C3 Deposition Research Articles

Altered Elastin Turnover, Immune Response, and Age-Related Retinal Thinning in a Transgenic Mouse Model With RPE-Specific HTRA1 Overexpression.

A single-nucleotide polymorphism in HTRA1 has been linked to age-related macular degeneration (AMD). Here we investigated the potential links between age-related retinal changes, elastin turnover, elastin autoantibody production, and complement C3 deposition in a mouse model with RPE-specific human HTRA1 overexpression. HTRA1 transgenic mice and age-matched CD1 wild-type mice were analyzed at 6 weeks and 4, 6, and 12 to 14months of age using in vivo retinal imaging by optical coherence tomography (OCT) and fundus photography, as well as molecular readouts, focusing on elastin and elastin-derived peptide quantification, antielastin autoantibody, and total Ig antibody measurements and immunohistochemistry to examine elastin, IgG, and C3 protein levels in retinal sections. OCT imaging indicated thinning of inner nuclear layer as an early phenotype in HTRA1 mice, followed by age and age/genotype-related thinning of the photoreceptor layer, RPE, and total retina. HTRA1 mice exhibited reduced elastin protein levels in the RPE/choroid and increased elastin breakdown products in the retina and serum. A corresponding age-dependent increase of serum antielastin IgG and IgM autoantibodies and total Ig antibody levels was observed. In the RPE/choroid, these changes were associated with an age-related increase of IgG and C3 deposition. Our results confirm that RPE-specific overexpression of human HTRA1 induces certain AMD-like phenotypes in mice. This includes altered elastin turnover, immune response, and complement deposition in the RPE/choroid in addition to age-related outer retinal and photoreceptor layer thinning. The identification of elastin-derived peptides and corresponding antielastin autoantibodies, together with increased C3 deposition in the RPE/choroid, provides a rationale for an overactive complement system in AMD irrespective of the underlying genetic risk.

Mannan-Binding Lectin Is Associated with Inflammation and Kidney Damage in a Mouse Model of Type 2 Diabetes.

Autoreactivity of the complement system may escalate the development of diabetic nephropathy. We used the BTBR OB mouse model of type 2 diabetes to investigate the role of the complement factor mannan-binding lectin (MBL) in diabetic nephropathy. Female BTBR OB mice (n = 30) and BTBR non-diabetic WT mice (n = 30) were included. Plasma samples (weeks 12 and 21) and urine samples (week 19) were analyzed for MBL, C3, C3-fragments, SAA3, and markers for renal function. Renal tissue sections were analyzed for fibrosis, inflammation, and complement deposition. The renal cortex was analyzed for gene expression (complement, inflammation, and fibrosis), and isolated glomerular cells were investigated for MBL protein. Human vascular endothelial cells cultured under normo- and hyperglycemic conditions were analyzed by flow cytometry. We found that the OB mice had elevated plasma and urine concentrations of MBL-C (p < 0.0001 and p < 0.001, respectively) and higher plasma C3 levels (p < 0.001) compared to WT mice. Renal cryosections from OB mice showed increased MBL-C and C4 deposition in the glomeruli and increased macrophage infiltration (p = 0.002). Isolated glomeruli revealed significantly higher MBL protein levels (p < 0.001) compared to the OB and WT mice, and no renal MBL expression was detected. We report that chronic inflammation plays an important role in the development of DN through the binding of MBL to hyperglycemia-exposed renal cells.

Complement C3a/C3aR and C5a/C5aR deposits accelerate the progression of advanced IgA nephropathy to end-stage renal disease

IgA nephropathy (IgAN) is still one of the leading causes of end-stage kidney disease (ESRD), and complement system activation is a key to the pathogenesis of IgAN. The role of complement C3a/C3aR and C5a/C5aR in late stage of IgAN remains unknown. Renal specimens of 75 IgAN patients at the stage 4 CKD were stained using immunofluorescence and immunohistochemistry. The primary outcome was a composite of end-stage renal disease (ESRD) and death. Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses. During a median follow-up of 15.0 months, 27 patients progressed to ESRD and none died. Lower eGFR [hazards ratio (HR), 0.827, 95% confidence interval (CI), 0.732–0.935; P = 0.002] and glomerular C3 deposition (HR, 3.179, 95% CI, 1.079–9.363; P = 0.036) were predictive of time to ESRD in stage 4 CKD IgAN. Higher expression of C3a (P = 0.010), C3aR (P = 0.005), C5a (P = 0.015), and C5aR (P < 0.001) was identified in ESRD group than in non-ESRD group. Glomerular C3a/C3aR and C5a/C5aR deposits were both correlated with a lower baseline eGFR, higher baseline 24 h-urinary protein (24 h-UP) and faster decline of eGFR. Besides, C3a and C5a deposits were found in patients with high S (S1) and T (T1/2) scores, respectively. Complement C3a/C3aR and C5a/C5aR in IgAN patients with stage 4 CKD may portend a faster deterioration of kidney function.

Anti-Glomerular Basement Membrane Antibody Disease: Clinicopathologic Profile and Outcomes

Background: Anti-glomerular basement membrane antibody disease is a rare autoimmune disease caused by antibodies to α3 chain of type 4 collagen. Patients presenting with severe renal involvement requiring dialysis have poor response to treatment. Materials and Methods: We conducted a retrospective and prospective study at Institute of Nephrology, Madras Medical College, Chennai, India by analyzing the data of patients with biopsy-proven anti-GBM antibody disease treated from January 2013 to December 2019. Results: There were 2,949 kidney biopsies in the study period and 92 showed crescentic glomerulonephritis (GN). Of those, 20 patients (10 males) had anti-GBM antibody disease. Mean age was 40.75 ± 14.75 years. Rapidly progressive renal failure was the most common mode of presentation (95%); five (25%) patients had diffuse alveolar hemorrhage (DAH) and nineteen patients (95%) required dialysis at presentation. Seven patients (35%) were positive for anti-neutrophil cytoplasmic antibody (anti-myeloperoxidase in six and anti-proteinase 3 in one). Of the twelve patients (60%) who received immunosuppression (cyclophosphamide, steroids, and plasma exchange), two patients (10%) attained remission, and two patients (10%) expired due to sepsis. Crescentic GN was the predominant pathology in kidney biopsy in 19 patients (95%). Mesangial hypercellularity with deposition of IgA and C3 in mesangium was present in one patient. Conclusion: In our study, anti-GBM antibody disease accounted for 21.7% of crescentic GN. Majority of patients presented late, requiring dialysis. Patient survival was 90%, while renal survival was only 10%. One patient had co-occurrence of IgA nephropathy with anti-GBM antibody disease.

