Serum free light-chain measurement

Immunoglobulin light chains that are circulating in serum in a free (unbound) state are called free light chains (FLCs). Measurement of the serum level of FLCs became practical as a clinical blood test in recent decades. These tests are used as an aid in the diagnosis and monitoring of multiple myeloma and related disorders. There are two types of immunoglobulin light chain produced in humans, designated by the Greek letters kappa (κ) and lambda (λ). Comparing the ratio of κ FLCs to λ FLCs in a person's serum against reference ranges indicates whether that person may have a plasma cell tumour such as multiple myeloma or AL amyloidosis.[1][2]

Structure

Each immunoglobulin light-chain molecule contains approximately 220 amino acids in a single polypeptide chain that is folded to form constant and variable region domains. Each domain comprises two β-pleated sheets. The sheets are linked by a disulfide bridge and together form a roughly barrel-shaped structure known as a β-barrel. The variable (V) domain of light chains has a high degree of structural diversity, particularly the antigen-binding region. In addition, the first 23 amino acids of the 1st variable domain framework region have a number of variations known as subgroups. Four kappa (Vκ1–Vκ4) and six lambda subgroups (Vλ1–Vλ6) can be identified.[3] The specific subgroup structures influence the potential of the free light chains to polymerise such that AL amyloidosis is associated with Vλ6 and light-chain deposition disease with Vκ1 and Vκ4.

Synthesis

Kappa light-chain molecules are constructed from approximately 40 functional Vκ gene segments (chromosome 2), five Jκ gene segments and a single Cκ gene. Lambda molecules (chromosome 22) are constructed from about 30 Vλ gene segments and four pairs of functional Jλ gene segments and a Cλ gene.[4]

Light chains are incorporated into immunoglobulin molecules during B-cell development and are expressed initially on the surface of pre B-cells. Production of light chains occurs throughout the rest of B-cell development and in plasma cells, where secretion is highest.

Production

The production of free immunoglobulin light chains in normal individuals is approximately 500 mg/day from bone marrow and lymph node cells.[3][5] There is approximately 40% excess immunoglobulin light-chain production over immunoglobulin heavy-chain synthesis. Possibly this is simply to allow proper conformation of the intact immunoglobulin molecules, but an immunological role for the free light chains has also been proposed.[6] There are approximately twice as many kappa-producing plasma cells as lambda plasma cells. Kappa free-light chains are normally monomeric, while lambda free-light chains tend to be dimeric, joined by disulphide bonds. Polymeric forms of both types of free light chain can also occur.[7]

Metabolism

In normal individuals, free light chains are rapidly cleared from the blood and catabolised by the kidneys. Monomeric free light chains are cleared in 2–4 hours, and dimeric light chains in 3–6 hours. Removal may be prolonged to 2–3 days in people with complete renal failure.[3][5][8] Human kidneys are composed of approximately half a million nephrons. Each nephron contains a glomerulus with basement membrane pores that allow filtration of immunoglobulin light chains and other small molecules from the blood into the proximal tubule of the nephron.

Filtered molecules are either excreted in the urine or may be specifically re-absorbed. Protein molecules that pass through the glomerular pores are either absorbed unchanged (such as albumin), degraded in the proximal tubular cells and absorbed (such as free light chains), or excreted as fragments.[9] This re-absorption is mediated by a receptor complex (megalin/cubulin) and prevents the loss of large amounts of protein into the urine. It is very efficient and can process10–30g of low-molecular-weight proteins per day, so under normal conditions no light chains pass beyond the proximal tubules.[10][11][12]

If immunoglobulin light chains are produced in sufficient amounts to overwhelm the proximal tubules’ absorption mechanisms (usually due to the presence of a plasma cell tumour) the light chains enter the distal tubules and can appear in the urine (Bence Jones protein). The passage of large amounts of immunoglobulin light chains through the kidneys may cause inflammation or blockage of the kidney tubules.

