Patients with the Goodpasture syndrome and severe renal failure should be considered for urgent immunosuppression therapy, including plasma exchange, to maximize the chance of renal recovery. Patients needing immediate dialysis are less likely to recover.

Background and Purpose-The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the incidence, characteristics, and outcome of lobar and nonlobar ICH. Methods-In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335. Results-There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.

To characterize the autoantigen of Goodpasture's (anti-glomerular basement membrane) disease, a molecule of 26-kD reactive with autoantibodies from patients' sera was purified from collagenase digests of sheep glomerular basement membrane. Short internal amino acid sequences were obtained after tryptic or cyanogen bromide cleavage, and used to deduce redundant oligonucleotides for use in the polymerase chain reaction on cDNA derived from sheep renal cortex. Molecules of 175 bp were amplified and found to come from two cDNA sequences. One was identical to that of a type IV collagen chain (a5) cloned from human placenta and shown to be expressed in human kidney. The other was from a type IV collagen chain with close similarities to al and a5 chains, and was used to obtain human cDNA sequences by cDNA library screening and by further polymerase chain reaction amplifications.

Class II molecules are believed to influence immune responses by selectively binding antigen-derived peptides for recognition by T cells. In Goodpasture's (antiglomerular basement membrane) disease, autoimmunity to the NC1 domain of the ␣3-chain of type IV collagen (␣3(IV)NC1) is strongly associated with HLA-DR15. We have examined the influence of the peptide binding preferences of DR15 molecules on the selection of ␣3(IV)NC1-derived peptides displayed bound to DR15 molecules on the surface of ␣3(IV)NC1-pulsed DR15-homozygous Epstein-Barr virus-transformed human B cells. The preferences of DR15 molecules were investigated using a panel of 24 overlapping peptides spanning the sequence of ␣3(IV)NC1. The ␣3(IV)NC1-derived peptides selected for display to T cells were determined by biochemical analysis as reported previously (Phelps, R. G., Turner, A. N., and Rees, A. J. (1996) J. Biol. Chem. 271, 18549 -18553).Three nested sets of naturally presented ␣3(IV)NC1 peptides were detectable bound to DR15 molecules. Peptides representative of each nested set bound to DR15 molecules, but almost two-thirds of the ␣3(IV)NC1 peptides studied had as good or better DR15 affinity than those identified as naturally processed. Thus ␣3(IV)NC1 presentation to T cells is determined more by "processing factors" than by the preferences of relatively indiscriminate DR15 molecules. The results have important implications for the use of class II peptide binding data to aid identification of potential T cell epitopes, especially for antigens which, like ␣3(IV)NC1, contain many sequences able to bind class II molecules. Antigen presenting cells (APC)1 potentially exert a profound influence on immune responses, including those to self antigens, because they regulate the way T cells recognize antigens. CD4 T cells recognize antigens in the form of processed peptides presented bound to MHC class II molecules on the surface of class II positive APC types (1, 2). These include cells important in the initiation of immune responses, such as dendritic cells, B cells, and macrophages, and cells important in regulating the T cell repertoire and self-tolerance, such as thymic epithelia. How APC select antigen-derived peptides for display to T cells therefore not only constrains the peptide specificity of responding T cells, but also influences the repertoire of T cells available to mount immune responses. Furthermore, the way APC present antigens may determine the immunodominant T cell response, which at least for some exogenous antigens is directed at the antigen-derived peptide displayed at the highest level (3). There is therefore great interest in understanding how APC generate antigen-derived peptides and make a selection for display to T cells, both as an approach to identifying T cell epitopes for specific immune modulation and toward understanding the basic biology of immune responses.APC, like many cell types, internalize extracellular proteins into their endosomal/lysosomal pathway where denaturing (low pH and reducing) conditions promote th...

Biochemical analysis of HLA class II-associated peptides from antigen-pulsed cells is a potentially useful approach to the analysis of antigen processing and presentation because it examines directly which antigen-derived peptides are presented. This is especially advantageous in the analysis of self-antigen presentation where conventional approaches utilizing antigen-specific T cells may be biased by the presence of self-tolerance. However, successful biochemical analysis has been reported for only one exogenous antigen and no autoantigens. We have used a novel analytical approach coupling biochemical data with the reported properties of class II-associated peptides to characterize the peptides derived from a clinically relevant autoantigen presented on the disease-associated class II type. Incubating the target of autoimmune attack in patients with Goodpasture's disease, the 230-amino acid NC1 domain of the alpha3 chain of type IV collagen (Goodpasture antigen, alpha3(IV)NC1), with human B cells homozygous for HLA-DR15, the allele carried by 80% of patients, we find that alpha3(IV)NC1 is presented as at least two sets of three to five peptides centered on common core sequences (nested sets). Synthetic peptides containing these core sequences bind to HLA-DR15 with intermediate affinity (IC50, 1.1-6 microM).