Inhibition of receptor interacting protein kinase-1 (RIPK1) in the treatment of murine lupus

ObjectiveSystemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is still challenging due to the...

#2865 The impact of glomerular C3 deposition in membranous nephropathy prognosis

Abstract Background and Aims Membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome in non-diabetic adults. Studies on MN have suggested a preponderant role of the complement. C3 deposits are common in primary and secondary MN and appear to be related to increased proteinuria. The prognostic role of proteinuria is well established, but the importance of C3 glomerular deposition in disease course is not clear. Our study aims to investigate the role of glomerular C3 deposition in the evolution of membranous nephropathy. Method We conducted a single-center retrospective study including 39 patients with histological diagnosis of MN. The patients were assembled in two groups according C3 deposition intensity in kidney biopsy: low intensity (C3+) and high intensity (C3 2 or more ++). The primary outcome was the development of end-stage kidney disease (ESKD). The rate of remission, the rate of relapse and a decreased of at least 30% of the estimated glomerular filtration rate (eGFR) was defined as secondary outcomes. Results Thirty-nine patients were included, 26 (66.7%) were male with a mean age at biopsy of 54 ± 17.5 years. Twenty-six (66.7%) patients had hypertension at diagnosis and four patients had a thrombotic event. The mean eGFR was 88.7 ± 34.3 ml/min/1.73 m2, and median UPCR was 5.55 g/g. Most patients had primary MN (82.1%). The patients with higher C3 deposition were more likely to response to ACEi/ARB (72.2% vs 42.9%, p = 0.06) and 29 patients did immunosuppression therapy during the follow-up period. There were no significant differences between groups, except the body mass index (BMI), which it was higher in the high C3 group (25.52 ± 3.14 vs 27.42 ± 5.45, p = 0.03) and the presence of thrombosis, which all occurred in the high C3 group (0 vs 4, p = 0.023). During a mean follow-up of 6 ± 4.2 years, 7 (17.9%) patients developed ESKD and 11 (33.3%) patients had a decreased of at least 30% eGFR at five years. The group with low C3 deposition had a higher rate of remission (81.0% vs 61.1%, p = 0.03), reaching remission earlier (9.75 ± 322.92 vs 17.8 ± 32, p = 0.021) comparing with the high C3 deposition. The rate of relapse was similar in both groups. Conclusion There is growing evidence that complement activation has a role in the pathophysiology and, probably, in prognosis of MN. Previous studies have correlated low serum C3 levels with poor long-term renal survival. In our study, the extensive C3 deposition in kidney biopsies was associated with lower and delayed remission rate. Furthermore, it was associated with more thrombotic complications. More patients of the higher C3 deposition group developed ESKD. It was not statistically significant, probably because of the small size of the sample, a limitation of our study. Nonetheless, we believe that C3 deposition is indicative of a worse prognosis of MN and therapeutic modulation of the complement can be a promising treatment strategy in MN.

#2811 Factor B inhibition with iptacopan in C3 glomerulopathy recurrence after transplantation: a case presentation

Abstract Background and Aims C3 glomerulopathy (C3G) is a clinical-pathological entity resulting from dysregulation of the alternative pathway of the complement system (APC) in the fluid phase. The recurrence risk of C3G after kidney transplantation is about 70% with high risk of graft loss. Standard treatment relies on nephroprotection and unspecific immunosuppression but there are currently new molecules that target specifically APC under development. A novel factor B inhibitor, iptacopan, has shown promising results both in native kidney and transplant recurrence cases in a phase II trial. Method We present a real-world clinical case of early C3G recurrence after kidney transplantation treated with iptacopan (Novartis MAPs program). Patient was vaccinated for encapsulated bacteria. Iptacopan was initiated 200 mg BID. We also present histological response. Results 38-year-old male with chronic kidney disease secondary to C3G initially presented with nephrotic syndrome and hematuria at the age of 31y following a respiratory infection. Blood test showed low serum C3 levels and the presence of C3 nephritic factor without pathological genetic alterations. Kidney biopsy confirmed membranoproliferative glomerulonephritis (MPGN) with predominant C3 deposition. He progressed to CKD stage G5 requiring hemodialysis instead of nephroprotection and immunosuppression with corticosteroids and mycophenolate; and addition with cyclophosphamide and rituximab after 19 months from onset. Five years later, the patient was admitted as first kidney transplant recipient from deceases donor Maastricht-III. Induction therapy included thymoglobulin, and tacrolimus, mycophenolate, and corticosteroids. He experienced delayed graft function requiring hemodialysis. An early biopsy proved C3G recurrence with endocapillary proliferation without C4d deposit and absence of donor specific antibodies. Despite conventional immunosuppression and addition of rituximab and plasma exchange; hemodialysis requirement still be present. So, because C3G pathophysiological base, iptacopan was begun with successful clinical response as he reached hemodialysis discontinuation; and kidney function stabilized after one year of treatment with an estimated glomerular filtration rate about 30 mL/min/1.73 m2. In the follow-up biopsy 5 months later, deposit of C3 in the glomerulus disappeared compared to the post-transplant recurrence but with persistence of endocapillary and mesangial proliferation (see Fig. 1). However, interestingly, he experienced a clinical recurrence with acute kidney injury and hematuria after unintentional iptacopan discontinuation, which was resolver after reinitiating and recovering its previous graft function. No infectious complications were observed after one year of treatment with factor B inhibitor. Conclusion New molecules under development that specifically target APC (fluid phase) may change the treatment scenario of C3G and its recurrence in kidney transplantation. We expose a real-practice early C3G recurrence after kidney transplantation successfully treated with iptacopan. The patient reached kidney function stabilization and disappearance of C3 deposits on immunofluorescence of the follow-up biopsy, identical results as the phase II clinical trial of iptacopan in C3G. So, we might conclude that iptacopan is an effective and safe option for C3G recurrence after kidney transplantation. But, data from randomized studies are needed in order to confirm the efficacy and safety of new inhibitors of the APC as iptacopan.

