum free light chains (FLCs). This article reviews the role and relevance of FLC as an immunological biomarker for AKI and MM. We discuss the utility of FLC measurement as a screening tool in the cast nephropathy clinical setting. We present its analytical pitfalls and evolving evidence for the integration of an FLC assay into clinical algorithms. Clinical Summary•Acute kidney injury (AKI) in plasma cell multiple myeloma (MM) is a medical emergency requiring a rapid, accurate diagnosis.•Most cases of AKI in MM are caused by cast nephropathy secondary to high levels of nephrotoxic serum free light chains (FLCs).•FLC assay is used as an immunological biomarker for AKI and MM, and despite all of the controversies overshadowing the assay for nearly a decade, FLC measurement proved to be a rapid, highly specific, and sensitive screening tool allowing prompt institution of therapy. •Acute kidney injury (AKI) in plasma cell multiple myeloma (MM) is a medical emergency requiring a rapid, accurate diagnosis.•Most cases of AKI in MM are caused by cast nephropathy secondary to high levels of nephrotoxic serum free light chains (FLCs).•FLC assay is used as an immunological biomarker for AKI and MM, and despite all of the controversies overshadowing the assay for nearly a decade, FLC measurement proved to be a rapid, highly specific, and sensitive screening tool allowing prompt institution of therapy. Multiple myeloma was the first malignancy to be diagnosed using chemical assays with the description of Bence Jones protein (immunoglobulin free light chains, or FLCs) in the urine in 1848, providing the first example of a tumor marker. In the 21st century, the International Myeloma Working Group recommends that myeloma screening should no longer use urine tests but instead rely on three serum tests in combination: protein electrophoresis, immunofixation, and the FLC assay.1Dispenzieri A. Kyle R. Merlini G. et al.International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders.Leukemia. 2009; 23: 215-224Crossref PubMed Scopus (682) Google Scholar Serum immunoglobulin FLCs are byproducts of immunoglobulin synthesis. In normal individuals, circulating FLCs are rapidly cleared and metabolized by the kidneys. However, in patients with multiple myeloma, the excessive production of nephrotoxic FLCs, as a result of the clonally proliferating plasma cells, overwhelms the tubular absorptive mechanisms of the kidney, causing inflammation, kidney pathologies, and more importantly cast nephropathy. Kidney impairment is seen in 30% to 40% of patients with myeloma, and early diagnosis is at a particular premium in patients presenting with acute kidney injury because without rapid treatment, approximately 25% of these patients progress to irreversible kidney failure that has severe consequences for prognosis and quality of life. Myeloma can cause end-stage kidney disease by various mechanisms such as cast nephropathy, AL amyloidosis, light-chain deposition disease, and direct tumor infiltration. Cast nephropathy is the most common of these, and recent advances in chemotherapy and dialysis techniques appear to be resulting in greatly improved outcomes provided treatment is commenced promptly.2Stringer S, Basnayake K, Hutchison C, Cockwell P. Recent advances in the pathogenesis and management of cast nephropathy (myeloma kidney). [e-pub ahead of print]. Bone Marrow Res. doi:10.1155/2011/493697.Google Scholar Multiple myeloma is considered the most common form of hematological malignancy after non-Hodgkin lymphoma. Its incidence in Caucasian populations is approximately 35 per million per year and increases with age with a slight male predilection. In the United Kingdom there are 3000–3500 new cases per year, almost 20,000 in the United States, and 86,000 worldwide with a median survival of 3 years.3Katzel J.A. Hari P. Vesole D.H. Multiple myeloma: charging toward a bright future.CA Cancer J Clin. 2007; 57: 301-308Crossref PubMed Scopus (90) Google Scholar Multiple myeloma is a part of a disease continuum ranging from monoclonal gammopathy of unknown significance to plasma cell leukemia. Multiple myeloma is characterized by a proliferation of malignant plasma cells and overproduction of monoclonal intact immunoglobulin and/or monoclonal FLC, which may be identified with serum protein electrophoresis or urine protein electrophoresis.4Raab M.S. Podar K. Breitkreutz I. Richardson P.G. Anderson K.C. Multiple myeloma.Lancet. 2009; 25: 324-339Abstract Full Text Full Text PDF Scopus (650) Google Scholar Multiple myeloma can vary from asymptomatic to severely symptomatic with complications requiring urgent treatment. Myeloma is characterized by five clinical criteria: anemia, monoclonal protein in serum or urine or both, bone pain with various bone lesions on X-ray, hypercalcemia, and kidney insufficiency or injury. Diagnosis is based on the presence of more than 10% of malignant monoclonal plasma cells in the bone marrow. Presentation of multiple myeloma with acute kidney injury is not uncommon; indeed, in one series it was the underlying diagnosis in 29% of 142 patients presenting with acute dialysis-dependent kidney injury.5Hutchison C.A. Plant T. Drayson M. et al.Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure.BMC Nephrol. 2008; 9: 11Crossref PubMed Scopus (149) Google Scholar The mechanisms of kidney injury in plasma cell malignancies can be broadly grouped into immunoglobulin-dependent and -independent categories, although in an individual patient several mechanisms can coexist and interact to produce kidney injury. The three most common forms of immunoglobulin-dependent kidney injury include cast nephropathy, in which casts and crystals composed of filtered monoclonal FLCs and other urinary proteins obstruct distal kidney tubules, often precipitously, and typically incite an accompanying tubulointerstitial nephritis; AL amyloidosis, in which primarily monoclonal FLC and other proteins together form β-pleated sheets within the kidney tissues; and monoclonal immunoglobulin deposition disease, in which intact or fragmented light chains, heavy chains, or both deposit along glomeruli and/or tubular basement membranes.6Heher E.C. Goes N.B. Spitzer T.R. et al.Kidney disease associated with plasma cell dyscrasias.Blood. 2010; 116: 1397-1404Crossref PubMed Scopus (45) Google Scholar The identification of monoclonal immunoglobulin in serum or urine is critical to the diagnosis of plasma cell malignancies. Protein electrophoresis is widely available and inexpensive, but it has a low detection limit of 500 mg/L and relatively poor sensitivity for FLCs. In addition, it cannot reliably differentiate monoclonal from polyclonal light-chain expansion. Immunofixation is more sensitive than protein electrophoresis with a lower detection limit of 150 mg/L, but it is labor-intensive, does not quantify the amount of monoclonal immunoglobulin present, and thus is of limited use in monitoring disease progression and response to treatment.7International Myeloma Working GroupCriteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group.Br J Haematol. 2003; 121: 749-757Crossref PubMed Scopus (1993) Google Scholar, 8Katzmann J.A. Clark R.J. Abraham R.S. et al.Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains.Clin Chem. 2002; 48: 1437-1444PubMed Google Scholar The newer nephelometric FLC immunoassay detects monomers and dimers of kappa and lambda at concentrations less than 2–4 mg/L without confounding from intact immunoglobulin.9Bradwell A.R. Carr-Smith H.D. Mead G.P. et al.Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine.Clin Chem. 2001; 47: 673-680PubMed Google Scholar The FLC assay does not directly detect clonality, but it suggests it through an increase or decrease in the kappa:lambda ratio. Kappa and lambda FLC levels may be elevated in patients with inflammatory diseases such as systemic lupus erythematosis and in those with chronic kidney disease, but the kappa:lambda ratio is usually normal.8Katzmann J.A. Clark R.J. Abraham R.S. et al.Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains.Clin Chem. 2002; 48: 1437-1444PubMed Google Scholar After a decade of controversy among clinicians and scientists over the usefulness and reliability of FLC assays,10Böer K. Deufel T. Quantitation of serum free light chains does not compensate for serum immunofixation only when screening for monoclonal gammopathies.Clin Chem Lab Med. 2009; 47: 1109-1115PubMed Google Scholar there is an increasing body of evidence that these tests now play a key role in the diagnosis, monitoring, and prognosis of patients with monoclonal gammopathy in general, and with minor modifications these tests are extremely useful even when complicated by acute kidney injury with changing levels of kidney function.1Dispenzieri A. Kyle R. Merlini G. et al.International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders.Leukemia. 2009; 23: 215-224Crossref PubMed Scopus (682) Google Scholar Quantitative FLC measurements correlate with disease activity and are recognized as an improvement in monitoring light-chain-only multiple myeloma, AL amyloidosis, and nonsecretory and oligosecretory multiple myeloma.11Bradwell A.R. Serum free light chain measurements move to center stage.Clin Chem. 2005; 51: 805-807Crossref PubMed Scopus (66) Google Scholar, 12Katzmann J.A. Snyder M.R. Rajkumar S.V. et al.Long-term biological variation of serum protein electrophoresis M-spike, urine M-spike, and monoclonal serum free light chain quantification: implications for monitoring monoclonal gammopathies.Clin Chem. 2011; 57: 1687-1692Crossref PubMed Scopus (70) Google Scholar, 13Lachmann H.J. Gallimore R. Gillmore J.D. et al.Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy.Br J Haematol. 2003; 122: 78-84Crossref PubMed Scopus (376) Google Scholar Kidney clearance of FLCs is influenced by molecular size and monomeric FLCs, which are characteristically kappa (κ) type, which are cleared in 2–4 hours whereas dimeric FLCs, typically lambda (λ) class, are cleared in 3–6 hours. Larger polymeric aggregates are cleared more slowly. Although κ-secreting plasma cells are more common and κ FLCs are normally produced at approximately twice the rate of λ FLCs, this differential clearance of FLCs by the normal kidney accounts for the minimal κ FLC bias in health with a normal reference range of the κ:λ ratio of 0.26–1.65 with a median of 0.58.1Dispenzieri A. Kyle R. Merlini G. et al.International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders.Leukemia. 