KEY POINTS:Among 72 patients with childhood-onset ANCA-associated vasculitis, kidney transplant survival was good (86%). ANCA-associated vasculitis relapse occurred in 8 patients (11%), a median of 71 months after transplantation and resulted in graft failure in only one case. Positive ANCA at the time of transplantation did not predict graft failure but was associated with a higher risk of relapse and worse graft function. BACKGROUND:ANCA-associated vasculitis (AAV) is rare in children, and results in kidney failure in up to one third of cases. There is very limited knowledge on kidney transplantation in childhood-onset AAV. We assessed kidney transplantation outcomes and prognostic factors in a multicenter cohort of patients with childhood-onset AAV. METHODS:Patients diagnosed with AAV during childhood (≤18 years) who received a kidney transplant were included in this retrospective study. We determined patient and graft survival, rates of chronic graft dysfunction (defined as eGFR <60 ml/min per 1.73 m 2 for ≥3 months) and AAV relapse, and assessed determinants of outcome with logistic regression models. Patients were matched 1:2 for age, sex, and era of transplantation with non-AAV recipients from the Hospital for Sick Children in Toronto, Canada, and their graft survival was compared. RESULTS:We included 72 patients, of whom 53 (74%) had microscopic polyangiitis and 19 (26%) granulomatosis with polyangiitis. Their median age (interquartile range at the time of diagnosis and transplantation was 12 (9-14) and 14 (12-16) years, respectively. After a median post-transplant follow-up of 53 months (interquartile range, 25-97), 70 patients (97%) were alive, 62 (86%) had a functioning graft, 28 (39%) had developed chronic graft dysfunction, and 8 (11%) had experienced AAV relapse. Graft survival was comparable between AAV and non-AAV recipients. Acute rejection was the only independent predictor of graft failure (hazard ratio [HR], 12.11; 95% confidence interval [CI], 1.19 to 122.49). Positive ANCA at the time of transplantation was significantly associated with a chronic graft dysfunction (HR, 4.16; 95% CI, 1.71 to 10.13) and AAV relapse (HR, 23.1; 95% CI, 2.67 to 200.28). CONCLUSIONS:Patients with childhood-onset AAV show good overall and graft survival after kidney transplantation and a low rate of post-transplant relapse. Further studies are warranted to confirm whether positive ANCA at the time of transplantation is associated with poorer graft outcomes.

Key Points Among 72 patients with childhood-onset ANCA-associated vasculitis, kidney transplant survival was good (86%). ANCA-associated vasculitis relapse occurred in 8 patients (11%), a median of 71 months after transplantation and resulted in graft failure in only one case. Positive ANCA at the time of transplantation did not predict graft failure but was associated with a higher risk of relapse and worse graft function. Background ANCA-associated vasculitis (AAV) is rare in children, and results in kidney failure in up to one third of cases. There is very limited knowledge on kidney transplantation in childhood-onset AAV. We assessed kidney transplantation outcomes and prognostic factors in a multicenter cohort of patients with childhood-onset AAV. Methods Patients diagnosed with AAV during childhood (≤18 years) who received a kidney transplant were included in this retrospective study. We determined patient and graft survival, rates of chronic graft dysfunction (defined as eGFR <60 ml/min per 1.73 m 2 for ≥3 months) and AAV relapse, and assessed determinants of outcome with logistic regression models. Patients were matched 1:2 for age, sex, and era of transplantation with non-AAV recipients from the Hospital for Sick Children in Toronto, Canada, and their graft survival was compared. Results We included 72 patients, of whom 53 (74%) had microscopic polyangiitis and 19 (26%) granulomatosis with polyangiitis. Their median age (interquartile range at the time of diagnosis and transplantation was 12 (9–14) and 14 (12–16) years, respectively. After a median post-transplant follow-up of 53 months (interquartile range, 25–97), 70 patients (97%) were alive, 62 (86%) had a functioning graft, 28 (39%) had developed chronic graft dysfunction, and 8 (11%) had experienced AAV relapse. Graft survival was comparable between AAV and non-AAV recipients. Acute rejection was the only independent predictor of graft failure (hazard ratio [HR], 12.11; 95% confidence interval [CI], 1.19 to 122.49). Positive ANCA at the time of transplantation was significantly associated with a chronic graft dysfunction (HR, 4.16; 95% CI, 1.71 to 10.13) and AAV relapse (HR, 23.1; 95% CI, 2.67 to 200.28). Conclusions Patients with childhood-onset AAV show good overall and graft survival after kidney transplantation and a low rate of post-transplant relapse. Further studies are warranted to confirm whether positive ANCA at the time of transplantation is associated with poorer graft outcomes.

