Abstract
Background
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by necrotizing inflammation of small vessels, typically affecting glomerular capillaries. However, small arteries can also be affected. The clinical significance of this subgroup of patients remains unclear. This study aimed to analyze the clinicopathologic features and prognostic significance of renal arteritis in Chinese patients with AAV.
Methods
A large multicenter cohort of 511 patients with renal biopsy-proven AAV, diagnosed between 2002 and 2023, was retrospectively enrolled. Clinicopathologic parameters were compared between those with and without renal arteritis (termed AAV_A+ and AAV_A-, respectively). The prognostic value of renal arteritis was further analyzed.
Results
Among the 511 patients with AAV, 73 (14.3%) had renal arteritis. Compared with patients with AAV_A-, patients with AAV_A+ were significantly older at diagnosis, with more pronounced systemic inflammation and more frequent extrarenal involvement. Although baseline renal function was comparable, patients with AAV_A+ exhibited a distinct histopathologic phenotype, with fewer crescentic lesions but more inflammatory and necrotizing injuries. Despite patients with AAV_A+ showed a better response to immunosuppressive therapy, renal survival was similar between the 2 groups. However, among patients classified as low or moderate risk by the ANCA kidney risk score (AKRiS), renal survival was significantly worse in patients with AAV_A+. For this subgroup, renal arteritis was independently associated with an increased risk of end-stage kidney disease (ESKD).
Conclusion
AAV with renal arteritis represents a distinct clinical and pathologic phenotype in the Chinese population. In patients classified as low or moderate risk by the AKRiS, renal arteritis was independently associated with an increased risk of ESKD.
Keywords: ANCA, renal arteritis, vasculitis
Graphical abstract
AAV is a group of systemic autoimmune diseases characterized by small-vessel vasculitis and the presence of circulating ANCAs directed primarily against myeloperoxidase (MPO) or proteinase 3 (PR3). The kidney is one of the most commonly affected organs, typically manifesting as rapidly progressive glomerulonephritis (GN) and associated with significant morbidity and mortality.1, 2, 3 AAV comprises granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. On the basis of our previous studies, microscopic polyangiitis and MPO-AAV predominate in China,3, 4, 5 in contrast with the higher prevalence of granulomatosis with polyangiitis and PR3-AAV in many Caucasian populations, especially in Northern Europe.6, 7, 8 Moreover, microscopic polyangiitis and MPO-AAV usually present with more frequent and severe renal disease, and are associated with worse survival.9 ANCA-associated GN (ANCA-GN) typically affects glomerular capillaries, manifesting as pauci-immune necrotizing crescentic GN. In addition to glomerular capillary lesions, involvement of small renal arteries, including interlobular and arcuate arteries, is increasingly recognized in ANCA-GN, with a reported prevalence ranging from 8% to 23% in ANCA-GN.10, 11, 12, 13, 14, 15, 16, 17 However, characteristics of patients with concomitant renal arteritis in ANCA-GN is not fully clear yet, especially in Chinese patients. Therefore, the current study aimed to analyze clinicopathologic characteristics and outcomes of patients with renal arteritis in ANCA-GN in a large multicenter cohort of Chinese patients.
Methods
Patients
This multicenter study included 511 patients with biopsy-confirmed ANCA-GN, diagnosed between 2002 and 2023, retrospectively enrolled from 4 tertiary medical centers—Peking University First Hospital, the Second Affiliated Hospital of Xi’an Jiaotong University, Peking University Third Hospital, and Peking University Shenzhen Hospital. The data were pooled to analyze clinicopathologic characteristics and outcomes in patients with or without renal arteritis. All these patients met the 2012 Chapel Hill Consensus Conference definition for AAV.18 The details of the recruitment process were shown in Figure 1. Patients were followed up in the outpatient clinics specific for AAV management. Clinical and laboratory data at the time of diagnosis as well as during follow-up were collected. The disease activity of AAV was assessed according to the Birmingham Vasculitis Activity Score.19 This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee.
Figure 1.
Flowchart of the inclusion and exclusion process.
Renal Histopathology
Renal histopathologic assessment is detailed in the Supplementary Methods, related supplementary references were cited.S1–S11
Treatment and Response
Treatment strategies are detailed in the Supplementary Methods.
Outcome
The primary end point was ESKD defined as the need for maintenance dialysis or kidney transplantation, and the secondary end point was all-cause mortality. Renal survival time was calculated from the date of AAV diagnosis to the time point of reaching ESKD or death before ESKD, or to the last follow-up; overall survival time was calculated as the time from AAV diagnosis to death due to any cause, or to the last follow-up.
Statistical Analysis
Statistical analyses were performed using SPSS (version 22.0, IBM Corp, Armonk, NY) and R (version 4.2.3, R Core Team, Vienna, Austria).