The distal tubules of the kidneys secrete large amounts of uromucoid (Tamm–Horsfall protein). This is the dominant protein in normal urine and is thought to be important in preventing ascending urinary infections. It is a relatively small glycoprotein (80kDa) that aggregates into polymers of 20–30 molecules. It contains a short amino-acid sequence that can specifically bind to some free light chains.[13] Together they can form an insoluble precipitate which blocks the distal part of the nephrons. This is termed "cast nephropathy" or "myeloma kidney" and is typically found in patients with multiple myeloma.[14][15] This can block the flow of urine causing the death of the respective nephrons. Rising concentrations of light chains are filtered by the remaining nephrons leading to a cycle of accelerating renal damage with rising concentrations of free light chains in the blood.[16] At the same time, the amount of free light chains entering the urine will be decreased and will be zero if the patient stops producing urine (anuria). Conversely, urine concentrations of free light chains could increase if renal function improved in a multiple myeloma patient receiving treatment. This could account for the poor correlation frequently seen when urine and serum free light-chain concentrations are compared.[17][18][19][20]

The 500 mg of FLCs produced per day by the normal lymphoid system, however, flows through the glomeruli and is completely processed by the proximal tubules. If the proximal tubules of the nephrons are damaged or stressed (such as in hard exercise), filtered FLCs may not be completely metabolised and small amounts may then appear in the urine.[9]

Clinical use

Serum free light-chain assays have been used in a number of published studies which have indicated superiority over the urine tests, particularly for patients producing low levels of monoclonal free light chains, as seen in nonsecretory multiple myeloma[21][22][23] and AL amyloidosis.[23][24][25][26] This is primarily because of the re-absorption of free light chains in the kidneys, creating a "threshold" of light chain production which must be exceeded before measurable quantities overflow into the urine.[17][18][19] While there are a number of publications indicating that serum free light chain analysis is preferable to urine analysis at diagnosis,[27][28][29][30] there is currently no consensus on whether urine tests for monitoring should be replaced.[18][19][20][31]

A series of studies, principally from the Mayo Clinic, have indicated that patients with an abnormal free kappa / free lambda ratio have an increased risk of progression to active myeloma from precursor conditions including Monoclonal gammopathy of undetermined significance (MGUS),[32][33] Smoldering myeloma[34] and solitary plasmacytoma of the bone.[35] Abnormal free light chain production has also been reported to be prognostic of a worse outcome in multiple myeloma[36][37][38] and chronic lymphocytic leukaemia.[39] An abnormal light-chain ratio has been defined as a kappa/lambda chain ratio of less than 0.26 or more than 1.65.[32]

Guidelines

In 2009, the International Myeloma Working Group published guidelines making recommendations of when serum free light-chain analysis should be used in the management of multiple myeloma.[40]

Diagnosis

The serum free light-chain assay in combination with serum protein electrophoresis and serum immunofixation electrophoresis is sufficient to screen for pathological monoclonal plasmaproliferative disorders other than AL amyloidosis which requires all the serum tests as well as 24 h urine immunofixation electrophoresis.

Prognosis

The serum free light-chain assay should be measured at diagnosis for all patients with MGUS, smoldering or active multiple myeloma. Solitary plasmacytoma and AL amyloidosis.

Monitoring

Serial FLC ascertainment should be routinely performed in patients with AL amyloidosis and multiple myeloma patients with oligosecretory disease. It should also be done in all patients who have achieved a complete response to determine whether they have attained a stringent complete response.

Other guidelines for the use of serum free light chain measurement in the management of AL amyloidosis,[41] plasmacytoma[42] and the comparison of treatment responses in clinical trials[43] have also been published.

Technical/clinical reviews of serum free light-chain assays have recently been written by Pratt and Jagannath.[44][45]

