Advertisement
Mayo Clinic Proceedings Home

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

      Abstract

      Objective

      To clarify the associations between polyclonal serum free light chain (sFLC) levels and adverse outcomes in patients with chronic kidney disease (CKD) by conducting a systematic review and individual patient data meta-analyses.

      Patients and Methods

      On December 28, 2016, we searched 4 databases (MEDLINE, Embase, CINAHL, and PubMed) and conference proceedings for studies presenting independent analyses of associations between sFLC levels and mortality or progression to end-stage renal disease (ESRD) in patients with CKD. Study quality was assessed in 5 domains: sample selection, measurement, attrition, reporting, and funding.

      Results

      Five prospective cohort studies were included, judged moderate to good quality, involving 3912 participants in total. In multivariable meta-analyses, sFLC (kappa+lambda) levels were independently associated with mortality (5 studies, 3680 participants; hazard ratio [HR], 1.04 [95% CI, 1.03-1.06] per 10 mg/L increase in sFLC levels) and progression to ESRD (3 studies, 1848 participants; HR, 1.01 [95% CI, 1.00-1.03] per 10 mg/L increase in sFLC levels). The sFLC values above the upper limit of normal (43.3 mg/L) were independently associated with mortality (HR, 1.45 [95% CI, 1.14-1.85]) and ESRD (HR, 3.25 [95% CI, 1.32-7.99]).

      Conclusion

      Higher levels of sFLCs are independently associated with higher risk of mortality and ESRD in patients with CKD. Future work is needed to explore the biological role of sFLCs in adverse outcomes in CKD, and their use in risk stratification.

      Abbreviations and Acronyms:

      CKD (chronic kidney disease), CVD (cardiovascular disease), DM (diabetes mellitus), eGFR (estimated glomerular filtration rate), ESRD (end-stage renal disease), HR (hazard ratio), MDRD (modification of diet in renal disease formula), hsCRP (high-sensitivity C-reactive protein), MGUS (monoclonal gammopathy of uncertain significance), NT-proBNP (N-terminal pro–B-type natriuretic peptide), PCR (protein to creatinine ratio), PWV (pulse wave velocity), RAAS (renin-angiotensin-aldosterone system), RRT (renal replacement therapy), SBP (systolic blood pressure), sFLC (serum free light chain), uACR (urine albumin to creatinine ratio)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Brück K.
        • Stel V.S.
        • Gambaro G.
        • et al.
        CKD prevalence varies across the European general population.
        J Am Soc Nephrol. 2016; 27: 2135-2147
        • Saran R.
        • Robinson B.
        • Abbott K.C.
        • et al.
        US Renal Data System 2016 annual data report: epidemiology of kidney disease in the United States.
        Am J Kidney Dis. 2017; 69: A7-A8
        • Matsushita K.
        • van der Velde M.
        • Astor B.C.
        • et al.
        • Chronic Kidney Disease Prognosis Consortium
        Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.
        Lancet. 2010; 375: 2073-2081
        • Hallan S.I.
        • Ritz E.
        • Lydersen S.
        • Romundstad S.
        • Kvenild K.
        • Orth S.R.
        Combining GFR and albuminuria to classify CKD improves prediction of ESRD.
        J Am Soc Nephrol. 2009; 20: 1069-1077
        • Go A.S.
        • Chertow G.M.
        • Fan D.J.
        • McCulloch C.E.
        • Hsu C.Y.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351: 1296-1305
        • Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
        KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
        Kidney Int Suppl. 2013; 3: 1-150
        • Taal M.W.
        Progress in risk prediction for people with chronic kidney disease.
        Curr Opin Nephrol Hypertens. 2014; 23: 519-524
        • Hutchison C.A.
        • Harding S.
        • Hewins P.
        • et al.
        Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease.
        Clin J Am Soc Nephrol. 2008; 3: 1684-1690
        • Stroup D.F.
        • Berlin J.A.
        • Morton S.C.
        • et al.
        • Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group
        Meta-analysis of observational studies in epidemiology: a proposal for reporting.
        JAMA. 2000; 283: 2008-2012
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Lancet. 2007; 370: 1453-1457
      1. Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration website. http://www.handbook.cochrane.org/. Updated March 2011. Accessed August 24, 2017.

