IgA vasculitis nephritis-outcomes in adult-onset disease.

OBJECTIVES: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes. METHODS: We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. RESULTS: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. CONCLUSIONS: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.

Postendoscopy Care for Patients Presenting With Esophageal Food Bolus Impaction: A Population-Based Multicenter Cohort Study.

INTRODUCTION: Esophageal food bolus impactions (FBI) are a common gastrointestinal emergency. Appropriate management includes not only index endoscopy for disimpaction but also medical follow-up and treatment for the underlying esophageal pathology. We evaluated the appropriateness of postendoscopy care for patients with FBI and assessed patient-related, physician-related, and system-related factors that may contribute to loss to follow-up. METHODS: We conducted a retrospective, population-based, multicenter cohort study of all adult patients undergoing endoscopy for FBI in the Calgary Health Zone, Canada, from 2016 to 2018. Appropriate postendoscopy care was defined by a composite of a clinical or endoscopic follow-up visit, appropriate investigations (e.g., manometry), or therapy (e.g., proton-pump inhibitors or endoscopic dilation). Predictors of inappropriate care were assessed using multivariable logistic regression. RESULTS: A total of 519 patients underwent endoscopy for FBI: 25.2% (131/519) did not receive appropriate postendoscopy care. Half of the patients (55.3%, 287/519) underwent follow-up endoscopy or attended clinic, and among this group, 22.3% (64/287) had a change in their initial diagnosis after follow-up, including 3 new cases of esophageal cancer. Patients in whom a suspected underlying esophageal pathology was not identified at the index endoscopy were 7-fold (adjusted odds ratio 7.28, 95% confidence interval 4.49-11.78, P < 0.001) more likely to receive inappropriate postendoscopy follow-up and treatment, even after adjusting for age, sex, rural residence, timing of endoscopy, weekend presentation, and endoscopic interventions. DISCUSSION: One-quarter of patients presenting with an FBI do not receive appropriate postendoscopy care. This is strongly associated with failure to identify a potential underlying pathology at index presentation.

"Catch-Store-Release" Strategy for the Stabilization of 4,4'-Methylene Diphenyl Diisocyanate (4,4'-MDI).

4,4'-Methylene diphenyl diisocyanate (MDI) is an industrially crucial compound, being one of the most utilized linkers in the polyurethane industry. However, its long-term stability is limited due to dimerization to form insoluble uretdione. Herein we demonstrate an organometallic "catch-store-release" concept aiming at improving the long-term chemical stability of MDI. Treatment of MDI with two equivalents of selected N-heterocyclic carbenes (NHC) forms stable MDI-NHC adducts. Treatment of the adducts with CuCl forms metastable di-CuI complexes that undergo decomposition to re-form MDI (up to 85 %), along with Cu-NHC complexes. The yield of re-formed MDI can be improved (up to 95 %) by the release of the NHC ligands in the form of thiourea; this prevents subsequent MDI dimerization/polymerization by the carbenes. Furthermore, the need to separate MDI from the reaction mixture can be eliminated by the direct reaction of MDI-NHC complexes with alcohols (as models for diols), that form dicarbamate (as a model for polyurethane) quantitatively.

Low tidal volume ventilation for patients undergoing laparoscopic surgery: a secondary analysis of a randomised clinical trial.

BACKGROUND: We recently reported the results for a large randomized controlled trial of low tidal volume ventilation (LTVV) versus conventional tidal volume (CTVV) during major surgery when positive end expiratory pressure (PEEP) was equal between groups. We found no difference in postoperative pulmonary complications (PPCs) in patients who received LTVV. However, in the subgroup of patients undergoing laparoscopic surgery, LTVV was associated with a numerically lower rate of PPCs after surgery. We aimed to further assess the relationship between LTVV versus CTVV during laparoscopic surgery. METHODS: We conducted a post-hoc analysis of this pre-specified subgroup. All patients received volume-controlled ventilation with an applied PEEP of 5 cmH2O and either LTVV (6 mL/kg predicted body weight [PBW]) or CTVV (10 mL/kg PBW). The primary outcome was the incidence of a composite of PPCs within seven days. RESULTS: Three hundred twenty-eight patients (27.2%) underwent laparoscopic surgeries, with 158 (48.2%) randomised to LTVV. Fifty two of 157 patients (33.1%) assigned to LTVV and 72 of 169 (42.6%) assigned to conventional tidal volume developed PPCs within 7 days (unadjusted absolute difference, - 9.48 [95% CI, - 19.86 to 1.05]; p = 0.076). After adjusting for pre-specified confounders, the LTVV group had a lower incidence of the primary outcome than patients receiving CTVV (adjusted absolute difference, - 10.36 [95% CI, - 20.52 to - 0.20]; p = 0.046). CONCLUSION: In this post-hoc analysis of a large, randomised trial of LTVV we found that during laparoscopic surgeries, LTVV was associated with a significantly reduced PPCs compared to CTVV when PEEP was applied equally between both groups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry no: 12614000790640.

