Proteinuria and hematuria after remission induction are associated with outcome in ANCA-associated vasculitis
2023; Elsevier BV; Volume: 103; Issue: 6 Linguagem: Inglês
10.1016/j.kint.2023.02.029
ISSN1523-1755
AutoresNicolas Bénichou, Pierre Charles, Benjamin Terrier, Rachel Jones, Thomas F. Hiemstra, Luc Mouthon, Ingeborg M. Bajema, Annelies E. Berden, Éric Thervet, Loı̈c Guillevin, David Jayne, Alexandre Karras,
Tópico(s)Renal Diseases and Glomerulopathies
ResumoIn anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting kidney damage or persistent disease, remains uncertain. To study this, our post hoc analysis included participants of five European randomized clinical trials on AAV (MAINRITSAN, MAINRITSAN2, RITUXVAS, MYCYC, IMPROVE). Urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy (four-six months after treatment initiation) were correlated with the occurrence of a combined end point of death and/or kidney failure, or relapses during follow-up. Among 571 patients (59% men, median age 60), 60% had anti–proteinase 3-ANCA and 35% had anti–myeloperoxidase-ANCA, while 77% had kidney involvement. After induction therapy, 157/526 (29.8%) had persistent hematuria and 165/481 (34.3%) had UPCR of 0.05 g/mmol or more. After a median follow-up of 28 months (interquartile range 18-42), and adjustment for age, ANCA type, maintenance therapy, serum creatinine and persistent hematuria after induction, a UPCR of 0.05 g/mmol or more after induction was associated with significant risk of death/kidney failure (adjusted Hazard Ratio [HR] 3.06, 95% confidence interval 1.09-8.59) and kidney relapse (adjusted subdistribution HR 2.22, 1.16-4.24). Persistent hematuria was associated with significant kidney relapse (adjusted subdistribution HR 2.16, 1.13-4.11) but not with relapse affecting any organ nor with death/kidney failure. Thus, in this large cohort of patients with AAV, persistent proteinuria after induction therapy was associated with death/kidney failure and kidney relapse, whereas persistent hematuria was an independent predictor of kidney relapse. Hence, these parameters must be considered to assess long-term kidney prognosis of patients with AAV. In anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting kidney damage or persistent disease, remains uncertain. To study this, our post hoc analysis included participants of five European randomized clinical trials on AAV (MAINRITSAN, MAINRITSAN2, RITUXVAS, MYCYC, IMPROVE). Urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy (four-six months after treatment initiation) were correlated with the occurrence of a combined end point of death and/or kidney failure, or relapses during follow-up. Among 571 patients (59% men, median age 60), 60% had anti–proteinase 3-ANCA and 35% had anti–myeloperoxidase-ANCA, while 77% had kidney involvement. After induction therapy, 157/526 (29.8%) had persistent hematuria and 165/481 (34.3%) had UPCR of 0.05 g/mmol or more. After a median follow-up of 28 months (interquartile range 18-42), and adjustment for age, ANCA type, maintenance therapy, serum creatinine and persistent hematuria after induction, a UPCR of 0.05 g/mmol or more after induction was associated with significant risk of death/kidney failure (adjusted Hazard Ratio [HR] 3.06, 95% confidence interval 1.09-8.59) and kidney relapse (adjusted subdistribution HR 2.22, 1.16-4.24). Persistent hematuria was associated with significant kidney relapse (adjusted subdistribution HR 2.16, 1.13-4.11) but not with relapse affecting any organ nor with death/kidney failure. Thus, in this large cohort of patients with AAV, persistent proteinuria after induction therapy was associated with death/kidney failure and kidney relapse, whereas persistent hematuria was an independent predictor of kidney relapse. Hence, these parameters must be considered to assess long-term kidney prognosis of patients with AAV. Lay SummaryAnti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitides are small vessels necrotizing diseases with multisystemic involvement, including the kidney. Hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting either kidney damage or persistent disease, remains uncertain. In this post hoc study including 571 participants (77% of whom had kidney involvement) of 5 European randomized clinical trials on ANCA-associated vasculitis, the prognostic value of urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy was studied. After induction therapy, 29.8% of patients had persistent hematuria and 34.3% had UPCR ≥0.05 g/mmol. After a median follow-up of 28 months and adjustment