References

  1. ↑ Bradwell AR, Carr-Smith HD, Mead GP; et al. (1 April 2001). "Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine". Clinical Chemistry 47 (4): 673–80. PMID 11274017.
  2. ↑ Katzmann JA, Clark RJ, Abraham RS; et al. (1 September 2002). "Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains". Clinical Chemistry 48 (9): 1437–44. PMID 12194920.
  3. 1 2 3 Solomon A (1985). "Light chains of human immunoglobulins". Methods in Enzymology. Methods in Enzymology 116: 101–21. doi:10.1016/S0076-6879(85)16008-8. ISBN 978-0-12-182016-9. PMID 3937021.
  4. ↑ Janeway CA, Travers P, Walport M, Slomchik MJ, “Immunobiology; the immune system in health and disease” (2005); Garland Science publishing. ISBN 0-443-07310-4 ISBN 978-0443073106
  5. 1 2 Waldmann TA, Strober W, Mogielnicki RP; Strober; Mogielnicki (August 1972). "The renal handling of low molecular weight proteins: II. Disorders of serum protein catabolism in patients with tubular proteinuria, the nephrotic syndrome, or uremia". The Journal of Clinical Investigation 51 (8): 2162–74. doi:10.1172/JCI107023. PMC 292373. PMID 5054468.
  6. ↑ Redegeld FA, Nijkamp FP; Nijkamp (April 2003). "Immunoglobulin free light chains and mast cells: pivotal role in T-cell-mediated immune reactions?". Trends in Immunology 24 (4): 181–5. doi:10.1016/S1471-4906(03)00059-0. PMID 12697449.
  7. ↑ Sölling K (September 1976). "Polymeric forms of free light chains in serum from normal individuals and from patients with renal diseases". Scandinavian Journal of Clinical and Laboratory Investigation 36 (5): 447–52. doi:10.3109/00365517609054462. PMID 824709.
  8. ↑ Miettinen, T; Kekki, M (1967). "Effect of impaired hepatic and renal function on [131]bence jones protein catabolism in human subjects". Clinica Chimica Acta 18 (3): 395. doi:10.1016/0009-8981(67)90036-8.
  9. 1 2 Russo LM, Bakris GL, Comper WD; Bakris; Comper (May 2002). "Renal handling of albumin: a critical review of basic concepts and perspective". Am. J. Kidney Dis. 39 (5): 899–919. doi:10.1053/ajkd.2002.32764. PMID 11979334.
  10. ↑ Abraham GN, Waterhouse C; Waterhouse (October 1974). "Evidence for defective immunoglobulin metabolism in severe renal insufficiency". The American Journal of the Medical Sciences 268 (4): 227–33. doi:10.1097/00000441-197410000-00003. PMID 4217565.
  11. ↑ Wochner RD, Strober W, Waldmann TA; Strober; Waldmann (August 1967). "THE ROLE OF THE KIDNEY IN THE CATABOLISM OF BENCE JONES PROTEINS AND IMMUNOGLOBULIN FRAGMENTS". The Journal of Experimental Medicine 126 (2): 207–21. doi:10.1084/jem.126.2.207. PMC 2138312. PMID 4165739.
  12. ↑ Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D; Johnson; Kau; Figueiredo; Sigulem (September 1979). "Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review". Kidney International 16 (3): 251–70. doi:10.1038/ki.1979.128. PMID 393891.
  13. ↑ Ying WZ, Sanders PW; Sanders (1 May 2001). "Mapping the Binding Domain of Immunoglobulin Light Chains for Tamm-Horsfall Protein". The American Journal of Pathology 158 (5): 1859–66. doi:10.1016/S0002-9440(10)64142-9. PMC 1891942. PMID 11337384.
  14. ↑ Sanders PW, Booker BB, Bishop JB, Cheung HC; Booker; Bishop; Cheung (February 1990). "Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins". The Journal of Clinical Investigation 85 (2): 570–6. doi:10.1172/JCI114474. PMC 296460. PMID 2298921.
  15. ↑ Sanders PW, Booker BB; Booker (February 1992). "Pathobiology of cast nephropathy from human Bence Jones proteins". The Journal of Clinical Investigation 89 (2): 630–9. doi:10.1172/JCI115629. PMC 442896. PMID 1737851.