Social dominance and rainfall predict telomere dynamics in a cooperative arid-zone bird.

In many vertebrate societies dominant individuals breed at substantially higher rates than subordinates, but whether this hastens ageing remains poorly understood. While frequent reproduction may trade off against somatic maintenance, the extraordinary fecundity and longevity of some social insect queens highlight that breeders need not always suffer more rapid somatic deterioration than their nonbreeding subordinates. Here, we used extensive longitudinal assessments of telomere dynamics to investigate the impact of dominance status on within-individual age-related changes in somatic integrity in a wild social bird, the white-browed sparrow-weaver (Plocepasser mahali). Dominant birds, who monopolise reproduction, had neither shorter telomeres nor faster telomere attrition rates over the long-term (1-5 years) than their subordinates. However, over shorter (half-year) time intervals dominants with shorter telomeres showed lower rates of telomere attrition (and evidence suggestive of telomere lengthening), while the same was not true among subordinates. Dominants may therefore invest more heavily in telomere length regulation (and/or somatic maintenance more broadly); a strategy that could mitigate the long-term costs of reproductive effort, leaving their long-term telomere dynamics comparable to those of subordinates. Consistent with the expectation that reproduction entails short-term costs to somatic integrity, telomere attrition rates were most severe for all birds during the breeding seasons of wetter years (rainfall is the key driver of reproductive activity in this arid-zone species). Our findings suggest that, even in vertebrate societies in which dominants monopolise reproduction, dominants may experience long-term somatic integrity trajectories indistinguishable from those of their nonreproductive subordinates.

Peptide GAM immunoadsorption in anti-PLA2 R positive autoimmune membranous nephropathy. The PRISM trial.

Membranous nephropathy associated with anti-PLA2 R autoantibody is a significant cause of nephrotic syndrome worldwide. Treatment remains empiric with a significant side-effect burden despite an increase in our understanding of the disease. We studied the effect of selectively removing this pathogenic autoantibody using immunoadsorption in adult patients with biopsy proven anti-PLA2 R membranous nephropathy. This was a multicenter, single-arm prospective clinical trial carried out in the United Kingdom. Twelve patients underwent five consecutive sessions of peptide GAM immunoadsorption with 12 months follow-up. Primary outcome was anti-PLA2 R titer at week 2. Secondary outcomes were safety and tolerability of therapy, antibody profile, and change in proteinuria, renal excretory function, serum albumin, total immunoglobulin, and quality of life at weeks 12, 24, and 52. Patients were also stratified by the presence or absence of the high-risk allele (heterozygous or homozygous for HLA-DQA1*05). Median pretreatment anti-PLA2 R was 702.50 U/mL, 1045.00 U/mL at week 2 (P-value .023) and 165.00 U/mL at week 52 (P-value .017). The treatment was well tolerated and safe. Two patients required rescue immunosuppression during the follow-up period. There was a significant improvement in serum albumin with a median at baseline of 20.50 g/L rising to 25.00 g/L at week 52 (P-value <.001). There was no statistical difference over the follow-up period in proteinuria or renal function. Patients in possession of a high-risk allele saw improvement in anti-PLA2 R titers, possibly representing a cohort more likely to benefit from immunoadsorption. Immunoadsorption therapy is a safe treatment and well-tolerated treatment in anti-PLA2 R positive autoimmune membranous nephropathy.

Intraoperative low tidal volume ventilation and the risk of ICD-10 coded delirium and the use for antipsychotic medications.