        • Desjardins L.
        • Liabeuf S.
        • Lenglet A.
        • et al.
        Association between free light chain levels, and disease progression and mortality in chronic kidney disease.
        Toxins (Basel). 2013; 5: 2058-2073
        • Haynes R.
        • Hutchison C.A.
        • Emberson J.
        • et al.
        Serum free light chains and the risk of ESRD and death in CKD.
        Clin J Am Soc Nephrol. 2011; 6: 2829-2837
        • Ritchie J.
        • Assi L.K.
        • Burmeister A.
        • et al.
        Association of serum Ig free light chains with mortality and ESRD among patients with nondialysis-dependent CKD.
        Clin J Am Soc Nephrol. 2015; 10: 740-749
        • Hutchison C.A.
        • Burmeister A.
        • Harding S.J.
        • et al.
        Serum polyclonal immunoglobulin free light chain levels predict mortality in people with chronic kidney disease.
        Mayo Clin Proc. 2014; 89: 615-622
        • Assi L.K.
        • McIntyre N.
        • Fraser S.
        • et al.
        The association between polyclonal combined serum free light chain concentration and mortality in individuals with early chronic kidney disease.
        PLoS One. 2015; 10: e0129980
        • Anandram S.
        • Assi L.K.
        • Lovatt T.
        • et al.
        Elevated, combined serum free light chain levels and increased mortality: a 5-year follow-up, UK study.
        J Clin Pathol. 2012; 65: 1036-1042
        • Dispenzieri A.
        • Katzmann J.A.
        • Kyle R.A.
        • et al.
        Use of nonclonal serum immunoglobulin free light chains to predict overall survival in the general population.
        Mayo Clin Proc. 2012; 87: 517-523
        • Cohen G.
        • Horl W.H.
        Free immunoglobulin light chains as a risk factor in renal and extrarenal complications.
        Semin Dial. 2009; 22: 369-372
        • Cohen G.
        • Haag-Weber M.
        • Mai B.
        • et al.
        Effect of immunoglobulin light chains from hemodialysis and continuous ambulatory peritoneal dialysis patients on polymorphonuclear leukocyte functions.
        J Am Soc Nephrol. 1995; 6: 1592-1599
        • Cohen G.
        • Rudnicki M.
        • Horl W.H.
        Uremic toxins modulate the spontaneous apoptotic cell death and essential functions of neutrophils.
        Kidney Int Suppl. 2001; 78: S48-S52
        • Holdsworth S.R.
        • Summers S.A.
        Role of mast cells in progressive renal diseases.
        J Am Soc Nephrol. 2008; 19: 2254-2261
        • Redegeld F.A.
        • van der Heijden M.W.
        • Kool M.
        • et al.
        Immunoglobulin-free light chains elicit immediate hypersensitivity-like responses.
        Nat Med. 2002; 8: 694-701
        • Thilo F.
        • Caspari C.
        • Scholze A.
        • Tepel M.
        Higher serum levels of free kappa plus lambda immunoglobulin light chains ameliorate survival of hemodialysis patients.
        Kidney Blood Press Res. 2011; 34: 344-349
        • Pote A.
        • Zwizinski C.
        • Simon E.E.
        • Meleg-Smith S.
        • Batuman V.
        Cytotoxicity of myeloma light chains in cultured human kidney proximal tubule cells.
        Am J Kidney Dis. 2000; 36: 735-744
        • Sengul S.
        • Zwizinski C.
        • Batuman V.
        Role of MAPK pathways in light chain-induced cytokine production in human proximal tubule cells.
        Am J Physiol Renal Physiol. 2003; 284: F1245-F1254
        • Sengul S.
        • Zwizinski C.
        • Simon E.E.
        • Kapasi A.
        • Singhal P.C.
        • Batuman V.
        Endocytosis of light chains induces cytokines through activation of NF-kappaB in human proximal tubule cells.
        Kidney Int. 2002; 62: 1977-1988
        • Batuman V.
        Proximal tubular injury in myeloma.
        Contrib Nephrol. 2007; 153: 87-104
        • Inker L.A.
        • Coresh J.
        • Sang Y.
        • et al.
        Filtration markers as predictors of ESRD and mortality: individual participant data meta-analysis.
        Clin J Am Soc Nephrol. 2017; 12: 69-78
        • Hutchison C.A.
        • Basnayake K.
        • Cockwell P.
        Serum free light chain assessment in monoclonal gammopathy and kidney disease.
        Nat Rev Nephrol. 2009; 5: 621-628
        • Jackson C.E.
        • Haig C.
        • Welsh P.
        • et al.
        Combined free light chains are novel predictors of prognosis in heart failure.
        JACC Heart Fail. 2015; 3: 618-625
        • Eisele L.
        • Dürig J.
        • Huttmann A.
        • et al.
        Polyclonal free light chain elevation and mortality in the German Heinz Nixdorf Recall Study.
        Blood. 2010; 116: 3903
        • Hampson J.A.
        • Stockley R.A.
        • Turner A.M.
        Free light chains: potential biomarker and predictor of mortality in alpha-1-antitrypsin deficiency and usual COPD.
        Respir Res. 2016; 17: 34
        • Tangri N.
        • Kitsios G.D.
        • Inker L.A.
        • et al.
        Risk prediction models for patients with chronic kidney disease: a systematic review.
        Ann Intern Med. 2013; 158: 596-603
        • Wang L.
        • Chan P.C.
        Measurement uncertainty for serum free light chain assays: estimation and implication on result interpretation.
        Clin Biochem. 2013; 46: 381-384

      Linked Article

      • Correction
        Mayo Clinic ProceedingsVol. 92Issue 12
        • Preview
          In the Original Article entitled, “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” published in the November 2017 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2017;92(11):1671-1681), the middle initial was not included for one of the authors. His name should be listed as Phil A. Kalra.
        • Full-Text
        • PDF