for age, ANCA type, maintenance therapy, serum creatinine, proteinuria and hematuria, persistence of a UPCR ≥0.05 g/mmol after induction therapy was associated with poorer kidney survival and increased risk of kidney relapse whereas persistent hematuria was an independent predictor of kidney relapse. These parameters must be taken into account to assess the long-term renal prognosis of patients with ANCA–associated vasculitis. Anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitides are small vessels necrotizing diseases with multisystemic involvement, including the kidney. Hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting either kidney damage or persistent disease, remains uncertain. In this post hoc study including 571 participants (77% of whom had kidney involvement) of 5 European randomized clinical trials on ANCA-associated vasculitis, the prognostic value of urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy was studied. After induction therapy, 29.8% of patients had persistent hematuria and 34.3% had UPCR ≥0.05 g/mmol. After a median follow-up of 28 months and adjustment for age, ANCA type, maintenance therapy, serum creatinine, proteinuria and hematuria, persistence of a UPCR ≥0.05 g/mmol after induction therapy was associated with poorer kidney survival and increased risk of kidney relapse whereas persistent hematuria was an independent predictor of kidney relapse. These parameters must be taken into account to assess the long-term renal prognosis of patients with ANCA–associated vasculitis. Anti-neutrophil cytoplasm antibody (ANCA)–associated vasculitides (AAVs) are a group of small vessel necrotizing vasculitis syndromes with multisystemic involvement, including the kidney.1Jennette J.C. Falk R.J. Bacon P.A. et al.2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.Arthritis Rheum. 2013; 65: 1-11Crossref PubMed Scopus (4136) Google Scholar Notwithstanding the significant progress achieved during these last decades regarding induction and maintenance immunosuppressive therapy,2de Groot K. Harper L. Jayne D.R.W. et al.Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial.Ann Intern Med. 2009; 150: 670-680Crossref PubMed Scopus (708) Google Scholar, 3Jones R.B. Tervaert J.W.C. Hauser T. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1223) Google Scholar, 4Stone J.H. Merkel P.A. Spiera R. et al.Rituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med. 2010; 363: 221-232Crossref PubMed Scopus (1926) Google Scholar, 5Flossmann O. Berden A. de Groot K. et al.Long-term patient survival in ANCA-associated vasculitis.Ann Rheum Dis. 2011; 70: 488-494Crossref PubMed Scopus (603) Google Scholar severe organ damage due to delayed diagnosis6de Joode A.A.E. Sanders J.S.F. Stegeman C.A. Renal survival in proteinase 3 and myeloperoxidase ANCA-associated systemic vasculitis.Clin J Am Soc Nephrol. 2013; 8: 1709-1717Crossref PubMed Scopus (125) Google Scholar remains a major concern for patients with AAV. Kidney involvement in AAV is characterized by pauci-immune necrotizing crescentic glomerulonephritis. The occurrence of glomerulonephritis is particularly frequent in microscopic polyangiitis and granulomatosis with polyangiitis, affecting >50% of all patients at diagnosis or during follow-up and sometimes leading to chronic kidney disease (CKD), which is independently associated with poor survival.7Robson J. Doll H. Suppiah R. et al.Damage in the ANCA-associated vasculitides: long-term data from the European vasculitis study group (EUVAS) therapeutic trials.Ann Rheum Dis. 2015; 74: 177-184Crossref PubMed Scopus (168) Google Scholar,8Rhee R.L. Hogan S.L. Poulton C.J. et al.Trends in long-term outcomes among patients with antineutrophil cytoplasmic antibody-associated vasculitis with renal disease.Arthritis Rheumatol. 2016; 68: 1711-1720Crossref PubMed Scopus (77) Google Scholar Kidney failure can result from irreversible initial acute kidney disease or occur years later because of the nonspecific progression of CKD or to vasculitis relapses.9Wester Trejo M.A.C. Floßmann O. Westman K.W. et al.Renal relapse in antineutrophil cytoplasmic autoantibody-associated vasculitis: unpredictable, but predictive of renal outcome.Rheumatology. 