Introduction
Kidney involvement is the most common severe manifestation of ANCA-associated vasculitis, occurring in 60%–80% of patients during the course of the disease, with a higher frequency in microscopic polyangiitis (MPA) than in granulomatosis with polyangiitis (GPA) (1
Immunosuppressive therapies have transformed the outcome of ANCA-associated vasculitis to that of chronic relapsing disorders. Current survival rates now reach 84% in MPA (2 3 4 5 6
Risk of vasculitis relapse, especially in patients with GPA, leads to the maintenance of immunosuppressive therapy for at least 2 years (7–9 10 11 12
Infections are a major cause of morbidity and mortality both in patients with vasculitis (13 14 15 16 17 infections were twice as frequent in patients on maintenance immunosuppression (11
In a previous work using data from the French national registry Renal Epidemiology and Information Network (REIN), we showed an overall survival of patients with ANCA-associated vasculitis similar to that of matched patients on dialysis but with a higher proportion of infectious deaths (6
Materials and Methods
Objectives
The objectives of this study were (1 ) to investigate the proportion of patients in remission off immunosuppression during follow-up on dialysis and to compare patients with GPA with patients with MPA; (2 ) to analyze the overall and event-free survival of patients remaining on dialysis and determine their causes of death; (3 ) to analyze the cumulative incidence of vasculitis relapses on dialysis and the characteristics of relapsing patients; (4 ) to analyze the cumulative incidence of serious infections and cardiovascular events on dialysis; and (5 ) to compare the rates of vasculitis relapse, serious infections , cardiovascular events, and cancers before and after dialysis initiation.
Ethics
The national ethics committee (Commission National Informatique et Liberté) approved the data collection conducted by REIN, and this study was approved by the scientific committee of REIN. It was conducted according to the principles of the Declaration of Helsinki and its amendments. No informed consent is required to participate in the REIN registry.
Patients
All adult patients with kidney failure secondary to GPA or MPA who started long-term dialysis (hemodialysis or peritoneal dialysis) in France between 2008 and 2012 were included using data from REIN. Patients who could not be paired with data from the French National Health System were excluded.
Data Collection
REIN is a comprehensive national registry of patients who start KRT in France (18
In order to gather data from the National Health System, a pairing algorithm was used for the correspondence of anonymous patients with REIN, as previously described (19
The National Health System database, accessible upon request from 2006, provides information from reimbursement of prescribed drugs and the coding of health care institution activity at hospital discharge. The main diagnoses retained for each hospital stay, the length of hospital stay, and the consumption of immunosuppressive therapies and corticosteroids were collected. The causes of hospital admission were identified by the main and secondary diagnosis coding (the International Classification of Diseases, 10th edition coding system is detailed in Supplemental Table 1
The comprehensive collection of data was initiated 1 year prior to dialysis initiation or at the time of vasculitis diagnosis, whichever was closer to dialysis initiation. Patients were followed up until kidney transplantation, death, loss of follow-up, recovery of kidney function, or end of the study in December 2017, whichever occurred first.
Extent of missing data is specified in Table 1 . Data concerning patients’ treatments and hospital stays were comprehensive in the National Health System database. Only one patient from the cohort was lost to follow-up after 1.6 years.
