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

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.

Investigation and management of the monoclonal gammopathy of undetermined significance

“…It should be remembered that falling GFRs have a differential effect on the clearance of kappa (monomers) and lambda (dimers) FLC causing the polyclonal kappa: lambda FLC ratio to increase, although this increase varies between methods for measuring FLC. For example, with the FREELITE™ method, the normal FLC ratio is 0.54–3.30 for an eGFR <30 mL/min 25 …”

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

“…Optilite iStopMM CKD pts 2002 [8] 2007 [9] 2013 [10] 2018 [11] 2017 [12] 2020 [13] 2022 [1] 2022 [1] 2022 [1] 2021 [7] (n=282…”

“…With great interest we have read the publication of Long et al in which they propose new reference intervals for serum free light chain (FLC) ratios in individuals with chronic kidney disease [ 1 ]. The kidney reference interval for FLC-ratio was introduced after Hutchison et al showed that both the serum FLC concentrations and the FLC-ratio increased with worsening kidney function [ 2 ].…”

“…1 illustrate that the increase in median FLC-ratios measured in large cohorts of blood bank donors is substantial. Even when measured with the same Freelite reagents measured on the same BNII nephelometer platform, a drift of more than 75% is observed [ 1 , 7 – 13 ].

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The force awakens, but questions remain: The future of MGUS

“…As noted by Stern and colleagues, an abnormal FLC ratio has since been shown to predict risk of MGUS progression and can also be diagnostic of light‐chain MGUS 1 . However, the FLC ratio is not sensitive for MGUS overall and is affected by renal function, and even though recently defined renal reference ranges improve the accuracy of the FLC ratio, it should be used in conjunction with traditional electrophoresis methods at this time 11 . In the last few years, a completely new way to detect monoclonal immunoglobulins by mass spectrometry (MS)‐based diagnostics has emerged as a potential replacement to Dr. Waldenström's SPEP.…”