Association of Serum Ig Free Light Chains with Mortality and ESRD among Patients with Nondialysis-Dependent CKD

Abstract

Background and objectives High levels of serum polyclonal combined Ig free light chains are associated with inflammation and decreased excretory kidney function, and they are an independent risk factor for mortality. Whether combined Ig free light chain predicted mortality and progression to ESRD in a stages 3-5 CKD cohort was assessed.Design, setting, participants, & measurements This was a prospective cohort study of 872 patients with stages 3-5 CKD (nondialysis) recruited into the Chronic Renal Insufficiency Standards Implementation Study. Patients were recruited to the Chronic Renal Insufficiency Standards Implementation Study in an unselected manner from secondary care nephrology clinics between 2004 and 2010. Combined Ig free light chain was measured at recruitment and analyzed by quartiles. The cohort was followed up for a median of 41.4 months (interquartile range =28.3-68.0 months). Cox regression analysis was undertaken to determine the variables associated with mortality and progression to ESRD.Results Combined Ig free light chain quartiles were ,49.4, 49.4-68.8, 68.9-100.7, and .100.7 mg/L. An independent association with death and progression to ESRD was associated with the third and fourth combined Ig free light chain quartiles (quartile 3: death: hazard ratio, 1.49; 95% confidence interval, 1.02 to 2.18; P=0.04; ESRD: hazard ratio, 1.72; 95% confidence interval, 1.0 to 2.97; P=0.05; quartile 4: death: hazard ratio, 1.99; 95% confidence interval, 1.34 to 2.93; P,0.001; ESRD: hazard ratio, 3.73; 95% confidence interval, 2.1 to 6.3; P,0.001). The other independent risk factors were (1) preexisting cardiovascular disease, age .65 years old, and eGFR=15-30 ml/ min per 1.73 m 2 for death and (2) age #65 years old, eGFR,30 ml/min per 1.73 m 2 , urinary protein-to-creatinine ratio .30 mg/mmol, and serum phosphate level .4.65 mg/dl for progression to ESRD.Conclusions An elevated serum combined Ig free light chain level is an independent risk factor for mortality and progression to ESRD in patients with stages 3-5 CKD managed in secondary care.

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

“…[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.…”

“…[13][14][15] We conducted combined analyses on the 1848 participants with complete data for exposure and ESRD as an outcome.…”

“…13,15 We incorporated additional data from a third study and identified a positive independent association between sFLC level and risk of ESRD.…”

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] .…”