Table 1. -
Characteristics of patients with ANCA-associated vasculitis from this cohort at the time of dialysis initiation
Characteristics
All Patients, n =229
Granulomatosis with Polyangiitis, n =142
Microscopic Polyangiitis, n =87
Age, yr
66±13
67±13
66±14
Sex, male
139 (61)
84 (59)
55 (63)
Body mass index, kg/m2
24±5
24±4
25±5
Kidney biopsy
181 (79)
111 (78)
70 (81)
Listed for kidney transplantation
100 (43)
69 (49)
31 (36)
Diabetes
49 (21)
29 (20)
20 (23)
Heart failure, n =225
29 (13)
16 (12)
13 (15)
Cardiac arrhythmia, n =228
34 (15)
22 (16)
12 (14)
Peripheral artery disease, n =225
16 (7)
9 (7)
7 (8)
Cerebrovascular disease, n =227
26 (11)
14 (10)
12 (14)
Coronary artery disease, n =227
32 (17)
16 (12)
16 (18)
Chronic respiratory disease, n =228
30 (13)
9 (6)
21 (24)
Chronic liver disease, n =225
5 (2)
2 (1)
3 (3)
Evolutive cancer, n =225
16 (7)
13 (10)
3 (3)
Behavioral disease, n =219
3 (1)
2 (1)
1 (1)
Vasculitis vintage, yr, n =198
1.7±1.9
1.8±2.0
1.6±1.8
Cause of kidney failure
First flare of ANCA-associated vasculitis
88 (38)
54 (38)
34 (39)
Relapse of ANCA-associated vasculitis
50 (22)
30 (21)
20 (23)
Progression of CKD
91 (40)
58 (41)
33 (38)
Peritoneal dialysis
11 (5)
5 (3)
6 (7)
Hemodialysis
218 (95)
137 (97)
81 (93)
Vascular access, n =192
Native arteriovenous fistula
69 (36)
38 (32)
31 (42)
Prosthetic arteriovenous fistula
2 (1)
1 (1)
1 (1)
Tunnelized catheter
98 (51)
62 (53)
36 (49)
Other
23 (12)
17 (14)
6 (8)
Dialysis initiation in emergency
85 (37)
52 (37)
33 (38)
Dialysis initiation on a catheter
159 (69)
101 (71)
58 (67)
Immunosuppressive therapy
189 (83)
117 (82)
72 (83)
Corticosteroids <7.5 mg/d
29 (13)
17 (12)
12 (14)
Corticosteroids ≥7.5 mg/d
46 (20)
23 (16)
23 (26)
Corticosteroids + intravenous therapy
65 (28)
40 (28)
25 (29)
Corticosteroids + azathioprine
24 (11)
20 (14)
4 (5)
Corticosteroids + mycophenolate
12 (5)
9 (6)
3 (3)
Other
13 (6)
8 (6)
5 (6)
In the case of missing data, the number of patients for whom data were available is indicated in the first column. Data are expressed as n (%) or as mean ± SD.
Definitions
Patients were considered “in remission off immunosuppression” at a given time if they were taking <7.5 mg/d of prednisone with no other current immunosuppressive therapy, received no intravenous immunosuppressive therapy (cyclophosphamide or rituximab) in the past 6 months, and had no subsequent vasculitis relapse within 6 months.
Vasculitis relapses were defined as serious if requiring hospitalization and nonserious if the patient only received increased doses of corticosteroids or immunosuppressive therapy.
Serious infections and cardiovascular events were defined as events requiring hospitalization. Cancers were defined by hospital codes for neoplastic disease.
Event-free survival was defined as survival on dialysis without death, relapse, serious infection, or cardiovascular event.
The date of diagnosis of ANCA-associated vasculitis was identified as the first hospitalization with this diagnosis from 2006 to 2012. These data were missing for patients diagnosed before 2006.
The initiation of long-term dialysis was considered to result from a first vasculitis flare (new-onset vasculitis leading to kidney failure within 6 months), from a vasculitis relapse (kidney relapse leading to kidney failure within 6 months), or from the progression of CKD (without evidence of active vasculitis for at least 6 months).
Statistical Analyses
For descriptive factors, results were expressed as frequencies and percentages for categorical variables. Means and SDs were used for continuous variables with symmetrical distribution. Results were compared using the t test for quantitative variables and the Fisher test for qualitative variables.
Patients' trajectories were reconstructed month by month by including information on treatment. After dialysis initiation, this trajectory was truncated when the patient received a kidney transplant. The proportion of patients in remission off immunosuppression was plotted with a time step of 1 month from −12 months up to 60 months.
For each patient, the total time at risk was calculated for the period before and after dialysis initiation. Incidence rates for each event were calculated as the ratio of the number of events to the total patient-years at risk for the period.
Cumulative incidence rates and their 95% confidence intervals (95% CIs) were obtained with the SAS macro %cuminc (20 20
Results
Baseline Characteristics of the Population at the Initiation of Dialysis
We identified 272 incident patients with ANCA-associated vasculitis registered in REIN between 2008 and 2012, of whom 230 (85%) were paired with the National Health System database. The final cohort comprised 229 patients (142 with GPA and 87 with MPA) (Figure 1 ). There was no difference in the characteristics of patients from REIN who could or could not be paired. Baseline characteristics of the 229 patients are detailed in Table 1 .
Figure 1.: Flow chart of the study population. REIN, Renal Epidemiology and Information Network.
Proportion of Patients with Antineutrophil Cytoplasmic Antibody–Associated Vasculitis in Remission off Immunosuppression
At dialysis initiation, 23% of patients responded to the definition criteria of remission off immunosuppression (Figure 2A ). This proportion increased to 42%, 53%, and 62% after 1, 3, and 5 years of dialysis, respectively.
