Introduction
ANCA-associated vasculitides are systemic autoimmune diseases characterized by small-vessel vasculitis and the frequent positivity of ANCA, usually directed against proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). Granulomatosis with polyangiitis (GPA; Wegener granulomatosis) and microscopic polyangiitis (MPA) are the most common forms of ANCA-associated vasculitis (1); although their clinical phenotypes are different, both frequently affect the kidney, with pauci-immune crescentic GN being their histologic hallmark (2).
ANCA-associated vasculitides are rare and mainly occur in adulthood, with a reported annual incidence of 1.2–2.0 cases per 100,000 (3). In children, their incidence drops to one to six cases per million per year (4,5); given their rarity, large collaborative studies are necessary to define their clinical presentation and outcome (6,7). The phenotype of ANCA-associated vasculitis in children is similar to that observed in adults; for instance, granulomatous lesions involving the respiratory tract occur almost exclusively in GPA, whereas vasculitic manifestations, such as pulmonary capillaritis, are found in comparable proportions of patients with GPA and MPA (6,7). As in adults, kidney involvement in children is frequent and severe. It usually presents as rapidly progressive GN (RPGN), although other kidney syndromes, such as isolated urinary abnormalities and CKD, are not uncommon (8).
Kidney outcome in pediatric, ANCA-associated vasculitis is often unfavorable: 20%–35% of patients reach kidney failure, while another 20%–30% develop CKD (8–12). However, most studies involve a small sample size or short follow-up. In this multicenter study, we analyzed the clinical presentation, kidney histologic findings, long-term outcomes, and prognostic factors of 85 pediatric patients with biopsy specimen–proven ANCA-associated kidney vasculitis managed at tertiary referral centers.
Materials and Methods
Patients
The study included all consecutive in- and outpatients with childhood-onset GPA or MPA and histologic evidence of pauci-immune GN, followed between 1999 and 2018 at the Italian centers and between 2000 and 2020 at the Toronto center (Supplemental Table 1). Of the 31 patients from the Toronto center, seven were new, whereas 24 had been included in a previous study (8); this study reports an extended follow-up for these 24 patients (median follow-up extension, 68 months; range, 0–86 months). Additional data (as compared with those collected in the previous study) were required for these patients to be included (Supplemental Table 1). All patients met the American College of Rheumatology classification criteria (13) or the Chapel Hill Consensus Conference definitions (14) for GPA or MPA, and the European League Against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PRES) criteria for childhood vasculitis (15). Patients with GPA also had to meet the Ankara 2008 criteria endorsed by EULAR/PRES/Pediatric Rheumatology International Trials Organization (16).
The patients were eligible if they were ≤18 years at diagnosis (kidney biopsy), if they had sufficient clinical and laboratory data at diagnosis and during the follow-up, and if their kidney biopsy specimen was adequate for histopathologic classification. Patients with vasculitis secondary to drugs, infections, or systemic autoimmune diseases were excluded. The positivity of ANCA (tested using immunofluorescence or ELISA for PR3 or MPO autoantibodies) was not required for inclusion in the study, provided that the kidney biopsy specimen showed pauci-immune necrotizing crescentic GN.
The study was coordinated by the Meyer Hospital in Florence, Italy; it was approved by the ethics committees of the Meyer Hospital (protocol number, l120/2019) and The Hospital for Sick Children (Toronto, ON, Canada; protocol number, 1000068739); and was conducted in accordance with the Declaration of Helsinki.
Data Collection and Definitions
Data were retrieved from the patients’ electronic records or the archived clinical charts. The main clinical and laboratory data were collected at diagnosis, at month 6, and at last follow-up; we also recorded the time at which remission, relapse, CKD stage 3–5, and kidney failure occurred.
At diagnosis, we collected data regarding organ involvement and laboratory findings, including ANCA, C3, C4, C-reactive protein, serum creatinine, eGFR, 24-hour proteinuria, and urinalysis. Disease activity was assessed using the Pediatric Vasculitis Activity Score (PVAS) (17).
Kidney syndromes or abnormalities at presentation were defined as follows: RPGN indicated a rapid deterioration in kidney function (eGFR decline >50% in up to 3 months) (2); nephrotic-range proteinuria was defined as a urinary protein excretion >3.5 g/m2 per 24 hours; isolated urinary abnormalities included proteinuria or glomerular hematuria (more than three cells per high-power field, red cell casts, or >11 cells/μl on urinalysis). eGFR was calculated using the modified Schwartz formula (18). CKD was staged following the National Kidney Foundation Kidney Disease and Outcome Quality Initiative criteria. Kidney failure was defined as dialysis dependence (evaluated acutely and confirmed after 3 months) or transplantation. Kidney survival indicated the time from diagnosis to kidney failure or last follow-up.
Remission was defined as a PVAS of zero and a dosage of prednisone (or equivalent) of 0.2 mg/kg per day, while relapse was defined as recurrence or new onset of disease activity attributable to active inflammation (19).