Quantitative data were presented as mean ± SD or median (interquartile range [IQR]), depending on the normality of the data distribution. The between-group differences were assessed by the Student t-test for normally distributed quantitative parameters and by the Mann-Whitney U test for continuous variables with skewed distribution. Qualitative data were presented as number (%) and differences between 2 groups were analyzed using the χ2test. To compare differences between semiquantitative variables, the Mann-Whitney U test was applied. Standardized mean differences (SMD) were calculated to quantify the magnitude of between-group differences, with an absolute SMD > 0.2 considered indicative of meaningful imbalance. Kaplan-Meier analyses were performed to estimate survival probabilities, and the log-rank test was used to assess differences in survival between groups. Cox proportional hazards regression analyses were performed to evaluate the association between renal arteritis and patient outcomes. Variables that achieved statistical significance in univariate survival analysis (P < 0.05), together with covariates of established clinical relevance regardless of their univariate significance were included in multivariable Cox regression models.20 Age and sex were forced into multivariable models, as they were potential confounding factors.21,22 Calendar year was included as a covariate to account for temporal trends,23 and the Cox regression models were stratified by center to allow for center-specific baseline hazard functions. Among the covariates included in the multivariable Cox regression models, missing data were present only for urinary protein (4.7%); whereas all other covariates were complete. Given the low proportion of missing data confined to a single covariate, a complete-case analysis was performed. Schoenfeld residual tests were used to examine the proportional hazards assumption, whereas the variance inflation factor was calculated to detect multicollinearity among the variables. To address the concern regarding competing risks, we performed Fine-Gray competing risk regression as a sensitivity analysis, treating death as a competing event for ESKD. Model performance was evaluated using Harrell C-statistic through the “survival” package in R, and the differences between C-statistics of different models were assessed using the “compareC” package in R.24 Internal validation was performed using bootstrap resampling with 1000 replicates to evaluate the robustness of the arteritis effect estimate. In each bootstrap sample, multivariable Cox regression models incorporating either the AKRiS or the Berden classification were applied, consistent with the methodological approach used in the original cohort. Statistical significance was defined as a two-sided P-value < 0.05.
Results
General Data of the Patients
Among the 511 patients with ANCA-GN enrolled in this study, 250 (48.9%) were male and 261 (51.1%) were female, with an age of 60.3 ± 12.5 (range, 14–83) years at diagnosis. MPO-ANCA and PR3-ANCA were positive in 459 (89.8%) and 45 (8.8%) patients, respectively, and the remaining 7 (1.4%) patients were negative for ANCA. 73 of the 511 (14.3%) patients with AAV were identified as having renal arteritis by histopathologic evaluation (Figure 1). Baseline data of the patients are presented in Table 1.
Table 1.
General data of patients with AAV with or without renal arteritis
| Variables | Total n = 511 | AAV_A− n = 438 | AAV_A+ n = 73 | P-value | SMD |
|---|---|---|---|---|---|
| Age, yr, mean ± SD | 60.3 ± 12.5 | 59.6 ± 12.6 | 64.4 ± 10.8 | 0.001 | 0.415 |
| Male/female | 250/261 | 205/233 | 45/28 | 0.019 | 0.301 |
| eGFR (ml/min per 1.73 m2), median (IQR) | 15.3 (8.7–28.3) | 15.2 (8.5–28.6) | 17.2 (9.3–27.0) | 0.786 | 0.062 |
| Serum creatinine, μmol/L, median (IQR) | 316.0 (187.6–517.0) | 317.0 (185.8–523.3) | 284.3 (194.8–498.9) | 0.969 | 0.075 |
| Dialysis dependence, n (%) | 122 (23.9) | 107 (24.4) | 15 (20.5) | 0.471 | 0.093 |
| Hematuria, n (%) | 478 (93.5) | 419 (95.7) | 59 (80.8) | <0.001 | 0.483 |
| Urinary protein, g/24 h, median (IQR) | 1.3 (0.7–2.3) | 1.4 (0.7–2.4) | 0.8 (0.5–1.6) | 0.001 | 0.401 |
| Hemoglobin, g/dl, mean ± SD | 9.3 ± 2.0 | 9.3 ± 2.0 | 9.3 ± 1.8 | 0.980 | 0.003 |
| Platelet count, ×109/L, median (IQR) | 248.0 (181.0–323.0) | 235.5 (175.0–315.5) | 317.0 (253.0–401.5) | <0.001 | 0.616 |
| ESR, mm/1 h, mean ± SD | 68.0 ± 39.4 | 64.3 ± 39.3 | 90.8 ± 31.5 | <0.001 | 0.744 |
| CRP, mg/l, median (IQR) | 18.3 (3.1–72.8) | 12.6 (2.5–47.6) | 111.0 (70.5–154.1) | <0.001 | 1.436 |
| D-Dimer, mg/l, median (IQR) | 0.7 (0.3–1.7) | 0.6 (0.3–1.2) | 1.6 (1.0–3.7) | <0.001 | 0.766 |
| FDP, mg/l, median (IQR) | 5.0 (2.5–10.0) | 4.6 (2.3–7.9) | 10.1 (6.9–23.5) | <0.001 | 0.464 |
| ANCA subtypes | 0.025 | 0.289 | |||
| MPO-ANCA, n (%) | 459 (89.8) | 395 (90.2) | 64 (87.7) | ||
| PR3-ANCA, n (%) | 45 (8.8) | 40 (9.1) | 5 (6.8) | ||