#567 Early application of treatment to patients with IgA nephropathy who were supposed to have steroid regimen predicts good renal outcome

Abstract Background and Aims Progressive deterioration of proteinuria and glomerular filtration rate (GFR) is notified in 20-30% of patients with IgA nephropathy during 20-30 years follow-up period. Popular traditional approach for patients with rapid deterioration of renal function is the immunosuppressive treatment with steroid, which efficacy is still remained in debate. We searched the factors related to renal outcomes among patients presumed to need steroid treatment. Method Among 472 adult patients with IgA nephropathy diagnosed by renal biopsy during 2003-2017 in a tertiary hospital, we selected 86 patients with initiation of steroid treatment for more than 1 months and with dose of more than 1000 mg of prednisolone after renal biopsy. We excluded patients with steroid treatment started one month or more before renal biopsy. The renal outcome was defined as decrease of GFR more than 50% from GFR at renal biopsy, decrease of GFR to less than 15 ml/min/1.73 m2, or a status to need renal replacement therapy during follow-up period after renal biopsy. Results At admission for renal biopsy, estimated GFR by CKD-EPI 2009 equation was 68.5 ± 33.3 ml/min/1.73 m2 and urine protein to creatinine ratio (UPCR) was 2.81 ± 2.23 g/g creatinine (no missing data). The renin-angiotensin-aldosterone inhibitor was used in 80 patients (93.0 %) after renal biopsy. Steroid was started at 8.4 ± 23.1 months after renal biopsy. Majority of patients (63 patients) had been prescribed steroid medication within 2 months after renal biopsy. Total dose of steroid was 13.5 ± 13.1 g. The results of eGFR and UPCR before starting steroid medication were 63.7 ± 31.2 ml/min/1.73 m2 and 2.82 ± 2.01 g/g creatinine, respectively. During 63.6 ± 48.8 months of follow-up period after renal biopsy, there were 39 patients (45.3 %) developed the renal outcome. Factors related to development of the renal outcome searched by correlation coefficient were eGFR and UPCR at renal biopsy, medications of anti-diabetic agent, anti-hypertensive agent, immunosuppressive agent other than steroid, dose of steroid, or vitamin D3 agent after renal biopsy, pathologic findings of segmental sclerosis, interstitial inflammation, and tubular atrophy on light microscopic examination, deposition of C3 and IgA on immunofluorescent staining, and Oxford classification of T, period of starting steroid treatment after renal biopsy, and eGFR before starting steroid medication. With Cox's hazard proportional model, the independent factors to predict the renal outcome were eGFR before steroid treatment or eGFR at renal biopsy, immunosuppressive medication other than steroid, pathologic finding of C3 deposition, and period of starting steroid treatment. Hazard ratio to estimate the renal outcome (HR) was 1.025 (95% CI: 1.010-1.039, p = 0.001) for one-month delay of starting steroid medication after renal biopsy. The HR for the renal outcome in patients started steroid medication at 2 months after renal biopsy was 2.353 (95% CI: 1.140-4.856, P = 0.021) compared to patients started steroid within 2 months after renal biopsy. Conclusion For the patients supposed to have indications for steroid treatment at renal biopsy, early initiation of steroid treatment would indicate better renal outcome.

#2018 Characteristics of patients with complement 3 glomerulopathy (C3G): a retrospective linked electronic medical record (EMR) and claims analysis

Abstract Background and Aims C3G is characterised by C3 deposition in the glomeruli, caused by dysregulation of the alternative complement pathway. Contemporary datasets on the clinical burden of patients with C3G in the United States (US) are limited. The aim of this analysis was to describe the demographics and clinical characteristics of patients diagnosed with C3G in the US. Methods This was a retrospective cohort analysis of patients with C3G included in the US HealthVerity database with an EMR and linked pharmacy and medical claims data, who were diagnosed between January 1, 2017 and March 31, 2022 and aged ≥12 years at diagnosis. The index date was the date of the first C3G diagnosis, identified by International Classification of Diseases 10th Revision Clinical Modification (ICD-10-CM) and Systematized Nomenclature of Medicine (SNOMED) diagnosis codes. Included patients had database records for ≥12 months before the index date (the baseline period). Patients aged ≥50 years with monoclonal gammopathy of unknown significance (MGUS) were excluded. Patient demographic and clinical characteristic data for the overall population, and stratified by transplant status, were summarised with descriptive statistics. Results Overall, 2021 patients had ≥1 diagnosis of C3G in the US HealthVerity database during the identification period. Of these, 1060 patients did not meet the criteria for the analysis, including 44 patients (2.2%) who were excluded due to the presence of a diagnostic code for MGUS at ≥50 years of age. The final cohort included 961 patients, of whom 62.4% were female. At the index date, mean (standard deviation [SD]) age was 44.4 (19.6) years (Table 1); 80 patients (8.3%) were aged &amp;lt;18 years, 881 (91.7%) were aged ≥18 years, and 156 (16.2%) were aged ≥65 years. Median (lower quartile [Q1], upper quartile [Q3]) database history was 41.7 (25.9, 66.8) months, and mean (SD) follow-up time from the index date was 22.7 months (16.4). Comorbidities recorded during the baseline period included hypertension (57.4%), type II diabetes (25.1%), and congestive heart failure (12.9%). Among patients who were aged ≥65 years vs &amp;lt;65 years at the index date, the proportion of patients with hypertension (93.6% vs 50.4%), type II diabetes (52.6% vs 19.8%), and congestive heart failure (32.1% vs 9.2%) were numerically higher. Of 461 patients (48.0%) with a known chronic kidney disease stage, 282 (61.2%) had stage 3–5 chronic kidney disease during the baseline period. Baseline estimated glomerular filtration rate (eGFR) data were available for 205 patients (21.3%); overall, median (Q1, Q3) eGFR values were 82.0 (48.0, 107.0) mL/min/1.73 m2, and 56.6% of patients had an eGFR value of &amp;lt;90 mL/min/1.73 m2. Among 78 patients (8.1%) with proteinuria data during the baseline period, median (Q1, Q3) proteinuria levels were 1.4 (0.3, 3.3) g/g, and 44 patients (56.4%) had a proteinuria level ≥1.0 g/g. Extrarenal manifestations including ocular haemorrhage/retinal occlusion, pulmonary haemorrhage, ocular drusen, and acquired partial lipodystrophy were recorded in 1.7%, 0.9%, 0.5%, and 0.1% of patients, respectively. Overall, 19 patients (2.0%) had previously undergone a kidney transplant; the proportion who had hypertension, type II diabetes, or congestive heart failure during the baseline period was 89.5%, 31.6%, and 10.5%, respectively. Baseline eGFR data were available for 4 patients (21.1%) who had previously received a kidney transplant (Table 1). Conclusions This contemporary assessment of patients with C3G, using real-world EMR and administrative claims data from a national US cohort, showed that comorbidities around the time of C3G diagnosis were common. Among patients with available eGFR data, the majority exhibited reduced kidney function during the baseline period.

