Rituximab for treatment of severe renal disease in ANCA associated vasculitis

Background: Rituximab (RTX) is approved for remission induction in ANCA associated vasculitis (AAV). However, data on use of RTX in patients with severe renal disease is lacking. Methods: We conducted a retrospective multi-center study to evaluate the efficacy and safety of RTX with glucocorticoids (GC) with and without use of concomitant cyclophosphamide (CYC) for remission induction in patients presenting with e GFR less than 20 ml/min/1.73 m2. We evaluated outcomes of remission at 6 months (6 M), renal recovery after acute dialysis at diagnosis, e-GFR rise at 6 M, patient and renal survival and adverse events. Results: A total 37 patients met the inclusion criteria. The median age was 61 years. (55–73), 62 % were males, 78 % had new diagnosis and 59 % were MPO ANCA positive. The median (IQR) e-GFR at diagnosis was 13 ml/min/1.73 m2 (7–16) and 15 required acute dialysis. Eleven (30 %) had alveolar hemorrhage. Twelve (32 %) received RTX with GC, 25 (68 %) received RTX with GC and CYC and seventeen (46 %) received plasma exchange. The median (IQR) follow up was 973 (200–1656) days. Thirty two of 33 patients (97 %) achieved remission at 6 M and 10 of 15 patients (67 %) requiring dialysis recovered renal function. The median prednisone dose at 6 M was 6 mg/day. The mean (SD) increase in e-GFR at 6 months was 14.5 (22) ml/min/m2. Twelve patients developed ESRD during follow up. There were 3 deaths in the first 6 months. When stratified by use of concomitant CYC, there were no differences in baseline e GFR, use of plasmapheresis, RTX dosing regimen or median follow up days between the groups. No differences in remission, renal recovery ESRD or death were observed. Conclusions: This study of AAV patients with severe renal disease demonstrates that the outcomes appear equivalent when treated with RTX and GC with or without concomitant CYC

Geometric algorithms for input constrained systems with application to flight control

In this thesis novel numerical algorithms are developed to solve some problems of analysis and control design for unstable linear dynamical systems having their input constrained by maximum amplitude and rate of the control signals. Although the results obtained are of a general nature, all the problems considered are induced by flight control applications. Moreover, all these problems are stated in terms of geometry, and because of this their solution in the thesis was effectively achieved by geometrically-oriented methods. The problems considered are mainly connected with the notions of the controllable and stability regions. The controllable region is defined as the set of states of an unstable dynamical system that can be stabilized by some realizable control action. This region is bounded due to input constraints and its size can serve as a controllability measure for the control design problem. A numerical algorithm for the computation of two-dimensional slices of the region is proposed. Moreover, the stability region design is also considered. The stability region of the closed-loop system is the set of states that can be stabilized by a particular controller. This region generally utilizes only a part of the controllable region. Therefore, the controller design objective may be formulated as maximizing this region. A controller that is optimal in this sense is proposed for the case of one and two exponentially unstable open-loop eigenvalues. In the final part of the thesis a linear control allocation problem is considered for overactuated systems and its real-time solution is suggested. Using the control allocation, the actuator selection task is separated from the regulation task in the control design. All fault detection and reconfiguration capabilities are concentrated in one special unit called the control allocator, while a general control algorithm, which produces 'virtual' input for the system, remains intact. In the case of an actuator fault, only the control allocation unit needs to be reconfigured and in many cases it can generate the same 'virtual' input using a different set of control effectors. A novel control allocation algorithm, which is proposed in the thesis, is based on multidimensional interval bisection techniques.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Antigen restriction and IgG subclasses among anti-GBM autoantibodies

Thirty-seven sera positive for anti-GBM antibodies (antibodies against the ‘Goodpasture antigen’ = NCI-domain of collagen IV) in routine analysis were studied for antigen restriction and IgG subclasses. Four different polypeptides, the four α-chains (α1, α2, α3 and α4) of human collagen IV NCI, were used as coating in ELISA assays. Autoantibodies were detected with monoclonal antibodies towards human IgG subclasses. All patients had antibodies to the α3 chain, and most patients reacted much more to the α3 peptide than to any of the other three peptides. This shows that the NCI domain of the α3 chain of collagen IV is the major target for anti-GBM antibodies. A minor group of patients, 6 of 37, showed no antigen restriction and had only moderate titres. It remains to be studied, however, whether they have antibodies to another epitope and a different clinical picture. All four subclasses of IgG antibodies were present, but IgGl antibodies dominated. A group, consisting of females mainly, had relatively high titres of IgG4 antibodies to the NCI domain of the α3 chain of collagen IV

Using imlifidase to elucidate the characteristics and importance of anti-GBM antibodies produced after start of treatment