Figure 2.: The proportion of patients with ANCA-associated vasculitis in remission off immunosuppression increased after dialysis initiation. Proportion of patients in remission off immunosuppression before and after dialysis initiation, in all patients (A) and in patients with granulomatosis with polyangiitis (GPA) (B). Data are expressed as percentage (95% confidence interval). *P =0.05 for the comparison of GPA versus microscopic polyangiitis (MPA).
The proportion of patients with MPA in remission off immunosuppression increased from 25% to 50%, 63%, and 73% at 0, 1, 3, and 5 years of dialysis, respectively (Figure 2B ). The proportion of patients with GPA in remission off immunosuppression increased from 22% to 37%, 47%, and 56% at 0, 1, 3, and 5 years of dialysis, respectively, lower than in MPA (Figure 2B ).
Overall Survival on Dialysis
The mean follow-up period for the 229 patients after dialysis initiation was 4.6±2.7 years. During this time, 82 (36%) patients received a kidney transplant (Figure 1 ). Among the 147 patients who remained on dialysis, 107 (73%) died after a median of 2.4 years. The comparison of baseline characteristics of patients who received a kidney transplant during the follow-up versus those who did not is detailed in Supplemental Table 2
Survival rates on dialysis at 1, 3, and 5 years were 86% (95% CI, 81 to 90), 69% (95% CI, 63 to 75), and 62% (95% CI, 55 to 68), respectively (Figure 3A ), with no difference between GPA and MPA (Figure 3B ).
Figure 3.: Survival analyses after dialysis initiation. (A) Overall survival in all patients. (B) Overall survival in patients with GPA and in patients with MPA. (C) Event-free survival in all patients. (D) Event-free survival in patients with GPA and in patients with MPA. 95% CI, 95% confidence interval.
Causes of Death
Infections were the leading cause of death (35%) on dialysis, followed by cardiovascular events (26%) (Table 2 ). Cancers accounted for 8% of deaths, and relapses of vasculitis accounted for 6% of deaths. There was no difference between GPA and MPA.
Table 2. -
Causes of death in all patients with ANCA-associated vasculitis, in patients with granulomatosis with polyangiitis, and in patients with microscopic polyangiitis
Causes of Death
All Patients, n =107
Granulomatosis with Polyangiitis, n =72
Microscopic Polyangiitis, n =35
Infection
37 (35)
27 (38)
10 (29)
Cardiovascular
28 (26)
17 (24)
11 (31)
Cancer
9 (8)
6 (8)
3 (9)
Other
8 (8)
5 (7)
3 (9)
Vasculitis flare
6 (6)
3 (4)
3 (9)
Cachexia
6 (6)
6 (8)
0 (0)
Dementia
1 (1)
1 (1)
0 (0)
Unknown
12 (11)
7 (10)
5 (14)
There was no significant difference between granulomatosis with polyangiitis and microscopic polyangiitis. Results are expressed as n (%).
Fatal vasculitis relapses occurred after a mean of 1.3±1.9 years on dialysis, whereas fatal infections occurred after 2.7±2.0 years, and fatal cardiovascular events occurred after 2.9±2.6 years.
Event-Free Survival
Median event-free survival on dialysis was 1.1±0.5 years. Event-free survival rates at 1, 3, and 5 years were 52% (95% CI, 46 to 59), 30% (95% CI, 25 to 37), and 27% (95% CI, 22 to 33), respectively (Figure 3C ). There was no difference between GPA and MPA (Figure 3D ).
Almost 50% of events occurred during the first year of dialysis (Table 3 ).
Table 3. -
Type of the first event and mean time between dialysis initiation and the first event in patients on dialysis affected by the event, in all patients with ANCA-associated vasculitis, in patients with granulomatosis with polyangiitis, and in patients with microscopic polyangiitis
First Event
All Patients, n =181
Granulomatosis with Polyangiitis, n =117
Microscopic Polyangiitis, n =64
P Value
n (%)
Time to Event, yr, Mean ± SD
n (%)
Time to Event, yr, Mean ± SD
n (%)
Time to Event, yr, Mean ± SD
Cardiovascular events
77 (43)
0.9±1.2
48 (41)
0.8±1.5
29 (45)
1.2±1
0.64
Infection
66 (37)
1.2±1.4
45 (39)
1.2±1.2
21 (33)
1.2±1.8
>0.99
Vasculitis relapse
22 (12)
1.1±1.2
18 (15)
0.9±0.8
4 (6)
2.0±2.2
0.09
Death
16 (9)
2.3±2.4
6 (5)
2.2±1.3
10 (16)
2.4±2.8
0.03
P values compare the proportion of each type of event between patients with granulomatosis with polyangiitis and patients with microscopic polyangiitis. Bold value indicates P <0.05.