  16. ↑ Merlini G, Pozzi C; Pozzi (2007). "Mechanisms of renal damage in plasma cell dyscrasias: an overview". Contributions to Nephrology. Contributions to Nephrology 153: 66–86. doi:10.1159/000096761. ISBN 3-8055-8178-5. PMID 17075224.
  17. 1 2 Bradwell AR, Carr-Smith HD, Mead GP, Harvey TC, Drayson MT; Carr-Smith; Mead; Harvey; Drayson (February 2003). "Serum test for assessment of patients with Bence Jones myeloma". Lancet 361 (9356): 489–91. doi:10.1016/S0140-6736(03)12457-9. PMID 12583950.
  18. 1 2 3 Alyanakian MA, Abbas A, Delarue R, Arnulf B, Aucouturier P; Abbas; Delarue; Arnulf; Aucouturier (April 2004). "Free immunoglobulin light-chain serum levels in the follow-up of patients with monoclonal gammopathies: correlation with 24-hr urinary light-chain excretion". American Journal of Hematology 75 (4): 246–8. doi:10.1002/ajh.20007. PMID 15054820.
  19. 1 2 3 Nowrousian MR, Brandhorst D, Sammet C; et al. (December 2005). "Serum free light chain analysis and urine immunofixation electrophoresis in patients with multiple myeloma". Clinical Cancer Research 11 (24 Pt 1): 8706–14. doi:10.1158/1078-0432.CCR-05-0486. PMID 16361557.
  20. 1 2 Dispenzieri A, Zhang L, Katzmann JA; et al. (May 2008). "Appraisal of immunoglobulin free light chain as a marker of response". Blood 111 (10): 4908–15. doi:10.1182/blood-2008-02-138602. PMC 2964259. PMID 18364469.
  21. ↑ Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR; Tang; Drew; Mead; Carr-Smith; Bradwell (May 2001). "Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma". Blood 97 (9): 2900–2. doi:10.1182/blood.V97.9.2900. PMID 11313287.
  22. ↑ Shaw GR (August 2006). "Nonsecretory plasma cell myeloma—becoming even more rare with serum free light-chain assay: a brief review". Archives of Pathology & Laboratory Medicine 130 (8): 1212–5. doi:10.1043/1543-2165(2006)130[1212:NPCMEM]2.0.CO;2 (inactive 2015-02-01). PMID 16879026.
  23. 1 2 Katzmann JA, Abraham RS, Dispenzieri A, Lust JA, Kyle RA; Abraham; Dispenzieri; Lust; Kyle (May 2005). "Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice". Clinical Chemistry 51 (5): 878–81. doi:10.1373/clinchem.2004.046870. PMID 15774572.
  24. ↑ Lachmann HJ, Gallimore R, Gillmore JD; et al. (July 2003). "Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy". British Journal of Haematology 122 (1): 78–84. doi:10.1046/j.1365-2141.2003.04433.x. PMID 12823348.
  25. ↑ Abraham RS, Katzmann JA, Clark RJ, Bradwell AR, Kyle RA, Gertz MA; Kyle; Bradwell; Katzmann; Abraham (February 2003). "Quantitative analysis of serum free light chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis". American Journal of Clinical Pathology 119 (2): 274–8. doi:10.1309/LYWM-47K2-L8XY-FFB3. PMID 12579999. Missing |last4= in Authors list (help)
  26. ↑ Akar H, Seldin DC, Magnani B; et al. (December 2005). "Quantitative serum free light chain assay in the diagnostic evaluation of AL amyloidosis". Amyloid 12 (4): 210–5. doi:10.1080/13506120500352339. PMID 16399645.
  27. ↑ Hill PG, Forsyth JM, Rai B, Mayne S; Forsyth; Rai; Mayne (September 2006). "Serum free light chains: an alternative to the urine Bence Jones proteins screening test for monoclonal gammopathies". Clinical Chemistry 52 (9): 1743–8. doi:10.1373/clinchem.2006.069104. PMID 16858075.
  28. ↑ Bakshi NA, Gulbranson R, Garstka D, Bradwell AR, Keren DF; Gulbranson; Garstka; Bradwell; Keren (August 2005). "Serum free light chain (FLC) measurement can aid capillary zone electrophoresis in detecting subtle FLC-producing M proteins". American Journal of Clinical Pathology 124 (2): 214–8. doi:10.1309/XE3U-DARK-W1B9-EMWM. PMID 16040291.
  29. ↑ Abadie JM, Bankson DD; Bankson (2006). "Assessment of serum free light chain assays for plasma cell disorder screening in a Veterans Affairs population". Annals of Clinical and Laboratory Science 36 (2): 157–62. PMID 16682511.
