Anti-ribonucleoprotein (RNP) (auto)antibodies are frequently detected in patients with systemic lupus erythematosus (SLE) although their associations with SLE disease activity remain incompletely understood. We compared patient characteristics, including disease severity outcomes, between adult patients with SLE with or without anti-RNP antibodies (RNP + versus RNP-). We used data from a national, multicentre registry of SLE patients in Australia, collected prospectively between 2007 and 2023. Anti-RNP status and other serological profiles along with demographics were recorded at enrolment. At each routine clinic visit, medication details and disease activity indicators (SLEDAI-2 K, PGA) were captured, and treat-to-target (T2T) states, lupus low disease activity state (LLDAS) and DORIS remission (REM), were determined. Clinical characteristics were compared between RNP + and RNP- patients at 6 months (182 ± 30 days) and 12 months (365 ± 30 days) from enrolment. A total of 587 patients were studied. 174 (29.6

BACKGROUND:The pharmacokinetics of immunosuppressive drugs during continuous kidney replacement therapy (CKRT) modalities such as continuous venovenous hemofiltration (CVVH) are poorly understood, yet these drugs are crucial for transplant and critically ill patients. METHODS:An ex vivo adult CVVH circuit with AN69ST membrane was established, using whole blood (WB) or blood-crystalloid (BC) to simulate hypoproteinemia and anemia, across a range of ultrafiltration rates (UFR) (1000-4000 mL/h) and point-of-dilution. Study drugs (tacrolimus, ciclosporin, mycophenolic acid (MPA), hydrocortisone, and methylprednisolone) were administered at clinically relevant concentrations. Drug concentrations were quantified by ultra-high-performance liquid chromatography-tandem mass spectrometry, and sieving coefficient (Sc) and clearance (Cl) were calculated. RESULTS:Mean Sc and Cl were significantly higher for BC than WB: methylprednisolone (Sc: 0.44 vs. 0.19 p < 0.001; Cl: 17.31 mL/min vs. 6.99 mL/min p < 0.001), hydrocortisone (Sc: 0.20 vs. 0.09 p = 0.005; Cl: 7.12 mL/min vs. 3.15 mL/min p = 0.01), MPA (Sc: 0.05 vs. 0.02 p < 0.001; Cl: 1.83 mL/min vs. 0.71 mL/min p < 0.001), ciclosporin (Sc: 0.00 vs. 0.00 p = 0.008; Cl: 0.02 mL/min vs. 0.01 mL/min p = 0.004). Tacrolimus was undetectable in ultrafiltrate. Point-of-dilution had minimal effect, except at UFR 4000 mL/h where pre-dilution increased MPA and methylprednisolone clearance. CONCLUSIONS:Hydrocortisone and methylprednisolone were cleared by CVVH, while tacrolimus, ciclosporin, and MPA Cl were negligible or absent. Hypoproteinemia and anemia significantly increased drug Cl. These findings provide mechanistic insights and support the need for validation in clinical studies to guide dosing during CKRT.

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.