Kidney Histopathology
Kidney biopsy specimens were reassessed by the pathologists of each recruiting center and classified as focal, crescentic, sclerotic, or mixed, according to Berden et al.’s (20) classification. Briefly, biopsy specimens with ≥50% normal glomeruli were classified as focal, those with ≥50% of glomeruli showing cellular crescents as crescentic, those with ≥50% sclerotic glomeruli as sclerotic, and those not classifiable in the above categories were classified as mixed.
Statistical Analysis
Continuous variables are presented as mean (SD) or median (interquartile range; IQR), depending on their distribution, and were compared using the t test and the Mann–Whitney U test, respectively. The Kruskal–Wallis test was used for the comparison of medians (range) between more than two groups. Categoric variables were presented as numbers (%) and compared using the Fisher exact test. Variables with >10% of missing data were excluded from the analyses, except for particularly relevant variables (e.g., ANCA).
Median eGFR levels measured at last follow-up were compared according to baseline patient characteristics (e.g., ANCA, histologic class) and treatments, using the Mann–Whitney U or Kruskal–Wallis tests.
Kaplan–Meier curves were derived for the occurrence of (1) kidney failure, (2) kidney failure and/or CKD stage 3–5 (whichever came first), and (3) kidney relapses, according to diagnosis, histologic class, and ANCA specificity. Cox unadjusted and multivariable regression models were used to estimate the risk of the outcomes of interest according to baseline demographic and clinical parameters, and results were reported as crude hazard ratios (HRs) with 95% confidence intervals (95% CIs). In the multivariable model, covariates were included on the basis of their statistical significance at unadjusted analysis; the diagnosis was also included given its clinical relevance. Multicollinearity was tested (by calculating the variance inflation factor) to exclude collinear variables from the multivariable analysis. Statistical analyses were performed using STATA software version 14 (StataCorp). Two-sided P values <0.05 were considered statistically significant.
Results
Clinical, Laboratory, and Kidney Biopsy Specimen Findings
A total of 85 consecutive patients with childhood-onset ANCA-associated vasculitis and histologic proof of ANCA-associated vasculitis-related GN were included. The patients’ main characteristics are reported in Table 1. Most patients were female (65%), and the median (IQR) age at diagnosis was 11 (9–14) years. A total of 53 patients (62%) had MPA and 32 (38%) had GPA. Most patients were perinuclear-ANCA and/or MPO-ANCA positive. There were no substantial differences in the main characteristics of the Italian and Canadian cohorts (Supplemental Table 2). The presentation of kidney manifestations of ANCA-associated vasculitis was usually severe: RPGN was the most common kidney syndrome, occurring in 39% of the patients (Table 2). The median (IQR) eGFR at diagnosis was 36 (16–69) ml/min per 1.73 m2; 91% of the patients had (either micro- or macro-) hematuria, and the median (IQR) level of proteinuria was 1561 (726–2986) mg/m2 per 24 hours; and nephrotic-range proteinuria was found in 28 patients (33%), 25 of whom (89%) had an eGFR of <60 ml/min per 1.73 m2.
Table 1. -
Main characteristics at the time of diagnosis of the 85 patients included in the study
|
|
Kidney Histology Classification |
| Characteristics |
All (n=85) |
Focal/mixed (n=29) |
Crescentic (n=43) |
Sclerotic (n=13) |
| Female sex, n (%) |
55 (65) |
20 (69) |
25 (58) |
10 (77) |
| Age at diagnosis (yr), median (IQR) |
11 (9–14) |
11 (9–15) |
11 (8.5–14) |
11 (10–13) |
| Time from symptom onset to diagnosis (mo), median (IQR) |
2 (0–5) |
3 (1–5.5) |
1 (0–3) |
2 (0–8) |
|
Diagnosis, n (%)
|
|
|
|
|
| MPA |
53 (62) |
18 (62) |
25 (58) |
10 (77) |
| GPA |
32 (38) |
11 (38) |
18 (42) |
3 (23) |