2019; 58: 103-109Crossref PubMed Scopus (16) Google Scholar At AAV diagnosis, hematuria and proteinuria are considered as biomarkers reflecting kidney involvement.10Jennette J.C. Rapidly progressive crescentic glomerulonephritis.Kidney Int. 2003; 63: 1164-1177Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar Yet, the prognostic value of their persistence after the induction of remission by immunosuppressive therapy remains uncertain, although it could reflect either kidney damage or persistent active disease. Albuminuria excretion rate,11Iseki K. Ikemiya Y. Iseki C. Takishita S. Proteinuria and the risk of developing end-stage renal disease.Kidney Int. 2003; 63: 1468-1474Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar, 12Matsushita K. van der Velde M. Astor B.C. et al.Chronic Kidney Disease Prognosis ConsortiumAssociation of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.Lancet. 2010; 375: 2073-2081Abstract Full Text Full Text PDF PubMed Scopus (2912) Google Scholar, 13Hemmelgarn B.R. Manns B.J. Lloyd A. et al.Relation between kidney function, proteinuria, and adverse outcomes.JAMA. 2010; 303: 423-429Crossref PubMed Scopus (827) Google Scholar and by extension proteinuria excretion rate,14Ruggenenti P. Perna A. Mosconi L. et al."Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN). Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies.Kidney Int. 1998; 53: 1209-1216Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar,15Sumida K. Nadkarni G.N. Grams M.E. et al.Conversion of urine protein-creatinine ratio or urine dipstick protein to urine albumin-creatinine ratio for use in chronic kidney disease screening and prognosis: an individual participant-based meta-analysis.Ann Intern Med. 2020; 173: 426-435Crossref PubMed Scopus (76) Google Scholar is a well-recognized predictive factor for kidney failure in the general population and especially in patients with glomerular diseases.16Reich H.N. Troyanov S. Scholey J.W. Cattran D.C. Toronto Glomerulonephritis RegistryRemission of proteinuria improves prognosis in IgA nephropathy.J Am Soc Nephrol. 2007; 18: 3177-3183Crossref PubMed Scopus (419) Google Scholar,17Moroni G. Gatto M. Tamborini F. et al.Lack of EULAR/ERA-EDTA response at 1 year predicts poor long-term renal outcome in patients with lupus nephritis.Ann Rheum Dis. 2020; 79: 1077-1083Crossref PubMed Scopus (26) Google Scholar However, in AAV, its persistence after induction therapy has seldom been investigated, and no study has demonstrated a prognostic value for this simple biomarker. In contrast, a recent study has suggested that persistent hematuria during the remission phase of AAV is associated with the subsequent risk of kidney relapse but not with the risk of progression to kidney failure.18Rhee R.L. Davis J.C. Ding L. et al.The utility of urinalysis in determining the risk of renal relapse in ANCA-associated vasculitis.Clin J Am Soc Nephrol. 2018; 13: 251-257Crossref PubMed Scopus (38) Google Scholar The aim of this study was to evaluate the prognostic value of persistent proteinuria and/or hematuria after induction therapy in a large population of patients with AAVs by using pooled individual participant data from 5 large randomized controlled trials. This study was a post hoc individual patient data analysis from 5 international multicenter randomized controlled trials on AAV published between 2010 and 2019. The Efficacy Study of Two Treatments in the Remission of Vasculitis (MAINRITSAN) and Comparison Study of Two Rituximab Regimens in the Remission of ANCA Associated Vasculitis (MAINRITSAN2) trials were coordinated by the French Vasculitis Study group, whereas RITUXVAS (An international, randomised, open label trial comparing a rituximab-based regimen with a standard cyclophosphamide/azathioprine based regimen in the treatment of active, generalised anti-neutrophilic cytoplasmic antibodies associated vasculitis), Clinical Trial of Mycophenolate Versus Cyclophosphamide in ANCA Vasculitis (MYCYC), and Mycophenolate Mofetil Versus Azathioprine for Maintenance Therapy in ANCA Associated Systemic Vasculitis (IMPROVE) were performed by the European Vasculitis Society network. Rationale, study design, and results of these studies have been published elsewhere,3Jones R.B. Tervaert J.W.C. Hauser T. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1223) Google Scholar,19Hiemstra T.F. Walsh M. Mahr A. et al.Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (457) Google Scholar, 20Guillevin L. Pagnoux C. Karras A. et al.Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (684) Google Scholar, 21Charles P. Terrier B. Perrodeau É. et al.Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2).Ann Rheum Dis. 2018; 77: 1143-1149Crossref PubMed Scopus (168) Google Scholar, 22Jones R.B. Hiemstra T.F. Ballarin J. et al.Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.Ann Rheum Dis. 2019; 78: 399-405Crossref PubMed Scopus (120) Google Scholar and their main characteristics are presented in Supplementary Tables S1 and S2. All 5 trials included either newly diagnosed or relapsing patients with granulomatosis with polyangiitis or microscopic polyangiitis (defined by 1994 Chapel Hill nomenclature)23Jennette J.C. Falk R.J. Andrassy K. et al.Nomenclature of systemic vasculitides: proposal of an international consensus conference.Arthritis Rheum. 1994; 37: 187-192Crossref PubMed Scopus (3735) Google Scholar and compared different induction or maintenance immunosuppressive therapy schemes. Local ethics committees approved each of the studies, and all patients gave written informed consent for participation. All adult patients included in these trials were eligible for this study. Patients were excluded from the analysis if death or kidney failure had occurred during induction therapy or if no serum creatinine (sCreat) measurement was available after the end of induction therapy. For patients included in the MAINRITSAN study, we retrospectively contacted investigators to request proteinuria data after induction therapy from individual patient medical file. For the other studies, data were prospectively collected and retrieved in electronic data sets. We reviewed the individual study protocols, template case report forms, and database dictionaries to harmonize study databases. We updated each database with unified coding across trials and merged them into a single database. The 2 main variables of interest were (i) proteinuria and (ii) hematuria, collected in a single measurement at the end of induction therapy, that is, between 4 and 6 months after treatment initiation for active disease (onset or flare; details in Supplementary Table S2). Proteinuria was quantitatively measured in either 24-hour urine samples or random spot urine samples, together with urinary creatinine level. Throughout this article, proteinuria excretion rate is defined and expressed as urine protein-creatinine ratio (UPCR) in grams per millimole. Hematuria was defined by the presence of ≥10 red blood cells per mm3 in cytological examination of the urine. If cytological urine data were missing, blood by dipstick was used to identify hematuria. Baseline clinical characteristics (age, sex, ANCA, and AAV type), immunosuppressive therapies, and clinical, biological, and histological data prospectively collected during follow-up visits were analyzed. Remission was defined as a Birmingham Vasculitis Activity Score of 0. Kidney involvement was defined as ≥1 kidney Birmingham Vasculitis Activity Score items present at entry or relapse, excluding hypertension alone (i.e., new or worsening hematuria, red blood cell casts, or new rise in sCreat ≥30%). Kidney function was assessed using sCreat and estimated glomerular filtration rate (eGFR), calculated using the Modified Diet in Renal Disease equation. Histological data, when available, were analyzed by a kidney pathologist at each center, with centralized review for biopsies from the RITUXVAS trial, and Berden classification24Berden A.E. Ferrario F. Hagen E.C. et al.Histopathologic classification of ANCA-associated glomerulonephritis.J Am Soc Nephrol. 2010; 21: 1628-1636Crossref PubMed Scopus (570) Google Scholar was retrospectively established. The main outcomes were time from the end of induction therapy to (i) a composite end point of death or incident kidney failure, whichever occurred first; (ii) first relapse; and (iii) first kidney relapse during follow-up. The secondary outcome included time from the end of induction therapy to (i) a composite end point of death or severe CKD, (ii) incident kidney failure, and (iii) severe CKD. Incident kidney failure was defined as dialysis dependence at 2 consecutive visits at least 1 month apart or kidney transplantation. Severe CKD was defined as eGFR 0. Kidney relapses were defined as relapses with kidney involvement as defined above. Categorical variables were summarized as number (percentage), and continuous variables were expressed as median (interquartile range [IQR]). To ensure a clear and simple clinical message, UPCR was coded as a binary variable (<0.05 or ≥0.05 g/mmol). The cumulative incidence of the composite outcome of death or kidney failure according to UPCR after induction therapy was determined using the Kaplan-Meier method with the use of the log-rank test. Cox proportional hazards regression models were used to estimate bivariate associations between patients' characteristics (at baseline and after induction therapy) and time to death/kidney failure. In multivariable Cox regression models, the effect of UPCR and hematuria after induction therapy on the composite end points of death or kidney failure and death or severe CKD, were adjusted for age, ANCA type, maintenance therapy, sCreat, UPCR, and hematuria after induction therapy. Patients without the occurrence of the end point were censored at the end of follow-up. Proportional hazards assumptions were graphically tested with Schoenfeld residuals. For the outcomes of kidney relapse and relapse affecting any organ, incident kidney failure, and severe CKD, competing risk regression was performed.25Fine J.P. Gray R.J. A proportional hazards model for the subdistribution of a competing risk.J Am Stat Assoc. 