Objective Childhood-onset SLE (cSLE) is often described as more severe than adult-onset disease (aSLE) based largely on cross-sectional studies. We examined differences in disease characteristics, medication use and long-term outcomes between cSLE and patients with aSLE in adulthood using longitudinal data from a national cohort to address this knowledge gap. Methods A retrospective cohort study was conducted using the Australian Lupus Registry and Biobank. Data included demographics, disease duration, autoantibody profile, classification criteria, time-adjusted mean SLE Disease Activity Index 2000 (SLEDAI-2K AMS), SLE Damage Index (SDI) and SF36 health-related quality of life data. Key outcomes were AMS and time in the Lupus Low Disease Activity State (LLDAS) and damage accrual. Bivariate tests were used for group comparisons. Results Of 519 patients with SLE enrolled between 2011 and 2022 with ≥12 months of data available, 68 (13%) had cSLE. Median (IQR) age at enrolment was 39 (30–51) years; 88.1% female; majority were of white or Asian ethnicity. At baseline, more patients with cSLE had damage (SDI≥1) (53% vs 40%, p=0·05) and renal involvement (62% vs 37%, p<0·001). Over median (IQR) follow-up of 5 (2·6–9·3) years, patients with cSLE had higher disease activity (median (IQR) AMS 5·0 (3·0–6·4) cSLE vs 3·6 (1·9–5·1) aSLE, p<0.001), were more likely to be in High Disease Activity Status (SLEDAI-2K ≥10 ever) and were less likely to achieve LLDAS-50 (36% vs 51%, p=0·036). Flare rates, damage accrual and quality of life during follow-up were similar between groups. Conclusions Adults with cSLE entered adult follow-up with higher baseline damage and continued to experience a higher longitudinal disease activity burden than patients with aSLE. These findings highlight the importance of early recognition, consistent longitudinal monitoring and timely escalation of therapy during earlier years of disease to reduce long-term disease burden.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by inflammation of small- to medium-sized blood vessels with ANCAs. Induction therapy has historically involved cyclophosphamide (CYC) and glucocorticoids (GCS), with rituximab (RTX) emerging as a preferred alternative. Studies addressed the efficacy of RTX in severe kidney diseases, showing results comparable to CYC. In severe diseases that are unsuitable for high-dose CYC, combined RTX and low-dose CYC demonstrate promising results. There is a recent trend to administer low-dose GCS to reduce infections and other complications. Recent trials have questioned the broader role of plasma exchange (PLEX), influencing guidelines’ updates. Current indications for PLEX include severe kidney dysfunction, positive glomerular basement membrane antibody, and diffuse alveolar hemorrhage that requires oxygen support at presentation. Maintenance therapy options include azathioprine, RTX, and methotrexate. RTX's efficacy as a maintenance agent was demonstrated in trials. However, controversies in dosing frequency persist. The optimal duration of maintenance therapy remains debated, with guidelines suggesting 18–48 months. More recent studies proposed longer durations to reduce the risk of relapse, thus challenging existing guidelines. Complement involvement in AAV has been increasingly recognized. Studies show that complement 3 depositions in the glomeruli correlate with severe disease and complement inhibitors such as avacopan demonstrated efficacy in the management of AAV. Other complement inhibitors, such as eculizumab and vilobelimab, are being explored. In conclusion, AAV management has made significant advances, but controversies persist. Future research should refine therapeutic regimens and explore novel targeted treatments for personalized medicine in AAV.

The impact of the coronavirus disease 2019 (COVID-19) pandemic extended beyond direct infection-associated complications to wide-reaching impacts on health system including workflow disruption, enhanced telehealth utilization, labor force changes, and access to procedures. Whilst it is clear that COVID-19 can affect histopathological findings on kidney biopsy, the impact of COVID-19 pandemic on non-COVID-19 kidney disease research remains unclear. This study reviewed kidney biopsy research activity (i.e., patient consent and bio-sample collection), kidney biopsy practice and histopathological findings over the COVID-19 pandemic in an Australian metropolitan health service network of 4 hospitals between 2018 and 2023. All kidney biopsies performed at the Metro North Kidney Health Service between 2018 and 2023 were divided into pre-pandemic (2018-2019), pandemic (2020-2021) and post-pandemic (2022-2023) eras. Demographic data, consent rates, bio-sample collection rates, and procedural complications were retrospectively compared between the 3 eras. Two hundred twenty-nine kidney biopsies were performed in 2018 to 2019, 223 in 2020 to2021 and 213 in 2022 to 2023. Participant consent for research reduced from 70% to 63% between pre-pandemic to pandemic eras but quickly recovered in the post-pandemic era (68%). Bio-sample collection decreased (pre-pandemic: 50%, pandemic: 47%, post-pandemic: 38%) and did not recover in the post-pandemic era indicating the long tail effect on research activities. Although there were changes in service provision (e.g., delay in elective procedures, lockdowns), these measures were not associated with changes in biopsy number, setting, and department over the course of the pandemic. Kidney disease biomarker research activities decreased during the COVID-19 pandemic as demonstrated by reductions in biomarker study consent and sample collection. Strategies to maintain non-pandemic research need to be built into pandemic preparedness plans to preserve the momentum of discoveries which improve clinical outcomes for non-pandemic diseases; discoveries which may well end up being repurposed for pandemic-related conditions (e.g., remdesivir from Ebola research).

Background: There has been growing interest in exploring combined interventions to achieve a more effective heparin-free treatment approach. Aim: to evaluate combination of interventions compared to standard practice (intermittent flushes) to prevent clotting and consequently reduce premature interruptions of hemodialysis. Methods: This open-label randomized controlled trial recruited chronic hemodialysis patients with contra-indication to systemic heparinization. Participants were randomized into one of five groups to receive different strategies of heparin-free hemodialysis treatment for up to three sessions. Primary endpoint: the successful completion of hemodialysis without clotting. Secondary outcomes: the clotting of the air traps assessed by a semi-quantitative scale, online KT/V, and safety of the interventions. Results: Forty participants were recruited and randomized between May and December 2020. Participants showed similar baseline biochemistry results and coagulation profiles. The highest success rates were observed in group 3 (heparin-coated dialyzers combined with intermittent flushes) (100%) and group 5 (hemodiafiltration with online predilution combined with heparin-coated dialyzers), with 91% vs. the control (intermittent flushes) (64%). Group 2 (heparin-coated dialyzers alone) had the poorest success rate, with 38% of the sessions being prematurely terminated due to clotting. KT/V and clotting scores were similar between groups. No adverse events related to the trial interventions were observed. Conclusions: The proposed combination of interventions may have had additive effects, leading to less frequent clotting and the premature termination of an HD/HDF session. Our study supports the feasibility of conducting a larger randomized controlled trial focusing on the efficacy of combined interventions for heparin-free HD in patients with a high risk of bleeding.