BACKGROUND: Low tidal volume (VT) ventilation and its associated increase in arterial carbon dioxide (PaCO2) may affect postoperative neurologic function. We aimed to test the hypothesis that intraoperative low VT ventilation affect the incidence of postoperative ICD-10 coded delirium and/or the need for antipsychotic medications. METHODS: This is a post-hoc analysis of a large randomized controlled trial evaluating low vs. conventional VT ventilation during major non-cardiothoracic, non-intracranial surgery. The primary outcome was the incidence of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay, and the absolute difference with its 95% confidence interval (CI) was calculated. RESULTS: We studied 1206 patients (median age of 64 [55-72] years, 59.0% males, median ARISCAT of 26 [19-37], and 47.6% of ASA 3). ICD-10 coded delirium and /or antipsychotic medication use was diagnosed in 11.2% with similar incidence between low and conventional VT ventilation (11.1% vs. 11.3%; absolute difference, -0.24 [95%CI, -3.82 to 3.32]; p = 0.894). There was no interaction between allocation group and type of surgery. CONCLUSION: In adult patients undergoing major surgery, low VT ventilation was not associated with increased risk of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12614000790640 .

Intra-operative ventilator mechanical power as a predictor of postoperative pulmonary complications in surgical patients: A secondary analysis of a randomised clinical trial.

BACKGROUND: Studies in critically ill patients suggest a relationship between mechanical power (an index of the energy delivered by the ventilator, which includes driving pressure, respiratory rate, tidal volume and inspiratory pressure) and complications. OBJECTIVE: We aimed to assess the association between intra-operative mechanical power and postoperative pulmonary complications (PPCs). DESIGN: Post hoc analysis of a large randomised clinical trial. SETTING: University-affiliated academic tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. PATIENTS: Adult patients undergoing major noncardiothoracic, nonintracranial surgery. INTERVENTION: Dynamic mechanical power was calculated using the power equation adjusted by the respiratory system compliance (CRS). Multivariable models were used to assess the independent association between mechanical power and outcomes. MAIN OUTCOME MEASURES: The primary outcome was the incidence of PPCs within the first seven postoperative days. The secondary outcome was the incidence of acute respiratory failure. RESULTS: We studied 1156 patients (median age [IQR]: 64 [55 to 72] years, 59.5% men). Median mechanical power adjusted by CRS was 0.32 [0.22 to 0.51] (J min-1)/(ml cmH2O-1). A higher mechanical power was also independently associated with increased risk of PPCs [odds ratio (OR 1.34, 95% CI, 1.17 to 1.52); P < 0.001) and acute respiratory failure (OR 1.40, 95% CI, 1.21 to 1.61; P < 0.001). CONCLUSION: In patients receiving ventilation during major noncardiothoracic, nonintracranial surgery, exposure to a higher mechanical power was independently associated with an increased risk of PPCs and acute respiratory failure. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry no: 12614000790640.

HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.

Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.

Chronic anticoagulation is not associated with a reduced risk of acute kidney injury in hospitalised Covid-19 patients.

BACKGROUND: Coronavirus-19 (COVID-19) has been declared a global pandemic by the World Health Organisation. Severe disease typically presents with respiratory failure but Acute Kidney Injury (AKI) and a hypercoagulable state can also occur. Early reports suggest that thrombosis may be linked with AKI. We studied the development of AKI and outcomes of patients with COVID-19 taking chronic anticoagulation therapy. METHODS: Electronic records were reviewed for all adult patients admitted to Manchester University Foundation Trust Hospitals between March 10 and April 302,020 with a diagnosis of COVID-19. Patients with end-stage kidney disease were excluded. AKI was classified as per KDIGO criteria. RESULTS: Of the 1032 patients with COVID-19 studied,164 (15.9%) were taking anticoagulant therapy prior to admission. There were similar rates of AKI between those on anticoagulants and those not anticoagulated (23.8% versus 19.7%) with no difference in the severity of AKI or requirement of renal replacement therapy between groups (1.2% versus 3.5%). Risk factors for AKI included hypertension, pre-existing renal disease and male sex. There was a higher mortality in those taking anticoagulant therapy (40.2% versus 30%). Patients taking anticoagulants were less likely to be admitted to the Intensive Care Unit (8.5% versus 17.4%) and to receive mechanical ventilation (42.9% versus 78.1%). CONCLUSION: Patients on chronic anticoagulant therapy did not have a reduced incidence or severity of AKI suggesting that AKI is unlikely to be thrombotic in nature. Therapeutic anticoagulation is currently still under investigation in randomised controlled studies to determine whether it has a potential role in COVID-19 treatment.

Investigation into Adaptation in Genes Associated with Response to Estrogenic Pollution in Populations of Roach (Rutilus rutilus) Living in English Rivers.