| PVAS, median (IQR) |
27 (20–34) |
26 (21–32) |
29 (22–38) |
24 (19–29) |
|
ANCA by immunofluorescence, n (%)
|
|
|
|
|
| Negative |
12 (14) |
6 (21) |
4 (9) |
2 (15) |
| C-ANCA |
24 (28) |
9 (31) |
13 (30) |
2 (15) |
| P-ANCA |
45 (53) |
13 (45) |
23 (54) |
9 (70) |
| P-ANCA and C-ANCA |
1 (1) |
0 (0) |
1 (2) |
0 (0) |
| Missing |
3 (4) |
1 (3) |
2 (5) |
0 (0) |
|
ANCA by ELISA, n (%)
|
|
|
|
|
| Negative |
11 (13) |
6 (21) |
4 (10) |
1 (8) |
| PR3-ANCA |
21 (25) |
7 (24) |
13 (30) |
1 (8) |
| MPO-ANCA |
38 (44) |
11 (38) |
19 (44) |
8 (61) |
| Missing |
15 (18) |
5 (17) |
7 (16) |
3 (23) |
| C3 <90 mg/dl, patients meeting criterion/patients tested (%) |
10/69 (14) |
3/20 (15) |
4/37 (11) |
3/12 (25) |
| C4 <10 mg/dl, patients meeting criterion/patients tested (%) |
4/40 (10) |
3/14 (21) |
1/19 (5) |
0/7 (0) |
| CRP (mg/dl), median (IQR) |
3.9 (1.2–8.5) |
3 (1.8–8) |
5 (1.9–8.6) |
1.65 (0.8–7.3) |
| Serum albumin (g/dl), median (IQR) |
3.1 (2.7–3.7) |
3.9 (3.5–4.1) |
2.95 (2.6–3.3) |
2.9 (2.6–3.1) |
| eGFR (ml/min per 1.73 m2), median (IQR) |
36 (16–69) |
68 (46–95) |
23 (12–58) |
21 (14–29) |
| Serum creatinine (mg/dl), median (IQR) |
1.6 (0.9–3.7) |
0.9 (0.7–1.3) |
2.62 (1.2–5.1) |
2.9 (1.7–5) |
| Proteinuria (mg/24 h), median (IQR) |
1940 (978–3228) |
1300 (440–2425) |
2800 (1010–3640) |
1855 (1226–3175) |
| Proteinuria (mg/m2 per 24 hours), median (IQR) |
1561 (726–2986) |
928 (342–1825) |
2053 (1187–3044) |
1403 (889–2954) |
| Nephrotic-range proteinuria, n (%) |
28 (33) |
7 (24) |
17 (40) |
4 (31) |
| Hematuria (either micro- or macrohematuria), n (%) |
77 (91) |
26 (90) |
40 (93) |
11 (85) |
IQR, interquartile range; MPA, microscopic polyangiitis; GPA, granulomatosis with polyangiitis; PVAS, Pediatric Vasculitis Activity Score; C-ANCA, cytoplasmic ANCA; P-ANCA, perinuclear ANCA; PR3-ANCA, proteinase 3 ANCA; MPO-ANCA, myeloperoxidase ANCA; CRP, C-reactive protein.
Table 2. -
Main clinical characteristics of the 85 patients with ANCA-associated vasculitis enrolled in the study on the basis of their clinical diagnosis (GPA versus MPA)
|
Clinical Diagnosis |
| Characteristics |
All (n=85) |
GPA (n=32) |
MPA (n=53) |
| Age at diagnosis (yr), median (IQR) |
11 (9–14) |
13 (10–15) |
11 (8–13) |
| Female sex, n (%) |
55 (65) |
19 (59) |
36 (68) |
|
Organ involvement, n (%)
|
|
|
|
| Constitutional symptoms |
64 (75) |
24 (75) |
40 (76) |
| Arthralgias |
27 (32) |
13 (41) |
14 (26) |
| Cardiovascular |
2 (2) |
2 (6) |
0 (0) |
| Skin |
21 (25) |
8 (25.0) |
13 (25) |
| Purpura |
10 (12) |
5 (16) |
5 (9) |
| CNS |
13 (15) |
2 (6) |
11 (21) |
| PNS |
1 (1) |
1 (3) |
0 (0) |
| Eyes |
11 (13) |
11 (34) |
0 (0) |
| ENT |
26 (31) |
17 (53) |
9 (17) |
| Lung |
38 (45) |
21 (66) |
17 (32) |
|
Alveolar hemorrhage
|
11 (13) |
5 (16) |
6 (11) |
|
Nodules and/or infiltrates
|
23 (27) |
13 (41) |
10 (19) |
| GI tract |
22 (26) |
8 (25) |
14 (26) |
|
Kidney involvement
|
|
|
|
| RPGN, n (%) |
33 (39) |
10 (31) |
23 (43) |
| Nephrotic-range proteinuria, n (%) |
28 (33) |
12 (38) |
16 (30) |
| Hypertension, n (%) |
44 (52) |
14 (44) |
30 (57) |
| eGFR (ml/min per 1.73 m2), median (IQR) |
36 (16–69) |
40 (15–74) |
34 (16–62) |
| Proteinuria (mg/m2 per 24 hours), median (IQR) |
1561(726–2986) |
1687 (658–3093) |
1473 (821–2784) |
| Proteinuria (mg/24 h), median (IQR) |
1940 (978–3228) |
1950 (900–3350) |
1660 (1000–3100) |
| Patients on KRT at diagnosis, n (%) |
11 (13) |
2 (6) |
9 (17) |
|
Kidney biopsy class, n (%)
a
|
|
|
|
| Focal |
18 (21) |
7 (22) |
11 (21) |
| Crescentic |
43 (51) |
18 (56) |
25 (47) |
| Sclerotic |
13 (15) |
3 (9) |
10 (19) |
| Mixed |
11 (13) |
4 (13) |
7 (13) |
GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; IQR, interquartile range; CNS, central nervous system; PNS, peripheral nervous system; ENT, ear, nose, and throat; GI, gastrointestinal; RPGN, rapidly progressive GN; KRT, kidney replacement therapy.
aKidney biopsy specimen class was defined according to Berden
et al. (
20).