2009; 23: 215-224Crossref PubMed Scopus (682) Google Scholar, 8Katzmann J.A. Clark R.J. Abraham R.S. et al.Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains.Clin Chem. 2002; 48: 1437-1444PubMed Google Scholar Because monoclonal FLCs are produced in approximately 95% of patients with multiple myeloma, independent of intact monoclonal immunoglobulin production, and because they have a short half-life compared with 20–25 days for IgG, 6 days for IgA, 3 days for IgD, and 2 days for IgE,14Bradwell A.R. Harding S.J. Fourrier N.J. et al.Assessment of monoclonal gammopathies by nephelometric measurement of individual immunoglobulin kappa/lambda ratios.Clin Chem. 2009; 55: 1646-1655Crossref PubMed Scopus (128) Google Scholar their measurement is of use in all stages of the disease, including assessment of response in the early stages of treatment, monitoring the duration of clinical remission and residual disease, and detecting relapse. Since their first description in 2001,9Bradwell A.R. Carr-Smith H.D. Mead G.P. et al.Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine.Clin Chem. 2001; 47: 673-680PubMed Google Scholar nephelometric FLC assays have been incorporated into several international clinical guidelines and algorithms.1Dispenzieri A. Kyle R. Merlini G. et al.International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders.Leukemia. 2009; 23: 215-224Crossref PubMed Scopus (682) Google Scholar, 7International Myeloma Working GroupCriteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group.Br J Haematol. 2003; 121: 749-757Crossref PubMed Scopus (1993) Google Scholar, 9Bradwell A.R. Carr-Smith H.D. Mead G.P. et al.Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine.Clin Chem. 2001; 47: 673-680PubMed Google Scholar, 15Cockwell P.A. Hutchison C.A. Management options for cast nephropathy in multiple myeloma.Curr Opin Nephrol Hypertens. 2010; 19: 550-555Crossref PubMed Scopus (30) Google Scholar The International Myeloma Working Group now promotes FLC assays as an essential component in the primary screening algorithm for suspected monoclonal plasma cell disorders.1Dispenzieri A. Kyle R. Merlini G. et al.International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders.Leukemia. 2009; 23: 215-224Crossref PubMed Scopus (682) Google Scholar This reflects the benefits of FLC assays, which include a rapid turnaround with same-day result reporting, and, because it recognizes previously hidden antigenic determinants of the light chain, recognition of previously up to two thirds of multiple myelomas that had previously been classified as nonsecretory.16Wirk B. Renal failure in multiple myeloma: a medical emergency.Bone Marrow Transplant. 2011; 46: 771-783Crossref PubMed Scopus (30) Google Scholar High FLC levels are known to be associated with an increased risk of kidney injury17van Rhee F. Bolejack V. Hollmig K. et al.High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis.Blood. 2007; 110: 827-832Crossref PubMed Scopus (163) Google Scholar in myeloma, and FLC assays have proved very sensitive in detecting plasma cell malignancies in patients presenting with acute severe kidney injury.5Hutchison C.A. Plant T. Drayson M. et al.Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure.BMC Nephrol. 2008; 9: 11Crossref PubMed Scopus (149) Google Scholar As the kidney's function declines, kidney clearance of FLCs is reduced, and the reticulo-endothelial system becomes an increasingly important route for FLC clearance. In complete kidney failure, the liver and other reticulo-endothelial tissues remove FLCs within 2–3 days, and the circulating levels of both classes of FLCs increase.15Cockwell P.A. Hutchison C.A. Management options for cast nephropathy in multiple myeloma.Curr Opin Nephrol Hypertens. 2010; 19: 550-555Crossref PubMed Scopus (30) Google Scholar, 17van Rhee F. Bolejack V. Hollmig K. et al.High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis.Blood. 2007; 110: 827-832Crossref PubMed Scopus (163) Google Scholar Because this uptake is not influenced by molecular weight, the serum half-lives of κ and λ FLCs become almost equivalent as kidney injury progresses. As a result of the normal greater production of κ FLCs, the reference range for the κ/λ FLC ratio in patients with kidney failure increases compared with that in healthy individuals to 0.37–3.1. Correction of the reference range in severe kidney failure increased the specificity of the FLC assays in the detection of monoclonal FLC production.18Hutchison C.A. Harding S. Hewins P. et al.Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease.Clin J Am Soc Nephrol. 