  30. ↑ Katzmann JA, Dispenzieri A, Kyle RA; et al. (December 2006). "Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays". Mayo Clinic Proceedings 81 (12): 1575–78. doi:10.4065/81.12.1575. PMID 17165636.
  31. ↑ Abraham RS, Clark RJ, Bryant SC; et al. (1 April 2002). "Correlation of serum immunoglobulin free light chain quantification with urinary Bence Jones protein in light chain myeloma". Clinical Chemistry 48 (4): 655–7. PMID 11901068.
  32. 1 2 Rajkumar SV, Kyle RA, Therneau TM; et al. (August 2005). "Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance". Blood 106 (3): 812–7. doi:10.1182/blood-2005-03-1038. PMC 1895159. PMID 15855274.
  33. ↑ Rajkumar SV, Lacy MQ, Kyle RA; Lacy; Kyle (September 2007). "Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". Blood Reviews 21 (5): 255–65. doi:10.1016/j.blre.2007.01.002. PMID 17367905.
  34. ↑ Dispenzieri A, Kyle RA, Katzmann JA; et al. (January 2008). "Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma". Blood 111 (2): 785–9. doi:10.1182/blood-2007-08-108357. PMC 2200851. PMID 17942755.
  35. ↑ Dingli D, Kyle RA, Rajkumar SV; et al. (September 2006). "Immunoglobulin free light chains and solitary plasmacytoma of bone". Blood 108 (6): 1979–83. doi:10.1182/blood-2006-04-015784. PMC 1895544. PMID 16741249.
  36. ↑ Kyrtsonis MC, Vassilakopoulos TP, Kafasi N; et al. (May 2007). "Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma". British Journal of Haematology 137 (3): 240–3. doi:10.1111/j.1365-2141.2007.06561.x. PMID 17408464.
  37. ↑ Snozek CL, Katzmann JA, Kyle RA; et al. (October 2008). "Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system". Leukemia 22 (10): 1933–7. doi:10.1038/leu.2008.171. PMC 2614406. PMID 18596742.
  38. ↑ van Rhee F, Bolejack V, Hollmig K; et al. (August 2007). "High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis". Blood 110 (3): 827–32. doi:10.1182/blood-2007-01-067728. PMC 1924775. PMID 17416735.
  39. ↑ Pratt G, Harding S, Holder R; et al. (January 2009). "Abnormal serum free light chain ratios are associated with poor survival and may reflect biological subgroups in patients with chronic lymphocytic leukaemia". British Journal of Haematology 144 (2): 217–22. doi:10.1111/j.1365-2141.2008.07456.x. PMID 19016722.
  40. ↑ Dispenzieri A, Kyle R, Merlini G; et al. (February 2009). "International Myeloma Working Group guidelines for serum-free light-chain analysis in multiple myeloma and related disorders". Leukemia 23 (2): 215–24. doi:10.1038/leu.2008.307. PMID 19020545.
  41. ↑ Gertz MA, Comenzo R, Falk RH; et al. (August 2005). "Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004". American Journal of Hematology 79 (4): 319–28. doi:10.1002/ajh.20381. PMID 16044444.
  42. ↑ Hughes M, Soutar R, Lucraft H, Owen R, Bird J. "Guidelines on the diagnosis and management of solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas: 2009 update" (PDF). UKMF Guidelines Working Group. Retrieved 8 July 2009.
  43. ↑ Durie BG, Harousseau JL, Miguel JS; et al. (September 2006). "International uniform response criteria for multiple myeloma". Leukemia 20 (9): 1467–73. doi:10.1038/sj.leu.2404284. PMID 16855634.
  44. ↑ Pratt G (May 2008). "The evolving use of serum free light chain assays in haematology". British Journal of Haematology 141 (4): 413–22. doi:10.1111/j.1365-2141.2008.07079.x. PMID 18318757.
  45. ↑ Jagannath S (September 2007). "Value of serum free light chain testing for the diagnosis and monitoring of monoclonal gammopathies in hematology". Clinical Lymphoma & Myeloma 7 (8): 518–23. doi:10.3816/CLM.2007.n.036. PMID 18021469.

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