Cumulative Incidence of Vasculitis Relapses
Cumulative incidence rates of vasculitis relapses (serious or not) were 3% (95% CI, 1 to 5), 8% (95% CI, 5 to 11), and 13% (95% CI, 9 to 18) at 1, 3, and 5 years of dialysis, respectively (Figure 4A ), with no significant difference between GPA and MPA (Figure 4B ).
Figure 4.: Cumulative incidence rates of adverse events and relapses on dialysis. (A) Relapses in all patients. (B) Relapses in patients with GPA and in patients with MPA. (C) Infections in all patients. (D) Infections in patients with GPA and in patients with MPA. (E) Cardiovascular events in all patients. (F) Cardiovascular events in patients with GPA and in patients with MPA. Events were recorded after dialysis initiation until kidney transplantation, loss of follow-up, recovery of kidney function, or end of the study in December 2017. *P =0.05 for the comparison of GPA versus MPA.
Among patients defined as in remission off immunosuppression at some point during the follow-up, only 18 of 156 (12%) ultimately relapsed, after a mean of 18 months.
Characteristics of Relapsing Patients
Forty-one (18%) patients presented at least one relapse (serious in 80%) on dialysis after a mean of 1.4±1.3 years. Their characteristics, compared with nonrelapsing patients, are detailed in Supplemental Table 3
Among relapsing patients, 24 (59%) died: seven of infection, four of relapse, two of cancer, three of a cardiovascular event, four of another disease, and four of unknown cause. Access to kidney transplantation was reduced in relapsing patients (Supplemental Table 3
Cumulative Incidences of Adverse Events
Cumulative incidence rates of serious infections were 23% (95% CI, 18 to 29), 42% (95% CI, 35 to 48), and 45% (95% CI, 39 to 52) at 1, 3, and 5 years of dialysis, respectively (Figure 4C ).
Patients with GPA were more likely to be infected, with cumulative incidence rates at 1, 3, and 5 years of 27% (95% CI, 20 to 34), 49% (95% CI, 40 to 57), and 53% (95% CI, 44 to 61), respectively, versus 18% (95% CI, 10 to 26), 31% (95% CI, 21 to 41), and 33% (95% CI, 23 to 43), respectively, for MPA (P =0.05) (Figure 4D ).
Among the 106 patients who presented at least one serious infection after dialysis initiation, 57 (54%) were receiving corticosteroids ≥7.5 mg/d and/or immunosuppressive therapy (19 had received cyclophosphamide or rituximab in the past 6 months), and 49 (46%) were off therapy (23 on corticosteroids <7.5 mg/d and 26 without any treatment) at the time of the first infectious event.
Cumulative incidence rates of cardiovascular events were 28% (95% CI, 22 to 34), 42% (95% CI, 36 to 49), and 45% (95% CI, 38 to 51) at 1, 3 and 5 years of dialysis, respectively (Figure 4E ), with no significant difference between GPA and MPA (Figure 4F ).
Descriptions of the first infectious and cardiovascular events are provided in Supplemental Tables 4 and 5
Rates of Vasculitis Relapses and Adverse Events before and after Dialysis Initiation
Rates of vasculitis relapses (serious or not) and rates of adverse events were compared before and after dialysis initiation in the 141 patients for whom dialysis initiation did not result from a first vasculitis flare (Table 4 ), with the comparison of GPA and MPA (Supplemental Table 6
Table 4. -
Rates of all vasculitis relapses,
infections , cardiovascular events, and cancers before and after dialysis initiation in the 141 patients for whom dialysis initiation did not result from a first vasculitis flare
Events
Patients (N )
Events (n )
Mean Follow-Up per Patient, yr, Mean±SD
Incidence (per 100 Patient-yr)
Days in Hospital (per Patient-yr)
All relapses
Before dialysis
141
78
1±0.2
57 (56–57)
a
13
a
After dialysis
141
32
3±2
7 (6–9)
a
1
a
Serious relapses
Before dialysis
141
70
1±0.2
51 (50–53)
a
13
a
After dialysis
141
25
3±2
6 (4–8)
a
1
a
Nonserious relapses
Before dialysis
141
8
1±0.2
6 (4–7)
a
After dialysis
141
7
3±2
2 (0–3)
a
Infections
Before dialysis
141
22
1±0.2
16 (14–18)
a
2
a
After dialysis
141
148
3±2
35 (33–38)
a
4
a
Cardiovascular events
Before dialysis
141
18
1±0.2
13 (11–15)
a
2
a
After dialysis
141
144
3±2
34 (33–36)
a
3
a
Cancer
Before dialysis
141
8
1±0.2
6 (4–8)
After dialysis
141
12
3±2
3 (1–5)
a P =0.05 between before and after dialysis initiation. Bold value indicates P <0.05.