Exposure of male fish to estrogenic substances from wastewater treatment works (WwTWs) results in feminization and reduced reproductive fitness. Nevertheless, self-sustaining populations of roach (Rutilus rutilus) inhabit river stretches polluted with estrogenic WwTW effluents. In this study, we examine whether such roach populations have evolved adaptations to tolerate estrogenic pollution by comparing frequency differences in single-nucleotide polymorphisms (SNPs) between populations sampled from rivers receiving either high- or low-level WwTW discharges. SNPs within 36 "candidate" genes, selected for their involvement in estrogenic responses, and 120 SNPs in reference genes were genotyped in 465 roaches. There was no evidence for selection in highly estrogen-dependent candidate genes, including those for the estrogen receptors, aromatases, and vitellogenins. The androgen receptor (ar) and cytochrome P450 1A genes were associated with large shifts in allele frequencies between catchments and in individual populations, but there is no clear link to estrogen pollution. Selection at ar in the effluent-dominated River Lee may have resulted from historical contamination with endocrine-disrupting pesticides. Critically, although our results suggest population-specific selection including at genes related to endocrine disruption, there was no strong evidence that the selection resulted from exposure to estrogen pollution.

Effect of Intraoperative Low Tidal Volume vs Conventional Tidal Volume on Postoperative Pulmonary Complications in Patients Undergoing Major Surgery: A Randomized Clinical Trial.

Importance: In patients who undergo mechanical ventilation during surgery, the ideal tidal volume is unclear. Objective: To determine whether low-tidal-volume ventilation compared with conventional ventilation during major surgery decreases postoperative pulmonary complications. Design, Setting, and Participants: Single-center, assessor-blinded, randomized clinical trial of 1236 patients older than 40 years undergoing major noncardiothoracic, nonintracranial surgery under general anesthesia lasting more than 2 hours in a tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. The last date of follow-up was February 17, 2019. Interventions: Patients were randomized to receive a tidal volume of 6 mL/kg predicted body weight (n = 614; low tidal volume group) or a tidal volume of 10 mL/kg predicted body weight (n = 592; conventional tidal volume group). All patients received positive end-expiratory pressure (PEEP) at 5 cm H2O. Main Outcomes and Measures: The primary outcome was a composite of postoperative pulmonary complications within the first 7 postoperative days, including pneumonia, bronchospasm, atelectasis, pulmonary congestion, respiratory failure, pleural effusion, pneumothorax, or unplanned requirement for postoperative invasive or noninvasive ventilation. Secondary outcomes were postoperative pulmonary complications including development of pulmonary embolism, acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis, acute kidney injury, wound infection (superficial and deep), rate of intraoperative need for vasopressor, incidence of unplanned intensive care unit admission, rate of need for rapid response team call, intensive care unit length of stay, hospital length of stay, and in-hospital mortality. Results: Among 1236 patients who were randomized, 1206 (98.9%) completed the trial (mean age, 63.5 years; 494 [40.9%] women; 681 [56.4%] undergoing abdominal surgery). The primary outcome occurred in 231 of 608 patients (38%) in the low tidal volume group compared with 232 of 590 patients (39%) in the conventional tidal volume group (difference, -1.3% [95% CI, -6.8% to 4.2%]; risk ratio, 0.97 [95% CI, 0.84-1.11]; P = .64). There were no significant differences in any of the secondary outcomes. Conclusions and Relevance: Among adult patients undergoing major surgery, intraoperative ventilation with low tidal volume compared with conventional tidal volume, with PEEP applied equally between groups, did not significantly reduce pulmonary complications within the first 7 postoperative days. Trial Registration: ANZCTR Identifier: ACTRN12614000790640.

Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous nephropathy: a Health Economic Model.

Background: Membranous nephropathy is among the most common causes of nephrotic syndrome worldwide, with a high healthcare burden. Treatment using the modified Ponticelli regimen (mPR) has remained the standard of care for decades, but newer therapies such as rituximab offer promising results with reduced side effects. The cost of this treatment, however, is perceived as a barrier to widespread use, especially in resource limited healthcare systems. Methods: We developed a decision-analytic model to estimate the cost-effectiveness of rituximab versus the mPR from the perspective of the National Health Service in the UK over a 1 year, 5 year and lifetime horizon. Primary outcome is the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes are cost-effectiveness at 1 and 10 years post-treatment and over a lifetime. Results: At 1-year post-treatment, rituximab therapy dominates mPR. At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 quality-adjusted life years (QALYs) with an incremental cost-effectiveness ratio (ICER) of £95 494.13. Over a lifetime, rituximab remains the cheaper option with an incremental cost of -£5251.03 but with a reduced quality of life (incremental QALY of -0.512) giving an ICER of £10 246.09. Conclusions: Our analysis indicates that rituximab has the potential to be a cost-effective treatment in the short and medium terms despite the high single-dose cost. This evaluation suggests that further research is warranted and highlights the need for a high-quality clinical trial to confirm the efficacy and cost-effectiveness of rituximab versus the current standard of care.

