8.5.2. Renal reference interval

Chapter 8

Patients with renal impairment but no evidence of monoclonal gammopathy may have κ/λ sFLC ratios (measured by Freelite) which are slightly above the normal range [96][161][162]. The reason is that as renal clearance of sFLCs declines, the sFLC concentrations increase to more closely reflect the production rates, which are higher for κ than λ FLCs. Consequently, a modified renal reference range for the Freelite κ/λ sFLC ratio (0.37 – 3.10) has been proposed [165]. Use of the renal reference range when screening for monoclonal gammopathy in patients with renal impairment may increase specificity and is further discussed in Section 6.3.

Jacobs et al. [206] studied the effect of renal impairment on N Latex FLC concentrations in 284 patients with chronic kidney disease (CKD, stage 1-5). κ and λ FLC concentrations increased through each CKD stage. However, whilst κ N Latex FLC assays gave similar results to Freelite, the increase in λ FLC concentrations in the CKD5/dialysis groups was significantly greater for the N Latex FLC assays (Figure 8.5, Figure 8.6A, Figure 8.6B). As a result, none of the patients with CKD had a κ/λ sFLC ratio exceeding the N Latex FLC reference interval and, in fact, the ratio was significantly lower in the CKD5/dialysis group compared to healthy controls (p<0.0001; Figure 8.6C).

Berlanga et al. [207] re-analysed the data reported by Jacobs et al., and plotted the percentage increase in sFLC levels relative to controls for both assays (Figure 8.7). Freelite measured a progressive elevation of κ over λ FLC with worsening renal function, which resulted in some patients having an abnormal κ/λ sFLC ratio. By contrast, N Latex FLC assays indicated an approximately equal increase of both FLCs throughout CKD1-4, but a sharp increase in λ FLC levels in the fifth group, that comprised both CKD5 and dialysis patients. One potential explanation for this anomaly was provided by Kennard et al. [922] who compared pre- and post-hemodialysis sFLC concentrations in 105 patients with end-stage kidney disease and no known lymphoplasmacytic disorder. Pre-dialysis λ sFLC concentrations were much higher as measured by the N Latex FLC assays than Freelite, but post-haemodialysis, a larger reduction in λ sFLCs was indicated by the N Latex FLC assays (Table 8.6). This resulted in similar post-dialysis λ sFLC concentrations as measured by both assays. One possibility proposed by the authors is that a positively interfering substance may have been present in pre-dialysis samples that selectively affected the λ N Latex FLC assay (causing an over-read). If this interfering substance was of low molecular weight and was removed by haemodialysis, this would explain the greater fall in λ FLC concentrations indicated by the N Latex FLC assays. Further investigations are now required to try and identify the putative interfering substance and test this hypothesis.

N Latex FLC Freelite
κ/λ (IQR) κ
κ/λ (IQR)
250 0.56 (0.47-0.63) 160 110 1.44 (1.14-1.74)
Post-haemodialysis 44 91 45 65

Table 8.6. Comparison of Freelite and N Latex sFLC concentrations pre- and post-haemodialysis. Median (interquartile range, IQR) values are reported [922].

There is only one published study to date that describes the use of the Seralite-FLC assay in patients with renal impairment: Heaney et al. [979] characterised Seralite-FLC sFLC concentrations in patients with new dialysis-dependent renal failure (AKI stage 3) due to causes other than MM. Similar to N Latex FLC assays, patients with renal failure had a lower Seralite-FLC κ/λ sFLC ratio (0.2 – 1.3) than healthy donors (0.5 – 2.5), due to an increase in λ sFLCs relative to κ sFLCs. Using ROC analysis, the authors define optimal cut-offs for the Seralite-FLC κ/λ sFLC ratio to identify κ (>2.02) and λ (<0.14) MM patients presenting with renal impairment. However, it should be noted that these cut-offs were developed using only the subgroup of MM patients classified as AKI stage 3, and therefore further validation is required before they can be more generally applied.