Causes and lengths of hospital stays before and after dialysis initiation are detailed in Supplemental Table 7
Discussion
To our knowledge, this is to date the largest national cohort study evaluating vasculitis activity and adverse events in patients with ANCA-associated vasculitis reaching kidney failure. We showed a significant increase in the proportion of patients in remission off immunosuppression with the time spent on dialysis. The incidence of relapses on dialysis was low. Conversely, >40% of patients presented serious infections and cardiovascular events.
Whether immunosuppressive therapy should be continued in patients with ANCA-associated vasculitides reaching kidney failure is a matter of debate. Its continuation in a vulnerable population can favor adverse outcomes, such as severe infections (21 22 23 et al. (24 25
Here, we first aimed to evaluate vasculitis activity before and after dialysis initiation. To avoid the underestimation of vasculitis activity on dialysis, we chose a stringent definition of remission. We also chose a broad definition of vasculitis relapse to ensure the capture of all diagnosed relapses. By doing so, we may have overestimated vasculitis activity in this work. We showed, nevertheless, a significant increase in the proportion of patients in remission off immunosuppression after dialysis initiation.
A few studies have specifically analyzed the relapse rate of vasculitis in patients on long-term dialysis in smaller cohorts and found very similar rates (0.05–0.09 episodes per patient-year [11 12 26
Several hypotheses have been raised to explain the sustained remission of ANCA-associated vasculitides on dialysis: exclusion of the target organ (the kidney) (27 28 29 30 31 32
The low risk of vasculitis relapse on dialysis contrasts with a high risk of infection. Infections are the second cause of death (after cardiovascular disease) in patients with kidney failure in France (33 et al. (11 infections on dialysis in patients with vasculitis on maintenance immunosuppression, with infections accounting for 43% of deaths. Weidanz et al. (12 infections of 0.89 episodes per patient-year. Haubitz et al. (34
Higher risks of cardiovascular events and death have been reported in ANCA-associated vasculitides, especially in GPA. Faurschou et al. (35 36 37 38
The mortality rates reported here are consistent with previous studies. We have reported before (6 et al. (39
Our study has some limitations. First, it is a retrospective analysis, although data were collected prospectively in REIN and in the National Health System database. The diagnosis of GPA or MPA was recorded in REIN by the attending nephrologist, with no data on ANCA specificity, and misdiagnosis cannot be excluded. In addition, the diagnosis of MPA may be under-reported in REIN (especially in patients with few extrarenal symptoms), which may explain the higher proportion of patients with GPA in this cohort. This calls for the cautious interpretation of the comparisons between GPA and MPA. Second, we did not have access to detailed clinical information (Birmingham Vasculitis Activity Score); analyses are on the basis of the delivery of drugs by pharmacists and coding of hospital stays, and therefore, diagnostic errors (i.e. , pulmonary infection versus vasculitis relapse) cannot be excluded. This study was conducted at a time when cyclophosphamide was the primary induction therapy and azathioprine was the primary maintenance therapy, and the translation of these results to a time when rituximab is widely used is uncertain. The cumulative doses of immunosuppressive therapies, which are a major contributor to infectious risk, could not be calculated in this work. The entire history of the vasculitis, from the diagnosis, was not analyzed in patients for whom the diagnosis was made more than a year before dialysis initiation. Finally, corticosteroids or increase in immunosuppression may have been related to other indications than vasculitis relapse, and nonsevere infections were not reported. Despite these limitations, the major strength of this study is the large number and relevance of the recorded variables and the unselected nature of the population, which is representative of patients with ANCA-associated vasculitis who reached kidney failure.
Overall, this work shows that the risk of serious infection or cardiovascular event far exceeds the risk of vasculitis relapse in patients with ANCA-associated vasculitis on long-term dialysis, with an increasing rate of patients in remission off immunosuppression over time. Yet, only a randomized controlled trial will fully address the benefit-risk balance of continued immunosuppression in these patients. This study is currently ongoing in France (NCT03323476), with the hypothesis that the absence of maintenance immunosuppression in patients with kidney failure would be noninferior in terms of extrarenal relapse and may reduce the risk of infections .
