Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the primary types of vasculitis that are associated with anti-neutrophil cytoplasm antibody (ANCA). Renal vasculitis is the most common severe manifestation of ANCA-associated vasculitis (AAV) typically presented with rapidly progressive glomerulonephritis (GN). Dialysis is often needed during the AAV diagnostic phase, although renal recovery and withdrawal from dialysis after treatment may occur. However, treatment per se may cause significant morbidity, and patients with impaired renal function may be particularly prone to treatment-emergent adverse events [
Medication based on cyclophosphamide (CYC) and corticosteroids (CS), which have been used since the 1970s [
Biopsy-proven pauci-immune necrotizing GN is a gold standard for the diagnosis of renal AAV. In 2010, a histopathologic classification with focal, crescentic, mixed, and sclerotic categories of GN in AAV (AAGN) was introduced [
The aim of the present study was to describe the clinical profile at diagnosis and the long-term outcome of newly diagnosed, biopsy-proven renal AAV patients during a follow-up of 20 years at a tertiary clinic. We also assessed prognostic factors, including histological classification, which influence patient and renal survival and relapse.
This longitudinal, retrospective cohort study was performed at the Division of Nephrology at the Helsinki University Hospital. The catchment area was Helsinki and Uusimaa Hospital District with 1.5 million inhabitants. The study was approved by the Department of Internal Medicine of the hospital. Since the data were retrospectively gathered from medical records, informed consent from the patients was not required, and permission from the Ethics Committee was not needed.
All consecutive patients diagnosed with kidney biopsy-proven ANCA-positive vasculitis between 1996 and 2005 were included. The patients were divided into MPA and GPA clinical diagnostic groups according to the European Medicines Agency algorithm [
Patients’ medical records were systematically reviewed from diagnosis until December 31, 2017, death, or loss to follow-up. The time of diagnosis was defined as the date of admission to the Department of Nephrology. The duration of AAV symptoms before diagnosis was recorded as self-reported by the patient. For ANCA-testing, ANCA specificity against myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA) obtained from the enzyme-linked immunosorbent assays (ELISA) were used. A kidney biopsy was performed in all patients within 1 week after admission.
Kidney function was measured using the estimated glomerular filtration rate (GFR) determined by the CKD-EPI formula [
Disease activity and organ involvement in vasculitis were measured using the Birmingham Vasculitis Activity Score (BVAS) [
Renal histology was re-evaluated by a single pathologist (TT) and categorized into four classes of AAGN: (A) focal (at least 50% of glomeruli were normal), (B) sclerotic (at least 50% of glomeruli were sclerotic), (C) crescentic (at least 50% of glomeruli presented with cellular crescents), and (D) mixed (not suitable with previous criteria) [
Induction treatment was administered according to the local treatment protocol based on a combination of CYC and CS. CYC was administered either orally (from 2 mg/kg/d) or intravenously (0.75 g/m2 every 2–3 weeks). CYC was administered for 3–6 months until stable remission was achieved. The initial CS dose was 1 mg/kg/day followed by dose tapering, aiming for 10 mg/day at 6 months. Intravenous pulses of 500–1000 mg methylprednisolone for 3 days were administered in cases exhibiting rapidly deteriorating renal function or other severe manifestation. Plasma exchange was considered for patients with alveolar hemorrhage or severe renal failure (GFR <15 ml/min). The treatment considered individually according to the clinical situation of the patient, taking into account the severity of the disease and the possible risks of the treatment for the patient.
Maintenance treatment was based on azathioprine (AZA) combined with low-dose CS.