Background The importance of patient-reported outcome measurement in chronic kidney disease (CKD) populations has been established. However, there remains a lack of research that has synthesised data around CKD-specific symptom and health-related quality of life (HRQOL) burden globally, to inform focused measurement of the most relevant patient-important information in a way that minimises patient burden. The aim of this review was to synthesise symptom prevalence/severity and HRQOL data across the following CKD clinical groups globally: (1) stage 1–5 and not on renal replacement therapy (RRT), (2) receiving dialysis, or (3) in receipt of a kidney transplant. Methods and findings MEDLINE, PsycINFO, and CINAHL were searched for English-language cross-sectional/longitudinal studies reporting prevalence and/or severity of symptoms and/or HRQOL in CKD, published between January 2000 and September 2021, including adult patients with CKD, and measuring symptom prevalence/severity and/or HRQOL using a patient-reported outcome measure (PROM). Random effects meta-analyses were used to pool data, stratified by CKD group: not on RRT, receiving dialysis, or in receipt of a kidney transplant. Methodological quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data, and an exploration of publication bias performed. The search identified 1,529 studies, of which 449, with 199,147 participants from 62 countries, were included in the analysis. Studies used 67 different symptom and HRQOL outcome measures, which provided data on 68 reported symptoms. Random effects meta-analyses highlighted the considerable symptom and HRQOL burden associated with CKD, with fatigue particularly prevalent, both in patients not on RRT (14 studies, 4,139 participants: 70%, 95% CI 60%–79%) and those receiving dialysis (21 studies, 2,943 participants: 70%, 95% CI 64%–76%). A number of symptoms were significantly (p < 0.05 after adjustment for multiple testing) less prevalent and/or less severe within the post-transplantation population, which may suggest attribution to CKD (fatigue, depression, itching, poor mobility, poor sleep, and dry mouth). Quality of life was commonly lower in patients on dialysis (36-Item Short Form Health Survey [SF-36] Mental Component Summary [MCS] 45.7 [95% CI 45.5–45.8]; SF-36 Physical Component Summary [PCS] 35.5 [95% CI 35.3–35.6]; 91 studies, 32,105 participants for MCS and PCS) than in other CKD populations (patients not on RRT: SF-36 MCS 66.6 [95% CI 66.5–66.6], p = 0.002; PCS 66.3 [95% CI 66.2–66.4], p = 0.002; 39 studies, 24,600 participants; transplant: MCS 50.0 [95% CI 49.9–50.1], p = 0.002; PCS 48.0 [95% CI 47.9–48.1], p = 0.002; 39 studies, 9,664 participants). Limitations of the analysis are the relatively few studies contributing to symptom severity estimates and inconsistent use of PROMs (different measures and time points) across the included literature, which hindered interpretation. Conclusions The main findings highlight the considerable symptom and HRQOL burden associated with CKD. The synthesis provides a detailed overview of the symptom/HRQOL profile across clinical groups, which may support healthcare professionals when discussing, measuring, and managing the potential treatment burden associated with CKD. Protocol registration PROSPERO CRD42020164737.

A minority of patients with Alport syndrome develop anti-GBM disease in their allografts after renal transplantation. Clinically, the renal disease appears indistinguishable from Goodpasture's disease of native kidneys, in which the target of autoantibodies had been identified as the NC1 domain of the alpha 3 chain of type IV collagen, alpha 3(IV)NC1. However, in the majority of cases, Alport syndrome is due to mutations in the gene encoding the alpha 5 chain of type IV collagen, located on the X chromosome. Neither chain is detectable in the glomerular basement membrane (GBM) of most patients with Alport syndrome. We investigated the targets of the alloantibodies of 12 Alport patients who developed post-transplant anti-GBM disease by Western blotting onto recombinant NC1 domains made in insect cells. Binding to these antigens, for both typical Goodpasture and Alport anti-GBM antibodies, was strong and conformation-sensitive. Nine antibodies showed selective binding to alpha 5(IV)NC1. This specificity was confirmed by the demonstration of binding to a 26 kDa band of collagenase-solubilized human GBM, and/or binding to normal epidermal as well as renal basement membranes by indirect immunofluorescence. One antibody showed binding to alpha 5 and alpha 3(IV)NC1, while two showed predominant binding to alpha 3(IV)NC1. All seven patients whose pedigree or mutation analysis showed X-linked inheritance had predominant anti-alpha 5 reactivity. One with predominant anti-alpha 3 reactivity had a COL4A3 mutation. These findings show that human anti-GBM disease can be associated with antibodies directed towards different molecular targets. Alpha 5(IV)NC1 is the primary target in most patients with X-linked Alport syndrome who develop post-transplant anti-GBM disease.

BackgroundOnline access to all or part of their health records is widely demanded by patients and, where provided in form of patient portals, has been substantially used by at least subgroups of patients, particularly those with chronic disease. However, little is reported regarding the longer-term patient use of patient-accessible electronic health record services, which is important in allocating resources. Renal PatientView (RPV) is an established system that gives patients with chronic kidney disease access to live test results and information about their condition and treatment. It is available in most UK renal units with up to 75% of particular patient groups registered in some centers. We have analyzed patient use out to 4 years and investigated factors associated with more persistent use.ObjectiveOur aim was to investigate RPV use by patients over time from initial registration in order to understand which patients choose to access RPV and the endurance of its appeal for different patient groups.MethodsWe analyzed an anonymized extract of the database underlying RPV containing information on patient registration and events including patient access and the arrival of new blood test results or letters that patients might wish to view.ResultsAt the time of the extract, there were 11,352 patients registered on RPV for 0-42 months (median 17). More than half of registrants became persistent users, logging in a median of 2.0 times each month over post-registration intervals of up to 42 months (median 18.9). Provision of assistance with first logon was strongly associated with becoming a persistent user, even at 3 years. Logons by persistent users occurred around the time of consultations/tests, strongly suggestive of patient engagement. While indices indicative of greater deprivation were the strongest determinants of non-participation, they had negligible influence on drop-out rates among established users.ConclusionsIn this mature patient portal system, a large proportion of patients made regular use of their online health records over protracted periods. The patterns and timing of use indicate strong patient interest in detailed information such as recent test results and clinic letters. Supporting patients through the first steps of establishing access to their online records is associated with much higher rates of long-term use of RPV and likely would increase use of other electronic health records provided for patients with chronic disease.