In summary, the proportion of patients with ANCA-associated vasculitis in remission off immunosuppression increases with the time spent on dialysis. Patients are less likely to experience a vasculitis relapse than a serious infection or cardiovascular event on dialysis, and infection is their main cause of mortality. This calls for the careful use of maintenance immunosuppressive therapies in these patients on dialysis.
Disclosures
M. Bobot reports serving as a member of the editorial board of Néphrologie et Thérapeutique and as a member of the scientific committee of the Association Club des Jeunes Néphrologues. P. Brunet reports consultancy agreements with Astellas, serving as a scientific advisor or member of Néphrologie et Thérapeutique , and serving as a member of the dialysis commission of the Societe Francophone de Nephrologie Dialyse et Transplantation. S. Burtey reports receiving honoraria from AstraZeneca, Fresenius Kabi, Gambro, and Nipro. C. Couchoud reports employment with the Biomedicine Agency; serving as an editor for BMC Nephrology and Nephrologie et Thérapeutique ; serving as a member of a not-for-profit association that aims to promote collaborations and research in renal epidemiology; and other interests/relationships with L'Association des Néphrologues pour la Recherche en Epidémiologie (EPINEPHRO). S. Faguer reports consultancy agreements with Abionyx Pharma and serving as a symposium speaker for Vifor Pharma. N. Jourde-Chiche reports receiving research funding from Fresenius Medical Care: Cinétique d'épuration des anticorps au cours des vascularites (CINEVAS) Study (NCT03635385). A. Karras reports consultancy agreements with Alnylam, GlaxoSmithKline, and Vifor and receiving honoraria from Abbvie, Amgen, Gilead, Pfizer, and Roche Pharmaceuticals. F. Lavainne reports employment with Association expansion des centres d'hémodialyse de l'ouest (ECHO), Etablissement de Santé, Activité de dialyse et néphrologie and Medical Structure: St. Herblain, Pôle Santé-Atlantique; receiving honoraria from Abbvie, Gilead, and Roche (before 2016 for all); and other interests/relationships with Agence de la biomédecine France as a regional network coordinator (REIN network) and a living donor committee member. X. Puéchal reports employment with the National Referral Centre for Rare Systemic Autoimmune Diseases and receiving research funding from Roche Pharma as an investigator in academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma; research funding from ChemoCentryx as an investigator in studies evaluating CCX168 in ANCA-associated vasculitis; and research funding from InflaRx as an investigator in studies evaluating IFX 1 in ANCA-associated vasculitis. T. Robert reports consultancy agreements with Travere, receiving honoraria from Asahi Kasei Medical (ASAHI) and Travere, and serving on the speakers bureau for ASAHI. B. Terrier reports receiving honoraria from AstraZeneca, GlaxoSmithKline, Grifols, LFB, Roche Chugai, Terumo BCT, and Vifor. B. Terrier received some consulting fees and/or grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Grifols, Lilly, LFB, Roche/Chugaï, Terumo BCT, and Vifor Pharma. All remaining authors have nothing to disclose.
Funding
None.