The associations between diagnoses and histopathological groups vs. clinical baseline characteristics were assessed using the Kruskal–Wallis and Mann–Whitney
Potential prognostic factors were diagnosis, ANCA specificity, histopathological class, sex, age, proteinuria, GFR, and CYC treatment. Univariate Cox proportional hazard models were used to assess the associations between these potential prognostic factors and the endpoints. Multivariate analyses were then performed to find the most important predictors. The models used the forward-stepping covariate selection procedure. Variables that were significant or almost significant (p<0.10) predictors in univariate models were introduced into the models. At each step, the criterion for entry was p<0.10. The results are expressed as the HR with 95% CI. Friedman’s two-way ANOVA was used to analyze GFR repeated measurements, and Bonferroni corrections were used to analyze the differences between time points. The Mann–Whitney U test was used to test the difference between diagnoses of GPA vs. MPA, and the Kruskal–Wallis test with Bonferroni pairwise corrections was used to test the differences between histopathological subgroups. If the patient was on dialysis, the GFR was estimated using a value of 2.5 (i.e., 5.0/2, where 5.0 was the minimum GFR in nondialysis patients). All statistical tests were two-sided, and P-values <0.05 were considered to be statistically significant. Analyses were performed using IBM SPSS Statistics for Windows (version 25.0, Armonk, NY, USA, IBM Corp.), and figures were created using SigmaPlot version 13.0 (Systat Software, Inc., San Jose California USA).
Overall, 85 patients were diagnosed with ANCA-positive vasculitis with renal biopsy verification. Time from the beginning of the symptoms to diagnosis was 4 months (IQR 2–6), with no significant difference between MPA (median 4, IQR 3–6) and GPA (4, 2–8; p=0.61). Three patients were lost to follow-up within 3 months of diagnosis, and therefore, they were excluded from the follow-up data analysis. The patient flow of the study is presented in Figure
Patient flowchart.
Demographics of the 85 patients at baseline are presented in Table
Baseline characteristics of all patients and diagnostic subgroups.
MPA | GPA | All | |||
---|---|---|---|---|---|
N=47 | N=38 | N=85 | P | ||
Males | 27 (57.4) | 26 (68.4) | 53 (62.4) | 0.30 | |
Age (years) | 62 (28-80) | 52 (22-77) | 58 (22-80) | 0.004 | |
Hypertonia | 14 (29.8) | 8 (21.1) | 22 (25.9) | 0.36 | |
CVD | 8 (17.0) | 3 (7.9) | 11 (12.9) | 0.21 | |
Creatinine ( | 250 (63-2332) | 164 (56-1600) | 208 (56-2332) | 0.02 | |
GFR (ml/min/1.73 m2) | 17 (1-91) | 35 (3-120) | 24 (1-120) | 0.01 | |
ANCA | PR3-ANCA | 6 (12.8) | 34 (89.5) | 40 (47.1) | <0.001 |
MPO-ANCA | 41 (87.2) | 4 (10.5) | 45 (52.9) | ||
BVAS | 15 (11-26) | 19 (5-39) | 17 (5-39) | <0.001 | |
Proteinuria (g/day) | <0.5 | 7 (14.9) | 6 (15.8) | 13 (15.3) | 0.31 |
0.5-3.0 | 26 (55.3) | 26 (68.4) | 52 (61.2) | ||
>3.0 | 14 (29.8) | 6 (15.8) | 20 (23.5) | ||
Organ involvement | Renal | 47 (100) | 38 (100) | 85 (100) | |
General symptoms | 33 (70.2) | 34 (89.5) | 67 (78.8) | 0.03 | |
Lung | 13 (27.7) | 18 (47.4) | 31 (36.5) | 0.06 | |
ENT | 2 (4.3) | 23 (60.5) | 25 (29.4) | <0.001 | |
Skin | 6 (12.8) | 9 (23.7) | 15 (17.6) | 0.19 | |
Eyes/mucous membranes | 3 (6.4) | 11 (28.9) | 14 (16.5) | 0.01 | |
Nervous system | 3 (6.4) | 5 (13.2) | 8 (9.4) | 0.49 | |
Abdominal | 5 (10.6) | 1 (2.6) | 6 (7.1) | 0.22 | |
Cardiac | 2 (4.3) | 0 (0.0) | 2 (2.4) | 0.50 |
Data are presented as the median (range) for continuous nonnormal variables and as the number (%) for categorical variables.
GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis (including two patients with renal limited vasculitis); CVD, cardiovascular disease; GFR, glomerular filtration rate; ANCA, anti-neutrophil cytoplasmic antibody; PR3, proteinase 3; MPO, myeloperoxidase; BVAS, Birmingham vasculitis activity score; ENT, ear, nose, and throat.
Within 1 month after diagnosis, 13 patients (15.3%) were on dialysis with no difference between MPA and GPA (17.0% vs. 13.2%, p=0.62). Renal function did not correlate with the duration of symptoms before diagnosis (Rho 0.16, p=0.14).
A renal histology report was available for 84 patients. The median number of glomeruli in the biopsy was 15 (range, 8–50). The patient distribution across the AAGN classes was as follows: 34.5% (29/84) were focal, 26.2% (22/84) were crescentic, 19.0% (16/84) were sclerotic, and 20.2% (17/84) were mixed. The histopathological classes according to diagnosis and ANCA specificity are shown in Table
(A) Histopathological class of AAV in renal biopsies according to diagnosis and ANCA specificity. (B) Baseline characteristics of patients per histopathological class.
Histopathological class of AAV in renal biopsies | ||||||||
---|---|---|---|---|---|---|---|---|
Focal | Crescentic | Sclerotic | Mixed | All | ||||
N=29 | N=22 | N=16 | N=17 | N=84 | P | |||
(A) | Diagnosis | MPA | 11 (23.9) | 10 (21.7) | 14 (30.4) | 11 (23.9) | 46 | |
GPA | 18 (47.2) | 12 (31.6) | 2 (5.3) | 6 (15.8) | 38 | 0.01 | ||
ANCA | MPO | 10 (22.7) | 9 (20.5) | 14 (31.8) | 11 (25.0) | 44 | 0.003 | |
PR3 | 19 (47.5) | 13 (32.5) | 2 (5.0) | 6 (15.0) | 40 | |||
| ||||||||
(B) | Males | 17 (58.6) | 15 (68.2) | 11 (68.8) | 9 (52.9) | 52 (61.9) | 0.71 | |
GFR, ml/min/1.73 m2 | 60 | 14 | 12 | 21 | 24 | <0.001 | ||
Age, years | 55 | 50 | 67 | 60 | 58 | 0.02 | ||
Proteinuria >3 g/day | 2 (6.9) | 4 (18.2) | 8 (50.0) | 5(29.4) | 19 (22.6) | 0.01 |
Data are presented as the median (range) for continuous nonnormal variables and as the number (%) for categorical variables.
AAV, ANCA-associated vasculitis; ANCA, anti-neutrophil cytoplasmic antibody; MPA, microscopic polyangiitis (including two patients with renal limited vasculitis); GPA, granulomatosis with polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3; GFR, glomerular filtration rate.
The median follow-up time was 16.2 years (95% CI 14.9-17.7). All patients, except two who died early, attained remission within a median time of 3 months (range 1–12).
Most of the patients (81.7%, 67/82) were initially treated with a combination of CYC and CS. CYC was administered intravenously to 61.2% (41/67) and orally to 38.8% (26/67) of the patients. The median cumulative CYC oral dose was 13250 mg (IQR, 7350–20900) and 9500 mg (7000–12000) for the cumulative CYC intravenous dose (p=0.01). In addition, 8.5% of the patients were treated with plasmapheresis, and 3.7% were administered intravenous immunoglobulins. AZA and CS or CS alone were used for remission induction in 11.0% and 4.9% of the patients, respectively.
In general, the patients who were not treated with CYC were older than those treated with CYC (median 71 vs. 53 years, p<0.001), had lower GFR (four patients needed dialysis; GFR 15 vs. 27ml/min, p=0.09) and renal histology was either dominated with sclerotic features or without active vasculitic lesions. Among the MPA patients, 68.9% (31/45) and 97.3% (36/37) of GPA patients were treated with CYC (p=0.001). CYC treatment was associated with histology (p=0.003) as follows: 53.3% of the patients with sclerotic AAGN, 82.4% with mixed AAGN, 85.2% with focal AAGN, and 100% with crescentic AAGN were treated with CYC (sclerotic vs. crescentic AAGN, p=0.002).
