Renal Tissue miRNA Expression Profiles in ANCA-Associated Vasculitis-A Comparative Analysis.
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SUBMITTER: Bosnjak M
PROVIDER: S-EPMC8745125 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AbstractTreatment of ANCA-associated vasculitis (AAV) improved over the last decades but disease-unspecific agents such as cyclophosphamide are still associated with serious adverse events, including high rates of infectious complications and malignancy with increased mortality.In this comparative cohort study, we included 121 AAV patients with renal involvement from 2 German vasculitis centers. Patients were separated into subsequent groups: 2.5 to 3 g vs >3 g cumulative cyclophosphamide induction dose. We investigated if a cyclophosphamide induction dose of 2.5 to 3 g could maintain efficacy while minimizing adverse events in AAV patients with renal involvement.Patients with 2.5 to 3 g vs >3 g cumulative cyclophosphamide (median 3.0 g vs 5.5 g, P < .001) had a comparable time to remission (median 4.0 vs 3.8 months, log-rank P = .87) with 90.6% and 91.5% achieving remission after 12 months. Refractory disease was low in both groups (median 3.6% vs 6.2%, P = .68) and relapse rate did not differ (median 36% vs 42%, log-rank P = .51). Kidney function was comparable at disease onset in both groups (eGFR, mean ± SD 29 ± 20 mL/min/1.73 m2 vs 35 ± 26 mL/min/1.73 m2, P = .34) and improved after 2 years irrespective of the cyclophosphamide dose (ΔeGFR, mean ± SD +8.9 ± 1.4 mL/min/1.73 m2 vs +6.0 ± 1.1 mL/min/1.73 m2, P = .33). The 2.5-3 g group had a lower rate of leukopenia (HR = 2.73 [95% CI, 1.2-6.3], P = .014) and less infectious episodes per patient (median 1.2 vs 0.7, P = .012), especially urinary tract infections (HR = 2.15 [95% CI, 1.1-4.5], P = .032).A cyclophosphamide induction dose of 2.5 to 3 g was able to induce remission and prevent from relapses with fewer cases of leukopenia and less infectious episodes during follow-up. Especially elderly AAV patients who are particularly susceptible to infectious complications could benefit from minimizing dosing regimens with maintained efficacy to control disease activity.
| S-EPMC8294897 | biostudies-literature
Project description:Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) × 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.
| S-EPMC4378104 | biostudies-literature
Project description:Background and objectivesThis study evaluated predictors for patient and renal survival in patients with ANCA-associated vasculitis (AAV) with and without renal involvement.Design, setting, participants, & measurementsThere were 273 consecutive AAV patients from January 1990 until December 2007 who were followed until death, loss to follow-up, or December 2010. Based on organ involvement, patients were divided into renal (n=212) and nonrenal groups (n=61). The primary end point was ESRD requiring renal replacement therapy (RRT) or renal transplantation or death.ResultsPatient survival was significantly better in the nonrenal group compared with the renal group (hazard ratio, 0.55; 95% confidence interval, 0.33 to 0.92; P=0.02). In the renal group, renal survival was significantly worse in MPO-ANCA-positive patients (n=65) compared with PR3-ANCA-positive patients (n=138) (hazard ratio, 2.1; 95% confidence interval, 1.11 to 3.8; P=0.01). Of 48 patients who needed RRT at diagnosis, 11 patients (23%) died within 6 months and 14 patients (29%) did not regain renal function. Of all 23 patients who regained renal function after RRT, 7 patients (30%) were temporarily dialysis independent and needed dialysis later (range, 13-63 months). Five patients had a renal relapse in the 6 months before restart of RRT. Of all 203 PR3-ANCA-positive and MPO-ANCA-positive patients with renal involvement, 12 patients (6%) developed ESRD during follow-up. These patients were classified as CKD stage 4 or 5 after initial treatment and eight patients had a renal relapse before becoming dialysis dependent.ConclusionsAAV patients with renal involvement who needed RRT had the worst survival probability. In multivariate analysis, the only major determinants for long-term renal survival were renal function at 6 months and renal relapses.