Acknowledgments
The REIN registry is funded by the French Government and the Agence de la Biomédecine. We thank all of the nephrologists in France who provide detailed information for the REIN registry and the research assistants of REIN who update this information.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.03190321/-/DCSupplemental
Supplemental Table 1
Supplemental Table 2
Supplemental Table 3
Supplemental Table 4
Supplemental Table 5
Supplemental Table 6
Supplemental Table 7
References
1. Kronbichler A, Shin JI, Lee KH, Nakagomi D, Quintana LF, Busch M, Craven A, Luqmani RA, Merkel PA, Mayer G, Jayne DRW, Watts RA: Clinical associations of renal involvement in ANCA-associated vasculitis. Autoimmun Rev 19: 102495, 2020
2. Nguyen Y, Pagnoux C, Karras A, Quéméneur T, Maurier F, Hamidou M, Le Quellec A, Chiche NJ, Cohen P, Régent A, Lifermann F, Mékinian A, Khouatra C, Hachulla E, Pourrat J, Ruivard M, Godmer P, Viallard JF, Terrier B, Mouthon L, Guillevin L, Puéchal X; French Vasculitis Study Group: Microscopic polyangiitis: Clinical characteristics and long-term outcomes of 378 patients from the French Vasculitis Study Group Registry. J Autoimmun 112: 102467, 2020
3. Wallace ZS, Lu N, Unizony S, Stone JH, Choi HK: Improved survival in granulomatosis with polyangiitis: A general population-based study. Semin Arthritis Rheum 45: 483–489, 2016
4. Brix SR, Noriega M, Tennstedt P, Vettorazzi E, Busch M, Nitschke M, Jabs WJ, Özcan F, Wendt R, Hausberg M, Sellin L, Panzer U, Huber TB, Waldherr R, Hopfer H, Stahl RAK, Wiech T: Development and validation of a renal risk score in ANCA-associated glomerulonephritis. Kidney Int 94: 1177–1188, 2018
5. de Joode AAE, Sanders JSF, Stegeman CA: Renal survival in proteinase 3 and myeloperoxidase ANCA-associated systemic vasculitis. Clin J Am Soc Nephrol 8: 1709–1717, 2013
6. Romeu M, Couchoud C, Delarozière J-C, Burtey S, Chiche L, Harlé J-R, Gondouin B, Brunet P, Berland Y, Jourde-Chiche N: Survival of patients with ANCA-associated vasculitis on chronic dialysis: Data from the French REIN registry from 2002 to 2011. QJM 107: 545–555, 2014
7. Jayne D: Current attitudes to the therapy of vasculitis. Kidney Blood Press Res 26: 231–239, 2003
8. Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, Maurier F, Decaux O, Ninet J, Gobert P, Quémeneur T, Blanchard-Delaunay C, Godmer P, Puéchal X, Carron PL, Hatron PY, Limal N, Hamidou M, Ducret M, Daugas E, Papo T, Bonnotte B, Mahr A, Ravaud P, Mouthon L; French Vasculitis Study Group: Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 371: 1771–1780, 2014
9. Charles P, Perrodeau É, Samson M, Bonnotte B, Néel A, Agard C, Huart A, Karras A, Lifermann F, Godmer P, Cohen P, Hanrotel-Saliou C, Martin-Silva N, Pugnet G, Maurier F, Sibilia J, Carron P-L, Gobert P, Meaux-Ruault N, Le Gallou T, Vinzio S, Viallard J-F, Hachulla E, Vinter C, Puéchal V, Terrier B, Ravaud P, Mouthon L, Guillevin L; French Vasculitis Study Group: Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med 173: 179–187, 2020
10. Walsh M, Flossmann O, Berden A, Westman K, Höglund P, Stegeman C, Jayne D; European Vasculitis Study Group: Risk factors for relapse of antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 64: 542–548, 2012
11. Lionaki S, Hogan SL, Jennette CE, Hu Y, Hamra JB, Jennette JC, Falk RJ, Nachman PH: The clinical course of ANCA small-vessel vasculitis on chronic dialysis. Kidney Int 76: 644–651, 2009
12. Weidanz F, Day CJ, Hewins P, Savage CO, Harper L: Recurrences and
infections during continuous immunosuppressive therapy after beginning dialysis in ANCA-associated vasculitis. Am J Kidney Dis 50: 36–46, 2007
13. Goupil R, Brachemi S, Nadeau-Fredette A-C, Déziel C, Troyanov Y, Lavergne V, Troyanov S: Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis. Clin J Am Soc Nephrol 8: 416–423, 2013
14. Reinhold-Keller E, Moosig F: [Development of morbidity and mortality in ANCA-associated vasculitis]. Z Rheumatol 70: 486–492, 2011
15. Vanholder R, Van Biesen W: Incidence of infectious morbidity and mortality in dialysis patients. Blood Purif 20: 477–480, 2002
16. Sarnak MJ, Jaber BL: Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int 58: 1758–1764, 2000
17. Chonchol M: Neutrophil dysfunction and infection risk in end-stage renal disease. Semin Dial 19: 291–296, 2006
