IgA vasculitis (IgAV) is an autoimmune disease that affects the small vessels of the skin, joints, gastrointestinal (GI) tract, and kidneys. In the long term, IgAV associated with nephritis (IgAV-N) can progress to kidney failure. Evidence-based clinical studies of IgAV-N are few, leading to huge variations in treatment approaches and suboptimal outcomes. The wealth of emerging efficacious treatments for IgA nephrology brings new opportunities to this disease. The aim of this report is to describe the proceedings of a multiprofessional collaborative workshop convened to identify the barriers to developing high quality evidence for patients with IgAV-N. A multiprofessional group consisting of 53 attendees from 13 countries met. The meeting was represented by a variety of professional backgrounds, including lay attendees, with different levels of expertise (32% professors and 19% midcareer doctors). Using predefined aims, key themes were extracted, and an action plan developed. Consensus was obtained that there is sufficient similarity between adults and children in terms of the organs involved, pathophysiology, histological features, and likely response to treatment. Important differences included the greater spontaneous improvement in children and worse kidney outcomes in some populations. It was agreed that patients at greatest risk of kidney failure should be the primary focus of initial clinical trials. Important considerations included the following: diagnostic classification for adult onset IgAV, observational data, evidence of scientific similarity to IgA nephropathy (IgAN), an age-inclusive approach to trial design, systemic disease secondary end points, and the inclusion of patient-reported outcomes. This manuscript communicates an expert-informed pathway to high-quality evidence for IgAV-N.

IgA nephropathy (IgAN), IgA vasculitis (IgAV), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and minimal change disease (MCD) account for the majority of idiopathic glomerulo-nephropathies (GN). These disorders involve immune system dysregulation and have a complex genetic architecture. Currently, there are no adequately powered blood transcriptomic datasets coupled to genetic data from patients with GN that can delineate disease-context specific genetic effects on the blood immune cell transcriptome. We performed whole genome sequencing coupled with bulk blood transcriptome sequencing on 1,822 participants from the CureGN study, a prospective cohort of participants with a kidney biopsy diagnosis of primary GN. We generated disease-context specific transcriptome-wide maps of gene expression QTL (eQTL), splicing QTL (sQTL), and double strand RNA-editing QTL (edQTL) for FSGS (N=447), IgAN (N=403), IgAV (N=123), MCD (N=408), and MN (N=441), as well as cross-disease maps for all 1,822 participants. Our QTL mapping identified 16,068 eGenes, 4,644 sGenes and 4,611 edQTLs with an FDR<0.05 in at least one GN type. Approximately 5-10% of the QTL signals were unique to a specific GN type, while ~90% were shared between at least two conditions. Colocalization analysis demonstrated that ~80% of shared eGenes between traits also shared the same causal variants, whereas ~2% had distinct causal variants, suggesting context-specific regulatory effects. Cross-phenotype QTL mapping uncovered 6,466 eGenes, 2,705 sGenes and 5,321 edQTLs not previously detected in GTEx. Age, eGFR, and proteinuria-interaction QTL analyses identified hundreds of loci modified by age or disease severity. Lastly, integrative analyses with GWAS nominated new candidate genes for each of the five GN types under study. In summary, we generated comprehensive maps of GN-context-specific genetic effects on the blood transcriptome, providing a powerful new resource for integrative gene discovery studies of primary GN.