| S-EPMC3789333 | biostudies-literature
Project description:The prognosis of patients with ANCA-associated vasculitis has improved over the past decades, but overall survival rates are still unsatisfactory. Recent research has focused on complications of immunosuppressive measures and comorbidities of ANCA-associated vasculitis. This review focuses on thromboembolic and cardiovascular events. A considerably increased risk of thromboembolic events has been reported, which is associated with active disease and impaired coagulation factors. There is mounting evidence that a hypercoagulable state is present even in patients in remission, and studies investigating the impact of tailored anticoagulation are needed to reduce the burden of thromboembolism. Cardiovascular mortality is one of the leading causes of death and accelerated atherosclerosis is frequently observed in patients with ANCA-associated vasculitis. A high frequency of patients develops hypertension, diabetes mellitus and hypercholesterolaemia, either as a consequence of immunosuppression or associated with the underlying disease. The current control of modifiable cardiovascular risk factors is insufficient and thorough reviews should be performed periodically. Treatment of these risk factors should be adopted according to current recommendations related to individual cardiovascular risk prediction.
| S-EPMC7190116 | biostudies-literature
Project description:Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated. Moreover, some MPO-ANCA subsets, which are directed against a few specific MPO epitopes, have recently been found to be better associated with disease activity, but a different method than the one presently used in routine detection is required to detect them. B cells possibly play a major role in the pathogenesis because they produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes [T helper (Th)1, Th2, Th17, regulatory cluster of differentiation (CD)4+ CD25+ forkhead box P3 (FoxP3)+ T cells] and/or cytokine-chemokine networks. The alternative complement pathway is also involved, and its blockade has been shown to prevent renal disease in an MPO-ANCA murine model. Other recent studies suggested strongest genetic associations by ANCA type rather than by clinical diagnosis. The induction treatment for severe granulomatosis with polyangiitis and microscopic polyangiitis is relatively well codified but does not (yet) really differ by precise diagnosis or ANCA type. It comprises glucocorticoids combined with another immunosuppressant, cyclophosphamide or rituximab. The choice between the two immunosuppressants must consider the comorbidities, past exposure to cyclophosphamide for relapsers, plans for pregnancy, and also the cost of rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate. The optimal maintenance strategy following rituximab-based induction therapy remains to be determined. Preliminary results on rituximab for maintenance therapy appear promising. Efforts are still under way to determine the optimal duration of maintenance therapy, ideally tailored according to the characteristics of each patient and the previous treatment received.
| S-EPMC5058451 | biostudies-literature
Project description:Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome.
| S-EPMC10229283 | biostudies-literature
Project description:Keratins are the main components of the cell cytoskeleton of epithelial cells. Epithelial cells under stressful stimuli react by modifying their keratin expression pattern. Glomerular diseases are pathological conditions that may lead to loss of kidney function if not timely diagnosed and treated properly. This study aims to examine glomerular and tubular keratin expression in podocytopathies, ANCA-associated vasculitis, and IgA nephropathy and how this expression correlates to clinical outcomes. We included 45 patients with podocytopathies (minimal change disease and focal segmental glomerulosclerosis), ANCA-associated vasculitis, and IgA nephropathy, with or without crescentic lesions, and healthy controls. All tissues were assessed by photon microscopy and immunohistochemistry. Biopsy sections were examined for keratins 7, 8, 18, and 19 expression in the glomerular and tubulointerstitial areas separately. Moreover, we examined how keratin expression was correlated with long-term kidney function outcomes. All four studied keratins had significantly increased glomerular expression in patients with ANCA vasculitis compared to controls and MCD patients. Tubular expression of keratins 7, 8, and 19 was related to kidney outcome in all groups. Patients with crescents had higher expression of all keratins in both glomeruli and tubulointerstitium. The presence of tubular atrophy, interstitial fibrosis, mesangial hyperplasia, and interstitial inflammation did not affect keratin expression. Keratins, an abundant component of renal epithelial cells, have the potential to be featured as a biomarker for kidney function prognosis in patients with glomerular diseases.