Intravenous pulse cyclophosphamide and steroids induce immunological and clinical remission in New-incident and relapsing primary membranous nephropathy.

AIM: Primary membranous nephropathy is associated with progression to end stage renal diseasein some patients. Standard therapy with cyclical cyclophosphamide and corticosteroids can be associated with significant adverse effects. We aimed to assess immunological and clinical response with intravenous pulse cyclophosphamide and oral steroids in patients with severe nephrotic syndrome - in a prospective observational cohort study. METHODS: A total of 17 consecutive patients (nine new-incident and eight relapses) with severe nephrotic syndrome received monthly intravenous pulse cyclophosphamide and oral steroids after failure to achieve remission with supportive therapy. Immunosuppressive therapy was discontinued at 6 months or earlier if proteinuria regressed to <100 mg/mmol and patients were followed for 12 months. Achievement of partial remission was primary outcome; changes in clinical parameters and anti-PLA2 R were secondary outcomes. RESULTS: Dose of cyclophosphamide received was 5.4 g in New-incident patients and 4.2 g in patients with relapses. All 17 patients achieved partial remission within 6 months: proteinuria improved from 656 to 102 mg/mmol at 6 months and 55 mg/mmol at 12 months (P < 0.001); eGFR improved from 31 to 48 mL/min per 1.73 m2 at 6 months and 45 mL/min per 1.73 m2 at 12 months (P < 0.05). Anti-PLA2 R levels reduced from 244 to 10 U/L at 6 months and 10 U/L at 12 months (P < 0.001). Two out of nine patients in the New-incident group developed subsequent relapse. Cumulative doses of cyclophosphamide and steroids that patients received was about half of the standard regime. CONCLUSION: Pulse cyclophosphamide with oral steroids induced immunological and clinical partial remission at significantly reduced doses in primary membranous nephropathy.

Peptide GAM immunoadsorption therapy in primary membranous nephropathy (PRISM): Phase II trial investigating the safety and feasibility of peptide GAM immunoadsorption in anti-PLA2 R positive primary membranous nephropathy.

INTRODUCTION: Membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in adults worldwide. Most patients have primary MN (PMN), an autoimmune condition associated with the IgG anti-PLA2 R autoantibody. For patients with severe disease, standard of care continues to be a 6-month regime of rotating high dose steroids and immunosuppression that comes with a significant side-effect profile. Immunoadsorption is a relatively safe procedure for the extracorporeal removal of specific immunoglobulins without the need for medications. DESIGN: This is a Phase II multi-centre, single arm prospective clinical trial carried out across Northwest region of the United Kingdom to assess the safety and clinical effectiveness of immunoadsorption therapy in PMN. 12 adult patients with biopsy proven MN, nephrotic range proteinuria and serum anti-PLA2 R antibody titers of more than 170 µ/mL will undergo 5 consecutive daily sessions of immunoadsorption. Primary outcome is the reduction of serum anti-PLA2 R antibodies at day 14. Secondary outcomes are the safety and tolerability of immunoadsorption therapy in patients with primary MN at all-time points, reduction of serum anti-PLA2 R levels, proteinuria and improvement in renal function. Quality of life and Cost-effectiveness of treatment will be assessed from a UK National Health Service perspective. DISCUSSION: With proven efficacy in removing IgG antibodies and its use as a relatively safe treatment option in a multitude of conditions, immunoadsorption has the potential to offer patients with primary MN a more directed therapy free from the short and long-term side-effects generally seen in this condition.