| ANCA-negative, n (%) | 7 (1.4) | 3 (0.7) | 4 (5.5) | ||
| Extrarenal involvement | |||||
| Fever, n (%) | 185 (36.2) | 139 (31.7) | 46 (63.0) | <0.001 | 0.660 |
| Myalgia, n (%) | 53 (10.4) | 34 (7.8) | 19 (26.0) | <0.001 | 0.503 |
| Arthralgia, n (%) | 63 (12.3) | 54 (12.3) | 9 (12.3) | 0.82 | 0.001 |
| Weight loss, n (%) | 164 (32.1) | 126 (28.8) | 38 (52.1) | <0.001 | 0.489 |
| ENT involvement, n (%) | 69 (13.5) | 55 (12.6) | 14 (19.2) | 0.125 | 0.182 |
| Ophthalmic involvement, n (%) | 58 (11.4) | 46 (10.5) | 12 (16.4) | 0.139 | 0.175 |
| Pulmonary involvement, n (%) | 212 (41.5) | 180 (41.1) | 32 (43.8) | 0.660 | 0.055 |
| Cardiac involvement, n (%) | 9 (1.8) | 7 (1.6) | 2 (2.7) | 0.623 | 0.078 |
| Gastrointestinal involvement, n (%) | 9 (1.8) | 7 (1.6) | 2 (2.7) | 0.623 | 0.078 |
| Peripheral nervous system involvement, n (%) | 37 (7.2) | 27 (6.2) | 10 (13.7) | 0.021 | 0.254 |
| Cutaneous involvement, n (%) | 19 (3.7) | 15 (3.4) | 4 (5.5) | 0.332 | 0.100 |
| BVAS, mean ± SD | 16.6 ± 5.0 | 16.3 ± 4.9 | 18.2 ± 5.2 | 0.002 | 0.377 |
| Induction therapy | |||||
| GCs combined with CTX, n (%) | 429 (84.0) | 369 (84.2) | 60 (82.2) | 0.658 | 0.055 |
| GCs combined with RTX, n (%) | 51 (10.0) | 43 (9.8) | 8 (11.0) | 0.763 | 0.037 |
| IVMeP, n (%) | 353 (69.1) | 293 (66.9) | 60 (82.2) | 0.009 | 0.357 |
| Plasma exchange, n (%) | 121 (23.7) | 104 (23.7) | 17 (23.3) | 0.924 | 0.012 |
| Renal response to treatment | |||||
| Died within 6 mo, n (%) | 27 (5.3) | 17 (3.9) | 10 (13.7) | ||
| Data unavailable at 6 mo, n (%) | 8 (1.6) | 8 (1.8) | 0 | ||
| Data available at 6 mo, n (%) | 476 (93.1) | 413 (94.3) | 63 (86.3) | 0.002 | 0.507 |
| remission, n (%) | 385 (80.1) | 325 (78.7) | 60 (95.2) | ||
| Treatment failure | 91 (19.9) | 88 (21.3) | 3 (4.8) | ||
| Systemic response to treatment | 0.806 | 0.136 | |||
| Complete recovery, n (%) | 295 (57.7) | 251 (57.3) | 44 (60.3) | ||
| Partial recovery, n (%) | 156 (30.5) | 133 (30.4) | 23 (31.5) | ||
| Treatment resistance, n (%) | 60 (11.7) | 54 (12.3) | 6 (8.2) |
AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; BVAS, Birmingham Vasculitis Activity Score; CRP, C-reactive protein; CTX, cyclophosphamide; eGFR, estimated glomerular filtration rate; ENT, ear, nose, and throat; ESR, erythrocyte sedimentation rate; FDP, fibrin degradation product; GCs, glucocorticoids; IQR, interquartile range; IVMeP, intravenous methylprednisolone pulse; MPO, myeloperoxidase; PR3, proteinase 3; RTX, rituximab; SD, standard deviation; SMD, standardized mean differences.
Patients with AAV_A+ were significantly older at diagnosis than those with AAV_A- (64.4 ± 10.8 vs. 59.6 ± 12.6 years, P = 0.001). There was no significant difference between patients with AAV_A+ and patients with AAV_A− in baseline estimated glomerular filtration rate (eGFR) (17.2 [IQR, 9.3–27.0] vs. 15.2 [IQR, 8.5–28.6] ml/min per 1.73 m2, P = 0.786), serum creatinine (284.3 [IQR, 194.8–498.9] vs. 317.0 [IQR, 185.8–523.3] μmol/l, P = 0.969), and dialysis requirements at diagnosis (20.5% vs. 24.4%, p = 0.471). Compared with patients with AAV_A−, patients with AAV_A+ exhibited a more pronounced systemic inflammation, as indicated by a significantly higher prevalence of fever (63.0% vs. 31.7%, P < 0.001), higher levels of C-reactive protein and erythrocyte sedimentation rate (111.0 [IQR, 70.5–154.1] vs. 12.6 [IQR, 2.5–47.6] mg/l, P < 0.001; 90.8 ± 31.5 vs. 64.3 ± 39.3 mm/1h, P < 0.001; respectively), and higher platelet counts in peripheral blood (317.0 [IQR, 253.0–401.5] vs. 235.5 [IQR, 175.0–315.5] ×109/L, P < 0.001). In addition, patients with AAV_A+ showed significantly more frequent extrarenal involvement, including myalgia (26.0% vs. 7.8%, p < 0.001) and peripheral nervous system involvement (13.7% vs. 6.2%, P = 0.021). Consistently, the Birmingham Vasculitis Activity Score at diagnosis was significantly higher in patients with AAV_A+ than that in patients with AAV_A− (18.2 ± 5.2 vs. 16.3 ± 4.9, P = 0.002).
Renal Histopathology
Renal histopathologic data of patients with AAV with and without renal arteritis were listed in Table 2. Arterial structures were identified in all biopsies. Among those with AAV_A+, arteritis affected interlobular and arcuate arteries in 69 (94.5%) and 9 (12.3%) of 73 patients, respectively. The median number of arterial sections with arteritis was 2 (range, 1–11). Segmental or circumferential fibrinoid necrosis of the arterial wall was identified in 60 (82.0%) patients. Arterial inflammation characterized by mixed lymphocytic, monocytic, and neutrophilic infiltrates was observed in 52 (71.2%) patients, with epithelioid cell and multinucleated giant cell granulomas in 29 (39.7%) patients. Mural or occlusive thrombosis of the arterial wall was noted in 8 (11.0%) patients. In addition to active arteritis, chronic scarred lesions of renal arteries were observed in 16 (21.9%) patients. Representative renal arteritis lesions in these patients are shown in Figure 2.
Table 2.