#2066 Treatment patterns of patients with complement 3 glomerulopathy (C3G): a retrospective linked electronic medical record (EMR) and claims analysis

Abstract Background and Aims C3G is characterised by C3 deposition in the glomeruli, caused by dysregulation of the alternative complement pathway. Currently, there are no approved therapies for C3G. The aim of this analysis was to evaluate treatment patterns in patients with C3G in the United States (US). Methods This was a retrospective cohort study of patients with C3G, with an EMR and linked pharmacy and medical claims data in the US HealthVerity database, who were diagnosed between Jan 1, 2017 and Sep 30, 2021 and aged ≥12 years at diagnosis. Included patients had database records for ≥12 months before (baseline period) and after (follow-up period) the index date (date of first C3G diagnosis, identified by International Classification of Diseases 10th Revision Clinical Modification [ICD-10-CM] and Systematized Nomenclature of Medicine [SNOMED] diagnosis codes). Endpoints included: proportion of patients receiving a treatment, including supportive care (angiotensin-converting enzyme inhibitors [ACEi]/angiotensin II receptor blockers [ARB]), immunosuppressants (IM; including corticosteroids [CS]/glucocorticoids [GC] and mycophenolate mofetil [MMF]), and eculizumab; proportion of patients discontinuing treatment; and duration of treatment. Discontinuing treatment was defined as the absence of a subsequent claim for medication for ≥60 days. Results were assessed using descriptive statistics and analysed by Fisher's exact test, Mann–Whitney U test, or Student's t-test, as appropriate. Results The final cohort included 683 patients. Overall, 346 (50.7%) patients had ≥1 treatment record for C3G during follow-up (median follow-up 24.0 months; median time from index to first treatment 1.1 months). Mean age (standard deviation) of treated and untreated patients was 47.7 (19.4) and 39.6 (18.0) years (P &amp;lt; 0.0001), respectively; 54.3% of treated patients and 72.7% of untreated patients were female (P &amp;lt; 0.0001). Comorbidities reported in treated and untreated patients, respectively, included: hypertension (75.1% and 33.5%; P &amp;lt; 0.0001) and type II diabetes (34.7% and 12.8%; P &amp;lt; 0.0001). Baseline proteinuria data were available for 39 (11.3%) treated patients and 11 (3.3%) untreated patients (P &amp;lt; 0.0001). Median (lower quartile, upper quartile) proteinuria levels were 1.9 (0.7, 3.3) g/g and 0.2 (0.1, 2.3) g/g for the treated and untreated populations, respectively (P = 0.05). Among treated patients (n = 346), most (76.0%) received an ACEi/ARB alone in the first line, 14.2% received IM alone, and 5.8% received concomitant ACEi/ARB and IM (Table 1). A small number of remaining patients received a sodium-glucose cotransporter-2 inhibitor (SGLT2i) ± ACEi/ARB (2.9%), or eculizumab ± IM (1.2%). Less than half of treated patients (43.9%) received second-line therapy, and 17.6%, 6.6%, and 2.0%, respectively, received subsequent lines of treatment. Among treated patients, the most common treatment sequence was ACEi/ARB alone in the first line, without subsequent lines of therapy (42.2%); 30.9% of treated patients received IM (alone or in combination with other treatments) at any time during follow-up. Median duration of treatment in months (95% confidence interval) in any line was 14.9 (9.9, 18.4) for ARB, 8.6 (7.5, 11.1) for ACEi, 7.4 (3.3, 22.6) for SGLT2i, 4.7 (3.0, 6.6) for MMF, and 1.0 (0.9, 3.0) for CS/GC. During follow-up, 225 (65.0%) patients discontinued treatment: 22 (9.8%) and 203 (90.2%) patients restarted and did not restart therapy, respectively. Conclusions These real-world data show that only half of patients with C3G had a record of treatment during follow-up. Compared with the untreated population, patients who received treatment were older, more likely to be male, and more likely to have hypertension or type II diabetes. Among treated patients, the most common treatment sequence was supportive care with an ACEi/ARB alone, and less than one-third received IM at any time during follow-up. Use of the complement inhibitor, eculizumab, was low in this population. A large proportion of patients discontinued treatment during follow-up; given the progressive nature of C3G, these data may highlight the need for novel therapies in the treatment of C3G.