Nephrotic syndrome (NS) encompasses a heterogeneous group of glomerular diseases characterized by heavy proteinuria, hypoalbuminemia, edema, and multiple systemic complications. Despite substantial advances in diagnostic techniques and targeted therapies, the management of NS remains challenging in clinical practice. In addition to complex treatment decisions, clinicians must address diagnostic uncertainty, recognize secondary causes, and prevent potentially serious complications including thrombosis, infections, cardiovascular disease, and progressive kidney dysfunction. Adverse outcomes in NS frequently arise not only from inappropriate management but also from overlooked steps in diagnosis, monitoring, and long-term care. Here, we present 10 practical tips to improve clinical decision-making in the diagnosis and management of NS. Key positive strategies include appropriate use of kidney biopsy and modern immunopathologic techniques, integration of immunologic biomarkers such as anti-phospholipase A2 receptor antibodies in the evaluation of membranous nephropathy, systematic exclusion of secondary causes, and comprehensive supportive care including blood pressure control, antiproteinuric therapy, and thrombosis prophylaxis in high-risk patients. In addition, evidence-based use of immunosuppressive therapies (IST) tailored to specific disease entities is emphasized. Equally important are commonly overlooked pitfalls that may compromise outcomes, including delayed genetic testing in steroid-resistant disease, prolonged ineffective immunosuppression, inadequate post-transplant surveillance for recurrence, under-recognition of cardiovascular risk, and failure to prevent complications associated with IST. Highlighting these practical considerations may help increase awareness of common pitfalls and support more attentive clinical management of patients with NS.

KEY POINTS:Lower kidney function is associated with higher concentrations of blood biomarkers for Alzheimer's disease and related dementia. Associations between kidney function and cerebrospinal fluid biomarkers for Alzheimer's disease and related dementia were heterogeneous and NS. Elevated blood biomarkers for Alzheimer's disease and related dementia in people with impaired kidney function may reflect reduced kidney clearance. BACKGROUND:Studies have shown that low kidney function may link to elevated Alzheimer's disease and related dementia fluid biomarkers, but the results are not consistent. This systematic review and meta-analysis aimed to investigate whether kidney function was associated with Alzheimer's disease and related dementia biomarkers (amyloid- β , tau, neurofilament light [NfL] protein, and glial fibrillary acidic protein [GFAP]) in blood and cerebrospinal fluid (CSF). METHODS:Human studies were identified through MEDLINE, EMBASE, Cochrane Library, and Web of Science (until May 2, 2025). Studies that reported the association between kidney function and Alzheimer's disease and related dementia biomarkers in blood or CSF among adults were included. Two authors independently screened and extracted data following preferred reporting items for systematic reviews and meta-analyses 2020 guidelines. Descriptive statistics and random-effects meta-analysis were used to analyze pooled effects. RESULTS:Of the 3024 studies screened, 93 met the inclusion criteria, encompassing 62,503 participants (mean age, 20-96 years; 54% female) from 21 countries. Ninety-one studies reported blood biomarkers, while ten reported CSF biomarkers. In meta-analysis of unadjusted correlation coefficients, kidney function (primarily eGFR) was inversely associated with concentrations of blood NfL, GFAP, Aβ40, β-amyloid 1-40 (A β 40), β-amyloid 1-42, and phosphorylated tau (p-tau181). In meta-analysis of adjusted regression coefficients, eGFR remained inversely associated with blood biomarker levels. Specifically, every 1 ml/min per 1.73 m 2 lower eGFR was associated with 0.19 pg/ml higher NfL (95% confidence interval [CI], 0.12 to 0.25), 0.11 pg/ml higher GFAP (95% CI, 0.04 to 0.18), and 0.29 pg/ml higher A β 40 (95% CI, 0.01 to 0.56). CSF biomarker findings were more heterogeneous and generally null. CONCLUSIONS:Low kidney function was associated with elevated blood biomarkers of Alzheimer's disease and related dementia (NfL, GFAP, and A β 40), whereas associations with CSF biomarkers were inconsistent and generally null.