The phospholipase A2 receptor antibody (PLA2R-Ab) test is a valuable first-line diagnostic tool for primary membranous nephropathy (MN), helping to identify PLA2R-related MN and potentially eliminating the need for a kidney biopsy in some individuals. By reducing the reliance on biopsies, the test streamlines diagnosis and improves patient care. However, determining the optimal PLA2R measurement method and cut-off is critical to maximizing the benefits of the test and minimizing any harms. A systematic review and meta-analysis were performed to evaluate serum- and urine-based biomarkers for distinguishing between PLA2R-related MN and non-PLA2R MN. Searches were conducted in databases including Medline, Embase, Cochrane Library, Scopus, Web of Science, International HTA Database and ClinicalTrials.gov. The methodology followed Cochrane-recommended guidelines for systematic reviews and meta-analyses, and the QUADAS-2 tool was utilized to assess the overall risk of bias. Ninety-one studies met the eligibility criteria for inclusion in the review. Of these, 38 studies reporting the accuracy of the PLA2R-Ab test using the EUROIMMUN enzyme-linked immunosorbent assay (ELISA) method and 27 using the EUROIMMUN immunofluorescence (IF) method were suitable for meta-analysis. The pooled sensitivity and specificity of EUROIMMUN ELISA at a cut-off value of 20 RU/mL were 0.64 [95% confidence interval (CI) 0.56-0.72] and 94.7% (95% CI 90.5-97.1%), respectively. The pooled sensitivity and specificity of EUROIMMUN IF at a threshold of 1:10 was 0.69 (95% CI 0.637-0.739) and 0.98 (95% CI 0.931-0.994), respectively. Risk of bias was higher for studies evaluating the IF compared with ELISA test. We also explored whether the timing of the index test had an impact on the pooled diagnostic accuracy results; no significant differences were found. By evaluating the specificity and sensitivity of EUROIMMUN ELISA PLA2R-Ab and IF, we demonstrate that at ELISA levels ≥20 RU/mL, alongside thorough secondary screening, a kidney biopsy may be unnecessary. However, lower or negative levels still warrant a biopsy.

Introduction: Despite new treatments, kidney dysfunction in autoimmune membranous nephropathy (aMN) remains challenging. Immunosuppression is initiated after ''watchful-wait'' to avoid side effects in patients who might achieve spontaneous remission; however, the impact of this approach on kidney function is unclear. Methods: This was a retrospective longitudinal cohort study of patients with new consecutive aMN from 2003 to 2019 from 3 UK centers. Patients were assigned to 5 categories, a priori based on baseline urinary protein-to-creatinine ratio (uPCR) and estimated glomerular filtration rate (eGFR). The analysis investigated change in eGFR based on these risk categories. Primary outcomes were spontaneous partial remission (SPR), rate of eGFR change before immunosuppression, and chronic kidney disease (CKD) stage 5 (CKD5). The secondary outcome was progression (composite of doubling serum creatinine, CKD5, and death). Cox proportional hazard models were used to assess association of outcomes with baseline categories. Results: A total of 312 patients were included with 5.0 years median follow-up from diagnosis. A significant association was found between waiting time to immunosuppression and decline in eGFR (P < 0.001) in patients who received immunosuppression. When change was regressed against time, eGFR loss was equivalent to 7.7 ml/min per 1.73 m2/yr of watchful wait. In the low-risk group, 71% achieved SPR and 2.4% progressed to CKD5, whereas in the high-2 risk group, 20% achieved SPR, and 25% developed CKD5. The strongest predictor of progression to CKD5 was the eGFR at the start of immunosuppression treatment, regardless of baseline function. Conclusion: In patients with aMN requiring immunosuppression, delayed treatment leads to worse kidney outcomes. A simple categorization using baseline eGFR and uPCR can help predict spontaneous remission and potential kidney function decline.

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% 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%) (chi(2) 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 estimated glomerular filtration rate < 30 ml/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. Conclusion: 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.

