Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multisystemic autoimmune disease characterized by a necrotizing inflammation in the small to medium vessels. According to the 2012 Chapel Hill International Consensus Conference nomenclature of vasculitis (CHCC) (1), AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, also known as Churg–Strauss syndrome). MPA is a kind of necrotizing vasculitis predominantly affecting the kidney. GPA is a necrotizing granulomatous vasculitis with more sinus and pulmonary involvement, but necrotizing glomerulonephritis is also common. EGPA is an eosinophil-rich and necrotizing granulomatous vasculitis affecting the respiratory tract. In addition, nervous system, skin, mucous, ocular, and cardiovascular involvement can occur in all kinds of AAV.

AAV is associated with the occurrence of circulating autoantibodies against myeloperoxidase (MPO), proteinase 3 (PR3), and other uncommon antigens. MPO-ANCA is common in patients with MPA and usually occurs as perinuclear immunofluorescence patterns (P-ANCA), while PR3-ANCA is commonly associated with GPA and presents as cytoplasmic immunofluorescence patterns (C-ANCA) (2). AAV mainly occurs in adults with an annual incidence of 13–20 cases/million in Europe. However, they are very rare in children with an estimated incidence of 1–6 cases per million (3). A combination of immunosuppression and glucocorticoids remains the mainstream treatment and has saved the lives of a lot of patients with AAV. Despite strong immunotherapy, many AAV patients still died of ESRD, infectious or cardiovascular complications, etc. According to previous reports (4–10), 20% to 45% of children with AAV eventually progressed to ESRD. A recent multicenter study of 85 children with AAV in Italy and Canada (9) has not found any independent prognostic factors of renal outcome in multivariable Cox regression analysis. In a French national study of 66 children with AAV (11), low baseline eGFR levels, non-Caucasian ethnicity, and sclerotic or mixed histopathological patterns were associated with the occurrence of ESRD. Since AAV in children is rare, risk factors of renal long-term outcomes have not been extensively studied. So far, there have been a few reports on the risk factors for renal prognosis in Chinese children with AAV, and there has been no study on the effect of induction therapy on renal long-term outcomes. Hence, the present study is intended to provide such information through analyzing the demographic, clinical, pathological, laboratory, and follow-up data in children with AAV in a single pediatric center.

AAV is a severe autoimmune disorder mainly affecting the kidney, lung, nose, paranasal sinus, skin, etc. (15). It mainly occurs in adults and rarely in children. So far, a few large cohorts are focusing on the long-term outcome of pediatric patients with AAV. Our study summarized the clinicopathological features, their relationship with response to induction treatment, and renal long-term outcome of pediatric AAV in a single center. The results showed that MPA accounted for the overwhelming majority (91.7%) of AAV in Chinese children, and female patients also made up the majority (81.25%) of AAV. The demographic and AAV-type distribution characteristics were consistent with other previous studies on Chinese and other East Asian children (10, 11, 16, 17). These were different from adult patients, suggesting a somewhat male predominance (18). It is interesting to note that an MPA majority not only existed in studies comprising Chinese pediatric (97.1%) (10) and adult patients (83.64%) (19) but also in Korean (59.4%) (20) and Japanese patients with AAV (21). It was different from AAV in Europe and North America where a GPA majority was more common (21). Renal involvement is much higher than pulmonary involvement in MPA patients. Similarly, our study showed renal and pulmonary involvement in 93.75% and 23% of patients, respectively.

As shown in the present paper, the effect of induction therapy significantly affected renal survival in patients with AAV. Currently, glucocorticoids combined with cyclophosphamide remain the “gold standard” treatment for induction therapy. Mycophenolate mofetil and azathioprine are the main immunosuppressants for maintenance therapy. In recent years, rituximab, immunoadsorption, and plasma exchange have also been successfully used in the treatment of AAV (3). Other biologics like anti-TNF-α and anti-BLyS monoclonal antibodies have been tried in the treatment of AAV. The overall remission rate was 56.3% after 6-month induction treatment in our patients, which was significantly lower than that in previously reported AAV cohorts (9, 10, 22). As shown in our study, baseline eGFR <60 ml/min/1.73 m² was an independent predictor of nonremission and found in a percentage as high as 71% of patients. Therefore, the reason for the lower remission rate of induction treatment was probably due to the higher proportion of eGFR <60 ml/min/1.73 m² at diagnosis.