Biological differences exist between males and females in kidney structure and function, leading to sex heterogeneity in the presentation and outcomes of chronic kidney disease (CKD) and response to novel therapeutics. However, treatment guidelines ignore sex-specific differences. This Series paper provides an integrated discussion of the complexity of sex differences in the context of kidney health and disease, from biology through clinical characteristics, treatment, evidence generation, and reporting. Throughout, we consider the effect of genetics, epigenetic regulation, and the role of sex hormones. We highlight substantial opportunities that exist for policy makers, scientific organisations, journal editors, funders, and individuals to change the current paradigm. Strategic and systematic acknowledgment, exploration, and reporting of these differences is needed in future research to continue to advance our understanding of pathophysiology, diagnostics, and novel therapeutics for CKD.

Glucocorticoids and antiproliferative agents, such as mycophenolate and cyclophosphamide, form the backbone of current therapy for lupus nephritis. Despite their ability to suppress inflammation, such treatments are often limited by their incomplete efficacy, substantial toxicity and failure to prevent disease progression. Many patients continue to relapse and accumulate kidney damage, underscoring the urgent need for new strategies. Advances in our understanding of the pathophysiology of lupus nephritis have provided insights into the mechanisms by which the impaired clearance of nuclear self-antigens drives innate immune activation, including excessive Toll-like receptor signalling, interferon pathway upregulation and B cell hyperactivation. These processes sustain autoantibody production and complement activation and contribute to progressive tissue injury. Emerging immunomodulatory therapies that are designed to target these pathways have the potential to restore immune balance, dampen systemic inflammation and protect the kidneys. These developments pave the way for a new treatment paradigm that focuses on disease modification, enabling early prevention of inflammation-driven kidney injury and protecting against disease progression. Fast-acting glucocorticoids and classic antiproliferative agents can be used to rapidly control systemic inflammation, although the early addition of immunomodulatory drugs is critical to promote sustained remission and prevent kidney damage. Integrated into a multitargeted, pathophysiology-based and personalized approach, this paradigm represents a departure from the conventional trial-and-error strategy of therapeutic switching and add-on regimens, and instead provides a more precise and effective framework for optimizing and individualizing disease management.

FGF23 excess is associated with morbidity and mortality, but the role of excessive circulating FGF23 concentrations as a causative factor of pathology is controversial. Here, we investigated the consequences of FGF23 excess in kidney disease. This study used three disease models: anti-glomerular basement membrane (anti-GBM) disease, Adriamycin nephropathy, and adenine-containing diets. Anti-GBM and Adriamycin mice and matched control mice received recombinant FGF23 (1 µg) or vehicle for six days (anti-GBM) or once (Adriamycin model), with dissection 24 h after the last injection. We established precision-cut kidney slices (PCKS) in adenine nephropathy for 24 h of treatment with recombinant FGF23 or vehicle. We assessed serum cytokines, biochemistry, and renal transcriptomes and histology of mice and patients with IgA nephropathy. RNA-Seq data and published transcriptomes underwent gene set enrichment, bulk ligand-receptor interaction analysis, and cell-type decomposition. Experimental anti-GBM disease caused decreased glomerular filtration rate, albuminuria, and renal tubular casts. FGF23 treatment increased phosphaturia and circulating soluble tumor necrosis factor receptor 1. The anti-GBM model showed FGF23-driven proinflammatory transcriptional signatures and Vcam1, Pdgfrb, and chemokine signaling, which were absent in FGF23-treated healthy mice. FGF23 increased renal macrophage content by transcriptome deconvolution and by immunofluorescence. In Adriamycin-induced nephropathy and in PCKS from adenine nephropathy, short-term FGF23 excess increased proinflammatory transcripts. Human data revealed associations between circulating FGF23 and renal immune cell infiltration. We found FGF23-driven renal patterns of proinflammatory gene and protein expression or leukocyte overabundance. The present data provide evidence that excess FGF23 directly drives inflammation in kidney disease and may serve as a therapeutic target.