Pathologic data of patients with AAV with or without renal arteritis
| Variables | Total n = 511 | AAV_A− n = 438 | AAV_A+ n = 73 | P-value | SMD |
|---|---|---|---|---|---|
| Total number of glomeruli, median (IQR) | 27.0 (19.0–35.0) | 27.0 (19.0–36.0) | 24.0 (18.0–32.0) | 0.283 | 0.156 |
| Normal glomeruli (%), median (IQR) | 26.7 (11.1–50.0) | 24.1 (9.7–46.4) | 50.0 (25.0–69.3) | <0.001 | 0.675 |
| Glomeruli fibrinoid necrosis (%), median (IQR) | 0 (0–6.3) | 0 (0–5.3) | 4.2 (0–12.1) | <0.001 | 0.502 |
| Crescent (%), median (IQR) | 56.5 (33.3–75.7) | 58.8 (35.4–76.7) | 40.0 (29.1–66.7) | <0.001 | 0.488 |
| Cellular crescents (%), median (IQR) | 36.4 (20.8–57.7) | 38.3 (21.7–58.3) | 26.1 (16.4–51.9) | 0.041 | 0.234 |
| Fibrous crescents (%), median (IQR) | 5.0 (0–19.4) | 6.1 (0–21.5) | 0 (0–6.0) | <0.001 | 0.389 |
| IF/TA > 25%, n (%) | 262 (51.3) | 231 (52.7) | 31 (42.5) | 0.104 | 0.207 |
| Interstitial infiltrate > 25%, n (%) | 376 (73.6) | 315 (71.9) | 61 (83.6) | 0.037 | 0.283 |
| C3 deposition >1+, n (%) | 190 (37.3) | 176 (40.2) | 14 (19.4) | 0.001 | 0.465 |
| Berden classification | <0.001 | 0.736 | |||
| Focal, n (%) | 135 (26.4) | 96 (21.9) | 39 (53.4) | ||
| Crescentic, n (%) | 168 (32.9) | 148 (33.8) | 20 (27.4) | ||
| Mixed, n (%) | 197 (38.6) | 184 (42.0) | 13 (17.8) | ||
| Sclerotic, n (%) | 11 (2.2) | 10 (2.3) | 1 (1.4) | ||
| AKRiS | 0.011 | 0.340 | |||
| Low, n (%) | 205 (40.1) | 167 (38.1) | 38 (52.1) | ||
| Moderate, n (%) | 138 (27.0) | 119 (27.2) | 19 (26.0) | ||
| High, n (%) | 123 (24.1) | 110 (25.1) | 13 (17.8) | ||
| Very high, n (%) | 45 (8.8) | 42 (9.6) | 3 (4.1) | ||
| ARRS | 0.002 | 0.532 | |||
| Low, n (%) | 124 (24.5) | 102 (23.3) | 22 (30.1) | ||
| Moderate, n (%) | 229 (44.8) | 187 (42.7) | 42 (57.5) | ||
| High, n (%) | 158 (30.9) | 149 (34.0) | 9 (12.3) | ||
| Renal arterial lesions, n (%) | 73 (14.3) | − | 73 (100) | ||
| Fibrinoid necrosis, n (%) | 60 (11.7) | − | 60 (82.0) | ||
| Inflammation, n (%) | 52 (10.2) | − | 52 (71.2) | ||
| Granulomatous, n (%) | 29 (5.7) | − | 29 (39.7) | ||
| Thrombosis, n (%) | 8 (1.6) | − | 8 (11.0) | ||
| Chronic scarred lesions, n (%) | 16 (3.1) | 16 (21.9) |
AAV, ANCA-associated vasculitis; AKRiS, ANCA kidney risk score; ANCA, antineutrophil cytoplasmic antibody; ARRS, ANCA renal risk score; C3, complement 3; IF/TA, interstitial fibrosis and tubular atrophy; IQR, interquartile range; SD, standard deviation; SMD, standardized mean difference.
Figure 2.
Representative renal arteritis lesions in patients with AAV. (a) Fibrinoid necrosis accompanied by palisading, mixed inflammatory infiltrate in an interlobular artery of a patient with MPO-AAV (periodic acid-silver metheramine [PASM]+Masson ×200). (b) Purely necrotizing arteritis in an interlobular artery with scarce inflammatory infiltrate in MPO-AAV (PASM+Masson ×200). (c) Renal arteritis with periarterial granulomatous inflammation in a patient with MPO-AAV (PASM+Masson ×200). (d) Necrotizing arteritis affected an arcuate artery in a patient with PR3-AAV (PASM+Masson ×100). (e) Fibrinoid necrosis in an interlobular artery, along with occlusive thrombosis, in a patient with MPO-AAV (PASM+Masson ×200). (f) Scarred arteritis with fibrous luminal occlusion in a patient with MPO-AAV (PASM+Masson ×200). (g) Distribution of the main arterial lesion patterns in patients with AAV_A+.
In renal histology, the distribution of histopathologic classification proposed by Berden et al.25 was significantly different between patients with AAV_A+ and patients with AAV_A− (P < 0.001). Patients with AAV_A+ were predominantly classified as the focal class, whereas patients with AAV_A− were predominantly categorized as the crescentic or mixed class. Specifically, patients with AAV_A+ were classified as having the focal class in 39 (53.4%) of cases, compared with 96 (21.9%) of patients with AAV_A−. The crescentic class was observed in 20 (27.4%) of patients with AAV_A+ versus 148 (33.8%) of patients with AAV_A−; the mixed class in 13 (17.8%) versus 184 (42.0%), and the sclerotic class in 1 (1.4%) versus 10 (2.3%), respectively (Figure 3a). Consistently, patients with AAV_A+ exhibited a significantly higher proportion of normal glomeruli (50.0% [IQR, 25.0–69.3%] vs. 24.1% [IQR, 9.7–46.4%], P < 0.001) and a lower proportion of crescentic lesions (40.0% [IQR, 29.1–66.7%] vs. 58.8% [IQR, 35.4–76.7%], P < 0.001) in renal specimens compared with patients with AAV_A−. However, a significantly higher proportion of fibrinoid necrosis in glomeruli was observed in patients with AAV_A+ compared with patients with AAV_A− (4.2% [IQR, 0–12.1%] vs. 0% [IQR, 0–5.3%], P < 0.001). Regarding tubulointerstitial lesions, significantly more prevalent inflammatory cell infiltration in tubulointerstitial compartment was observed in patients with AAV_A+ (P = 0.037), whereas no significant difference in tubular atrophy was found between the 2 groups (P = 0.104). These findings indicate that patients with AAV_A+ exhibit distinct histologic features compared with patients with AAV_A−, showing significantly fewer crescentic lesions but more frequent inflammatory and necrotizing injuries.