| S-EPMC10855225 | biostudies-literature
Project description:The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of disorders characterized by necrotizing inflammation of the small to medium vessels in association with autoantibodies against the cytoplasmic region of the neutrophil. Included in this definition are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). AAV are chronic, often relapsing diseases that can be organ or life threatening. Despite immunosuppression, the morbidity and mortality remain high. Renal involvement contributes significantly to the morbidity with high numbers of patients progressing to end-stage kidney disease. Current therapies have enabled improvements in renal function in the short term, but evidence for long-term protection is lacking. In MPA, renal involvement is common at presentation (90%) and often follows a more severe course than that seen in paediatric GPA. Renal biopsy remains the 'gold standard' in diagnosing ANCA-associated glomerulonephritis. While GPA and MPA are considered separate entities, the two are managed identically. Current treatment regimens are extrapolated from adult studies, although it is encouraging to see recruitment of paediatric patients to recent vasculitis trials. Traditionally more severe disease has been managed with the 'gold standard' treatment of glucocorticoids and cyclophosphamide, with remission rates achieved of between 70 and 100%. Other agents employed in remission induction include anti-tumor necrosis factor-alpha therapy and mycophenolate mofetil. Recently, however, increasing consideration is being given to rituximab as a therapy for children in severe or relapsing disease, particularly for those at risk for glucocorticoid or cyclophosphamide toxicity. Removal of circulating ANCA through plasma exchange is a short-term measure reserved for severe or refractory disease. Maintenance therapy usually involves azathioprine. The aim of this article is to provide a comprehensive review of paediatric AAV, with a focus on renal manifestations, and to highlight the recent advances made in therapeutic management.
| S-EPMC5700225 | biostudies-literature
Project description:BackgroundRenal involvement in ANCA-associated vasculitis (AAV) is associated with poor outcomes. The clinical significance of arteritis of the small kidney arteries has not been evaluated in detail.MethodsIn a multicenter cohort of patients with AAV and renal involvement, we sought to describe the clinicopathologic characteristics of patients with AAV who had renal arteritis at diagnosis, and to retrospectively analyze their prognostic value.ResultsWe included 251 patients diagnosed with AAV and renal involvement between 2000 and 2019, including 34 patients (13.5%) with arteritis. Patients with AAV-associated arteritis were older, and had a more pronounced inflammatory syndrome compared with patients without arteritis; they also had significantly lower renal survival (P=0.01). In multivariable analysis, the ANCA renal risk score, age at diagnosis, history of diabetes mellitus, and arteritis on index kidney biopsy were independently associated with ESKD. The addition of the arteritis status significantly improved the discrimination of the ANCA renal risk score, with a concordance index (C-index) of 0.77 for the ANCA renal risk score alone, versus a C-index of 0.80 for the ANCA renal risk score plus arteritis status (P=0.008); ESKD-free survival was significantly worse for patients with an arteritis involving small arteries who were classified as having low or moderate risk, according to the ANCA renal risk score. In two external validation cohorts, we confirmed the incidence and phenotype of this AAV subtype.ConclusionsOur findings suggest AAV with renal arteritis represents a different subtype of AAV with specific clinical and histologic characteristics. The prognostic contribution of the arteritis status remains to be prospectively confirmed.
| S-EPMC8729836 | biostudies-literature
Project description:In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacific, with the exception of New Zealand and Australia. A genetic contribution has been extensively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele in patients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy controls. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differences when analyzed carefully. Clinically, both serotypes are difficult to distinguish, but quantitative differences are present. More organs are affected in PR3-AAV, whereas renal limited vasculitis occurs more often in patients with MPO-AAV. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classification.
| S-EPMC4587702 | biostudies-literature