The Association between Polyclonal Combined Serum Free Light Chain Concentration and Mortality in Individuals with Early Chronic Kidney Disease

Abstract

A major component of increased mortality risk in people with chronic kidney disease (CKD) is associated with non-traditional cardiovascular risk factors including markers of inflammation. We studied whether a novel marker of systemic inflammation, elevated serum combined polyclonal immunoglobulin free light chains (cFLC), was an independent risk factor for increased all-cause mortality in people with CKD stage 3. In a prospective community based cohort study, 1695 participants with stage 3 CKD and no cases of monoclonal gammopathy had cFLC concentrations measured. cFLC levels were determined using the summation of Freelite kappa and lambda assays. All other bioclinical variables were collected at the time of sample collection. Kaplan-Meier plots and Cox proportional hazards analysis was used to assess the relationship between high cFLC levels (>43.3 mg/L) and mortality. There were 167 deaths (10%) after a median of 1375 days. cFLC levels at recruitment were higher in participants who died compared with those who were alive at the end of the study; median: 46.5 mg/L (IQR: 36.1-65.4 mg/L) and 35.4 mg/L (28.1-46.6 mg/L) respectively, P <0.001. Kaplan-Meier survival analysis demonstrated participants with cFLC >43.3 mg/L levels had an increased risk of mortality compared to people with normal cFLC levels (P <0.001). Elevated cFLC levels were independently associated with worse survival (Hazard ratio: 1.50; 95% confidence interval: 1.04-2.16; P=0.03). Other independent risk factors for worse survival were: older age, male gender, previous cardiovascular event, lower eGFR and higher high sensitivity C-reactive protein (hsCRP). To conclude, high cFLC levels predict increased mortality in people with stage 3 CKD, independent of established risk factors and other markers of inflammation.

The Association of Serum Free Light Chains With Mortality and Progression to End-Stage Renal Disease in Chronic Kidney Disease: Systematic Review and Individual Patient Data Meta-analysis

“…We included five moderate to good quality prospective cohort studies that included people across the full spectrum of pre-dialysis CKD. 12- 16 We found an independent association between sFLC and both mortality and progression to ESRD in an analysis that included conventional risk factors for these outcomes. Moreover, the hazard ratio for mortality observed in participants with sFLC above the upper limit of normal was similar in magnitude to that associated with diabetes or previous cardiovascular disease.…”

“…[14][15][16] Although we had only 17 (0.4%) participants with CKD category G1 in the meta-analysis, the results indicate that sFLC may have a role in all stages of pre-dialysis CKD. This is consistent with general population studies identifying an association between elevated sFLC and mortality in individuals without CKD.…”

“…29 Second, in the studies included in this meta-analysis, the correlation between eGFR and sFLC (where reported) is moderate (r values of -0.56 and -0.49). 15,16 This indicates that whilst sFLC is in part associated with eGFR, a substantial contribution to differences in sFLC levels is independent of kidney function. For example, FLC undergo significant non-renal clearance through the reticulo-endothelial system, which accounts for a greater portion of clearance in CKD as kidney function declines.…”

Uremia Retention Molecules and Clinical Outcomes

“…Clinical studies in CKD patients have demonstrated that high FLC levels are independently associated with overall mortality risk across different stages of CKD [40,41] . Not all studies were able to demonstrate this association though [42] .…”

“…Differences on the clinical and demographic characteristics of the study population, number of patients included, and follow-up duration may account for these conflicting findings. FLC κ and λ levels have also been associated with inflammation, vascular calcification, and levels of other uremic toxins, such as β2M, indoxyl sulphate, and para-cresyl sulfate, and with progression to ESRD [40,42] .…”