Figure 3.
Comparison of the distribution of Berden classification, ARRS stratification and AKRiS stratification between patients with AAV with and without renal arteritis. (a) Comparison of the distribution between patients with AAV with and without renal arteritis in Berden classification. (b) Comparison of the distribution between patients with AAV with and without renal arteritis in AKRiS stratification. (c) Comparison of the distribution between patients with AAV with and without renal arteritis in ARRS stratification.
The AKRiS, a recently proposed prognostic model that refines the original ANCA renal risk score (ARRS) by replacing eGFR with serum creatinine and expanding risk stratification from 3 to 4 tiers, has shown improved predictive performance for ESKD in patients with AAV.26,27 In the current study, patients with AAV_A+ and AAV_A− showed a significant difference in the AKRiS risk stratification (P = 0.011). Specifically, 38 (52.1%) of patients with AAV_A+ were classified as low risk, compared with 167 (38.1%) of patients with AAV_A−. Moderate risk was observed in 19 (26.0%) of patients with AAV_A+ versus 119 (27.2%) of patients with AAV_A−; high risk in 13 (17.8%) versus 110 (25.1%); and very high risk in 3 (4.1%) versus 42 (9.6%) (Figure 3b).
Similarly, the distribution of the ARRS, which incorporates the percentage of normal glomeruli, interstitial fibrosis and tubular atrophy, and baseline eGFR, differed significantly between the 2 groups (p = 0.002). Patients with AAV_A+ were predominantly classified as low or moderate risk, whereas patients with AAV_A− showed a higher proportion of high risk according to the ARRS (Figure 3c).
Treatment and Response to Therapy
Treatment regimens were listed in Table 1. For induction therapy, 60 of 73 patients (82.2%) with AAV_A+ and 369 of 438 patients (84.2%) with AAV_A− received corticosteroids in combination with cyclophosphamide therapy. A total of 8 (11.0%) patients with AAV_A+ and 43 (9.8%) patients with AAV_A− received corticosteroids in combination with rituximab therapy. No significant difference was observed in the induction therapy between the 2 groups, with the exception of methylprednisolone pulse therapy, the proportion of which was significantly higher in the AAV_A+ group than that in the AAV_A− group (82.2% vs. 66.9%, P = 0.009).
Regarding renal response to treatment, patients who died within 6 months were excluded since early death precluded this assessment. Ultimately, 476 patients were included for the analysis. Of the remaining 35 patients, 27 died within 6 months and 8 lacked serum creatinine data at that timepoint. At 6 months after initiation of induction therapy, 60 of 63 (95.2%) patients with AAV_A+ achieved renal remission; 3 (4.8%) patients experienced treatment failure. Among 413 patients in the AAV_A− group, 325 (78.7%) achieved renal remission; 88 (21.3%) experienced treatment failure. Compared with patients with AAV_A−, patients with AAV_A+ showed significantly higher rates of renal remission and lower rates of treatment failure (P = 0.002).
No significant difference in systemic response to treatment was found between patients with AAV_A+ and patients with AAV_A− (P = 0.806).
Outcomes
All patients were regularly followed up. A total of 148 (29.0%) patients progressed to ESKD, including 18 (24.7%) patients in the AAV_A+ group and 130 (29.7%) patients in the AAV_A− group, with a median renal survival time of 33.0 (IQR, 11.0–71.0) months. In the whole cohort, the AKRiS, ARRS and the Berden classification were significantly associated with renal survival (Figure 4a–c). The discriminative ability of the AKRiS (concordance index [C-index], 0.810; 95% confidence interval [CI], 0.775–0.845) was significantly higher than that of the ARRS (C-index, 0.771; 95% CI, 0.738–0.805; P = 0.004) and the Berden classification (C-index, 0.639; 95% CI, 0.599–0.679; P < 0.001).
Figure 4.
Comparison of renal survival in the whole cohort stratified by 3 prognostic systems (Kaplan-Meier analysis, log-rank test). (a) Survival according to the AKRiS stratification. (b) Survival according to the ARRS stratification. (c) Survival according to the Berden histopathologic classification.