Introduction:Cyclophosphamide (CYC) and rituximab (RTX), alone or combined, are the mainstays of induction therapy in antineutrophil cytoplasmic autoantibody (ANCA)-glomerulonephritis. It is unknown whether the response to induction is differentially affected by kidney histopathology. Methods:This is a retrospective, multicenter study including patients with biopsy-proven ANCA-glomerulonephritis. Cases were grouped according to the Berden nephropathology classification. Estimated glomerular filtration rate (eGFR) recovery at 6 months was defined as eGFR increase ≥ 15 ml/min per 1.73 m2 or discontinuation of kidney replacement therapy (KRT); kidney failure was defined as sustained eGFR < 15 ml/min per 1.73 m2 or long-term KRT. Multivariable regression models were used to explore independent predictors of kidney outcomes across Berden classes. Results:The cohort included 304 patients; median baseline eGFR was 20 ml/min per 1.73 m2 (interquartile range [IQR]: 11-35). Induction immunosuppression was with CYC in 59%, with RTX in 17%, and with RTX-CYC in 24%. Overall, 50% recovered kidney function and 19.4% had kidney failure over a median follow-up of 42 months (IQR: 18-72). In the crescentic class, the RTX group had lower chances of eGFR recovery than CYC (odds ratio [OR]: 0.23, 95% confidence interval [CI]: 0.05-0.98, P = 0.047); the trend was similar in comparison with RTX-CYC (OR: 0.20, 95% CI: 0.03-1.19, P = 0.077). In the crescentic class, RTX monotherapy was marginally associated with increased risk of kidney failure, compared with both CYC (hazard ratio [HR]: 3.42, 95% CI: 1.03-11.35, P = 0.045) and RTX-CYC (HR: 5.33, 95% CI: 0.91-31.18, P = 0.063). No significant differences were observed in the other Berden classes. Conclusion:Patients with crescentic class ANCA-glomerulonephritis receiving RTX monotherapy may have worse kidney outcomes than those treated with CYC-based regimens. Further studies are needed to validate these results and better understand how to personalize treatment.

Biological differences exist between males and females in kidney structure and function, leading to sex heterogeneity in the presentation and outcomes of chronic kidney disease (CKD) and response to novel therapeutics. However, treatment guidelines ignore sex-specific differences. This Series paper provides an integrated discussion of the complexity of sex differences in the context of kidney health and disease, from biology through clinical characteristics, treatment, evidence generation, and reporting. Throughout, we consider the effect of genetics, epigenetic regulation, and the role of sex hormones. We highlight substantial opportunities that exist for policy makers, scientific organisations, journal editors, funders, and individuals to change the current paradigm. Strategic and systematic acknowledgment, exploration, and reporting of these differences is needed in future research to continue to advance our understanding of pathophysiology, diagnostics, and novel therapeutics for CKD.