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

Long-term outcomes of persistent disease and relapse in primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood. METHODS: We performed a retrospective study of 128 consecutive adult patients diagnosed with biopsy proven PMN at a single UK centre between 1980 and 2010. These patients were followed prospectively over a median of 128 months. We assessed impact of persistent disease and relapse on Stage 5 chronic kidney disease (CKD-5) and patient survival and present longer term cumulative incidences of different end points. RESULTS: One hundred patients achieved partial remission (PartRem) and 28 patients did not achieve remission (NoRem). Nine per cent of patients achieving first remission developed CKD-5 and 75% of those with NoRem developed CKD-5 [hazard ratio (HR) 0.07, 95% confidence interval 0.03-0.19). Relapse following PartRem occurred in 31 patients (31%) during follow-up and was significantly associated with progression to CKD-5. Progression to CKD-5 was strongly associated with death (47 versus 6%, HR 23.4; P < 0.01). Cumulative incidence at 15 years following first presentation included: death, 14%; CKD-5, 28%; and relapse 40% (in patients who achieved first remission). CONCLUSIONS: Our data strongly suggest that mortality in PMN is seen in patients with disease progression to CKD-5. Achieving remission is strongly associated with improved renal survival after first presentation and following relapse. We suggest that patients who achieve remission should be followed up in longer term, and better strategies to help improve outcomes are needed in clinical practice.

The economic burden of cancer in the UK: a study of survivors treated with curative intent.

OBJECTIVE: We aim to describe the economic burden of UK cancer survivorship for breast, colorectal and prostate cancer patients treated with curative intent, 1 year post-diagnosis. METHODS: Patient-level data were collected over a 3-month period 12-15 months post-diagnosis to estimate the monthly societal costs incurred by cancer survivors. Self-reported resource utilisation data were obtained via the electronic Patient-reported Outcomes from Cancer Survivors system and included community-based health and social care, medications, travel costs and informal care. Hospital costs were retrieved through data linkage. Multivariate regression analysis was used to examine cost predictors. RESULTS: Overall, 298 patients were included in the analysis, including 136 breast cancer, 83 colorectal cancer and 79 prostate cancer patients. The average monthly societal cost was $ US 409 (95%CI: $ US 316-$ US 502) [mean: £ 260, 95%CI: £ 198-£ 322] and was incurred by 92% of patients. This was divided into costs to the National Health Service (mean: $ US 279, 95%CI: $ US 207-$ US 351) [mean: £ 177, 95%CI: £ 131-£ 224], patients' out-of-pocket (OOP) expenses (mean: $ US 40, 95%CI: $ US 15-$ US 65) [mean: £ 25, 95%CI: £ 9-£ 42] and the cost of informal care (mean: $ US 110, 95%CI: $ US 57-$ US 162) [mean: £ 70, 95%CI: £ 38-£ 102]. The distribution of costs was skewed with a small number of patients incurring very high costs. Multivariate analyses showed higher societal costs for breast cancer patients. Significant predictors of OOP costs included age and socioeconomic deprivation. CONCLUSIONS: This study found the economic burden of cancer survivorship is unevenly distributed in the population and that cancer survivors may still incur substantial costs over 1 year post-diagnosis. In addition, this study illustrates the feasibility of using an innovative online data collection platform to collect patient-reported resource utilisation information.

Successful outcome of pregnancy in patients with anti-neutrophil cytoplasm antibody-associated small vessel vasculitis.

Pregnancy in patients with anti-neutrophil cytoplasm antibody-associated vasculitis is reportedly associated with a high risk of fetal and maternal complications. Here we describe the outcome of pregnancies in patients with granulomatosis with polyangiitis and microscopic polyangiitis at five centers in the United Kingdom using a retrospective case review of all women who became pregnant following diagnosis. We report 15 pregnancies in 13 women resulting in 15 live births including one twin pregnancy and 13 singleton pregnancies. One patient had an unplanned pregnancy and a first trimester miscarriage while taking methotrexate. All other pregnancies were planned following a minimum of 6 months clinical remission. Eleven successful pregnancies were delivered vaginally at full term, whereas three were delivered by cesarean section. All infants were healthy with no neonatal complications on their initial health check within the first 24 h of delivery and no evidence of neonatal vasculitis. One relapse occurred during pregnancy and was successfully treated with an increased dose of azathioprine and corticosteroids, intravenous immunoglobulin, and plasma exchange therapy. One patient developed tracheal crusting and subglottic stenosis of infective etiology in the third trimester requiring tracheal debridement post delivery. No patient had a relapse in the first 12 months postpartum. Thus, successful pregnancy outcomes can occur following planned pregnancy in women in sustained remission on non-teratogenic therapies.