Abstract
Background and Aims
Uremic toxins, poor removed by conventional hemodialysis (HD), represent independent risk factors for mortality in end-stage renal disease (ESRD).
Middle uremic toxin molecules were associated to pathological features of uremia, such as immune dysfunction and inflammation. These two entities are not mutually exclusive, but they could represent two sides of the same coin. ESRD-associated inflammation is closely related to the activation of innate immune system. Free light chain (FLC) may be a specific assessment of inflammation, representing a direct function of adaptive immunity through B-cell lineage production rather than a general marker of inflammation.
While several studies have assessed the relation between FLCs and mortality risk in chronic kidney disease (CKD), FLCs, as uremic toxins in non-multiple myeloma dialyzed patients, were marginally analyzed.
The aim of this prospective study was to evaluate the clinical impact of FLCs levels in HD patients, during a 2-years follow-up analysing the relations with biomarkers of inflammation, such as C-reactive protein (CRP) and procalcitonin (PCT), main lymphocytes subsets, such as CD4+ and CD8+ T cell count and high mobility group box (HMGB) -1 levels, as expression of the innate immune system. The potential link between FLCs levels and mortality risk was assessed.
Method
190 patients on chronic hemodialysis at the Nephrology and Dialysis Unit of Papardo Hospital in Messina, Italy, were enrolled and followed for 2 years. Inclusion criteria were: age >18 years, absence or <200 ml/die residual diuresis, κ/λ ratio within the renal reference range (0.37–3.1).
Receiver operating characteristics (ROC) analysis was performed to estimate the cut-off points of HMGB-1 and cFLC. Kaplan-Meier survival analysis and Cox proportional multivariate hazards model were used for clinical outcome.
Results
HD patients were characterized by high FLC levels. κFLC values were 182.3 (IQR: 140.2 – 216.1) mg/L, whereas λFLC levels were 108.2 (IQR: 72.7 – 143.2) mg/L. The median combined (c) FLC concentration was 182.9 mg/L (IQR = 207.8 – 330.2), which was extremely greater than the median reported in the general population (normal range = 9.3 – 43.3 mg/L) and in CKD patients [68.9 mg/L (IQR = 49.4 – 100.9)].
No differences in cFLC levels were revealed according to dialysis techniques.
HD patients showed significant reduction of CD4+ and CD4+/CD8+ ratio. High HMGB1 levels were detected in HD patients (161.3 ± 39.7 ng/ml) and positively related to PCT and cFLC (r = - 0.38; p < 0.001), with an inverse relation to CD4+/CD8+ ratio.
cFLC positively correlated with β2 microglobulin, hemoglobin, and HMGB1. Conversely, an inverse correlation was revealed with surrogate markers of inflammation, such as CRP, procalcitonin, neutrophil counts.
There were 49 deaths during the follow-up. The majority (23/49) of deaths were attributed to cardiovascular disease, the remainder to infection and malignancy.
cFLCs and sHMGB-1 levels in this group were significantly elevated. By ROC analysis, HMGB-1 levels > 100.9 ng/mL and cFLC > 223.4 mg/l were associated with a significantly lower survival rate (p < 0.02 by log-rank test) than for patients with lower levels when using Kaplan-Meier analysis. After adjusting for confounding factors, by Cox proportional hazards method, the difference remained statistically significant (p = 0.02)
Conclusion
Our study demonstrated an independent relation between high cFLC levels and mortality in HD patients. cFLCs represent a potential biomarker of “inflammunity”, a physiopathological process playing a pivotal role in ESRD, based on a vicious circle between inflammation and immune dysfunction.
Further in-depth examinations should be verify our findings, determining whether therapeutic measures targeting cFLC balance, such as hemodiafiltration and expanded dialysis, would be helpful to reduce the “inflammunity” process, characterizing dialyzed patients.
Introductory Chapter: Immune System Dysfunction and Autoimmune Diseases