Key PointsLower kidney function is associated with higher concentrations of blood biomarkers for Alzheimer's disease and related dementia.Associations between kidney function and cerebrospinal fluid biomarkers for Alzheimer's disease and related dementia were heterogeneous and NS.Elevated blood biomarkers for Alzheimer's disease and related dementia in people with impaired kidney function may reflect reduced kidney clearance.BackgroundStudies have shown that low kidney function may link to elevated Alzheimer's disease and related dementia fluid biomarkers, but the results are not consistent. This systematic review and meta-analysis aimed to investigate whether kidney function was associated with Alzheimer's disease and related dementia biomarkers (amyloid-beta, tau, neurofilament light [NfL] protein, and glial fibrillary acidic protein [GFAP]) in blood and cerebrospinal fluid (CSF).MethodsHuman studies were identified through MEDLINE, EMBASE, Cochrane Library, and Web of Science (until May 2, 2025). Studies that reported the association between kidney function and Alzheimer's disease and related dementia biomarkers in blood or CSF among adults were included. Two authors independently screened and extracted data following preferred reporting items for systematic reviews and meta-analyses 2020 guidelines. Descriptive statistics and random-effects meta-analysis were used to analyze pooled effects.ResultsOf the 3024 studies screened, 93 met the inclusion criteria, encompassing 62,503 participants (mean age, 20-96 years; 54% female) from 21 countries. Ninety-one studies reported blood biomarkers, while ten reported CSF biomarkers. In meta-analysis of unadjusted correlation coefficients, kidney function (primarily eGFR) was inversely associated with concentrations of blood NfL, GFAP, A beta 40, beta-amyloid 1-40 (A beta 40), beta-amyloid 1-42, and phosphorylated tau (p-tau181). In meta-analysis of adjusted regression coefficients, eGFR remained inversely associated with blood biomarker levels. Specifically, every 1 ml/min per 1.73 m2 lower eGFR was associated with 0.19 pg/ml higher NfL (95% confidence interval [CI], 0.12 to 0.25), 0.11 pg/ml higher GFAP (95% CI, 0.04 to 0.18), and 0.29 pg/ml higher A beta 40 (95% CI, 0.01 to 0.56). CSF biomarker findings were more heterogeneous and generally null.ConclusionsLow kidney function was associated with elevated blood biomarkers of Alzheimer's disease and related dementia (NfL, GFAP, and A beta 40), whereas associations with CSF biomarkers were inconsistent and generally null.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic small-vessel necrotizing vasculitides, including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Genetic factors, particularly human leukocyte antigen (HLA) variants, contribute to disease susceptibility and define distinct myeloperoxidase (MPO) and proteinase-3 (PR3) associated phenotypes. This review summarizes current understanding of organ-specific manifestations, therapeutic advances, and prognostic determinants of AAV, with particular relevance for nephrologists. Kidney involvement is common, particularly in MPA, whereas GPA and EGPA more frequently present with extrarenal manifestations. Pulmonary involvement is also frequent, ranging from alveolar haemorrhage and interstitial lung disease (ILD) in MPA to granulomatous nodules and airway disease in GPA, while asthma dominates in EGPA. Other frequent manifestations include ear, nose and throat (ENT), peripheral nervous system, cutaneous, and constitutional manifestations, with ENT activity and non-haemorrhagic respiratory manifestations correlating with relapse risk. Current treatment emphasizes rituximab or cyclophosphamide with reduced-dose glucocorticoids for induction, avacopan for glucocorticoid-sparing strategies, and rituximab for maintenance. Avacopan has shown benefits beyond renal outcomes. Furthermore, anti-interleukin-5 therapies have recently been approved for the treatment of EGPA. Contrarily, ILD remains a therapeutic challenge, with limited evidence for antifibrotic agents. AAV patients are at high risk of infections, thromboembolism, and malignancy, influenced by both disease activity and treatment exposure. Mortality remains high, driven mainly by infections, with kidney and lung involvement serving as major prognostic determinants. For nephrologists, early recognition of extrarenal manifestations, vigilance for relapse beyond the kidney, and multidisciplinary collaboration are crucial for optimizing long-term outcomes.

Lupus nephritis (LN) is a major driver of morbidity and kidney failure in systemic lupus erythematosus, and its management has grown substantially more complex with the emergence of targeted therapies. Between 2024 and 2025, the American College of Rheumatology, the European Alliance of Associations for Rheumatology, and Kidney Disease: Improving Global Outcomes each released updated recommendations grounded in a largely shared evidence base but differing in scope, clinical profiling, and operational emphasis. This review compares the three frameworks, highlighting key areas of convergence and divergence relevant to contemporary clinical practice. The main themes include the shift toward early combination regimens targeting complementary immune pathways, driven by the emergence of targeted therapies such as belimumab, voclosporin, and obinutuzumab; the incorporation of clinical profiling to guide therapy selection and monitoring; strategies aimed at rapid glucocorticoid minimization; and the growing recognition of renoprotective therapy as a central pillar of LN care within a chronic kidney disease management strategy.

ObjectiveAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are chronic, relapsing inflammatory diseases, yet reliable biomarkers for detecting relapse and organ involvement remain limited. This study aimed to identify plasma protein biomarkers that distinguish active disease from remission and to explore markers associated with lung and kidney involvement.MethodsPlasma samples from 113 patients with granulomatosis with polyangiitis or microscopic polyangiitis (68 active disease and 45 remission) were profiled using a proximity extension assay targeting 181 inflammation- and cardiovascular-related proteins. Clinical data, including CRP and Birmingham vasculitis activity score (BVAS), were collected at sampling. Differential protein expression was assessed using ANOVA, with top candidates validated in independent sample cohorts (plasma samples, n = 74; serum samples, n = 34). Correlations with BVAS and CRP and discriminatory performance (AUC) were evaluated. Associations with chest- and kidney-specific BVAS were also examined.ResultsA total of 57 proteins were differentially expressed between active disease and remission. Seven proteins (ST2, OPN, IL-2RA, CCL23, IL-6, Flt3L, and SCF) were validated in independent cohorts and showed strong associations with disease activity. Several demonstrated high discriminatory ability (AUC ≥ 0.80) between active disease and remission. Multiple proteins correlated with organ-specific BVAS scores: seven for chest involvement and 16 for kidney involvement, after adjustment for kidney function-related protein variation.ConclusionThis study identifies a robust panel of plasma proteins that differentiate active AAV from remission and correlate with global and organ-specific disease activity. These biomarkers may enhance non-invasive disease monitoring and support earlier recognition of relapse and organ involvement in AAV.

Objective: To investigate nationwide mortality in incident Granulomatosis with polyangiitis (GPA) between 1 January 2004 until 31 December 2019 in Sweden.Method: Using the population-based National Patient Register, we identified patients with incident GPA, 2004-2019. Each patient with GPA was matched on sex and birth year to ten general population comparators. Follow-up began at disease incidence and continued until death, emigration or 31 December 2021. Mortality was assessed overall and stratified by sex and calendar time. Mortality rates (MRs) were calculated for patients with GPA and general populations comparators, and hazard ratios (HR) were calculated using weighted Cox proportional hazards regression.Results: Among 2322 patients with GPA and 22551 general population comparators, the crude MRs were 41.1 vs 26.5/1000 person-years (py), respectively. MRs were stable over calendar time. All-cause mortality was elevated in patients with GPA (HR: 1.5, 95% CI: 1.3-1.7), with similar results stratified by sex. The excess in mortality was ten times higher in the oldest age quartile (age at diagnosis) compared to the youngest (50 vs. 4 per 1000 py). Cumulative survival in GPA patients at 1, 5, 10, and 15 years was 93%, 82%, 68%, and 53%, respectively.,High risk of frailty was associated with more than doubled mortality (HR 2.4; 95% CI 1.8-3.1) compared to non-frail GPA patients, adjusted for age and sex in those aged ≥60.Conclusion: Patients with GPA had increased mortality compared to general population comparators, with the highest excess in mortality in older patients. Mortality remained stable over the study period.

BackgroundRituximab is effective for induction and maintenance of remission in relapsing ANCA-associated vasculitis (AAV), but some patients do not achieve complete remission or experience relapse despite treatment. We aimed to describe the frequency, characteristics, and outcomes of patients with suboptimal response to rituximab within the RITAZAREM trial.MethodsPost hoc descriptive analysis, including patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) treated with rituximab for induction (N = 188) and those receiving rituximab maintenance (N = 85). Three scenarios of suboptimal response were examined: (i) failure to achieve protocol-defined remission at month 4 (n = 6); (ii) incomplete remission at month 4, defined as BVAS/WG = 1 (n = 10); and (iii) relapse during rituximab maintenance (n = 13). Data were summarized descriptively. Time to relapse from month 4 in patients with BVAS/WG = 1 versus BVAS/WG = 0 was explored using Kaplan–Meier analysis.ResultsSix of 188 patients (3%) did not achieve protocol-defined remission by month 4, 10 (5%) had residual low-grade disease activity (BVAS/WG = 1), and 13 of 85 patients (15%) receiving rituximab maintenance relapsed within 24 months during maintenance treatment. All patients with BVAS/WG = 1 at month 4 had a history of PR3-ANCA positivity and ear/nose/throat (ENT) baseline manifestations. Relapse occurred more frequently in this subgroup than in patients with BVAS/WG = 0, and time-to-relapse analysis showed shorter relapse-free survival, although interpretation is limited by the small sample size. Most first relapses were minor, and some patients subsequently experienced additional relapses, including major relapses.ConclusionIn this exploratory and hypothesis-generating analysis, a small subset of patients with relapsing AAV showed suboptimal outcomes with rituximab. Residual disease activity at month 4, particularly in patients with PR3-ANCA positivity and ENT involvement, may represent a clinical subgroup associated with an increased frequency of earlier relapse, although this observation requires confirmation.