Background: Autoantibodies are common in glomerulonephritis, but the clinical benefit of rapid elimination has not been determined, even in anti-glomerular basement membrane (GBM) disease. Even less is known about the importance of autoantibody characteristics, including epitope specificity and immunoglobulin G (IgG) subclass distribution. We aimed to address this by characterizing the autoantibody profile in anti-GBM patients: we utilized samples from the GOOD-IDES-01 (treating GOODpastures disease with Imunoglobulin G Degrading Enzyme of Streptococcus pyogenous) ( identifier: NCT03157037) trial , where imlifidase, which cleaves all IgG in vivo within hours, was given to 15 anti-GBM patients.Methods: In the GOOD-IDES-01 trial, plasmapheresis was (re)started if anti-GBM antibodies rebounded. Serum samples were collected prospectively for 6 months and analyzed for anti-GBM epitope specificity using recombinant constructs of the E-A and E-B epitopes, IgG subclass using monoclonal antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). The results were correlated with clinical data.Results: Patients with a rebound (n = 10) tended to have lower eGFR at 6 months (11 vs 34 mL/min/1.73 m(2), P = .055), and patients with dialysis at 6 months had a higher E-B/E-A ratio at rebound (0.8 vs 0.5, P = .047). Moreover, two patients demonstrated increasing epitope restriction and several patients displayed a shift in subclass distribution at rebound. Six patients were double positive for ANCA. ANCA rebound was seen in 50% of patients; only one patient remained ANCA positive at 6 months.Conclusions: In this study, rebound of anti-GBM antibodies, especially if directed against the E-B epitope, was associated with a worse outcome. This supports the notion that all means should be used to eliminate anti-GBM antibodies. In this study ANCA was removed early and long-term by imlifidase and cyclophosphamide.Funding Agencies|Skane University Hospital Research Foundations (SUS Stiftelser och fonder); Region Skane [2020-O000028]; Region Ostergotland [LIO-755 381]; Ingrid Asp Foundation [991 602]; Hansa Biopharma [IMH-2016-00286]; Inga-Britt and Arne Lundberg Foundation [LU-2021]; Swedish Research Council; Thelma Zoegas Fund for Medical Research [91 282]</p

Replacement of acetate with citrate in dialysis fluid: a randomized clinical trial of short term safety and fluid biocompatibility

Background The majority of bicarbonate based dialysis fluids are acidified with acetate. Citrate, a well known anticoagulant and antioxidant, has been suggested as a biocompatible alternative. The objective of this study was to evaluate short term safety and biocompatibility of a citrate containing acetate-free dialysis fluid. Methods Twenty four (24) patients on maintenance dialysis three times per week, 13 on on-line hemodiafiltration (HDF) and 11 on hemodialysis (HD), were randomly assigned to start with either citrate dialysis fluid (1 mM citrate, 1.5 mM calcium) or control fluid (3 mM acetate, 1.5 mM calcium) in an open-labeled cross-over trial (6 + 6 weeks with 8 treatments wash-out in between). Twenty (20) patients, 11 on HDF and 9 on HD were included in the analyses. Main objective was short term safety assessed by acid–base status, plasma ionized calcium and parathyroid hormone (PTH). In addition, biocompatibility was assessed by markers of inflammation (pentraxin 3 (PTX-3), CRP, IL-6, TNF-α and IL-1β) and thrombogenicity (activated partial thromboplastin time (APTT) and visual clotting scores). Results No differences dependent on randomization order or treatment mode (HD vs. HDF) were detected. Citrate in the dialysis fluid reduced the intra-dialytic shift in pH (+0.04 week 6 vs. +0.06 week 0, p = 0.046) and base excess (+3.9 mM week 6 vs. +5.6 mM week 0, p = 0.006) over the study period. Using the same calcium concentration (1.5 mM), citrate dialysis fluid resulted in lower post-dialysis plasma ionized calcium level (1.10 mM vs. 1.27 mM for control, p &lt; 0.0001) and higher post-dialysis PTH level (28.8 pM vs. 14.7 pM for control, p &lt; 0.0001) while pre-dialysis levels were unaffected. Citrate reduced intra-dialytic induction of PTX-3 (+1.1 ng/ml vs. +1.4 ng/ml for control, p = 0.04) but had no effect on other markers of inflammation or oxidative stress. Citrate reduced visual clotting in the arterial air chamber during HDF (1.0 vs. 1.8 for control, p = 0.03) and caused an intra-dialytic increase in APTT (+6.8 s, p = 0.003) without affecting post-dialysis values compared to control. Conclusions During this small short term study citrate dialysis fluid was apparently safe to use in HD and on-line HDF treatments. Indications of reduced treatment-induced inflammation and thrombogenicity suggest citrate as a biocompatible alternative to acetate in dialysis fluid. However, the results need to be confirmed in long term studies.Funding Agencies|Gambro Lundia AB||</p

Natural anti-GBM antibodies from normal human sera recognize alpha 3(IV)NC1 restrictively and recognize the same epitopes as anti-GBM antibodies from patients with anti-GBM disease