#2864 IgA dominant post-infectious glomerulonephritis secondary to the infected left ankle joint in a non-diabetic patient, a case report

Abstract Introduction Post-infectious glomerulonephritis (PIGN) is an immune complex glomerulonephritis that commonly affects children and young adults following beta haemolytic Streptococcal throat or skin infections. Kidney biopsy is characterised by Segmental or global endocapillary hypercellularity, and crescents may be present. In immunofluorescence, post-infectious glomerulonephritis typically shows IgG and C3 deposition. A rare type of PIGN is IgA-dominant post-infection glomerulonephritis. It commonly occurs in the setting of active infection. It usually presents in patients &amp;gt; 60 years old with diabetes mellitus, alcohol consumption, and Staphylococcal infections. It can present with RPGN, AKI, and nephrotic syndrome. Hypocomplementemia can be present, and immunofluorescence is characterised by IgA dominance with C3 co-dominance and no IgG. Despite the strong association with Staph aureus, however, it has been reported with other types of infections. The main line of treatment is antibiotic eradication of the infection. Steroids can be used based on the severity of the lesion and the presence of crescents. Its prognosis is worse than that of the traditional PIGN. In this case, we report a case of IgA-dominant post-infectious glomerulonephritis secondary to left ankle osteomyelitis with Staph aureus infection. Case Presentation A 65-year-old lady had open reduction and internal fixation of a left trimalleolar ankle fracture in June 2023 at a district general hospital. Unfortunately, the post-operative course was complicated by wound infection. The wound swab showed Heavy growth of Staphylococcus aureus. This was followed by Acute Kidney Injury (AKI) stage 3; therefore, she was transferred from her hospital to our renal ward. On admission to the ward, her creatinine was 388 μmol/L(baseline creatinine was 73 μmol/L one month before admission), urine dipstick was positive for blood and protein, and urine protein creatinine ratio was 480 mg/mmol. She had only a medical background of bronchial asthma for which she was only on Inhalers (Beta Agonist) as a regular medication. CT scan of the left ankle revealed appearances consistent with osteomyelitis of both the lateral and medial malleoli. This finding was discussed with microbiology and orthopaedic teams, and the patient was started on intravenous antibiotics (Vancomycin followed by doxycycline). A kidney biopsy was done. Mesangial electron-dense deposits were identified. Immunohistochemistry revealed IgA dominant, predominantly mesangial positivity, with associated C3. The picture was consistent with IgA acute glomerulonephritis associated with S. aureus, which is a post-infectious Glomerulonephritis with dominant IgA staining (rather than conventional IgA nephropathy). With proper intravenous hydration and antibiotics, her inflammatory markers started to improve, and her renal chemistry followed the inflammatory markers, and her last creatinine improved to 146 μmol/L, eGFR 31 ml/min and UPCR was 40 mg/mmol. Discussion IgA-dominant post-infectious glomerulonephritis is now a distinct form of PIGN, which usually presents with acute kidney injury, haematuria, and proteinuria and is typically related to Staph aureus infection. In contrast to typical IgA nephropathy, there is no role for steroid or immunosuppression in the treatment of IgA-dominant post-infectious glomerulonephritis, and the treatment is mainly dependent on the treatment of infection.

#2672 Cryoglobulin-Induced membranoproliferative glomerulonephritis in a HEV-infected kidney transplant recipient: outcomes post ribavirin failure

Abstract Background and Aims Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. It is the most prevalent hepatitis virus worldwide. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced in immunocompromised patients such as transplant recipients. CHE can induce extra-hepatic manifestations, such as immune-mediated thrombocytopenia, neurological symptoms, and kidney injuries. Few cases of glomerulonephritis (GN) and cryoglobulinemia in transplant patients have been related with CHE, with a good progression thanks to viral control with ribavirin introduction. There have been no reported cases in the literature of good progress in renal function in renal transplant patients despite failure of treatment with Ribavirin. Method We report here what is to our knowledge, the first documented case of HEV-induced de novo cryoglobulinemic membranoproliferative glomerulonephritis in a renal transplant patient with a ten-year history of CHE infection unsuccessfully treated with ribavirin. Results A 69-year-old man underwent a kidney transplant for diabetes type 1. 7 years after transplantation, he was diagnosed with a chronic genotype 3.1H-HEV infection. He was treated by Ribavirin, but it did not allow to eradicate HEV but a biochemical response. At 18 years post transplant, he presented with asthenia, abdominal pains and increased liver enzyme levels: liver tests were disrupted with cytolysis and cholestasis. He presented also a nephritic syndrome with high blood pressure, oedemas, increased serum creatinine level, proteinuria with hypoalbuminemia and de novo microscopic hematuria. Biological analysis revealed presence of type 2 cryoglobulinemia with monoclonal IgM Kappa (2285 mg/L), and polyclonal immunoglobulins association. Rheumatoid factor was increased (573 UI/ml) and C4 level was reduced (0.04 g/L). The concentration of HEV RNA in the serum was 750 000 UI/mL. Viral serologies were performed for HBV, HCV, HAV, HIV, EBV, CMV. Hematologic diseases were ruled out by analyzing a bone marrow biopsy specimen. Histologic analysis of a kidney biopsy specimen revealed diffuse endocapillary proliferation, diffuse mesangial proliferation and focal glomerular basal membrane duplication. One arteriolar section showed a focal lesion of vasculitis (Fig. 1). There was no argument for allograft rejection. Immunofluorescence microscopy revealed mesangial and capillary wall deposits of IgM, IgG, C3 and C1q, polytypic for k and l light chains. We suspected cryoglobulinemic membranoproliferative glomerulonephritis induced by VHE. The initial treatment plan involved 10 sessions of plasmapheresis and steroid pulses (500 mg/d for 3 days), alongside a course of rituximab (1 g/week for 4 weeks). However, the patient experienced intolerance to rituximab, prompting a switch to Obinutuzumab. Subsequently, the anti-HEV therapy was modified, and the patient was placed on a course of Sofosbuvir. Consequently, three months after treatment kidney function kidney improved with return to baseline and cryoglobulinemia became undetectable. However, proteinuria remained impaired and VHE RNA was still present. Conclusion Cryoglobulinemia is rarely associated with glomerular disease in HEV infection, and cases currently reported in the literature showed a favorable outcome with ribavirin. This case is the first to display a chronic HEV infection with cryoglobulin-induced glomerulonephritis with global improvement despite unsuccessful treatment with ribavirin. Although the difficulty of managing immunity in the treatment of cryoglobulinemia by immunodepleting treatment, with the risk of increased viral replication in the absence of an effective antiviral, it seems interesting to offer a first-line treatment of cryoglobulinemia that appears to improve renal function despite continued viral replication. These results need to be confirmed in further studies.