18. Réseau Epidémiologique et Information en Néphrologie: [REIN’s objectives and organization]. Nephrol Ther 5[Suppl 2]: S145–S176, 2009
19. Raffray M, Bayat S, Lassalle M, Couchoud C: Linking disease registries and nationwide healthcare administrative databases: The French Renal Epidemiology and Information Network (REIN) insight. BMC Nephrol 21: 25, 2020
20. Rosthøj S, Andersen PK, Abildstrom SZ: SAS macros for estimation of the cumulative incidence functions based on a Cox regression model for competing risks survival data. Comput Methods Programs Biomed 74: 69–75, 2004
21. Grams ME, Coresh J, Segev DL, Kucirka LM, Tighiouart H, Sarnak MJ: Vascular disease, ESRD, and death: Interpreting competing risk analyses. Clin J Am Soc Nephrol 7: 1606–1614, 2012
22. McGregor JG, Hogan SL, Hu Y, Jennette CE, Falk RJ, Nachman PH: Glucocorticoids and relapse and infection rates in anti-neutrophil cytoplasmic antibody disease. Clin J Am Soc Nephrol 7: 240–247, 2012
23. Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GH, Plaisance M, Pusey CD, Jayne DR; Pan-Thames Renal Research Group: Outcome of ANCA-associated renal vasculitis: A 5-year retrospective study. Am J Kidney Dis 41: 776–784, 2003
24. Lee T, Gasim A, Derebail VK, Chung Y, McGregor JG, Lionaki S, Poulton CJ, Hogan SL, Jennette JC, Falk RJ, Nachman PH: Predictors of treatment outcomes in ANCA-associated vasculitis with severe kidney failure. Clin J Am Soc Nephrol 9: 905–913, 2014
25. Büyüktas D, Hatemi G, Tascilar K, Fresko I, Yurdakul S: Should immunosuppressives be stopped in granulomatosis with polyangiitis (Wegener’s granulomatosis) patients undergoing dialysis? Clin Exp Rheumatol 30[Suppl 70]: S104–S106, 2012
26. Allen A, Pusey C, Gaskin G: Outcome of renal replacement therapy in antineutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 9: 1258–1263, 1998
27. Hasegawa M, Hattori K, Sugiyama S, Asada H, Yamashita H, Takahashi K, Hayashi H, Koide S, Sato W, Yuzawa Y: A retrospective study on the outcomes of MPO-ANCA-associated vasculitis in dialysis-dependent patients. Mod Rheumatol 26: 110–114, 2016
28. Descamps-Latscha B, Jungers P, Witko-Sarsat V: Immune system dysregulation in uremia: Role of oxidative stress. Blood Purif 20: 481–484, 2002
29. Jourde-Chiche N, Fakhouri F, Dou L, Bellien J, Burtey S, Frimat M, Jarrot PA, Kaplanski G, Le Quintrec M, Pernin V, Rigothier C, Sallée M, Fremeaux-Bacchi V, Guerrot D, Roumenina LT: Endothelium structure and function in kidney health and disease. Nat Rev Nephrol 15: 87–108, 2019
30. Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P: Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction. Semin Dial 24: 327–337, 2011
31. Mattos P, Santiago MB: Disease activity in systemic lupus erythematosus patients with end-stage renal disease: Systematic review of the literature. Clin Rheumatol 31: 897–905, 2012
32. Nossent HC, Swaak TJ, Berden JH; Dutch Working Party on SLE: Systemic lupus erythematosus: Analysis of disease activity in 55 patients with end-stage renal failure treated with hemodialysis or continuous ambulatory peritoneal dialysis. Am J Med 89: 169–174, 1990
33. Couchoud C, Lassalle M, Jacquelinet C: [REIN Report 2011--summary]. Nephrol Ther 9[Suppl 1]: S3–S6, 2013
34. Haubitz M, Koch KM, Brunkhorst R: Survival and vasculitis activity in patients with end-stage renal disease due to Wegener’s granulomatosis. Nephrol Dial Transplant 13: 1713–1718, 1998
35. Faurschou M, Mellemkjaer L, Sorensen IJ, Svalgaard Thomsen B, Dreyer L, Baslund B: Increased morbidity from ischemic heart disease in patients with Wegener’s granulomatosis. Arthritis Rheum 60: 1187–1192, 2009
36. Cohen Tervaert JW: Cardiovascular disease due to accelerated atherosclerosis in systemic vasculitides. Best Pract Res Clin Rheumatol 27: 33–44, 2013
37. Foley RN, Parfrey PS, Sarnak MJ: Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 9[Suppl]: S16–S23, 1998
38. Amann K, Tyralla K, Gross ML, Eifert T, Adamczak M, Ritz E: Special characteristics of atherosclerosis in chronic renal failure. Clin Nephrol 60[Suppl 1]: S13–S21, 2003
39. Tang W, Bose B, McDonald SP, Hawley CM, Badve SV, Boudville N, Brown FG, Clayton PA, Campbell SB, Peh CA, Johnson DW: The outcomes of patients with ESRD and ANCA-associated vasculitis in Australia and New Zealand. Clin J Am Soc Nephrol 8: 773–780, 2013