Maintenance therapy was administered to 96.3% (77/80) of the patients. The most common combination was AZA and CS in 79.2% (61/77) of the patients. Other maintenance medications used were CS alone in 10.4% or in combination with mycophenolate mofetil (MMF) in 5.2% or CYC in 3.9% of the patients.
The cumulative patient survival after 20 years was 45% (95% CI 31.2-59.2%) as shown in Figure
(a) Kaplan-Meier patient survival curve for all patients. (b) Kaplan-Meier patient survival curve for ANCA subgroups. The univariate Cox proportional hazards model: HR (95% CI) 2.67 (1.37-5.19), p=0.004, when the MPO-ANCA-positive patients were compared to PR3-ANCA-positive patients.
The median survival time was 18.2 years (95% CI 13.2-23.2). The results from the univariate and multivariate Cox regression analysis predicting patient survival are presented in Table
Diagnostic, histological, and clinical factors to predict patient survival, renal survival, and relapse-free survival (N=82).
Univariate analysis | Multivariate analysis | |||||
---|---|---|---|---|---|---|
Endpoints | Predictors | HR (95% CI) | P | HR (95% CI) | P | |
Patient survival | Dg MPA | 2.71 (1.37-5.35) | 0.004 | |||
ANCA MPO | 2.67 (1.37-5.19) | 0.004 | 2.12 (1.08-4.17) | 0.03 | ||
Histopathological class | Focal | 0.29 (0.12-0.69) | 0.005 | |||
Crescentic | 0.26 (0.10-0.67) | 0.006 | ||||
Mixed | 0.69 (0.30-1.59) | 0.38 | ||||
Female | 0.67 (0.34-1.32) | 0.25 | ||||
Age ≥58 years | 8.50 (3.84-18.79) | <0.001 | 7.64 (3.44-16.95) | <0.001 | ||
Proteinuria >3g/d | 0.94 (0.43-2.04) | 0.87 | ||||
GFR <30ml/min/1.73m | 2.08 (1.07-4.04) | 0.03 | ||||
Treatment with CYC | 0.42 (0.20-0.88) | 0.02 | ||||
| ||||||
Renal survival | Dg MPA | 2.71 (1.13-6.52) | 0.03 | |||
ANCA MPO | 3.17 (1.31-7.64) | 0.01 | 3.10 (1.21-7.95) | 0.02 | ||
Histopathological class | Focal | 0.11 (0.03-0.41) | 0.001 | |||
Crescentic | 0.32 (0.11-0.90) | 0.03 | ||||
Mixed | 0.49 (0.18-1.33) | 0.16 | ||||
Female | 0.36 (0.14-0.96) | 0.04 | 0.26 (0.10-0.73) | 0.01 | ||
Age ≥58 years | 2.50 (1.10-5.71) | 0.03 | ||||
Proteinuria >3g/day | 2.46 (1.08-5.60) | 0.03 | ||||
GFR <30ml/min/1.73 | 5.63 (1.92-16.49) | 0.002 | 4.10 (1.35-12.49) | 0.01 | ||
Treatment with CYC | 0.43 (0.18-1.04) | 0.06 | ||||
| ||||||
Relapse free | Dg MPA | 0.48 (0.28-0.82) | 0.01 | 0.48 (0.28-0.82) | 0.01 | |
survival | ANCA MPO | 0.59 (0.34-1.01) | 0.05 | |||
Histopathological class | Focal | 1.29 (0.54-3.08) | 0.56 | |||
Crescentic | 1.82 (0.75-4.41) | 0.19 | ||||
Mixed | 1.07 (0.40-2.82) | 0.90 | ||||
Female | 1.19 (0.70-2.02) | 0.53 | ||||
Age ≥58 years | 0.70 (0.41-1.20) | 0.20 | ||||
Proteinuria >3g/d | 0.75 (0.38-1.49) | 0.42 | ||||
GFR <30ml/min/1.73m | 0.59 (0.35-1.00) | 0.05 | ||||
Treatment with CYC | 2.04 (0.92-4.52) | 0.08 |
Reference groups:
Changes of GFR during the follow-up are shown in Figure
(a) Median GFR during follow-up in diagnostic groups GPA and MPA. For up to 5 years, the difference between the diagnostic groups was significant (p<0.02, Mann–Whitney U test). (b) Median GFR during follow-up in renal histology categories. For up to 5 years, the difference between histology categories was significant (p≤0.001, Kruskal–Wallis test), and the Bonferroni-corrected pairwise comparisons detected a significant difference between the focal and sclerotic AAGN (p<0.001). The error bars indicate the interquartile range.