#1976 Non-IgA mesangial proliferative glomerulonephritis in a patient with IgA deficiency, a case report

Abstract Background and Aims IgA deficiency (IgAD) is the most common primary immunoglobulin deficiency in western countries. This entity is associated with increased risk of other autoimmune diseases. Mesangial proliferative glomerulonephritis (MesPGN) is a histological pattern defined by mesangial cell proliferation and expansion of the extracellular matrix within the mesangium. The clinical presentation can vary, from nephrotic syndrome to isolated hematuria. 30-40% of MesPGN cases are associated with IgA nephropathy. Other common diagnostic entities that present with this pattern include IgM nephropathy, C1q nephropathy or lupus nephritis, as well as Hepatitis B or C virus infection; idiopathic MesPGN is poorly described in the literature. To the best of our knowledge, this is the first report of idiopathic MesPGN associated with IgAD. Results A 17-year old woman with a background of IgAD and occasional episodes of bronchitis in her childhood presented in January 2022 with nonspecific abdominal pain and macroscopic hematuria. She had been suffering these symptoms for the last few weeks, usually after physical exercise. She was normotensive and showed no fever, skin rashes or other symptoms. Laboratory tests revealed normal renal function (serum creatinine 0.65 mg/dL), urinary albumin-to-creatinine ratio of 23.9 mg/g, a 24-h protein excretion ranging from 40 to 240 mg and non-dysmorphic hematuria of up to 51-150 erythrocytes/field. Additional laboratory tests repeatedly showed only low IgA serum levels, with normal ANA, ANCA or complement levels. Renal ultrasound showed both kidneys with normal size and cortical thickness. A CT urogram observed multiple, bilateral, non-obstructive small-sized kidney stones and a persistent nephrogram. Genetic tests were negative for Alport syndrome-related mutations. Additional workup included occult blood in the stool, stool culture, rectal biopsy and colonoscopy, which were all negative. Symptoms persisted during the following 12 months. A kidney biopsy was performed, finding 40 glomeruli with normal optical appearance, none of them sclerosed. Discrete mesangial expansion and cell proliferation was observed, with capillary lumens with occasional congestion but without thrombi or fibrinoid necrosis. Tubules and interstitium showed no sign of sclerosis or fibrosis, with conserved basement membranes and brush borders. In vessels, subintimal fibrosis, hyalinosis or concentric arteriolar hyperplasia or endarteritis were ruled out. Immunofluorescence showed low-intensity, discrete granular C3 mesangial deposits and no deposition of IgA, IgG, IgM, fibrinogen, C4, C1q or albumin. A diagnosis of non-IgA MesPGN was reached. The patient stopped performing intense physical exercise on a regular basis. This translated in hematuria and abdominal pain of much lower intensity. The patient is currently receiving only supportive therapy and maintains a normal renal function, with persistence of microscopic non-dysmorphic hematuria and occasional, low-grade proteinuria as described. Conclusion MesPGN is the most diagnosed form of glomerulonephritis worldwide. However, most cases are associated with granular IgA deposition in the mesangium, which was absent in this case. Idiopathic, non-IgA MesPGN is a much rarer condition that has been considered by some authors as a form focal segmental glomerulosclerosis or minimal change disease, although others believe it to be a separate condition. IgAD has been previously associated with Crohn's disease, which could explain this patient's symptoms. Crohn's disease has also been associated with non-IgA MesPGN in a low number of patients. Nevertheless, no findings in the patient workup were suggestive of Crohn's disease. A capsule endoscopy study will be performed to clearly rule out such diagnosis.

#1707 Antiphospholipid antibodies in lupus nephritis

Abstract Background and Aims Antiphospholipid antibodies (aPL) constitute a heterogeneous family of antibodies against anionic phospholipids or phospholipid-binding proteins. They may occur in association with autoimmune diseases, infections, and sometimes in the general population. Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). The aim of this study was to investigate the association of aPL with clinical activity, renal damage, renal activity and outcomes in patients with LN. Method A total of 157 patients (11 male, 146 female, age between 17 and 58 years) with LN were included in this study. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN was used to classify the patients into LN subsets. Histopathological renal activity and damage were estimated using the Activity Index (AI) and Chronicity Index (CI), respectively. Levels of anticardiolipin (aCL) antibodies, anti-β2-glycoprotein I (anti-β2-GPI) antibodies and lupus anticoagulant (LAC) were measured, and other clinical and pathological data were also obtained. Long-term renal outcome was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease stage, after a median follow-up of 20,5 ± 8, 7 years, counting from the occasion of the first renal biopsy. Renal and extra-renal symptoms were analyzed. Patients which have more than one class LN features, were excluded from the study. The treatment includes standard treatment for LN, inhibitors of the angiotensin system in patients with hypertension and proteinuria, steroids, anticoagulants, cyclophosphamide, mycophenolate mofetil, azathioprine. Results LN patients were classified according to the baseline renal biopsies as patients with: minimal mesangial LN (4), mesangial-proliferative LN (30), focal proliferative LN (31), diffuse proliferative LN (48), membranous LN (44). aPL antibodies were detected in 89 (56,69%) patients, aCL antibodies – in 72 (45,86%), anti-β2-GPI antibodies – in 58 (36,94%) and LAC were detected in 46 (29,30%) patients. None of these patients had a concomitant diagnosis of antiphospholipid syndrome nephropathy. Follow-up was similar between aPL-positive and aPL-negative patients. LN patients with positive aPL antibodies had significantly higher SLEDAI (p &amp;lt; 0,05), anti-dsDNA levels (p &amp;lt; 0,05), anti-ribosomal-P antibodies levels (p &amp;lt; 0,05), anti-C1q antibodies (p &amp;lt; 0,05), lower serum C3 (p &amp;lt; 0,005) and C4 (p &amp;lt; 0,05) levels, and higher intensity of complement C3 (p &amp;lt; 0,05) deposits in kidney tissue than the aCL antibody–negative LN patients. aPL-seropositivity was associated with more rapid decline in eGFR (–1,06 mL/min/year compared to –0,45 mL/min/year in aPL-seronegative patients) and showed inferior patient survival (89,8% and 67,9% at 10 and 15 years, respectively, compared to 97,3% and 76% in aPL-seronegative patients). No significant correlation was found between serum aPL antibodies levels and activity or chronicity index scores in renal biopsies at baseline, ANA levels, or age. Conclusion We concluded that aPL-seropositivity are correlated with clinical activity in patients with LN and are associated with inferior long-term patient survival.

