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

A total of 75,422 participants in the iStopMM study were screened with SPEP, IFE, and FLC. After application of exclusion criteria, 6503 (12%) participants with eGFR < 60 mL/min/1.73 m2 and without evidence of heavy chain MGUS were included (Fig. 1). Ten (0.2%) participants were on dialysis and 32 (0.5%) had a functioning kidney transplant at the time of screening and both groups were analyzed seperately. The baseline characteristics of the study cohort are demonstrated in Table 1.

Fig. 1: Flowchart outlining the study population and excluded participants.figure 1

SPEP Serum protein electrophoresis, IFE Immunofixation, FLC Free light chains, SCr Serum creatinine, eGFR Estimated glomerular filtration rate.

Table 1 Baseline characteristics of iStopMM participants with chronic kidney disease stages 3–5, stratified by estimated glomerular filtration rate at the time of screening.

Among the 6503 participants, the median (interquartile range [IQR]) kappa FLC level was 21.7 mg/L (16.6–29.4), lambda FLC level was 19.0 mg/L (14.8–25.0), and the FLC ratio was 1.16 (0.97–1.39). Median (IQR) of serum kappa and lambda FLC levels, and the FLC ratio stratified by age, sex, and eGFR is shown in Table 2. Serum FLCs increased with declining eGFR, with a negative correlation between eGFR and serum kappa FLC (ρ = −0.44, p < 0.001) and lambda FLC (ρ = −0.38, p < 0.001) levels, and the FLC ratio (ρ = −0.15, p < 0.001) (Fig. 2A–C). Furthermore, older age was associated with increasing FLCs with a positive correlation between age and kappa FLC (ρ = 0.28, p < 0.001), lambda FLC (ρ = 0.19, p < 0.001), and FLC ratio (ρ = 0.18, p < 0.001). However, when stratified by eGFR categories this age-related increase in kappa and lambda FLC, and FLC ratio was substantially less pronounced although it remained statistically significant (Supplementary Figure 1A–C; Supplementary Table II). A weak but statistically significant positive correlation was noted between male sex and kappa FLC (ρ = 0.12, p < 0.001), lambda FLC (ρ = 0.09, p < 0.001), and the FLC ratio (ρ = 0.06, p < 0.001).

Table 2 Median (IQR) levels of serum kappa and lambda FLC and FLC ratio in subgroups according to age, sex, and categories of reduced estimated glomerular filtration rate.Fig. 2: Demonstration of the correlation between serum free light chains and kidney function.figure 2

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.

Current reference intervals for kappa, lambda, and FLC ratio

A well calibrated central 99% reference interval should partition an unselected sample from the target population such that 0.5% of persons lie below the lower limit and 0.5% above the upper limit. Using the current reference interval for serum kappa FLC (3.3–19.4 mg/L) among individuals with eGFR <60 mL/min/1.73 m2, 3890 (60%) participants had a kappa FLC level above the upper reference limit and no participant (0%) had a kappa FLC level below the lower reference limit (Fig. 3A). Similarly, using the current reference interval for serum lambda FLC (5.7–26.3 mg/L), 1375 (21%) participants had a lambda FLC level above the upper reference limit and only seven (0.1%) participants had a lambda FLC level below the lower reference limit (Fig. 3B). Finally, when the standard FLC ratio reference interval (0.26–1.65) was used, 597 (9%) participants had an FLC ratio above the upper reference limit and ten (0.1%) below the lower limit (Fig. 3C). Using the current kidney reference interval (0.37–3.10), 28 (0.4%) participants had an FLC ratio above the upper reference limit and 16 (0.3%) below the lower limit (Fig. 3C).

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.figure 3

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.

Redefining FLC reference intervals for patients with chronic kidney disease

A single reference interval was constructed for all participants with eGFR <60 mL/min/1.73 m2 for serum kappa and lambda FLCs, and the FLC ratio. Using this reference interval would result in large proportions of participants in subgroups based on age, sex, and eGFR being diagnosed with light chain disease (abnormal FLC results; Supplementary Tables IA–C). The proportion of abnormal kappa and lambda FLC values would be highest in eGFR categories 15–29 and <15 mL/min/1.73 m2 with a rate of 14% and 55% for kappa FLC and 13% and 49% for lambda FLC, respectively. This whole-group reference interval for the FLC ratio was associated with lower rates of abnormal values with the highest rate of 7% in the eGFR 15–29 mL/min/1.73 m2 subgroup.