BackgroundSince the emergence of the anti-PLA2R antibody (PLA2R-Ab) test, nephrology practice has not changed dramatically, with most nephrologists still relying on a kidney biopsy to diagnose membranous nephropathy. In this study, we examined the clinical accuracy of the anti-PLA2R antibody test using ELISA in routine clinical care.MethodsWe conducted a retrospective analysis of PLA2R-Ab testing in 187 consecutive patients seen at a single UK centre between 2003 and 2020. We compared the kidney biopsy findings with the PLA2R-ab antibody test. Patients' demography, urine protein creatinine ratios, serum albumin, and treatment characteristics including supportive and immunosuppressive treatment were recorded. The clinical accuracy of the test (e.g. sensitivity and specificity, positive [PPV] and negative [NPV] predictive values) was calculated using the kidney biopsy findings as the diagnostic reference.ResultsMean levels of PLA2R-Ab titre in primary membranous nephropathy were 217RU/ml in comparison to 3RU/ml for both secondary membranous nephropathy and other diagnoses. Most patients with a positive PLA2R-Ab test had a confirmed renal biopsy diagnosis of primary membranous nephropathy with: PPV of 97.3%, sensitivity 75.5%, NPV was 79.8% and specificity was 97.8% at a cut-off threshold of >20 RU/ml.ConclusionThe anti-PLA2R antibody test is a highly specific test for diagnosing membranous nephropathy, and the test has the potential to allow for the diagnosis and treatment in up to 75% of PMN cases without the need for a renal biopsy. Nevertheless, patients with negative PLA2R-Ab tests will still require a biopsy to confirm their diagnosis.

BACKGROUND:Despite MN being one of the most common causes of nephrotic syndrome worldwide, its biological and environmental determinants are poorly understood in large-part due to it being a rare disease. Making use of the UK Biobank, a unique resource holding a clinical dataset and stored DNA, serum and urine for ~500,000 participants, this study aims to address this gap in understanding.METHODS:The primary outcome was putative MN as defined by ICD-10 codes occurring in the UK Biobank. Univariate relative risk regression modelling was used to assess the associations between the incidence of MN and related phenotypes with sociodemographic, environmental exposures, and previously described increased-risk SNPs.RESULTS:502,507 patients were included in the study of whom 100 were found to have a putative diagnosis of MN; 36 at baseline and 64 during the follow-up. Prevalence at baseline and last follow-up were 72 and 199 cases/million respectively. At baseline, as expected, the majority of those previously diagnosed with MN had proteinuria, and there was already evidence of proteinuria in patients diagnosed within the first 5 years of follow-up. The highest incidence rate for MN in patients was seen in those homozygous for the high-risk alleles (9.9/100,000 person-years).CONCLUSION:It is feasible to putatively identify patients with MN in the UK Biobank and cases are still accumulating. This study shows the chronicity of disease with proteinuria present years before diagnosis. Genetics plays an important role in disease pathogenesis, with the at-risk group providing a potential population for recall.

Thromboembolism is one of the most serious complications of nephrotic syndrome, including both arterial and venous thromboembolic events. Rates of thromboembolism depend on a multitude of factors, including the severity and cause of nephrotic syndrome, with primary membranous nephropathy having the highest reported rates. In relation to arterial thromboembolism, the risk can be as high as 8 times that of an age- and sex-matched population. However, extrapolating risks is challenging, with published studies not being homogeneous, several being single center and retrospective, and including different causes of primary nephrotic syndrome. Determining thromboembolic risk in nephrotic syndrome is essential to enable decision making on preventive strategies. However, lack of proven strategies to help estimate risk-benefit aspects underpins variations in clinical practice. Although the use of anticoagulation following a thrombotic event is clear, this still leaves us with a clinical dilemma as to if, and who, should receive prophylactic anticoagulation, with what agent, and for how long. In the absence of clear evidence to answer these questions, prophylactic anticoagulation strategies for nephrotic syndrome currently rely on expert consensus opinion, such as in the recently published 2021 Kidney Disease Improving Global Outcomes glomerular disease guidelines. In the mainstay, these recommendations relate to patients with membranous nephropathy. Here, we detail the current controversies still faced by clinicians around the risk of thromboembolism in nephrotic syndrome, use of prophylactic anticoagulation in nephrotic syndrome and propose ways of advancing existing knowledge and practice in this field to unravel the conundrum.