1999; 94: 496-509Crossref Scopus (9493) Google Scholar For the outcome of kidney relapse, occurrence of death, kidney failure, and non-kidney relapse were considered competing events. For the outcome of relapse affecting any organ, death and kidney failure were considered competing events. For the outcomes of incident kidney failure and severe CKD, death was considered a competing event. Patients without the occurrence of the end point or any competing event were censored at the end of follow-up. The cumulative incidence of outcomes according to hematuria or UPCR was estimated, and adjusted analyses were performed accounting for age, ANCA type, maintenance therapy, sCreat, and hematuria or UPCR after induction therapy. The association between risk factors and outcome was expressed as subdistribution hazard ratio (sHR) or hazard ratio (HR) with 95% confidence interval (95% CI). Covariates included in multivariable analyses were selected from among those with P < 0.05 in bivariate analyses or those with a known prognostic impact in the literature. Statistical significance was set at 2-sidedP < 0.05. Analyses were performed with R Studio software version 1.2.5033 (R Project for Statistical Computing, R Foundation). Subgroup analysis including (i) only patients with kidney involvement at baseline, (ii) patients with myeloperoxidase (MPO)–ANCA antibodies, (iii) patients with proteinase 3 (PR3)–ANCA antibodies, and (iv) patients with kidney pathology available at induction therapy initiation was performed. The complete case method was adopted in the primary statistical analysis. To address missing data, the analysis assessing the time from the end of induction therapy to the composite end point of death or kidney failure was repeated with the entire cohort using the technique of multiple imputations by chained equations. The variables with missing data were imputed using all covariates of interest except those with >20% missing data. Using the "mice" package in R Studio,26van Buuren S. Groothuis-Oudshoorn K. mice: Multivariate Imputation by Chained Equations in R.J Stat Softw. 2011; 45: 1-67Google Scholar 5 imputations were performed with 5 iterations per imputation. Sensitivity analyses were performed using sCreat at induction therapy initiation and delta sCreat (sCreat before minus sCreat after induction) instead of sCreat after induction in the kidney survival models. An additional analysis was performed including ANCA persistence after induction therapy as an additional covariate for relapse-related outcomes. At last, sensitivity analyses with UPCR coded as a continuous variable were implemented. Of the 617 patients enrolled in the 5 trials (MAINRITSAN, MAINRITSAN2, RITUXVAS, MYCYC, and IMPROVE),3Jones R.B. Tervaert J.W.C. Hauser T. et al.Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1223) Google Scholar,19Hiemstra T.F. Walsh M. Mahr A. et al.Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial.JAMA. 2010; 304: 2381-2388Crossref PubMed Scopus (457) Google Scholar, 20Guillevin L. Pagnoux C. Karras A. et al.Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (684) Google Scholar, 21Charles P. Terrier B. Perrodeau É. et al.Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2).Ann Rheum Dis. 2018; 77: 1143-1149Crossref PubMed Scopus (168) Google Scholar, 22Jones R.B. Hiemstra T.F. Ballarin J. et al.Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial.Ann Rheum Dis. 2019; 78: 399-405Crossref PubMed Scopus (120) Google Scholar data were available for 614. After exclusion of 43 participants, 571 were included in the present study (Figure 1). Baseline characteristics, clinical data, and biological data at the initiation of and after induction therapy are detailed for these 571 patients in Table 1. Briefly, there were 59% men, the median age was 60 years (IQR 50–68 years), 60% had anti–PR3-ANCA, 35% had anti–MPO-ANCA, and 77% had kidney involvement with a median sCreat of 133 μmol/l (IQR 84.3–241.8 μmol/l) at induction therapy initiation. Cyclophosphamide was used for the induction of remission in 75% of cases (63% i.v., 12% orally), rituximab for 15%, and mycophenolate mofetil for 10%. Rituximab and azathioprine were used as maintenance therapy in 37% and 46% of cases, respectively.Table 1Characteristics at the initiation of and after induction therapy (N = 571)CharacteristicValueMale sex336/571 (58.8)Age, yr60 (50–68)ANCA type (ELISA) Proteinase 3318/532 (59.8) Myeloperoxidase185/532 (34.8) Negative29/532 (5.5)AAV type Granulomatosis with polyangiitis386/571 (67.6) Microscopic polyangiitis185/571 (32.4)Induction therapy i.v. cyclophosphamide359/571 (62.9) p.o. cyclophosphamide70/571 (12.3) Rituximab84/571 (14.7) Mycophenolate mofetil57/571 (10.0) Methotrexate1/571 (0.2)Maintenance therapy Rituximab212/571 (37.1) Azathioprine261/571 (45.7) Mycophenolate mofetil71/571 (12.4) None27/571 (4.7)Kidney involvement441/571 (77.2)De novo AAV flare (vs. relapse)495/571 (86.7)Data at induction therapy initiation Serum creatinine, μmol/laSerum creatinine at induction therapy initiation replaced by 800 μmol/l for 2 patients under renal replacement therapy; 3 missing values.133 (84.8–246.3) eGFR, ml/min per 1.73 m2beGFR at induction therapy initiation replaced by 5 ml/min per 1.73 m2 for 2 patients under renal replacement therapy; 3 missing values.45 (21–77) UPCR, g/mmolc226 missing values for UPCR at induction therapy initiation.0.082 (0.022–0.175) Hematuria153/269 (56.9) Pulmonary involvement141/270 (52.2) Intra-alveolar hemorrhage47/269 (17.5)Data at the end of induction therapy Serum creatinine, μmol/l105 (88–142) eGFR, ml/min per 1.73 m258 (40–77) ANCA positivity313/534 (58.6) Hematuria157/526 (29.8) UPCR, g/mmold90 missing values for UPCR after induction therapy.0.025 (0.007–0.081) UPCR 0.1 g/mmold90 missing values for UPCR after induction therapy.101/480 (21.0) UPCR <0.05 g/mmold90 missing values for UPCR after induction therapy.316/481 (65.7) UPCR ≥0.05 g/mmold90 missing values for UPCR after induction therapy.165/481 (34.3)AAV, anti-neutrophil cytoplasmic autoantibody–associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody; eGFR, estimated glomerular filtration rate (Modified Diet in Renal Disease equation); ELISA, enzyme-linked immunosorbent assay; IQR, interquartile range; UPCR, urine protein-creatinine ratio.Quantitative values are given as median (IQR), and qualitative values are given as n/total n (%).a Serum creatinine at induction therapy initiation replaced by 800 μmol/l for 2 patients under renal replacement therapy; 3 missing values.b eGFR at induction therapy initiation replaced by 5 ml/min per 1.73 m2 for 2 patients under renal replacement therapy; 3 missing values.c 226 missing values for UPCR at induction therapy initiation.d 90 missing values for UPCR after induction therapy. Open table in a new tab AAV, anti-neutrophil cytoplasmic autoantibody–associated vasculitis; ANCA, anti-neutrophil cytoplasmic autoantibody; eGFR, estimated glomerular filtration rate (Modified Diet in Renal Disease equation); ELISA, enzyme-linked immunosorbent assay; IQR, interquartile range; UPCR, urine protein-creatinine ratio. Quantitative values are given as median (IQR), and qualitative values are given as n/total n (%). At the end of induction therapy, the median UPCR was 0.025 g/mmol (IQR 0.007–0.081 g/mmol), with 34.3% of patients (165 of 481) displaying UPCR ≥0.05 g/mmol. At this time point, persistent hematuria was noted in 29.8% of cases (157 of 526). After a median follow-up of 28 months (IQR 18–42 months) from the end of induction therapy, the composite outcome of death or kidney failure occurred in 5.1% of patients (29 of 571), including 2.3% of deaths (13 of 571) and 2.8% of incident kidney failure cases (16 of 571). Factors associated with this outcome in bivariate and multivariable analysis are listed in Table 2. In multivariable analysis, the only factors independently associated with the occurrence of this end point were higher sCreat and UPCR ≥0.05 g/mmol after induction therapy (vs. <0.05 g/mmol: HR 3.06; 95% CI 1.09–8.59; P = 0.034; Kaplan-Meier survival curve shown in Figure 2) whereas persistent hematuria was not. UPCR after induction therapy was also independently associated with this outcome when sCreat after induction therapy was replaced by sCreat at induction therapy initiation and by delta sCreat. Overall, there were 12.1% of deaths/kidney failure cases (20 of 165) among patients with UPCR ≥0.05 g/mmol versu
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