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. 2022 Sep 14;12(9):133.
doi: 10.1038/s41408-022-00732-3.

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study

Thorir Einarsson Long  1   2   3 , Olafur Skuli Indridason  3 , Runolfur Palsson  1   3 , Sæmundur Rognvaldsson  1   3 , Thorvardur Jon Love  1   3 , Sigrun Thorsteinsdottir  1   4 , Ingigerdur Solveig Sverrisdottir  1   5 , Brynjar Vidarsson  3 , Pall Torfi Onundarson  1   3 , Bjarni Agnar Agnarsson  1   3 , Margret Sigurdardottir  3 , Ingunn Thorsteinsdottir  3 , Isleifur Olafsson  3 , Asdis Rosa Thordardottir  1 , Elias Eythorsson  3 , Asbjorn Jonsson  1   3 , Gauti Gislason  1 , Andri Olafsson  1 , Hlif Steingrimsdottir  3 , Malin Hultcrantz  6 , Brian G M Durie  7 , Stephen Harding  8 , Ola Landgren #  9 , Sigurdur Yngvi Kristinsson #  10   11
Affiliations

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study

Thorir Einarsson Long et al. Blood Cancer J. .

Abstract

Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.

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Conflict of interest statement

Dr. Landgren has received grant support from: NCI/NIH, FDA, LLS, Rising Tide Foundation, Memorial Sloan Kettering Cancer Center, MMRF, IMF, Paula, and Rodger Riney Foundation, Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; has received honoraria for scientific talks/participated in advisory boards for: Adaptive, Amgen, Binding Site, BMS, Celgene, Cellectis, Glenmark, Janssen, Juno, Pfizer; and served on Independent Data Monitoring Committees (IDMC) for international randomized trials by: Takeda, Merck, Janssen, Theradex. Dr. Hultcrantz has recevied grant support from GSK, Amgen, Daiichi Sankyo, Cosette Pharmaceuticals, and has received honoraria for scientific talks/participated in advisory boards for BMS, Curio Science, and Intellisphere LLC. All other authors declare no potential conflicts of interest.

Figures

Fig. 1
Fig. 1. Flowchart outlining the study population and excluded participants.
SPEP Serum protein electrophoresis, IFE Immunofixation, FLC Free light chains, SCr Serum creatinine, eGFR Estimated glomerular filtration rate.
Fig. 2
Fig. 2. Demonstration of the correlation between serum free light chains and kidney function.
Correlation between kappa FLC (A), lambda FLC (B), and FLC (C) ratio and eGFR. Red line demonstrates linear correlation and blue line local regression (loess). The standard reference intervals for kappa FLC (A), lambda FLC (B) and FLC ratio (C) are demonstrated with dashed lines. The y axis for kappa FLC and lambda FLC are truncated at 125 mg/L and FLC ratio at 3.
Fig. 3
Fig. 3. Comparison of the distribution of kappa and lambda free light chains (FLC) and FLC ratios to current reference intervals by estimated glomerular filtration rate (eGFR) subgroups.
The portion of the distribution below the 0.5th percentile is shaded red and the portion above the 99.5th percentile is shaded blue. A Serum kappa FLC (green lines 3.3–19.4 mg/L). B Serum lambda FLC (green lines 5.7–26.3 mg/L). C FLC ratio (green lines – conventional reference interval: 0.26–1.65; brown lines – current kidney reference interval: 0.37–3.10). Kappa and lambda FLC are truncated at 120 mg/L and FLC ratio at 3.5 in the figures for better visualization. eGFR Estimated glomerular filtration rate, FLC Free light chains.
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