Introduction and Aims Therapy of Primary Membranous nephropathy (PMN) with progressive advanced kidney dysfunction is challenging with limited literature and no clear therapeutic strategies. This is due to the scant evidence of effectiveness and uncertainty around the risk-benefit profile of immunosuppression (ImS) when eGFR is less than 30 ml/min. We aimed to determine long term clinical outcomes in patients with PMN and severe renal impairment treated with combined cyclophosphamide and steroids. Methods The study is a single-centre retrospective longitudinal cohort study. All patients (between 2004-2019) with biopsy confirmed PMN who initiated combination therapy with steroids and cyclophosphamide and had an eGFR of ≤30ml/min/1.73m2 at the time of initiation of therapy were included for analysis. Clinical and laboratory parameters including Anti-PLA2R-Ab were monitored as per standard clinical guidance. Primary outcome was achievement of partial remission. Secondary outcomes included immunological remission, need for renal replacement therapy, and adverse effects. Results Eighteen patients with median age of 68 (IQR 58-73) years and 5:1 M:F ratio received the combination therapy when eGFR was ≤30ml/min/1.73m2 (CKD-EPI). At time of immunosuppression, median eGFR and uPCR were 23 (IQR 18-27) ml/min/1.73m2 and 1000 (IQR 838-1285) mg/mmol respectively. Median follow-up was for 67 (IQR 27-80) months. 16 patients (89%) achieved partial Remission and 7 (39%) achieved complete remission. eGFR increased by 7ml/min/1.73m2 (27%) after one year of starting immunosuppression treatment and 12ml/min/1.73m2 at end of follow-up. Two patients (11%) developed end stage renal disease needing renal replacement therapy. 67% achieved both immunological and clinical remission. Two (11%) patients required hospitalization secondary to infections, 4 (22%) patients developed cancer and 4 patients died (22%). Conclusion Combination therapy with cyclophosphamide and steroids is effective in achieving partial remission and improving renal function in PMN with advanced renal dysfunction. Prospective controlled studies are required to provide further evidence and improve outcomes in such patients.

Abstract Background and Aims Patients who inject drugs (PWIDs) represent a uniquely difficult population to manage with haemodialysis, often with reliance on tunneled venous access. This population is historically difficult to reach, and their care is usually associated with higher per capita healthcare costs [1], unsurprisingly poor outcomes are reported [2] with a multitude of likely causes. Here we show the time associated opportunity costs these patients experience including the significant complication of tunnelled dialysis line infection in a person who actively injects drugs. Method This study follows on from the work by Burns [3]. In this retrospective observational study, the electronic health records of patients who were known to be ongoing users of recreational drugs were reviewed from January 2015 – August 2021. Patients were reviewed from their first tunneled line placement until either their death or until the end of the study time period. Stata 14 was used to generate descriptive statistics. Results 6 Patients were identified, 5 had a primary diagnosis of AA Amyloidosis with the other being IgA. This cohort of patients did poorly, 5 out of 6 of the cohort had died with a mean survival of 27 months. Patients were followed for an average of 769 days (range 485 - 1052). The majority of this time alive was spent as an inpatient with the mean percentage of time as an inpatient being 55% (Range 35–81%) with a mean of 411 total inpatient days. The first confirmed bacteraemia occurred within the first 100 days in 4 out of 6 of the patients. Conclusion With this case series we demonstrate the opportunity cost PWIDs experience in the form of time spent as an inpatient. This cost is further added to by the burden of outpatient maintenance haemodialysis. Consideration should also be given to the excess burden their care places on over-stretched healthcare systems. Infections and dialysis compliance are key components in the care of PWIDs and while moving away from tunneled access should be sought whenever possible a multidisciplinary approach should also be considered; these patients commonly lead chaotic lifestyles and in-center dialysis is usually the only option. Including addiction, social and psychiatric services alongside dialysis may be a way to engage with this historically difficult to reach population. The hope is that this study provides the incentive for further studies focusing on the opportunity costs and the quality of life this population can expect when embarking on haemodialysis. This would provide patients with realistic expectations while also aiding clinicians in navigating this difficult ethical situation.