Because the whole-group reference interval resulted in an unreasonably high proportion of participants in the reduced eGFR subgroups being classified as having LC disease, the reference intervals were partitioned by eGFR categories. Due to few number of participants with eGFR < 15 mL/min/1.73 m2 (N = 55), a single combined reference interval was determined for eGFR < 15 and 15–29 mL/min/1.73 m2. The novel central 99% reference intervals for kappa FLC, lambda FLC, and FLC ratio that were determined separately for individuals with eGFR 45–59, 30–44, and < 30 mL/min/1.73 m2 are displayed in Table 3. Central 95% reference intervals for kappa FLC, lambda FLC, and FLC ratio were also determined and are demonstrated in Supplementary Table III. Sensitivity analyses of participants with SCr measured at the time of screening yielded similar results displayed in Supplementary Tables IVA–C.

Table 3 Novel reference intervals for serum kappa FLC (mg/L), serum lambda FLC (mg/L), and FLC ratio in individuals with eGFR of 45–59, 30–44, and < 30 mL/min/1.73 m2.FLC and FLC ratio in participants treated for end-stage kidney disease

Of the 42 participants receiving RRT for end-stage kidney disease at the time of screening and therefore analysed seperately were ten receiving dialysis, of whom eight were on hemodialysis and two on peritoneal dialysis, and 32 had a functioning kidney graft. Participants on dialysis had a significantly higher median (IQR) serum kappa FLC level of 89.0 mg/L (67.2–137.2; p = 0.002) and lambda FLC of 66.9 mg/L (57.9–91.6; p = 0.004), than those with eGFR 30–59 mL/min/1.73 m2 or eGFR < 30 mL/min/1.73 m2 (kappa FLC, p = 0.02; lambda FLC, p = 0.02). The median (IQR) FLC ratio in participants on dialysis was 1.27 (1.22–1.49), which was similar as in participants with eGFR 45–59 mL/min/1.73 m2 (p = 0.33) and 30–44 mL/min/1.73 m2 (p = 0.95). Participants on dialysis also had a similar FLC ratio as participants with eGFR < 30 mL/min/1.73 m2 (p = 0.37). Both participants on peritoneal dialysis had FLC and FLC ratio within our novel reference interval for eGFR <30 mL/min/1.73 m2. Of the eight participants on hemodialysis during screening, none (0%) had abnormally high serum kappa FLC level and two (25%) abnormally high serum lambda FLC level. However, all the participants had a normal FLC ratio, and therefore, no individual fulfilled criteria for LC-MGUS.

Of the 32 participants with functioning kidney transplant at the time of screening, 16 (50%), 13 (41%) and 3 (9%) had eGFR 45–59, 30–44, and < 30 mL/min/1.73 m2, respectively. No statistical difference was observed between serum kappa FLC and lambda FLC levels or the FLC ratio in participants with a kidney transplant and the corresponding eGFR subgroups among other participants. There was one (3%) participant with abnormally low kappa FLC results, but none with abnormal kappa FLC or FLC ratio. No participant fulfilled the criteria for LC-MGUS.

Prevalence of LC-MGUS in individuals with CKD

Using conventional reference intervals for kappa FLC and lambda FLC and previously published kidney reference intervals for FLC ratio, the crude rate of LC-MGUS was 44 (0.7%), of whom 28 (63%) had kappa LC-MGUS and 16 (37%) lambda LC-MGUS. However, employing our novel reference intervals, the crude prevalence of LC-MGUS in participants with eGFR <60 mL/min/1.73 m2 decreased significantly to 31 (0.5%, p < 0.001), with 19 (61%) having kappa LC-MGUS and 12 (39%) lambda LC-MGUS. Using the novel reference intervals, the prevalence of LC-MGUS decreased in the 45–59 and 30–44 mL/min/1.73 m2 eGFR subgroups compared with the prevalence based on standard intervals with 22 (0.5%), and eight (0.5%) participants with eGFR of 45–59 and 30–44 mL/min/1.73 m2, respectively (p < 0.001; Table 4). The prevalence of participants with eGFR < 30 mL/min/1.73 m2 remained similar with 1 (0.3%) in each group. The crude prevalence of LC-MGUS in individuals with eGFR < 60 mL/min/1.73 m2 increased significantly with age, yielding prevalence rates of 0.0%, 0.4%, 0.3%, 0.5%, and 0.7% in age groups <50, 50–59, 60–69, 70–79, and 80 years and above, respectively (p < 0.001). The crude prevalence rate of LC-MGUS based on the novel central 95% reference interval was higher or 1.2% (Supplementary Table V).

Table 4 Comparison of LC-MGUS rates using standard reference intervals and new reference intervals (FLC ratio and kappa, and lambda FLCs) in participants with eGFR < 60 mL/min/1.73 m2.

留言 (0)

沒有登入
gif