#626 C3 glomerulonephritis and thrombotic microangiopathy—a prospective observational study

Abstract Background and Aims Complement mediated TMA (cTMA) and complement component 3 glomerulonephritis (C3GN) are two distinct complement mediated kidney diseases. cTMA is characterized by acute kidney injury, thrombocytopenia and microangiopathic hemolytic anemia. C3GN results from uncontrolled activation of the alternative complement pathway leading to the deposition of C3 in the glomerulus. We sought to describe characteristic differences between these two conditions in a large cohort of patients from Bengaluru, India. Method All cases of cTMA and kidney biopsy proven C3GN from 2019-2022 at a tertiary care centre in India were included. Patients with C3GN had persistently low C3 for more than 12 weeks and no identifiable source of infection. All patients received protocolized medical therapy; patients with C3GN were treated with steroids and cyclophosphamide, while those with complement mediated TMA received plasmapheresis in addition to cyclophosphamide and steroids. Protocolised medical management (renin-angiotensin-aldosterone inhibition and diuretics) was provided in both the cases. Demographic, clinical and lab parameters were reported and compared. Results A total of 25 cTMA cases and 19 C3GN cases were included in the study. Both C3GN (52.7%) and cTMA (48%) were more common in males. Patients with C3GN typically presented in the third decade of life while cTMA cases presented in the fourth decade. Secondary hypertension was common in the cTMA group (92% vs 78.9%, compared to C3GN). 60% of patients with cTMA had either recent or current infection compared to 21.1% of C3GN patients (P = 0.04). The majority of cTMA cases had IFTA of &amp;lt;25% (84%) compared to C3GN (57.9%) although this was not statistically significant. Both C3GN and cTMA most commonly presented as rapidly progressive kidney failure and acute kidney injury. A total of 76% of patients in the cTMA group required kidney replacement therapy as compared to 47.4% in the C3GN group (P = 0.009). 44% of cTMA cases had anti factor H antibody positivity compared to 15.8% of C3GN patients (P = 0.02). Finally, 44% of cases in cTMA group had complete recovery compared to 47.4% in C3GN group at the end of 2.8 years of followup. Conclusion Although both conditions result from dysregulation of the alternative pathway, there are several important clinical characteristic differences between patients with cTMA and C3GN including presence or absence of secondary hypertension, concurrent infection, anti-factor H positivity and requirement of kidney replacement therapy. This information may be helpful to inform both diagnosis and prognosis for patients presenting with a complement mediated kidney disease.

#3051 Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a case report

Abstract Background and Aims Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is an entity characterized by glomerular deposition of monoclonal immunoglobulins, typically IgG. Recently, a cohort of 17 patients presenting with light chain only variant of PGNMID was published. Strikingly, in this cohort, glomerular deposition of C3 was detected in all cases. We herein report a case of PGNMID with a rare presentation on the kidney biopsy. Case presentation We present the case of a 73-year-old female with a past medical history of rheumatoid arthritis and hypertension, under methotrexate 10 mg per week, prednisone 2.5 mg per day, amlodipine, nebivolol, azilsartan, and a recurrent naproxen intake. She presented with fatigue, anorexia, weight loss of about 12% of her body weight, epistaxis, oral bleeding ulcers, and lower extremities oedema. Pancytopenia, acute kidney injury (urea 150 mg/dL, creatinine 2.92 mg/dL), and nephrotic syndrome (serum albumin of 2.7 mg/dL and proteinuria of 12 g/day) were noted. Further evaluation showed an imbalance of the free light chains’ ratio with kappa light chain's level of 1250 mg/dL. Serum protein electrophoresis and immunofixation were normal. A CT scan showed numerous cervical, mediastinal, and iliac enlarged lymph nodes. Kidney biopsy showed an increase in mesangial cells and matrix and capillary walls’ thickening without nodular lesions under a light microscope. Immunofluorescence microscopy showed granular deposits of kappa light chains and no deposition IgA, IgG, IgM, C1q, C3, fibrin and lambda. Considering the previous literature, C3 was reanalyzed, with a consistent negative staining. Based on the above findings, a diagnosis of Light chain only variant of PGNMID was made. Concomitantly, evaluation of the bone marrow sample showed Small lymphocytic lymphoma. The patient was started on Bortezomib, cyclophosphamide and dexamethasone. Three months after proteinuria was 0.47 g/g and creatinine 1.7 mg/dL. Conclusion This case highlights the rare occurrence of a PGNMID with light chains only deposition (without C3 co-deposition) as a complication of small lymphocytic lymphoma. This contributes to the growing body of evidence surrounding this entity, with the particularity being that C3 was not detected. The authors hypothesized some pathophysiologic mechanisms to justify the absence of C3 co-deposition.

