Complement activation profile of patients with primary focal segmental glomerulosclerosis.

Jing Huang,Xu-Yang Cheng,Li-Qiang Meng,Zhen Qu,Qiu-Hua Gu,Yi-Miao Zhang,Xin Wang,Ming-Hui Zhao,Gang Liu,Fang Wang,Zhao Cui,Zhanjun Jia

doi:10.1371/journal.pone.0234934

Abstract

Studies on adriamycin mice model suggest complement system is activated and together with IgM contributes to the glomerular injury of primary focal segmental glomerulosclerosis (FSGS). We recently reported primary FSGS patients with IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes. Here we examined the plasma and urinary complement profile of patients with primary FSGS, aiming to investigate the complement participation in FSGS pathogenesis. Seventy patients with biopsy-proven primary FSGS were enrolled. The plasma and urinary levels of C3a, C5a, soluble C5b-9, C4d, C1q, MBL, and Bb were determined by commercial ELISA kits. The levels of C3a, C5a and C5b-9 in plasma and urine of FSGS patients were significantly higher than those in normal controls. The plasma and urinary levels of C5b-9 were positively correlated with urinary protein, renal dysfunction and interstitial fibrosis. The plasma C5a levels were positively correlated with the proportion of segmental sclerotic glomeruli. The urinary levels of Bb were elevated, positively correlated with C3a and C5b-9 levels, renal dysfunction, and interstitial fibrosis. The plasma C1q level was significantly decreased, and negatively correlated with urinary protein excretion. Urinary Bb level was a risk factor for no remission (HR = 3.348, 95% CI 1.264-8.870, P = 0.015) and ESRD (HR = 2.323, 95% CI 1.222-4.418, P = 0.010). In conclusion, our results identified the systemic activation of complement in human primary FSGS, possibly via the classical and alternative pathway. The activation of complement system was partly associated with the clinical manifestations, kidney pathological damage, and renal outcomes.

Highlights

Focal segmental glomerulosclerosis (FSGS) is a group of clinical-pathologic syndromes sharing a common glomerular lesion and mediated by diverse insults directed to or inherent within the podocyte [1,2,3,4,5]
In primary FSGS patients, we recently reported 54.7% of consecutive patients had immunoglobulin M (IgM) deposits on the sclerotic segments, and complement 3 (C3) deposits exclusively shown in those patients with IgM glomerular deposit
Complement activation has been identified in adriamycin-induced animal models of glomerulosclerosis [14, 15], which is associated with the progression of glomerulosclerosis

Summary

Introduction

Focal segmental glomerulosclerosis (FSGS) is a group of clinical-pathologic syndromes sharing a common glomerular lesion and mediated by diverse insults directed to or inherent within the podocyte [1,2,3,4,5]. Proteinuria, usually present with nephrotic syndrome, is the most common clinical presentation of primary FSGS For pathological features, it charactered as focal and segmental glomerular sclerosis by light microscope, and the deposition of immunoglobulin M (IgM) in combination with or without complement 3 (C3) in the sclerotic segment without an obvious granular or linear pattern by immunefluorescence microscopy [6]. The patients with IgM and C3 deposition presented unfavorable treatment response and worse renal outcomes [9]. All these findings indicate that IgM deposition may involve disease progression via complement activation. We recently reported primary FSGS patients with IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes.

Methods

Results

Discussion

Conclusion