For the entire cohort, no significant difference in renal survival was observed between patients with and without renal arteritis (log-rank test, P = 0.443) (Figure 5a). However, renal arteritis status was significantly associated with the distribution of risk categories across all 3 prognostic classification systems (Figure 3), with the majority of patients with AAV_A+ being classified into lower risk categories. Nevertheless, patients with AAV_A+ were not associated with favorable renal outcome. These findings suggest that the prognostic impact of renal arteritis may vary across different risk strata. Given the superior discriminative performance of the AKRiS for predicting ESKD compared with the ARRS and the Berden classification, we subsequently performed an interaction analysis to assess whether the prognostic effect of renal arteritis varied across different risk strata within this novel model. Notably, a significant interaction was observed between the renal arteritis status and the AKRiS risk stratification (P for interaction = 0.010, Figure 6). Consistently, subgroup analysis showed that among patients classified as low or moderate risk by the AKRiS, those with AAV_A+ had significantly worse renal survival compared with patients with AAV_A− (log-rank test, P = 0.021) (Figure 5b), whereas this difference did not reach statistical significance among those classified as high risk by the AKRiS (log-rank test, P = 0.075). Thus, we further evaluated the prognostic contribution of renal arteritis to ESKD in patients categorized as low or moderate risk on the basis of the AKRiS. There were 343 patients in this subgroup, encompassing 57 and 286 in the AAV_A+ and AAV_A− group, respectively. A total of 46 (13.4%) patients developed ESKD during follow-up, including 12 (21.1%) and 34 (11.9%) in the AAV_A+ and AAV_A− group, respectively. Univariate survival analysis showed that renal arteritis was associated with an increased risk of ESKD in patients with AAV who were classified as having low or moderate risk according to the AKRiS (P = 0.016; hazard ratio [HR], 2.26; 95 % CI, 1.17–4.37). In addition to renal arteritis, other variables significantly associated with the risk of ESKD included 3 biological variables (baseline eGFR, urinary protein, and hemoglobin), 3 histologic variables (the percentage of normal glomeruli, the percentage of cellular crescents, and C3 deposition in renal specimens), and 2 prognostic classifications (the Berden classification and the AKRiS) (Supplementary Table S1). In addition, clinically relevant covariates, including Birmingham Vasculitis Activity Score and receipt of intravenous methylprednisolone pulse therapy, were also included in the multivariable models, regardless of their statistical significance in the univariable analyses. Due to the strong correlations among variables, including baseline eGFR, the percentage of normal glomeruli, the percentage of cellular crescents, and the 2 prognostic classifications, 2 distinct multivariable models were constructed, the approach used in a previous study.11 Multivariable analysis showed that renal arteritis was independently associated with worse renal outcomes in patients with AAV classified as low or moderate risk according to the AKRiS, after adjustment for the abovementioned predictive factors (P = 0.001; HR, 3.89; 95% CI, 1.71–8.82 in model 1; P < 0.001; HR, 5.24; 95% CI, 2.18–12.63 in model 2) (Table 3). In addition, with death treated as a competing event, a sensitivity analysis using Fine-Gray competing risk regression yielded findings consistent with those of the primary Cox regression analysis (Supplementary Table S2). Consistent findings were observed in the subanalysis in patients with microscopic polyangiitis (n = 436) (Supplementary Table S3).
Figure 5.
Comparison of prognosis between patients with AAV with and without renal arteritis (Kaplan-Meier analysis, log-rank test). (a) Comparison of renal survival in the entire cohort. (b) Comparison of renal survival in the patients categorized as low or moderate risk by AKRiS. (c) Comparison of patients’ overall survival.
Figure 6.
Subgroup analysis of the association between renal arteritis and renal survival (Cox proportional hazards model). The forest plot displays the HR and 95% CI for the risk of ESKD in patients with renal arteritis compared with those without, stratified by different clinical and pathologic characteristics. The P-value for interaction indicates whether the prognostic effect of renal arteritis differs significantly across subgroups. Note the significant interaction between renal arteritis and the AKRiS stratification (P for interaction = 0.010).
Table 3.
Multivariable Cox analysis of ESKD in patients with AAV categorized as low or moderate risk by the AKRiS
| Parameters | Label | Model 1 |
Model 2 |
||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P-value | HR | 95% CI | P-value | ||
| Renal arteritis | Yes vs. No | 3.89 | 1.71–8.82 | 0.001 | 5.24 | 2.18–12.63 | <0.001 |
| Calendar year | Per 1-yr increment | 0.98 | 0.91–1.05 | 0.527 | 0.93 | 0.86–1.01 | 0.053 |
| Age | Per 10-yr increment | 0.95 | 0.75–1.20 | 0.650 | 0.95 | 0.74–1.21 | 0.675 |
| Sex | Female vs. Male | 0.95 | 0.47–1.92 | 0.887 | 0.80 | 0.39–1.64 | 0.535 |
| eGFR | Per 1 ml/min per 1.73 m2 increment | − | − | − | 0.94 | 0.90–0.98 | 0.001 |
| Urinary protein | Per 1 g/24 h increment | 1.43 | 1.21–1.69 | <0.001 | 1.36 | 1.13–1.67 | 0.003 |
| Hemoglobin | Per 1 g/dl increment | 0.91 | 0.75–1.11 | 0.364 | 1.03 | 0.84–1.28 | 0.760 |
| BVAS | Per 1 score increment | 0.98 | 0.91–1.05 | 0.527 | 0.93 | 0.86–1.01 | 0.069 |
| IVMeP | Yes vs. No | 0.80 | 0.40–1.63 | 0.545 | 0.68 | 0.32–1.45 | 0.318 |
| C3 deposition | >1+ vs. ≤1+ | 2.67 | 1.37–5.22 | 0.004 | 2.53 | 1.29–4.96 | 0.008 |
| AKRiS | Moderate vs. Low | 4.35 | 2.17–8.73 | <0.001 | − | − | − |
| Berden classification | − | − | − | − | − | − | 0.002 |
| Focal | − | − | − | Ref. | − | − | |
| Crescentic | − | − | − | 6.98 | 2.32–21.00 | <0.001 | |
| Mixed | − | − | − | 4.23 | 1.34–13.38 | 0.014 | |
| Sclerotic | − | − | − | 15.44 | 2.25–105.74 | 0.005 | |
AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibodies; AKRiS, ANCA renal risk score; BVAS, Birmingham Vasculitis Activity Score; C3, complement 3; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HR, hazard ratio; IVMeP, intravenous methylprednisolone pulse.