2008; 3: 1684-1690Crossref PubMed Scopus (276) Google Scholar When monitoring light-chain-producing clones in the presence of changing kidney function, absolute values of FLCs may be less useful than measuring differential FLC concentration. These are generated by subtracting the concentration of the uninvolved light chain from that of the clonal light chain to obtain the FLC difference. This strategy has been validated in the follow-up of patients with myeloma19Dispenzieri A. Zhang L. Katzmann J.A. et al.Appraisal of immunoglobulin free light chain as a marker of response.Blood. 2008; 111: 4908-4915Crossref PubMed Scopus (122) Google Scholar and AL amyloidosis.20Pinney J.H. Lachmann H.J. Bansi L. et al.Outcome in renal AL amyloidosis following chemotherapy.J Clin Oncol. 2011; 29: 674-681Crossref PubMed Scopus (119) Google Scholar There has been speculation that the high levels of FLCs seen in all patients with chronic kidney disease might contribute to an increased risk of end-stage kidney disease and mortality. A recent large retrospective study of 364 patients seen in general nephrology outpatients suggested that FLCs were of little utility in predicting patient outcome and that the association between raised FLC levels and risk of end-stage kidney disease was largely due to decreasing kidney clearance, although there was a weak association between polyclonal increases in λ FLCs and mortality.21Haynes R. Hutchison C.A. Emberson J. et al.Serum free light chains and the risk of ESRD and death in CKD.Clin J Am Soc Nephrol. 2011; 6: 2829-2837Crossref PubMed Scopus (31) Google Scholar Serum FLC immunoassays consist of polyclonal latex-conjugated anti-FLC antibodies with high specificity and affinity for serum FLCs. The binding of the antibodies to light chains can be measured by nephelometry or turbidimetry using many different laboratory analyzers. The FLC assay has its pitfalls and technical limitations that make its uses as a serial measurement potentially problematic. For example, when FLC quantities are very high, the assay may yield paradoxically normal results because of the antigen excess, a problem common to turbidimetric and nephelometric techniques. The absence of worldwide standardization and the nonlinearity of the assay may lead to significant interinstrument variability as shown by the National External Quality Assessment Service.22Pratt G. The evolving use of serum free light chain assays in haematology.Haematol. 2008; 141: 413-422Crossref PubMed Scopus (80) Google Scholar, 23Sheldon J. Free light chains.Ann Clin Biochem. 2007; 44: 503-505Crossref PubMed Scopus (13) Google Scholar The polymerization of monoclonal FLCs and the presence of polyclonal light chains might lead to the overestimation of monoclonal light chains. On the basis of the above caveats, the FLC assay has been criticized for having a degree of inaccuracy. However, this does not preclude its importance as a screening tool for diagnosing and monitoring plasma cell disorders. FLC measurements have become incorporated into clinical algorithms and have energized clinical research and interest in the augmented removal of FLCs in the setting of acute kidney injury due to multiple myeloma.24Hutchison CA, Heyne N, Airia P, et al. Immunoglobulin free light chain levels and recovery from myeloma kidney on treatment with chemotherapy and high cut-off haemodialysis. [e-pub ahead of print]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr773.Google Scholar The utility of a screening assay lies in its specificity and sensitivity. A FLC ratio of 0.26–1.65 provides 93% specificity in diagnosing multiple myeloma patients with kidney failure, but this was improved to 99% with lower false positives when an extended FLC ratio of 0.37–3.1 was used.16Wirk B. Renal failure in multiple myeloma: a medical emergency.Bone Marrow Transplant. 2011; 46: 771-783Crossref PubMed Scopus (30) Google Scholar, 18Hutchison C.A. Harding S. Hewins P. et al.Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease.Clin J Am Soc Nephrol. 2008; 3: 1684-1690Crossref PubMed Scopus (276) Google Scholar, 25Hutchison C.A. Basnayake K. Cockwell P. Serum free light chain assessment in monoclonal gammopathy and kidney disease.Nat Rev Nephrol. 2009; 5: 621-628Crossref PubMed Scopus (60) Google Scholar In addition, the use of FLCs as a tumor marker in the management of multiple myeloma provides prognostic information because the light-chain kinetics mirror disease pathogenesis.26Kyrtsonis M.C. Vassilakopoulos T.P. Kafasi N. et al.Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma.Br J Haematol. 2007; 137: 240-243Crossref PubMed Scopus (109) Google Scholar FLC measurements have energized clinical research in several areas, including acute kidney injury caused by cast nephropathy, one of the gravest complications of multiple myeloma. Despite all of the controversies overshadowing the assay for nearly a decade, FLC measurement proved to be a rapid, highly specific, and sensitive screening tool for acute kidney injury due to multiple myeloma, allowing prompt institution of therapy." @default.
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• W2023082867 title "The Role of Immunological Assessment in Patients With Acute Kidney Injury and Possible Myeloma" @default.
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