As in previous pediatric studies (6,7,21), the main patterns of organ involvement in our patients were comparable with those observed in adults (22,23). Ear-nose-throat manifestations (e.g., chronic rhinosinusitis with purulent-bloody nasal discharge), eye involvement (e.g., scleritis, episcleritis, retro-orbital masses), and lung lesions (nodules or infiltrates) were more frequent in GPA than in MPA (Table 2). Conversely, the presentation of kidney clinical manifestations was more severe in MPA than in GPA, as demonstrated by the higher frequency of RPGN and hypertension and lower eGFR in the former, although these differences were not statistically significant. The proportion of patients on KRT at the time of diagnosis also tended to be higher in those with MPA. The distribution of kidney biopsy specimen classes did not significantly differ between MPA and GPA (Table 2).
In contrast with adults, our patients showed a remarkably lower frequency of peripheral neuropathy (1% in our series versus 24%–30% in adult series) (22,23), as shown in other pediatric studies (12).
Treatments and Main Outcomes
All patients received remission-induction therapies: 55% of patients were treated with cyclophosphamide and glucocorticoids; 19% with glucocorticoids alone; and the remaining with different combinations of glucocorticoids, cyclophosphamide, rituximab, and plasma exchange. Maintenance therapy was variable and included glucocorticoids in 91% of patients, while the most-used steroid-sparing agents were azathioprine (52%) and mycophenolate mofetil (31%) (Supplemental Table 3).
The median (IQR) time to kidney failure or last follow-up was 35 (6–89) months in the whole study cohort (55 and 28.5 months for those with GPA and MPA, respectively), and 73 (24–109) months among the patients who did not reach kidney failure; all patients were alive at last follow-up. Of the 85 patients included, 11 (13%) were on KRT at diagnosis, 20 were on KRT at month 6 (24%), and 25 (29%) were on KRT at last follow-up. Of these 25 patients, 19 had MPA and six had GPA, which corresponded to 36% and 19% of the initial patients with MPA and GPA, respectively (Supplemental Table 4). Supplemental Figure 1 shows kidney survival in the whole cohort. In the first 6 months, a steep decline was observed, followed by a prolonged flattening of the curve. The median (IQR) time to kidney failure was 1 (0–6) month among the patients who reached this outcome.
No statistically significant differences in kidney survival were observed with respect to diagnosis or ANCA specificity, although patients with MPA and those positive for MPO-ANCA tended to fare worse than those with GPA and those positive for PR3-ANCA, respectively (Supplemental Figure 1). Conversely, the pattern of histology on the kidney biopsy specimen did have a prognostic effect. Patients with focal and mixed classes had a similar kidney survival (Supplemental Figure 2), therefore, we grouped them together. As compared with focal and mixed cases, those with a sclerotic histology had a significantly shorter kidney survival (HR, 11.80; 95% CI, 2.49 to 55.99), whereas those with a crescentic histology an intermediate prognosis (Figure 1).
;)
Figure 1.: Kidney survival analyses. (A) Kaplan–Meier curves of the time from diagnosis to kidney failure or last follow-up (“kidney survival”) in patients with different kidney histologic classes. (B) Kaplan–Meier curves of the time from diagnosis to CKD stage 3–5/kidney failure in patients with different kidney histologic classes. The plots also report hazard ratios (HR) from unadjusted Cox regression models. Ref., reference category.
The occurrence of CKD followed a pattern similar to that of kidney survival: most of the patients who reached CKD 3–5 did so during the first few months (Supplemental Figure 1). Kidney histology also influenced this outcome, with a poorer survival free of CKD 3–5 in patients with sclerotic histology as compared with those with focal and mixed histology (HR, 8.88; 95% CI, 2.43 to 32.48; Figure 1). The distribution of the different CKD stages at last follow-up on the basis of histologic classes is shown in Figure 2. Proteinuria markedly improved over time, with no overt differences between GPA and MPA (Supplemental Table 4).
Figure 2.: CKD stages at last follow-up in the different histologic classes. Proportions of CKD stages at last follow-up in patients with different kidney histologic classes.
Prognostic Factors of Kidney Outcome
We conducted unadjusted Cox regression analyses to explore the clinical, laboratory, or histologic factors associated with kidney failure or CKD stage 3–5/kidney failure. As shown in Supplemental Table 5, serum creatinine and eGFR at baseline, low serum albumin, hypertension, central nervous system (CNS) involvement, sclerotic or crescentic kidney biopsy specimen patterns, and the use of plasma exchange were all associated with a higher risk of reaching both outcomes. All of these factors defined an aggressive kidney disease, including CNS involvement, which was often due to hypertensive encephalopathy; therefore, their association with a poor kidney outcome is biologically sound. The association with plasma exchange most likely reflected the use of this treatment for patients with severe kidney disease. We also conducted a multivariable analysis, but none of the tested clinical, laboratory, or histologic parameters proved an independent prognostic factor of kidney outcome apart from eGFR, which was, however, intrinsically inter-related with the main outcomes (Supplemental Table 6).