Regarding overall survival, after a median follow-up of 43.0 (IQR, 21.0–79.0) months, 127 (24.9%) patients died, including 29 (39.7%) in the AAV_A+ group and 98 (22.3%) in the AAV_A− group. Kaplan-Meier survival analysis revealed that the overall survival was significantly worse in patients with AAV_A+ than in patients with AAV_A− patients (log-rank test, P < 0.001) (Figure 5c). Consistently, univariate survival analysis showed that renal arteritis was significantly associated with a higher risk of all-cause mortality in patients with AAV (P < 0.001; HR, 2.05; 95 % CI, 1.36–3.11). However, this association was attenuated and no longer statistically significant after multivariable adjustment for age, sex, eGFR, Birmingham Vasculitis Activity Score, hemoglobin, intravenous methylprednisolone pulse therapy, and calendar time, stratified by center (P = 0.298; HR 1.27; 95% CI, 0.81–2.00) (Supplementary Table S4). Within the AAV_A+ group, the presence of chronic scarred arterial lesions was not associated with renal survival (P = 0.399; HR, 0.61; 95% CI, 0.20–1.91) or overall survival (P = 0.887; HR, 0.94; 95% CI, 0.41–2.15) (Figure S1).
Internal Validation
Internal validation corroborated the prognostic value of arteritis status for renal outcomes in patients classified as low- or moderate-risk by the AKRiS score. In 1000 bootstrap samples, renal arteritis remained independently associated with ESKD in 84.1% (Model 1) and 89.5% (Model 2) of replicates, with HRs of 3.89 (bootstrap 95% CI, 1.61–9.60) and 5.24 (bootstrap 95% CI, 1.91–18.43), respectively.
Discussion
Although renal arteritis in AAV is increasingly recognized by pathologists, its clinical significance remains incompletely understood. Moreover, the characteristics of patients with AAV with renal arteritis varied across different studies, which may be attributable, at least in part, to differences in ANCA specificity among cohorts. As abovementioned, ANCA specificity differs across populations, with MPO-ANCA is predominant among patients with AAV in China,3, 4, 5 whereas PR3-ANCA is more prevalence in Caucasian patients with AAV, particularly those from northern European regions at high latitudes.6, 7, 8 In this study, we analyzed the clinical and pathologic characteristics of patients with renal arteritis in a large, multicenter cohort of patients with AAV from China. Moreover, we evaluated the prognostic impact of renal arteritis using the novel AKRiS model, which showed superior discriminative performance for ESKD prediction both in our cohort and previous studies.26,27
We found that AAV with renal arteritis was not rare, with a prevalence of 14.3%, which was consistent with previously reports.10, 11, 12, 13, 14, 15, 16, 17 Patients with histologic evidence of renal arteritis were significantly older at diagnosis and presented with more pronounced systemic inflammation and more frequent extrarenal involvement, consistent with previous findings.10,11 In particular, a marked elevation of C-reactive protein was observed in patients with AAV_A+, suggesting that C-reactive protein elevation may reflect inflammatory progression from intraglomerular capillaries to small arteries of the renal parenchyma and/or systemic small vessels.14 The presence of renal arteritis may represent a widespread systemic arteritis associated with increased disease activity of AAV.15
The characteristics of renal injury in patients with AAV_A+ had substantial variability across different studies. Although a recent study conducted by Aendekerk et al.10 in a Dutch cohort reported that patients with AAV_A+ had more severe renal disease, our current study together with a recent retrospective study involving a French cohort by Boudhabhay et al.,11 as well as previous series studies,13,14 showed comparable baseline renal function between patients with AAV_A+ and AAV_A−. Regarding renal histopathology, our findings contrasted with those of Boudhabhay et al.,11 who reported a higher proportion of the mixed class of the Berden histopathologic classification in patients with AAV_A+. In our cohort, however, patients with AAV_A+ exhibited significantly fewer crescentic lesions. This aligned with our previous study including 39 patients with microscopic polyangiitis, showing that crescentic lesions were milder in patients with AAV with arcuate or interlobular arteritis.13 Although Aendekerk et al.10 observed no significant difference in the Berden histopathologic classification, 7 of 25 (28%) patients with AAV_A+ in their study had isolated renal arteritis without GN. It supported that there was a considerable proportion of patients with AAV_A+ without typical crescentic GN. Therefore, in patients with AAV without typical manifestations of crescentic GN, attention should be directed toward renal arteritis, particularly in those with severe renal dysfunction that cannot be explained by glomerular capillary damage.
In both our current and previous studies,13 patients with AAV_A+ showed a better response to immunosuppressive therapy compared with patients with AAV_A−. This may be attributable to a more acute form of renal injury driven by extensive renal arteritis, fewer glomerular capillary lesions, and the more frequent use of intravenous methylprednisolone pulse therapy in the AAV_A+ group. Despite this, the long-term renal outcome was comparable between the 2 groups. This finding was consistent with the recent study by Aendekerk et al.,10 which did not find significant association between renal arteritis and the risk of ESKD. We speculated that, although immunosuppressive therapy alleviates acute inflammation in the small arteries of the renal parenchyma, chronic scarring may develop subsequently. This process leads to persistent glomerular ischemia, ultimately contributing to the decline in renal function. Moreover, we observed that although a substantial proportion of patients with AAV_A+ were classified as low or moderate risk according to the AKRiS, their renal outcomes were not better than those of patients with AAV_A−. It suggests that renal arteritis may contribute to the risk of ESKD, which may be potentially underestimated because of the imbalanced distribution of AKRiS risk categories. Notably, a significant interaction between arteritis status and AKRiS was identified, indicating that the prognostic impact of renal arteritis varies across different risk strata. Subsequent subgroup analyses revealed that, among patients classified as low or moderate risk, the presence of renal arteritis was independently associated with an increased risk of ESKD. Our findings align with the observation by Boudhabhay et al.11 in a French cohort, who reported similar prognostic significance of arteritis specifically in low or moderate risk patients, providing independent validation across geographically distinct populations. Therefore, arteritis status should be considered in risk assessment for AAV patients categorized as low or moderate risk, as the risk of ESKD may be underestimated in those individuals. It also underscores the need for more intensive monitoring and care during follow-up in those patient subgroups with concomitant renal arteritis. Regarding overall survival, patients with AAV_A+ showed poorer outcomes compared with patients with AAV_A−, a finding consistent with those reported by Boudhabhay et al.11 and Aendekerk et al.10 Based on previous findings10,11,13,14 and our own results, patients with AAV with renal arteritis exhibited more pronounced systemic inflammation and more frequent extrarenal involvement. We speculate that systemic small-vessel arteritis may contribute to poorer overall survival, as the arteritis observed on kidney biopsy likely represents only a focal manifestation of a more widespread systemic vasculopathy. However, after multivariable adjustment, arteritis was no longer independently associated with all-cause mortality. Although Boudhabhay et al.28 reported that renal arteritis remained independently associated with all-cause mortality after adjustment for age, sex, extrarenal involvement, and dialysis at diagnosis, the authors also noted that this association between pathologic findings and all-cause mortality should be interpreted cautiously. Differences in patient characteristics, covariate adjustment, and sample size may partly explain these discrepancies, and further studies are warranted to clarify the relationship between renal arteritis and overall survival in AAV.