Anti-GBM disease is a rare autoimmune condition characterized by autoantibodies targeting the alpha 3 chain non-collagen 1 domain of type IV collagen (alpha 3(IV)NC1). Recently, we isolated IgG reacting with alpha 3(IV)NC1 from normal healthy human sera. The current study examined the antigen and epitope specificity of these natural autoantibodies (NAA) using recombinant human alpha 1, 3, 5(IV)NC1 and three constructs expressing, previously defined epitope regions designated E-A, E-B and S2, in the alpha 1(IV)NC1 background. The NAA preparations reacted with recombinant human alpha 3(IV) NC1 to the same extent as with purified bovine alpha(IV)NC1, but not with recombinant human alpha 1 and alpha 5 (IV)NC1. NAA preparations recognized the three chimeric proteins (E-A, E-B and S2) yielding similar absorbance values. We conclude that anti-GBM NAA recognize the same major epitopes as anti-GBM antibodies from patients with Goodpasture's disease

Recurrent ANCA-associated small vessel vasculitis after transplantation : A pooled analysis

Background. Recurrent antineutrophil cytoplasmic antibody (ANCA)- associated small vessel vasculitis (ANCA-SVV) after renal transplantation has been described in case series. However, general information regarding the frequency, character, and predictors of recurrent disease after transplantation is currently lacking. We considered the rate of relapse, whether a positive ANCA at the time of transplantation predicted relapse, and whether cyclosporine A prevented recurrent disease. Methods. We performed a pooled analysis of published data, added to the experience at the Universities of North Carolina (14 patients) and Lund, Sweden (11 patients). To avoid reporting bias, only case series were included for analysis. Subgroup analysis was performed by disease category (Wegener's granulomatosis, microscopic polyangiitis, or necrotizing crescentic glomerulonephritis) and ANCA staining pattern. Results. ANCA-SVV recurred in 17.3% of all patients (N = 127), in 20% of cyclosporine A-treated patients (N = 85), and in 25.6% of patients with circulating ANCA at the time of transplantation (N = 39). There was no statistically significant difference in the relapse rate between patients treated and those not treated with cyclosporine A (P = 0.45), between those with and without circulating ANCA at the time of transplant (P = 0.75), or between patients with Wegener's granulomatosis and those with microscopic polyangiitis or necrotizing crescentic glomerulonephritis alone (P = 0.62). Conclusion. There is a substantial relapse rate in the ANCA-SVV population. Therapy with cyclosporine A does not protect against recurrent ANCA-SVV, and the presence of a positive ANCA at the time of transplantation does not preclude transplantation. These conclusions must be substantiated with a prospective study of renal transplantation in patients with ANCA-SVV so as to optimize their management

Different fractions of human serum glycoproteins bind galectin-1 or galectin-8, and their ratio may provide a refined biomarker for pathophysiological conditions in cancer and inflammatory disease

Background: Changes in glycosylation of serum proteins are common, and various glycoforms are being explored as biomarkers in cancer and inflammation. We recently showed that glycoforms detected by endogenous galectins not only provide potential biomarkers, but also have different functions when they encounter galectins in tissue cells. Now we have explored the use of a combination of two galectins with different specificities, to further increase biomarker sensitivity and specificity. less thanbrgreater than less thanbrgreater thanMethods: Sera from 14 women with metastatic breast cancer, 12 healthy controls, 14 patients with IgA-nephritis (IgAN), and 12 patients with other glomerulonephritis were fractionated by affinity chromatography on immobilized human galectin-1 or galectin-8N, and the protein amounts of the bound and unbound fractions for each galectin were determined. less thanbrgreater than less thanbrgreater thanResults: Each galectin bound largely different fractions of the serum glycoproteins, including different glycoforms of haptoglobin. In the cancer sera, the level of galectin-1 bound glycoproteins was higher and galectin-8N bound glycoproteins lower compared to the other patients groups, whereas in IgAN sera the level of galectin-8N bound glycoproteins were higher. less thanbrgreater than less thanbrgreater thanConclusion: The ratio of galectin-1 bound/galectin-8N bound glycoproteins showed high discriminatory power between cancer patients and healthy, with AUC of 0.98 in ROC analysis, and thus provides an interesting novel cancer biomarker candidate. less thanbrgreater than less thanbrgreater thanGeneral significance: The galectin-binding ability of a glycoprotein is not only a promising biomarker candidate but may also have a specific function when the glycoprotein encounters the galectin in tissue cells, and thus be related to the pathophysiological state of the patient. This article is part of a Special Issue entitled Glycoproteomics.Funding Agencies|Swedish Research Council (Vetenskapsradet)||Region Skane||Swedish Cancer Society||Lund University Hospital Foundation||Swedish Research Council|2008-3356|Swedish Foundation for Swedish Research|FFL4|Crafoord Foundation||Swedish Healthcare System||</p