Abstract
Background and Aims
Mechanisms of kidney injury by monoclonal free light chains in myeloma kidney are well established. The role polyclonal free light chains (pFLC) in pathogenesis of renal interstitial inflammation and fibrosis in primary glomerulonephritis is still poorly investigated. We hypothesize that increased level of pFLC could have the similar role in activation of interstitial inflammation and fibrosis formation and impact chronic kidney disease (CKD) progression in the most prevalent form of chronic glomerulonephritis - IgA-nephropathy (IgAN).
The aim of this retrospective study was to analyze the association of pFLC kappa (pFLC-κ) and lambda (pFLC-λ) assessed in serum by Freelite® with clinical and morphological parameters and CKD progression in IgA-nephropathy cohort.
Method
In this study we enrolled 23 patients with biopsy-confirmed diagnosis of IgAN. pFLC-κ and pFLC-λ levels were assessed in all cases at the time of kidney biopsy (KBx) by Freelite method. Normal range for pFLC-κ and pFLC-λ was 3,3-19,4 mg/l and 5,7-26,3 mg/l, respectively. The following clinical parameters were evaluated at the time of KBx: estimated glomerular filtration rate (eGFR) by CKD-EPI, daily proteinuria, serum albumin and microhematuria. Morphological findings were investigated by light and immunofluorescence (IgA, IgM, IgG, C3, C1, lambda, kappa, fibrinogen) microscopy. Oxford MEST-C score was evaluated as well as % of sclerotic glomeruli. Additionally we semiquantitatively measured (0- absent, 1- mild, 2 – moderate, 3 - severe) mesangial proliferation, endocapillary proliferation, glomerular basement membrane (GBM) thickening, interstitial inflammation, interstitial edema, tubular atrophy (TA), peritubular capillaritis (PTC), interstitial fibrosis (IF) according to currently accepted criteria. The demographic, clinical and morphological parameters at the time of KBx are presented in Table 1. Patients were treated with nephroprotective agents (n=23) and steroids/cyclophosphamide (n=21). Correlation between parameters were assessed by Spearman’s coefficient. Progression of CKD was determined as decline of eGFR >25% from the initial level at the end of follow-up period. Prognostic analysis was performed with Cox proportional hazards regression. Median follow-up was 28 (7; 37) months.
Results
Correlations between clinical and morphological parameters and pFLC levels are presented in Table 2.
Univariate Cox regression analysis has shown that pFLC-κ (Exp(β)=1,051; 95% CI: 1,001-1,104, p=0,045) and FLC- λ (Exp(β)=1,040; 95% CI: 1,001-1,081, p=0,044) as well as other well-known clinical (daily proteinuria (Exp(β)=1,177; 95% CI: 1,003-1,382, p=0,045), eGFR at the KBx time (Exp(β)=2,981; 95% CI:1,112-20,124, p=0,042)) and morphological parameters (% of sclerotic glomeruli (Exp(β)=1,031; 95% CI: 1,001-1,062, p=0,046), T-score (Expβ=10,784; 95% СI: 1,364-85,246, p=0,024) are associated with CKD progression.
Conclusion
In IgAN higher levels of pFLC, both kappa and lambda, are associated with renal interstitial inflammation and fibrosis, tubular atrophy and chronic glomerular injury and could be used as predictors of CKD progression. Mechanisms of pFLC effects on the formation of renal tubular and interstitial inflammation and fibrosis require further studies.