Membranous nephropathy is one of the leading causes of nephrotic syndrome in adults. The disease manifests in different forms with varying severity and outcomes range from spontaneous remission to rapid disease progression. The effects of the disease are so far best understood using conventional histopathological morphology and clinical phenotype. Being an autoimmune condition subject to a multi-hit hypothesis, the notion of underlying genetic risks is being examined in recent times. Current evidence points to significant heterogeneity in the gene expression profiles in both the immune system and at the glomerular level, with potential implications for disease management. Further proteomic and transcriptomic analysis can instruct classification, prognostication, and treatment pathways. This chapter focuses on the links identified between primary membranous nephropathy and underlying gene polymorphism, and pathways using both proteomics and transcriptomic analysis. We discuss the potential impact this could have on future management to try to minimize the patient’s immunosuppression exposure and find the most effective targeted immunosuppressive therapy.

Membranous nephropathy associated with anti-PLA(2)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-PLA(2)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-PLA(2)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-PLA(2)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-PLA(2)R titers, possibly representing a cohort more likely to benefit from immunoadsorption. Immunoadsorption therapy is a safe treatment and well-tolerated treatment in anti-PLA(2)R positive autoimmune membranous nephropathy.

Abstract Background and Aims Intravenous drug users (IVDU) face significant challenges when requiring long-term therapies such as dialysis and pose management dilemma to clinicians. Many patients present late, complicated by erratic lifestyles and complex mental health needs, often requiring urgent renal replacement therapy (RRT). Decisions regarding modality can be difficult due to the lack of evidence for outcomes in this cohort. We investigated the clinical outcomes of patients with history of IVDU in our service who presented with ESRD. Method A single-centre retrospective analysis of ESRD patients with a background of IVDU. Incidence of hospital and ICU admission, length of stay and frequency of culture positive sepsis following the initiation of RRT were investigated. Primary outcome was days admitted versus days spent in the community, frequency of life-threatening sepsis and tunnelled catheter replacement. Data was collected from the date of first RRT (earliest April 2015 and latest November 2019) to last follow-up in September 2020 or patient death. An admission was included when the patient was admitted for at least an overnight stay in hospital. Admission days calculated do not include attendance for outpatient haemodialysis. Bacteraemia’s were included when a report confirming a positive culture associated with clinical features of infection; paired samples were counted as a single episode. Results Six patients initiated RRT during the study period and included four males and two females. Mean age of 46.6 years (32-54 years). Cause of ESRD was Amyloid AA in 5) and IgA nephropathy in 1). Mean follow-up was 677 days till censor (range 313 to 932 days). There was an average of nine inpatient admissions (range 3 to 17) averaging 280 inpatient days (range 29 to 637 days) across the cohort. At last follow-up, three patients died with an average time to death of 833 days from initiation of RRT (range 664 to 932 days). Four patients required at least one admission to the Intensive Care Unit (ITU) with an average length of stay of 10.3 days (range 1 to 47 days). All patients experienced at least two episodes of culture positive sepsis with a total of 72 bacteraemia’s across the cohort (range 2 to 41). Four patients required tunnelled catheter replacement ranging from 2 to 7 catheters. Results are summarised in Table 1. Conclusion IVDU patients represent a challenging patient population to manage with limited options available for RRT. This study highlights these difficulties particularly with the use of tunnelled catheters for haemodialysis. Our results indicate RRT in IVDUs is associated with frequent and prolonged hospital stays with multiple bacteraemia’s, ICU admissions and significant mortality. Clinicians are faced with a significant ethical dilemma as tunnelled catheters represent both a lifeline for continued survival and a perfect access to recreational drugs. If patients are to be offered haemodialysis via tunnelled access, more intensive and earlier multidisciplinary planning and counselling needs to be employed to ensure patients are aware of the significance of the associated risks. Psychological therapy and social care input would be essential to help reduce morbidity and mortality.