Annals of Hematology

, Volume 98, Issue 3, pp 625–632 | Cite as

Serum-free light chains adjusted for renal function are a potential biomarker for post-transplant lymphoproliferative disorders

  • R. Borrows
  • A. Scheer
  • P. Cockwell
  • F. Braun
  • I. Anagnostopoulos
  • H. Riess
  • H. Zimmermann
  • R. U. TrappeEmail author
Original Article


Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management.


PTLD Serum-free light chain Serum-free heavy chain Biomarker 



Chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone


Combined free light chain


Complete remission


C-reactive protein


Diffuse large B cell lymphoma


Epstein–Barr virus


Eastern Cooperative Oncology Group


Free light chain


Adjusted free light chain


Serum heavy/light chain


Mucosal-associated lymphoid tumour


Odds ratio


Post-transplant lymphoproliferative disorder


Receiver operating characteristic


Upper limit of normal



We thank the Binding Site Ltd. for the provision of the assays for this study and for technical support, in particular, Dr. Anne Burmeister.

Author contributions

RB and RUT are the principal investigators, coordinated the research and take primary responsibility for the paper. HZ, HR and RUT recruited the patients and collected clinical data. FB, RB and PC recruited the controls. AS did the laboratory work. AS, RB, PC and RUT analysed and interpreted the data. IA served as reference pathologists. AS, RB, PC, HZ and RUT wrote the paper. All authors had full access to the final version of the manuscript and agreed to publication.

Compliance with ethical standards

Ethical approval for this study was provided by the local committees of both institutions. The study was conducted according to the guidelines of the Declaration of Helsinki.


The Binding Site provided FLC, HLC and cystatin C assays free of charge. The Binding Site played no role in the analysis of the clinical data, its interpretation or the manuscript preparation. The content of the manuscript remains the responsibility of the listed authors.