Our study has several limitations. First, the small sample size of AAV_A+ cases, particularly the limited number of outcome events relative to the number of covariates, may increase the risk of model overfitting. However, the association between renal arteritis and the risk of ESKD in patients classified as low or moderate risk by the AKRiS was further supported by several additional analyses, including bootstrap resampling of the multivariable Cox models and Firth penalized maximum likelihood estimation. Second, arterial lesions in AAV can be focal or segmental; thus, percutaneous kidney biopsy may fail to capture all affected vessels, potentially leading to the misclassification of some patients with AAV_A− who actually had arteritis. Third, because of the retrospective nature of this study, direct evidence of extrarenal arteritis was unavailable, particularly during follow-up, limiting the ability to identify the underlying causes of increased mortality in patients with AAV_A+. Large-scale prospective studies are warranted to address these uncertainties.
Conclusion
In conclusion, AAV with renal arteritis is not rare and represents a distinct clinical and pathologic phenotype in Chinese population. Renal arteritis was independently associated with an increased risk of ESKD in patients classified as low or moderate risk by the AKRiS.
Disclosure
All the authors declared no competing interests.
Acknowledgments
We gratefully acknowledge the Clinical Research Department of Peking University First Hospital for their statistical support and methodological guidance.
Funding
This study is supported by the National key research and development program (2024YFC2510300/2024YFC2510305), National Natural Science Fund (grant numbers 82270754, 81900640, 82090021), National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital, 2024HQ01), Capital’s Funds for Health Improvement and Research (2026-2-4079), Beijing Physician Scientist Training Project (BJPSTP-2024-15), Peking University Clinical Scientist Training Program supported by "the Fundamental Research Funds for the Central Universities" (BMU2024PYJH009).
Data Availability Statement
The data underlying this article will not be made publicly available to protect patient privacy, as required by the Ethics Committee of Peking University First Hospital, the Second Affiliated Hospital of Xi’an Jiaotong University, Peking University Third Hospital, and Peking University Shenzhen Hospital. These data will be shared upon reasonable request to the corresponding author.
Footnotes
Supplementary Methods.
Supplementary References.
Figure S1. Comparison of prognosis between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) A+ patients with and without chronic scarred arterial lesions (Kaplan-Meier analysis, log-rank test).
Table S1. Univariable Cox analysis of ESKD in AAV patients categorized as low or moderate risk by the AKRiS.
Table S2. Multivariable Fine-Gray competing risks regression analysis of ESKD in AAV patients categorized as low or moderate risk by the AKRiS.
Table S3. Multivariable Cox analysis of ESKD in MPA patients categorized as low or moderate risk by the AKRiS.
Table S4. Multivariable Cox regression analysis of all-cause mortality in patients with AAV.
STROBE checklist.
Contributor Information
Su-Fang Chen, Email: chensufang2006@sina.com.
Min Chen, Email: chenmin74@sina.com.
Supplementary Material
Supplementary Methods. Supplementary References. Figure S1. Comparison of prognosis between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) A+ patients with and without chronic scarred arterial lesions (Kaplan-Meier analysis, log-rank test). Table S1. Univariable Cox analysis of ESKD in AAV patients categorized as low or moderate risk by the AKRiS. Table S2. Multivariable Fine-Gray competing risks regression analysis of ESKD in AAV patients categorized as low or moderate risk by the AKRiS. Table S3. Multivariable Cox analysis of ESKD in MPA patients categorized as low or moderate risk by the AKRiS. Table S4. Multivariable Cox regression analysis of all-cause mortality in patients with AAV. .STROBE checklist
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Methods. Supplementary References. Figure S1. Comparison of prognosis between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) A+ patients with and without chronic scarred arterial lesions (Kaplan-Meier analysis, log-rank test). Table S1. Univariable Cox analysis of ESKD in AAV patients categorized as low or moderate risk by the AKRiS. Table S2. Multivariable Fine-Gray competing risks regression analysis of ESKD in AAV patients categorized as low or moderate risk by the AKRiS. Table S3. Multivariable Cox analysis of ESKD in MPA patients categorized as low or moderate risk by the AKRiS. Table S4. Multivariable Cox regression analysis of all-cause mortality in patients with AAV. .STROBE checklist
Data Availability Statement
The data underlying this article will not be made publicly available to protect patient privacy, as required by the Ethics Committee of Peking University First Hospital, the Second Affiliated Hospital of Xi’an Jiaotong University, Peking University Third Hospital, and Peking University Shenzhen Hospital. These data will be shared upon reasonable request to the corresponding author.