Elsevier

Clinical Immunology

Volume 211, February 2020, 108331
Clinical Immunology

Predictive value of mesangial C3 and C4d deposition in IgA nephropathy

https://doi.org/10.1016/j.clim.2019.108331Get rights and content

Abstract

We aimed to determine the relative contribution of each complement (C3 and C4d) deposition to the progression of IgA nephropathy (IgAN). We enrolled a total of 380 patients with biopsy-confirmed IgAN. Mesangial deposition of C3(<2+ vs. ≥2+) and C4d(positive vs. negative) was evaluated by immunofluorescence staining and immunohistochemistry, respectively. Study endpoint was the composite of a 30% decline in eGFR or ESRD. The risk of reaching the primary outcome was significantly higher in patients having C3 ≥ 2+ and C4d(+) than in corresponding counterparts. Adding C3 deposition to clinical data acquired at kidney biopsy modestly increased the area under the receiver-operating characteristic curve, net reclassification improvement, and integrated discrimination improvement (IDI); adding C4d increased IDI only. In conclusion, mesangial C3 and C4d deposition was an independent risk factor for progression of IgAN. C3 showed better predictability than C4d, suggesting that lectin pathway alone has limited clinical prognostic value.

Introduction

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. Patients with IgAN present with a wide range of clinical features, ranging from benign conditions to slowly progressing chronic renal impairment, which eventually leads to end-stage renal disease (ESRD) [1,2]. Because IgAN is not a benign disease, numerous studies have developed independent predictors of progression to kidney failure over time; these include hypertension, assessment of kidney function, proteinuria, and pathologic lesions at biopsy [[3], [4], [5], [6], [7], [8], [9]]. Quantifying blood pressure (BP) and proteinuria over longer periods of observation can provide a more accurate prediction of future loss of kidney function [3,6,[10], [11], [12]]. However, because the effects of these factors become more pronounced in the advanced stages of chronic kidney disease, risk stratification remains a challenge in IgAN. Current guidelines suggest that treatment should be based on clinical features at the time of presentation [13]; for that reason, risk-stratification methods that require prolonged periods of time have limited utility in clinical practice [14]. Therefore, identifying new prognostic markers that are independent of currently available risk factors will enable earlier detection of patients at high risk for disease progression.

Although mesangial IgA deposition is the defining hallmark of IgAN, C3 and properdin are almost always present within the mesangium [[15], [16], [17]]. Additionally, mannose-binding lectin (MBL) deposits, which are colocalized with IgA, C3, MBL-associated serine proteases, L-ficolin, and C4d deposits, are also detected in 17 to 25% of patients, whereas C1q is usually absent [[18], [19], [20]]. These findings suggest that the alternative and lectin pathways are involved in complement activation in IgAN. Indeed, previous studies have shown that biopsy-based complement immunostaining can potentially be used as a prognostic marker [19,[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]]. However, there have been no studies to compare the ability of mesangial C3 and C4d deposition to predict disease progression in IgAN. Interestingly, a recent study in 112 Spanish patients with IgAN showed elevated levels of the complement factor H-related protein (FHR)-1. FHR-1 competes with complement factor H for binding to C3b, thereby amplifying the complement cascade. Unlike C4d+, which is not associated with disease progression when assessed using renal biopsy, FHR-1 is associated with progression of kidney disease [33]. Based on these previous findings, we hypothesized that C4d deposition alone might have limited clinical prognostic implication in IgAN. In this observational cohort study of Korean patients with IgAN, we aimed to establish the individual prognostic value of mesangial C3 and C4d deposition, and to compare the utility of these two complement products in predicting kidney outcome.

Section snippets

Ethics statement

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Yonsei University Health System (YUHS) Clinical Trial Center. Written informed consent was obtained from all the participants enrolled in this study.

Patient selection

A flowchart of participants is shown in Supplementary Fig. S1. A total of 435 patients were pathologically diagnosed with IgAN in Yonsei University Severance Hospital between 2003 and 2011. Patients with Henoch-Schonlein

Baseline characteristics

The baseline characteristics of the study participants are shown in Table 1. The mean age at the time of renal biopsy was 36.1 ± 12.3 years, and 164 patients (43.2%) were male. Additionally, 175 (46.1%) patients were being treated with anti-hypertensive drugs before kidney biopsy. The mean level of eGFR was 85.2 ± 27.7 ml/min/1.73 m2, and median level of UPCR was 0.8 (0.3–1.7) g/g. Pathologic findings, analyzed using the Oxford classification system, showed: 119 (31.3%), 51 (13.4%), 242

Discussion

In this study, we examined the clinical implication of mesangial C3 and C4d deposition, and compared the ability of these two complement products to predict adverse kidney outcome in patients with IgAN. We showed that strong mesangial C3 deposition was significantly associated with an increased risk of the composite kidney outcome. In addition, adding mesangial C3 deposition to conventional risk factors improved the predictability of kidney disease progression. However, the association between

Declaration of Competing Interest

All the authors declared no competing interests.

Acknowledgements

This research was supported by a faculty research grant of Yonsei University College of Medicine for 2015, Seoul, Korea (4-2015-1084) and the Research Program funded by the Korea Centers for Disease Control and Prevention (2019ER690100).

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    These authors contributed equally to the study.

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