Around 50% of patients progressed to ESRD, higher than in other reports showing only between 20% and 45% (4–10). Through multivariate Cox regression analysis, we identified eGFR <60 ml/min/1.73 m² and hypertension at the time of diagnosis as independent risk predictors for progression to ESRD. Our results confirmed the poor prognostic value of decreased eGFR at diagnosis, which was consistent with previous studies (4, 8–10, 23). Additionally, this study revealed a new finding that hypertension at diagnosis was also an independent risk predictor for progression to ESRD in childhood-onset AAV. Moreover, this study also identified nephrotic-range proteinuria and PVAS >11 at the time of diagnosis as risk factors for ESRD in univariate analysis. PVAS was established in 2012 when redefining the Birmingham Vasculitis Activity Score (BVAS) components and adding eight pediatric items (13). The present study also confirmed high PVAS as a risk factor of renal long-term outcome in pediatric AAV patients (24–26). A total of eight patients reached ESRD at the time of diagnosis, and four patients progressed to ESRD in the periods of remission-induction treatment. Considering that immunosuppressants were not necessarily needed in these cases, they received a shorter period of induction therapy to avoid adverse effects, and this might have an impact on renal outcomes.

Our results also demonstrated that renal pathological patterns were significantly associated with long-term renal outcomes, as shown in adult AAV patients. There were studies even showing that renal pathological patterns affected the outcome more than baseline eGFR (27, 28). As in adults, those with a sclerotic subtype rapidly progressed to ESRD. Sclerotic lesions were thought to result not only from vasculitis but also from other factors, such as aging, atherosclerosis, dyslipidemia, and hypertension (9, 29). Patients with focal subtype showed a favorable renal outcome. Interestingly, the outcome of those with crescentic subtype turned out to see many variations, and whether they restored to normal eGFR levels or progressed to ESRD (CKD stage V) was significantly associated with baseline eGFR levels and with response to induction treatment. There were three patients with eGFR levels between 30 and 60 ml/min/1.73 m² and one patient with an eGFR level between 15 and 30 ml/min/1.73 m²; they all finally returned to normal eGFR levels following a 6-month remission-induction treatment. These results demonstrated the importance of treatment responsiveness in affecting the outcome. Of course, the active lesions were more likely to be reversible if treated in a timely and effective manner (30). In addition to glucocorticoid and CYC, RTX was also proven to be as effective as CYC in remission-induction and relapse treatment of AAV (31, 32). Among seven serious AAV patients treated with RTX, three patients obtained a significant improvement in eGFR and proteinuria, which demonstrated the promising prospects of RTX in the treatment of pediatric patients with AAV.

The advantages of this study were based on the fact that it represented the largest pediatric cohort of AAV in Chinese children and provided actual clinicopathological features different from adults and children in the EU and North America. Secondly, our study demonstrated that eGFR <60 ml/min/1.73 m² and hypertension at diagnosis were independent predictors for progression to ESRD. Moreover, the study particularly pointed out the importance of induction treatment responsiveness in affecting the outcome of AAV. Through multivariate logistic regression analysis, hypertension and eGFR <60 ml/min/1.73 m² at diagnosis were also considered risk factors associated with failure of induction therapies. Thus, these risk factors might affect the long-term renal outcomes by influencing the response to induction treatment. However, the limitations of this study lie mainly in its retrospective nature, and the total number of included cases is not large enough to allow further statistical analysis. In addition, since we included only hospitalized patients, a selection bias may exist in that some patients with mild AAV in the outpatient were omitted.

In conclusion, our study demonstrates that women, MPA, and crescentic subtypes are predominant in pediatric AAV in China. Initial renal failure (eGFR <60 ml/min/1.73 m²), hypertension, sclerotic pathological pattern at diagnosis, and nonremission to induction treatment are predictors of poor long-term renal outcome. Apparently, AAV remains a rough challenge to the pediatric community.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Human Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

All authors contributed to the intellectual content of this manuscript and approved the final manuscript as submitted. JY collected data, performed the statistical analysis, and drafted the manuscript with the help of YX, YY, LQZ, LWZ, XY, FY, YH, JP, YL, YXC, and JZ. HY, LQ, YZ, YC, TL, and JT were responsible for the renal pathological interpretation and patients’ care. JZ interpreted the data and revised the article for important intellectual content. All authors have critically read and approved the manuscript.

This work was supported by a grant (No. 81873596) from the National Natural Science Foundation of China to JZ.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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