Relapses
After induction therapy, 72 (85%) patients (42 patients with MPA and 30 with GPA) achieved remission, while the remaining 13 were either refractory or not assessable for response. Of these 72 patients, 26 (36%) relapsed (Supplemental Figure 3) and their median (IQR) time to relapse was 20 (10–32) months. Unlike in adults (24), the probability of relapse was not influenced by ANCA specificity, although the sample size was probably not large enough to address this point. Likewise, relapse was not influenced by clinical diagnosis, kidney histopathologic class, or ANCA type (Supplemental Figure 3).
Discussion
ANCA-associated vasculitides are severe autoimmune disorders that rarely occur in childhood, and only a few large studies focusing on prognosis and long-term kidney outcome have been performed in the pediatric population (6–8,11,12,19). In this work, we analyzed the clinical presentation and kidney outcome of the largest pediatric cohort of patients with kidney biopsy specimen–proven ANCA-associated vasculitis reported so far, and identified prognostic indicators of kidney survival. Previous studies had defined the effect of kidney histology on kidney survival, but had not assessed the role of other prognostic factors (8).
The clinical phenotype of our cohort, which comprised 53 patients with MPA and 32 with GPA, confirmed that the presenting features of adult and pediatric ANCA-associated vasculitis are strikingly similar: the prevalence of ear-nose-throat manifestations, eye involvement, and nodular lung lesions (mostly due to granulomatous disease) was higher in those with GPA than in MPA, whereas other manifestations due to small-vessel vasculitis (e.g., skin lesions, alveolar hemorrhage) were equally distributed. CNS manifestations, often resulting from hypertensive encephalopathy, tended to be more frequent among patients with MPA.
Kidney involvement was present in all patients, as per the study eligibility criteria. RPGN was the most frequent kidney syndrome, but a substantial number of patients presented with varying degrees of CKD accompanied by severe proteinuria, which was in the nephrotic range in one third of the cases. Kidney disease was slightly more severe in MPA than in GPA because the former showed a lower eGFR, a higher frequency of RPGN and hypertension, and a higher proportion of patients on KRT at diagnosis. However, these differences failed to reach statistical significance.
The frequencies of the different kidney histologic patterns (defined according to Berden et al.’s [20] classification) in our pediatric cohort also overlapped those reported in adults. In Berden et al.’s (20) original work, on the basis of kidney biopsy specimens from 100 adult patients with ANCA-associated vasculitis (61 patients with MPA and 39 with GPA; a distribution comparable to ours), the proportions of focal, crescentic, sclerotic, and mixed patterns were 16%, 55%, 13%, and 16%, respectively; whereas, in our case, these were 21%, 51%, 15%, and 13%, respectively. The similarity in this distribution is quite impressive, and it is even more remarkable to observe that children, as adults, have a significant proportion of sclerotic histology. Sclerotic lesions in ANCA-related GN were thought to result not only from vasculitis but also from other factors, such as aging, atherosclerosis, dyslipidemia, and a history of hypertension (25,26). The comparable proportion of sclerotic biopsy specimens in children and adults suggests instead that ANCA-associated vasculitis per se is the major determinant of sclerotic kidney lesions.
Traditional immunosuppressive therapies are able to switch off the systemic manifestations of ANCA-associated vasculitis in children; however, a substantial proportion of these children develop kidney failure. Kidney survival among children with ANCA-associated vasculitis varies among the published series, with reported rates of kidney failure of 20%–35% after follow-up periods of different durations (2.4–5.8 years) (8,11,12,27). In our study, the median (IQR) time to kidney failure or last follow-up was 35 (6–89) months in the whole study cohort, and 73 (24–109) months among the patients who remained free of kidney failure. In our cohort, 29% the patients reached kidney failure, despite an appropriate treatment (78% received cyclophosphamide as induction therapy). It is interesting to analyze the kidney survival profiles of our patients: the vast majority of those who developed kidney failure did so very early, as reflected by the extremely short time to kidney failure (median, 1 month; IQR, 0–6 months). Essentially, if our patients did not develop advanced kidney failure within the first few months of diagnosis, they were likely to maintain a good kidney function in the long term. This differs from what is observed in adults, whose risk of kidney failure after ANCA-related RPGN steadily increases over time. As an example, the long-term follow-up analysis of the high-dose Methylprednisolone or Plasma Exchange for severe renal vasculitis trial demonstrated a progressive increase in the cumulative incidence of kidney failure until the sixth year after diagnosis (28). Although the studies performed in adults and children are difficult to compare, this difference in kidney survival profile might suggest that children—if effectively treated—respond better than adults in the long term.
Our study also identified factors associated with kidney survival. eGFR and serum creatinine at baseline proved to be strong prognostic factors at unadjusted analyses, but the presence of hypertension and CNS complications were also significantly associated with kidney outcome. The association between plasma exchange and kidney failure or advanced CKD clearly reflected the use of this treatment in patients with severe disease. Altogether, these findings suggest that a severe kidney involvement at baseline is the most important prognostic indicator of long-term kidney outcome in childhood-onset ANCA-associated vasculitis. Because these factors were probably highly inter-related, none of them emerged as an independent predictor in multivariable analysis. We also showed that kidney histology had a strong prognostic role, as already pointed out by previous studies (8,10,12). In our cohort, patients with sclerotic biopsy specimens had a significantly higher risk of kidney failure than those with focal or mixed biopsy specimens, whereas patients with crescentic biopsy specimens had an intermediate prognosis. Likewise, patients with focal/mixed, crescentic, and sclerotic specimens were associated with a continuum of CKD stages at the end of the follow-up. Therefore, the kidney biopsy specimen emerges as an important guide for tailored therapeutic approaches. It is conceivable that patients with crescentic specimens warrant an aggressive immunosuppressive treatment, whereas those with sclerotic specimens have lower chances of improvement after immunosuppression.