Among the 13 patients who were on dialysis within 1 month after diagnosis, five had reversible renal failure and were withdrawn from dialysis. Overall, 25 patients developed ESRD. One-year renal survival was 84% (95% CI 76.2-97.0), 5-year was 79% (95% CI 70.1-87.9) and 10-year was 71% (95% CI 60.5-80.8). After 10 years, two cases of ESRD occurred, with the last one at 11.3 years. The overall renal survival was 68% (95% CI 57.1-78.2) (Figure
(a) Kaplan-Meier renal survival curve for all patients. (b) Kaplan-Meier renal survival curve for histology groups. The univariate Cox proportional hazards model HR (95% CI) 0.11 (0.03-0.41), p=0.001 in focal; 0.32 (0.11–0.90), p=0.03 in crescentic; and 0.49 (0.18–1.33), p=0.16 in mixed AAGN when sclerotic AAGN was included as a reference. (c) Kaplan-Meier for renal survival for ANCA subgroups. The univariate HR (95% CI) was 3.17 (1.31-7.64), p=0.01, when the MPO-ANCA-positive patients were compared to PR3-ANCA-positive patients. (d) Kaplan-Meier renal survival curves for female and male. The univariate Cox proportional hazards model: HR (95% CI) 0.36 (0.14-0.96), p=0.04, when the female patients were compared to male patients.
The renal survival rate according to histopathological class was as follows: 88.1% in focal, 70.6% in crescentic, 55.8% in mixed and 37.3% in sclerotic AAGN (p=0.01, Figure
The results from univariate and multivariate Cox regression analyses predicting renal survival are presented in Table
To elucidate the possible reasons for the better renal survival in women, we made a post hoc analysis regarding the gender-specific differences and the following variables were included: age, ANCA specificity, AAGN class, diagnostic delay, baseline GFR, proteinuria (≤3g/day vs. >3g/day) and treatment with CYC (or no CYC). However, no significant differences between men and women were found.
As the incidence of ESRD was highest within the first year after diagnosis, we also analyzed the potential risk factors for progression to ESRD more than 1-year after diagnosis. For that purpose, the predictive effects of the following variables on renal survival were analyzed: gender, age, ANCA specificity, diagnosis, AAGN class, proteinuria, and treatment with CYC and GFR at 12 months. Only GFR <30ml/min at 12 months was found to be predictive for renal survival (HR 13.72, 95% CI 4.26-44.16; p<0.001).
Relapse-free survival was 47% (95% CI 36.1-58.4) at 5 years. Thereafter, 10-year relapse-free survival was 30% (95% CI 19.1-40.8), 15-year was 26% (95% CI 15.0-36.6%), and 20-year was as low as 10% (95% CI 0.0-24.7) (Figure
(a) Kaplan-Meier survival curve for relapse-free survival for all patients. (b) Kaplan-Meier survival curves (time without relapse) for GPA and MPA. The univariate Cox proportional hazards model: HR (95% CI) 0.48 (0.28–0.82), p=0.01, when the MPA patients were compared to GPA patients.