Background Pregnancies in women on dialysis remain rare but are increasing in numbers.Methods Retrospective observational audit of seven cases from 1977 to 2022 of all women who conceived prior to dialysis or conceived whilst on dialysis.Results Of a total of seven women, three were referred from regional centres in Australia, between the 6 and 20 weeks of gestation, generally without any opportunity for pre-conception counselling. Five were managed with intensive haemodialysis aiming for six sessions per week; one patient continued peritoneal dialysis until birth by caesarean section. Five women out of seven had live births, two of which were conceived whilst on dialysis. Four were delivered prematurely between 27 and 31 weeks of gestation, and one at term via spontaneous vaginal delivery.Conclusions Outcomes for women with pregnancies on dialysis benefit from intensive dialysis management however the practical implementation remains challenging. Our cases highlight the diversity of experience in our centre across two decades.

AbstractObjectivesDysregulation of Epstein–Barr virus (EBV)‐specific cellular immunity has been hypothesised as one of the contributing factors in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis is a major risk factor for overall morbidity in SLE. Immune‐based strategies directed to EBV have been proposed as potential therapeutic strategy for SLE and lupus nephritis.MethodsAutologous EBV latent antigen‐specific CD4+ and CD8+ T cells were expanded in vitro and adoptively transferred to a lupus nephritis patient.ResultsThis adoptive immunotherapy had no immediate adverse effects, and the patient was subsequently treated with the anti‐CD20 antibody, obinutuzumab. The patient showed a reduction in anti‐dsDNA antibodies and improved glomerular filtration rate but remained nephrotic. These observations were coincident with a reduction in anti‐viral and global T‐cell activation.ConclusionTo our knowledge, this is the first report of the use of EBV‐specific adoptive immunotherapy to treat a patient with lupus nephritis.

INTROUDCTION:There is increased risk of skin cancer in patients with gloermular disease or those with renal transplant.OBJECTIVES:To compare the risk of skin cancer between kidney recipients (KTRs) and patients with glomerular disease (GD).DESIGN:The cohort comprised patients with KTRs (n = 61) and GD (n = 51) in Central and Central West Queensland, Australia. A quantitative cohort study was undertaken to study the risk of skin cancer in rural communities between two subgroups of patients with kidney diseases in relationship to immunosuppression. Statistical analyses of the differences in incidence of skin cancers between the two groups were done by chi-square test, Fisher's exact test, independent t-test and McNemar's test.FINDINGS:KTRs with non-melanoma skin carcinoma (NMSC) increased significantly after treatment with immunosuppressants (pre-transplantation, n = 11 [18.0%], post-transplantation, n = 28 [45.9%]; p < 0.001). There were no differences in number of patients with NMSC observed in the GD group (pre-diagnosis, n = 6 [11.8%], post-diagnosis, n = 7 [13.7%]; p = 1.000). Compared to the risks at 1 year post-immunosuppressants, the incidence of NMSC of KTRs increased significantly at 3 years (20.3% vs. 35.4%, p < 0.001) and 5 years (20.3% vs. 62.2%, p < 0.001) post-immunosuppressants, whereas the increased incidence of NMSC was observed only at 5 years (2.1% vs. 11.8%, p = 0.012) in the GD cohort. The mean cumulative number of NMSC in KTRs increased significantly at 3 years (p = 0.011), and 5 years (p = 0.001) post-immunosuppressants, compared to the risks at 1 year post-immunosuppressants, however, no differences were noted in the GD cohort.DISCUSSION:Immunosuppressants increased the risk of NMSC in KTRs. The increased risk is likely dependent on the intensity and duration of immunosuppressants.CONCLUSION:In patients with a high risk of NMSC, reducing skin cancer risk should be considered in conjunction with the optimisation of treatment.

OBJECTIVE:Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS:RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS:Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS:Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER:NCT01697267; ClinicalTrials.gov identifier.