The shortcomings of our study mainly relate to its retrospective nature. Additionally, our cohort—despite being the largest reported so far of kidney biopsy specimen–proven pediatric ANCA-associated vasculitis—was probably not large enough to allow the detection of differences in outcome on the basis of ANCA specificity or clinical diagnoses. Finally, most of our patients were treated with cyclophosphamide-based induction regimens; therefore, our results cannot inform about the outcome after alternative treatments, such as rituximab, which is noninferior to cyclophosphamide in adults (24,29–31) and is likely to be increasingly prescribed in children.
In conclusion, the systemic and kidney phenotype of pediatric ANCA-associated vasculitis is similar to that of its adult counterpart. A substantial proportion of patients with kidney involvement still develop kidney failure, especially in the first few months after diagnosis. Baseline clinical features, kidney function parameters, and kidney histopathology are associated with a long-term kidney prognosis of pediatric ANCA-associated vasculitis.
Disclosures
S. Abu Rumeileh reports being employed by the University of Florence. M. Allinovi reports serving as a member of the editorial board of BMC Nephrology, British Medical Journal Case Reports, and Frontiers in Pharmacology; and being employed by the Nephrology, Dialysis and Transplantation Unit, Careggi University Hospital, Florence, Italy. S. Badalamenti reports being employed by Humanitas Clinical and Research Center. C. Bracaglia reports being employed by Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Bambino Gesù Children’s Hospital and having consultancy agreements with Novartis and Sobi. M. Calatroni reports being employed by Humanitas Research Hospital, Rozzano, Milan, Italy. M.G. Catanoso reports being employed by Azienda Unità Sanitaria Locale/IRCCS Reggio Emilia. B. Crapella reports being employed by Paediatric Nephrology, Dialysis and Transplant Unit, IRCCS Policlinico of Milan, Milano, Italy. P. Esposito reports being employed by Unit of Nephrology, Department of Internal Medicine, University of Genoa. S. Fiasella reports being employed by Ospedale Santa Maria Annunziata. L. Fortunato reports being employed by Unità Sanitaria Locale Toscana Centro. N. Jawa reports being employed by The Hospital for Sick Children. G. Jeannin reports being employed by Spedali Civili Brescia. S. Monti reports being employed by IRCCS Policlinico S. Matteo, University of Pavia. G. Montini reports having consultancy agreements with Alnylam Pharmaceuticals, Bayer, and Kiowa Kyrin and being employed by IRCCS Policlinico of Milan, University of Milan. G. Moroni reports having consultancy agreements with GlaxoSmithKline and being employed by IRCCS Policlinico of Milan. D. Noone reports serving as an editorial board member for CJASN and as an associate editor and section editor for the renal section of Current Pediatric Reports; serving as a chapter medical advisor for Make-A-Wish Canada; and being employed by The Hospital for Sick Children. S. Pastore reports being employed by the Institute for Maternal and Child Health, IRCCS Burlo Garofolo. P. Romagnani reports receiving research funding from AstraZeneca; serving on the editorial board for Journal of Clinical Medicine and Kidney International; and being employed by University of Florence. R. Roperto reports being employed by University Hospital Meyer. G.M. Rossi reports being employed by the University of Parma. C. Salviani reports being employed by Azienda Socio-Sanitaria Territoriale Spedali Civili Brescia. R.A. Sinico reports having consultancy agreements with GlaxoSmithKline Italy and being employed by University of Milano-Bicocca. E. Tombetti reports being employed by Milan University. L. Tomei reports being employed by the University of Florence. A. Vaglio reports being employed by Meyer Children’s Hospital and the University of Florence. R.S.M. Yeung reports serving as a board member of Evaxion Biotech and receiving research funding from Roche as site principal investigator for clinical trial. All remaining authors have nothing to disclose.
Funding
None.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.19181220/-/DCSupplemental.
Supplemental Table 1. Recruiting centers.
Supplemental Table 2. Differences in terms of demographics, diagnosis, and induction treatment between the Italian and Canadian cohorts.
Supplemental Table 3. Main immunosuppressive therapies used for remission induction and maintenance.
Supplemental Table 4. Main kidney parameters at different time points.
Supplemental Table 5. Prognostic indicators of kidney failure and of kidney failure/chronic kidney disease (CKD) stage 3-5 (composite outcome) analyzed using Cox regression models.
Supplemental Table 6. Predictors of kidney failure or kidney failure/chronic kidney disease (CKD) stage 3-5 (composite outcome) analyzed using multivariable Cox regression models.