Conflicts of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Clarke CA, Morton LM, Lynch C, Pfeiffer RM, Hall EC, Gibson TM, Weisenburger DD, Martínez-Maza O, Hussain SK, Yang J, Chang ET, Engels EA (2013) Risk of lymphoma subtypes after solid organ transplantation in the United States. Br J Cancer 109(1):280–288. CrossRefGoogle Scholar
  2. 2.
    Dispenzieri A, Kyle R, Merlini G et al (2009) International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 23(2):215–224. CrossRefGoogle Scholar
  3. 3.
    Landgren O, Goedert JJ, Rabkin CS, Wilson WH, Dunleavy K, Kyle RA, Katzmann JA, Rajkumar SV, Engels EA (2010) Circulating serum free light chains as predictive markers of AIDS-related lymphoma. J Clin Oncol 28(5):773–779. CrossRefGoogle Scholar
  4. 4.
    Engels EA, Preiksaitis J, Zingone A, Landgren O (2012) Circulating antibody free light chains and risk of posttransplant lymphoproliferative disorder. Am J Transplant 12(5):1268–1274. CrossRefGoogle Scholar
  5. 5.
    Fernando RC, Rizzatti EG, Braga WMT, Santos MG, de Oliveira MB, Pestana JOM, Baiocchi OCG, Colleoni GWB (2013) Serum free light chains and post-transplant lymphoproliferative disorder in patients with renal transplant. Leuk Lymphoma 54(10):2177–2180. CrossRefGoogle Scholar
  6. 6.
    Hutchison CA, Harding S, Hewins P, Mead GP, Townsend J, Bradwell AR, Cockwell P (2008) Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease. Clin J Am Soc Nephrol 3(6):1684–1690. CrossRefGoogle Scholar
  7. 7.
    Jardin F, Delfau-Larue MH, Molina TJ, Copie-Bergman C, Brière J, Petrella T, Canioni D, Fabiani B, Jais JP, Figeac M, Leroy K, Mareschal S, Salles GA, Coiffier B, Delarue R, Peyrade F, Bosly A, André M, Ketterer N, Haioun C, Tilly H (2013) Immunoglobulin heavy chain/light chain pair measurement is associated with survival in diffuse large B-cell lymphoma. Leuk Lymphoma 54(9):1898–1907. CrossRefGoogle Scholar
  8. 8.
    Bradwell A, Harding S, Fourrier N, Mathiot C, Attal M, Moreau P, Harousseau JL, Avet-Loiseau H (2013) Prognostic utility of intact immunoglobulin Ig'κ/Ig'λ ratios in multiple myeloma patients. Leukemia 27(1):202–207. CrossRefGoogle Scholar
  9. 9.
    Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, Neuhaus R, Lehmkuhl H, Horst HA, Salles G, Morschhauser F, Jaccard A, Lamy T, Leithäuser M, Zimmermann H, Anagnostopoulos I, Raphael M, Riess H, Choquet S (2012) Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD). The prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol 13(2):196–206. CrossRefGoogle Scholar
  10. 10.
    Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, Mollee P, Zaucha JM, Dreyling MH, Dührsen U, Reinke P, Verhoef G, Subklewe M, Hüttmann A, Tousseyn T, Salles G, Kliem V, Hauser IA, Tarella C, van den Neste E, Gheysens O, Anagnostopoulos I, Leblond V, Riess H, Choquet S (2017) Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or R-CHOP consolidation in an international, prospective, Multicenter Phase II Trial. J Clin Oncol 35(5):536–543. CrossRefGoogle Scholar
  11. 11.
    Zimmermann H, Trappe RU (2013) EBV and posttransplantation lymphoproliferative disease: what to do? Hematology Am Soc Hematol Educ Program 2013:95–102. CrossRefGoogle Scholar
  12. 12.
    Katzmann JA, Clark RJ, Abraham RS et al (2002) Serum reference intervals and diagnostic ranges for free κ and free λ immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 48(9):1437–1444Google Scholar
  13. 13.
    Trappe R, Zimmermann H, Fink S, Reinke P, Dreyling M, Pascher A, Lehmkuhl H, Gartner B, Anagnostopoulos I, Riess H (2011) Plasmacytoma-like post-transplant lymphoproliferative disorder, a rare subtype of monomorphic B-cell post-transplant lymphoproliferation, is associated with a favorable outcome in localized as well as in advanced disease: a prospective analysis of 8 cases. Haematologica 96(7):1067–1071. CrossRefGoogle Scholar
  14. 14.
    Bargnoux A-S, Simon N, Garrigue V, Dupuy AM, Badiou S, Mourad G, Cristol JP (2013) Glomerular filtration rate as a determinant of free light chains in renal transplantation. Clin Biochem 46(16–17):1764–1766. CrossRefGoogle Scholar
  15. 15.
    Bradwell AR, Carr-Smith HD, Mead GP et al (2001) Highly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem 47(4):673–680Google Scholar
  16. 16.
    Charafeddine KM, Jabbour MN, Kadi RH, Daher RT (2012) Extended use of serum free light chain as a biomarker in lymphoproliferative disorders: a comprehensive review. Am J Clin Pathol 137(6):890–897. CrossRefGoogle Scholar
  17. 17.
    Vendrame E, Martínez-Maza O (2011) Assessment of pre-diagnosis biomarkers of immune activation and inflammation: insights on the etiology of lymphoma. J Proteome Res 10(1):113–119. CrossRefGoogle Scholar
  18. 18.
    Bradwell AR, Carr-Smith HD, Mead GP, Harvey TC, Drayson MT (2003) Serum test for assessment of patients with Bence Jones myeloma. Lancet 361(9356):489–491. CrossRefGoogle Scholar
  19. 19.
    Hutchison CA, Landgren O (2011) Polyclonal immunoglobulin free light chains as a potential biomarker of immune stimulation and inflammation. Clin Chem 57(10):1387–1389. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • R. Borrows
    • 1
    • 2
  • A. Scheer
    • 3
  • P. Cockwell
    • 1
  • F. Braun
    • 4
  • I. Anagnostopoulos
    • 5
  • H. Riess
    • 6
  • H. Zimmermann
    • 3
    • 7
  • R. U. Trappe
    • 3
    • 6
    • 7
    Email author
  1. 1.Department of Nephrology and Kidney TransplantationQueen Elizabeth Hospital BirminghamBirminghamUK
  2. 2.University of BirminghamBirminghamUK
  3. 3.Department of Internal Medicine II: Hematology and OncologyUniversity Medical Centre Schleswig-HolsteinKielGermany
  4. 4.Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric SurgeryUniversity Medical Centre Schleswig-HolsteinKielGermany
  5. 5.Department of PathologyCharité-Universitätsmedizin BerlinBerlinGermany
  6. 6.Department of Hematology and OncologyCharité-Universitätsmedizin BerlinBerlinGermany
  7. 7.German PTLD Study Group, Department of Hematology and OncologyDIAKO Ev. Diakonie-Krankenhaus gGmbH BremenBremenGermany

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