Background The complement system is crucial in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) pathogenesis. Extracellular vesicles (EVs) serve as carriers of bioactive substances, influencing the immune system. We aimed to investigate myeloperoxidase-positive EVs (MPO(+)EVs) exposing complement components (C3a, C4d), terminal complement complex (TCC) and complement factor B (CFB) in relation to disease activity and kidney involvement. Methods Plasma MPO(+)EVs carrying complement products, C3a, C4d, TCC or CFB, were analysed by flow cytometry. Clinical data, including kidney biopsy findings, were retrieved. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). Results Eighty-one patients with AAV with granulomatosis with polyangiitis (n=59) or microscopic polyangiitis (n=22) were included. Active disease was noted in 73 (90.1%) patients and 50 (68.5%) had kidney involvement. Patients with kidney involvement had higher concentrations of MPO+, MPO(+)C3a(+), MPO(+)C4d(+) and MPO(+)TCC(+)EVs compared to patients without, and concentrations correlated positively with BVAS (p<0.05), respectively. Levels of EVs showed a negative correlation with estimated glomerular filtration rate, and a positive correlation with the proportions of necrosis and crescents in kidney biopsies. ROC curve analysis indicated that MPO(+)EVs could distinguish patients with kidney involvement from non-renal AAV. A binary multivariable logistic regression confirmed an independent association between levels of EV subsets and kidney involvement. Conclusions Elevated levels of MPO(+)EVs exposing complement components in patients with kidney involvement indicate activation of the classical or lectin and common complement pathways in renal AAV. Furthermore, the association between levels of MPO(+)EVs with the presence of crescents and necrotic lesions in kidney tissue supports a role in renal inflammatory activity.

IntroductionSide effects of calcineurin inhibitors (CNI) comprise hypertension, diabetes and nephrotoxicity, and endothelial dysfunction (ED) has often been implicated. Belatacept, a co-stimulation blocker, may offer a more favourable vascular profile.MethodsWe investigated markers of endothelial function in blood samples from kidney transplant recipients (KTR) that were converted from CNI to belatacept. We assessed established markers of ED including soluble thrombomodulin, P-selectin and angiopoietin 1 and 2. In addition, we assessed expression levels of microRNAs (miRNAs), which have been identified as discriminative markers for ED, rejection and renal fibrosis in the setting of transplantation. Lastly, we used patient samples and CNI-dilution series in a validated model of ED in which changes in morphological characteristics of endothelial cells were evaluated.ResultsUnexpectedly, we found no differences in our assays between both groups. We did observe dose-related effects of CNI on endothelial cell (EC) morphology upon direct exposure of EC to tacrolimus and ciclosporin A, but a similar effect was not seen when plasma samples of KTR who were converted to belatacept were compared with samples from KTR on CNI's.DiscussionThese data suggest that CNI-side-effects bundled under the term “CNI-toxicity” are not derived from a significant clinical effect of CNI on endothelial function.

IgA vasculitis (IgAV) is an immune complex-mediated small-vessel vasculitis that typically affects the skin, gastrointestinal tract, kidneys and joints. Childhood-onset IgAV is a common disease and usually follows a self-limiting course, whereas adult-onset IgAV is considerably less frequent and is associated with a poorer prognosis. The diagnosis, assessment and management of adult-onset IgAV remain challenging owing to the absence of validated diagnostic criteria for adults and lack of IgAV-specific standardized disease activity scores. Short-term outcomes are mainly determined by gastrointestinal complications, whereas kidney involvement and the risk of progression to chronic kidney disease are the major determinants of long-term prognosis. The treatment of adult-onset IgAV is limited by the paucity of high-quality clinical trials and standardized therapeutic approaches. Here, we present evidence-based, multidisciplinary guidelines for the diagnosis and management of adult-onset IgAV that reflect advances in understanding of pathogenesis, differential diagnoses and treatment over the past two decades. Developed by a panel of leading European experts on the basis of systematic literature review and expert opinion, these guidelines comprise 14 recommendation statements and overarching principles that provide a structured and pragmatic clinical framework for the diagnosis, treatment and follow-up of adult-onset IgAV.