Supplemental Figure 1. Time to kidney failure or to CKD 3-5/kidney failure, overall and according to diagnosis and ANCA specificity.
Supplemental Figure 2. Kidney survival in the different histological classes.
Supplemental Figure 3. Time to relapse in the whole cohort and based on histological class, diagnosis, and ANCA specificity.
References
1. Chaigne B, Guillevin L: Vasculitis for the internist: Focus on ANCA-associated vasculitis. Intern Emerg Med 12: 577–585, 2017 28623488
2. Sinico RA, Di Toma L, Radice A: Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis. Autoimmun Rev 12: 477–482, 2013 22921791
3. Watts RA, Mahr A, Mohammad AJ, Gatenby P, Basu N, Flores-Suárez LF: Classification, epidemiology and clinical subgrouping of
antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant 30[Suppl 1]: i14–i22, 2015 25805746
4. Calatroni M, Oliva E, Gianfreda D, Gregorini G, Allinovi M, Ramirez GA, Bozzolo EP, Monti S, Bracaglia C, Marucci G, Bodria M, Sinico RA, Pieruzzi F, Moroni G, Pastore S, Emmi G, Esposito P, Catanoso M, Barbano G, Bonanni A, Vaglio A: ANCA-associated vasculitis in childhood: Recent advances. Ital J Pediatr 43: 46, 2017 28476172
5. Grisaru S, Yuen GW, Miettunen PM, Hamiwka LA: Incidence of Wegener’s granulomatosis in children. J Rheumatol 37: 440–442, 2010 20032105
6. Cabral DA, Canter DL, Muscal E, Nanda K, Wahezi DM, Spalding SJ, Twilt M, Benseler SM, Campillo S, Charuvanij S, Dancey P, Eberhard BA, Elder ME, Hersh A, Higgins GC, Huber AM, Khubchandani R, Kim S, Klein-Gitelman M, Kostik MM, Lawson EF, Lee T, Lubieniecka JM, McCurdy D, Moorthy LN, Morishita KA, Nielsen SM, O’Neil KM, Reiff A, Ristic G, Robinson AB, Sarmiento A, Shenoi S, Toth MB, Van Mater HA, Wagner-Weiner L, Weiss JE, White AJ, Yeung RS; ARChiVe Investigators Network within the PedVas Initiative: Comparing presenting clinical features in 48 children with microscopic polyangiitis to 183 children who have granulomatosis with polyangiitis (Wegener’s): An ARChiVe cohort study. Arthritis Rheumatol 68: 2514–2526, 2016 27111558
7. Sacri AS, Chambaraud T, Ranchin B, Florkin B, Sée H, Decramer S, Flodrops H, Ulinski T, Allain-Launay E, Boyer O, Dunand O, Fischbach M, Hachulla E, Pietrement C, Le Pogamp P, Stephan JL, Belot A, Nivet H, Nobili F, Guillevin L, Quartier P, Deschênes G, Salomon R, Essig M, Harambat J: Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: A French nationwide study. Nephrol Dial Transplant 30[Suppl 1]: i104–i112, 2015 25676121
8. Noone DG, Twilt M, Hayes WN, Thorner PS, Benseler S, Laxer RM, Parekh RS, Hebert D: The new histopathologic classification of ANCA-associated GN and its association with renal outcomes in childhood. Clin J Am Soc Nephrol 9: 1684–1691, 2014 25147157
9. Basu B, Mahapatra TK, Mondal N: Favourable renal survival in paediatric microscopic polyangiitis: Efficacy of a novel treatment algorithm. Nephrol Dial Transplant 30[Suppl 1]: i113–i118, 2015 25758433
10. Khalighi MA, Wang S, Henriksen KJ, Bock M, Keswani M, Chang A, Meehan SM: Pauci-immune glomerulonephritis in children: A clinicopathologic study of 21 patients. Pediatr Nephrol 30: 953–959, 2015 25669759
11. Kouri AM, Andreoli SP: Clinical presentation and outcome of pediatric ANCA-associated glomerulonephritis. Pediatr Nephrol 32: 449–455, 2017 27677979
12. Özçelik G, Sönmez HE, Şahin S, Özağarı A, Bayram MT, Çiçek RY, Çakıcı EK, Çomak E, Barut K, Şahin N, Bakkaloğlu S, Gökçe İ, Düzova A, Bilginer Y, Açarı C, Melek E, Kılıç BD, Özdel S, Adroviç A, Kasapçopur Ö, Ünsal E, Alpay H, Orhan D, Topaloğlu R, Düşünsel R, Özen S: Clinical and histopathological prognostic factors affecting the renal outcomes in childhood ANCA-associated vasculitis. Pediatr Nephrol 34: 847–854, 2019 30607566
13. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, Calabrese LH, Fries JF, Lie JT, Lightfoot RW Jr, Masi AT, McShane DJ, Mills JA, Stevens MB, Wallace SL, Zvaifler NJ: The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 33: 1101–1107, 1990 2202308
14. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA: 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum 65: 1–11, 2013 23045170
15. Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, Kawasaki T, Lindsley C, Petty RE, Prieur AM, Ravelli A, Woo P: EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis 65: 936–941, 2006 16322081
16. Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, Buoncompagni A, Lazar C, Bilge I, Uziel Y, Rigante D, Cantarini L, Hilario MO, Silva CA, Alegria M, Norambuena X, Belot A, Berkun Y, Estrella AI, Olivieri AN, Alpigiani MG, Rumba I, Sztajnbok F, Tambic-Bukovac L, Breda L, Al-Mayouf S, Mihaylova D, Chasnyk V, Sengler C, Klein-Gitelman M, Djeddi D, Nuno L, Pruunsild C, Brunner J, Kondi A, Pagava K, Pederzoli S, Martini A, Ruperto N; Paediatric Rheumatology International Trials Organisation (PRINTO): EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis 69: 798–806, 2010 20413568
17. Dolezalova P, Price-Kuehne FE, Özen S, Benseler SM, Cabral DA, Anton J, Brunner J, Cimaz R, O’Neil KM, Wallace CA, Wilkinson N, Eleftheriou D, Demirkaya E, Böhm M, Krol P, Luqmani RA, Brogan PA: Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS). Ann Rheum Dis 72: 1628–1633, 2013 23100606
18. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL: New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20: 629–637, 2009 19158356
19. Morishita KA, Moorthy LN, Lubieniecka JM, Twilt M, Yeung RSM, Toth MB, Shenoi S, Ristic G, Nielsen SM, Luqmani RA, Li SC, Lee T, Lawson EF, Kostik MM, Klein-Gitelman M, Huber AM, Hersh AO, Foell D, Elder ME, Eberhard BA, Dancey P, Charuvanij S, Benseler SM, Cabral DA; ARChiVe Investigators Network within the PedVas Initiative: Early outcomes in children with
antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 69: 1470–1479, 2017 28371513
20. Berden AE, Ferrario F, Hagen EC, Jayne DR, Jennette JC, Joh K, Neumann I, Noël LH, Pusey CD, Waldherr R, Bruijn JA, Bajema IM: Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol 21: 1628–1636, 2010 20616173
21. Belostotsky VM, Shah V, Dillon MJ: Clinical features in 17 paediatric patients with Wegener granulomatosis. Pediatr Nephrol 17: 754–761, 2002 12215830
22. Martorana D, Maritati F, Malerba G, Bonatti F, Alberici F, Oliva E, Sebastio P, Manenti L, Brugnano R, Catanoso MG, Fraticelli P, Guida G, Gregorini G, Possenti S, Moroni G, Leoni A, Pavone L, Pesci A, Sinico RA, Di Toma L, D’Amico M, Tumiati B, D’Ippolito R, Buzio C, Neri TM, Vaglio A: PTPN22 R620W polymorphism in the ANCA-associated vasculitides. Rheumatology (Oxford) 51: 805–812, 2012 22237046
23. Mahr A, Katsahian S, Varet H, Guillevin L, Hagen EC, Höglund P, Merkel PA, Pagnoux C, Rasmussen N, Westman K, Jayne DR; French Vasculitis Study Group (FVSG) and the European Vasculitis Society (EUVAS): Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: A cluster analysis. Ann Rheum Dis 72: 1003–1010, 2013 22962314
24. Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Fessler BJ, Ding L, Viviano L, Tchao NK, Phippard DJ, Asare AL, Lim N, Ikle D, Jepson B, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh K, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Mueller M, Sejismundo LP, Mieras K, Stone JH; RAVE-ITN Research Group: Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 369: 417–427, 2013 23902481
25. Hauer HA, Bajema IM, van Houwelingen HC, Ferrario F, Noël LH, Waldherr R, Jayne DR, Rasmussen N, Bruijn JA, Hagen EC; European Vasculitis Study Group (EUVAS): Renal histology in ANCA-associated vasculitis: Differences between diagnostic and serologic subgroups. Kidney Int 61: 80–89, 2002 11786087
26. Menez S, Hruskova Z, Scott J, Cormican S, Chen M, Salama AD, Alasfar S, Little MA, Safrankova H, Honsova E, Tesar V, Geetha D: Predictors of renal outcomes in sclerotic class anti-neutrophil cytoplasmic antibody glomerulonephritis. Am J Nephrol 48: 465–471, 2018 30472700
27. Hattori M, Kurayama H, Koitabashi Y; Japanese Society for Pediatric Nephrology: Antineutrophil cytoplasmic autoantibody-associated glomerulonephritis in children. J Am Soc Nephrol 12: 1493–1500, 2001 11423578
28. Walsh M, Casian A, Flossmann O, Westman K, Höglund P, Pusey C, Jayne DR; European Vasculitis Study Group (EUVAS): Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int 84: 397–402, 2013 23615499
29. Jones RB, Furuta S, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh M, Westman K, Jayne DR; European Vasculitis Society (EUVAS): Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial. Ann Rheum Dis 74: 1178–1182, 2015 25739829
30. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; European Vasculitis Study Group: Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 363: 211–220, 2010 20647198
31. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group: Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 363: 221–232, 2010 Published online ahead of print. Publication date available at
www.cjasn.org.