The overall median time to first relapse was 4.6 years (95% CI 3.0-6.2). In patients with GPA, the relapse-free survival was shorter than in patients with MPA (3.4 years, 95% CI 1.3-5.5 vs. 5.9 years, 95% CI 0.9–10.9; HR 0.48, 95% CI 0.28–0.82; p=0.01). Diagnosis was the only significant predictor of relapse-free survival in the multivariate analysis (Table
At the first relapse, 55.4% (31/56) of the patients were without immunosuppression, whereas no relapse occurred in patients on CYC treatment. Of the relapsing patients, 35.7% (20/56) used AZA (with or without GC) at the time of relapse and 8.9% (5/56) were taking only GC. Overall, CYC treatment was not predictive for relapse-free survival (Table
During the 20-year follow-up, 56 patients (68.3%) had at least one relapse. Of all relapsing patients, 57.1% (32/56) had more than one relapse, and the total number of relapses was 129. Of all relapses, 40.3% included renal activity.
AZA combined with GC was used as a relapse treatment in 41.1%, CYC in 23.3%, GC alone in 13.9%, MMF in 12.4%, and methotrexate or cyclosporine in 2.3% of the relapses. From the year 2011 onward, the relapses of five patients (nine relapses altogether) were treated with rituximab (RTX).
This study presents the clinical pattern at diagnosis and the outcome of a 20-year follow-up in patients with renal AAV confirmed with kidney biopsy from a single tertiary center. Twenty-year patient and renal survival were 45% and 68%, respectively. As expected, patient survival was influenced by older age and renal survival by lower GFR. Both patient and renal survival were negatively determined by MPO-ANCA subtype. Furthermore, we found that female sex was related to favorable renal survival. Twenty-year relapse-free survival was 10%, and relapse was more common in patients with GPA.
In our cohort, MPA was more common than GPA. Accordingly, 87% of MPA patients were MPO-ANCA-positive, and 89% of GPA patients were PR3-ANCA-positive. The catchment area of our study was Helsinki and its surroundings in southern Finland, North Europe. Thus, we cannot confirm the observation that GPA or PR3ANCA vasculitis would have a higher incidence in the north [
The diagnostic delay of 4 months was equivalent in MPA and GPA. This is consistent with recent studies reporting a shortening of the gap between the start of symptoms and diagnosis [
Since the introduction of the histopathological classification of AAGN in 2010 [
Survival of AAV patients has improved continually over the past decades [
One explanation for our relatively good long-term patient survival might be the rather low cumulative dose of CYC, which was high enough to induce remission but low enough to minimize complications and mortality. In addition, patient survival is due to good renal survival and short diagnostic delay. The fact that all patients had biopsy-confirmed renal vasculitis comprises a selection bias and may overestimate the patient survival but also confirms that all patients had a severe form of AAV.
Despite improved patient survival over the past decades, the relapse risk has remained high [
The strengths of our study are the long follow-up time of 20 years and the diagnosis based on renal biopsy in all patients. The limitations of our study are the retrospective nature and the relatively small number of patients. Also, renal histology was reviewed by a single pathologist.
In our cohort of renal AAV, a younger age was related to a favorable patient survival, and better GFR at diagnosis was related to improved renal survival, as may be anticipated. MPO-ANCA was a negative predictor of both patient and renal survival. Patients with GPA were more prone to relapse than MPA patients. In addition, we observed that AAGN classification was predictive, as the risk of progressing to ESRD increased with the ascending category of focal, crescentic, mixed and sclerotic AAGN. However, in the multivariate model, the histological class was not associated with renal-free survival. Our cohort confirms the data showing improved patient survival but constantly high relapse risk also in renal patients. The ongoing challenge is to define the factors associated with a higher relapse risk and individualize the maintenance therapy accordingly.
The data used to support the findings of this study are available from the corresponding author upon request.
All authors report no conflicts of interest.
Anna Salmela was financially supported by the Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital, Medical Society of Finland (Finska Läkaresällskapet), Kidney Foundation in Finland, Medical foundation of Vaasa, and Jussi Lall’s and Eeva Meripori-Lall’s Foundation.