#1467 Pegcetacoplan for post-transplant recurrent C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis in NOBLE: 12-week evolution

Abstract Background and Aims C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases caused by uncontrolled complement activation, resulting in excess deposition of C3 breakdown products in the kidneys, which leads to kidney damage and eventually kidney failure. Kidney transplantation is an option for end-stage kidney disease, but disease recurrence is common (up to 67% of patients), and up to 50% of transplant recipients lose renal allografts due to recurrence. Pegcetacoplan is a targeted C3 and C3b inhibitor that may prevent excess deposition of C3 and C5 breakdown products and subsequent glomerular inflammation and kidney damage in patients with C3G or IC-MPGN, potentially improving clinical outcomes. NOBLE (NCT04572854) was the first prospective randomized controlled trial of pegcetacoplan vs standard of care (SOC) in post-transplant patients with recurrent C3G or IC-MPGN. Method Adult patients were randomized 3:1 to subcutaneous pegcetacoplan 1080 mg twice weekly plus SOC (n = 10) or SOC only (n = 3) for 12 weeks followed by a 40-week non-controlled period in which all patients received pegcetacoplan. Primary and secondary endpoint results for Week-12 data have been reported. We conducted a patient-level post hoc analysis to describe key histology changes from renal biopsy (C3c staining, C3G histologic index activity score), clinical parameters (urine protein-to-creatinine ratio [uPCR; calculated from triplicate first-morning spot urine], estimated glomerular filtration rate [eGFR]), and biomarkers (serum C3, plasma sC5b-9) through Week 12. The C3G histologic index uses a semiquantitative scale of 0–3 for 7 markers of activity (mesangial hypercellularity, endocapillary proliferation, membranoproliferative morphology, leukocyte infiltration, cellular and/or microcellular crescent formation, fibrinoid necrosis, and interstitial inflammation), for a total activity score of 0–21. eGFR stability was defined as a decrease of no more than 25% versus baseline. Results Among the 10 pegcetacoplan-treated patients, 7 (70%) had 1 previous kidney transplant, 2 (20%) had 2, and 1 (10%) had 3. The mean (range) time to disease recurrence after most recent transplant was 10.8 (0.4–31.8) months and from most recent recurrence to randomization was 12.2 (2.1–37.7) months, with 60% randomized &amp;gt;6 months post-disease recurrence. Among the 3 SOC-only patients, 2 (66.7%) had 1 transplant and 1 (33.3%) had 2. Mean (range) time to recurrence was 32.8 (4.6–63.8) months and to randomization was 33.9 (7.0–65.4) months. At Week 12, 8 (80%) pegcetacoplan-treated patients had a reduction in C3c staining of at least 1 order of magnitude. Of these 8, 7 (70%) had a decrease in activity score, and 6 of these 7 (60%) had a decrease in proteinuria. Four (40%) patients had reduced C3c staining, decreased activity score, and cleared electron microscopy deposits at Week 12. eGFR remained stable in 9 (90%) patients. Six of 9 (67%) patients with available Week-12 data (4 of 5 patients with &amp;gt;1 g/g uPCR at baseline) had a reduction in uPCR with 5 of the 6 achieving ≥50% uPCR reduction (Table). All pegcetacoplan-treated patients had increased serum C3, as expected, and 9 (90%) had decreased sC5b-9. At Week 12, no TEAEs led to study discontinuation, treatment withdrawal, or death. No encapsulated bacterial infections or events of rejection/graft loss related to the study drug were reported. Conclusion As early as Week 12, more than half (6/10 [60%]) of post-transplant patients with recurrent C3G or IC-MPGN treated with pegcetacoplan achieved reductions in C3c staining, activity score of C3G histology index, and proteinuria, suggesting that pegcetacoplan targets the underlying pathophysiology of the C3G/IC-MPGN in kidney transplant recipients. The safety and efficacy of pegcetacoplan will be further evaluated at Week 52 of the NOBLE study and as part of the Phase 3 VALIANT (NCT05067127) trial, which enrolled patients with C3G or primary IC-MPGN who have native kidney or post-transplant disease.

#2187 Rare disease, novel approach: C3GN and Iptacopan case report

Abstract Background and Aims C3 glomerulonephritis (C3GN) is a rare disease characterised on biopsy by proliferative lesions of predominant C3 deposition on immunofluorescence, particularly deposits within the mesangium and capillary walls. Dysregulation of the alternative complement pathway is thought to be the underlying mechanism [1]. There are no approved treatments for C3G and prognosis is poor, with 50% progression to kidney failure over 10 years and similar rates of transplant loss due to disease recurrence. Iptacopan (a selective Factor B complement inhibitor) is proposed to suppress key enzymes involved in the alternative pathway cascade [2]. It is being studied in clinical trials of C3G [3]. We sought to describe our experience in diagnosing and managing a 25-year-old with C3GN who presents with nephrotic syndrome, hypertension, and a reduction in his estimated glomerular filtration rate (eGFR) with a novel small molecule therapeutic. Method This report charts the clinical course of one male patient over 11 months from presentation with C3GN, to the introduction of immunosuppression and of Iptacopan, and the assessment of his response to the foregoing. The patient consented to the publication of his case. Results A 25-year-old male with a background of autism spectrum disorder was referred to his regional nephrology service due to reduction in his eGFR and proteinuria. His creatinine was 158 µmol/L with an eGFR was 51.8 ml/ml/1.73 m2 (CKD-EPI equation); urinary protein creatinine ratio (uPCR) 500 mg/mmol; urinary albumin creatinine ratio (uACR) 400.2 mg/mmol. Serum album 32g/L. His C3 0.22 (normal range 0.82–1.85 g/L); C4 0.27 (normal 0.15–0.53 g/L). A renal biopsy was performed which demonstrated diffuse MPGN dominant C3 staining; cholesterol crystals; and moderate to severe chronic tubulointerstitial damage. 1 mg/kg oral prednisolone with mycophenolate mofetil (MMF) titrated up to a dose of 1g twice a day was initiated. As he was established on the therapy his eGFR rose back to 57.9 ml/min over approximately 8 weeks from a nadir of 33.8 ml/min. Following initial weaning of his prednisolone dose, his eGFR dropped back down to 29.7 ml/min with a creatinine of 250 µmol/L. With involvement and clinical support from the National Renal Complement Therapeutics Centre an application was made to Novartis for the compassionate use of Iptacopan which was commenced early August 2023 (he would not have been eligible for recruitment into any current clinical trials). His latest eGFR is 47.5 ml/ml/1.73 m2 with a uACR of 9.1 mg/mmol and normal C3 and C5b-9 levels after 5 months of Iptacopan. His prednisolone dose is 10 mg. MMF continues at 2g total dose. Conclusion Iptacopan has so far resulted in the normalisation of serum C3 levels, reduction of uACR and stabilisation of serum creatinine as we have reduced the prednisolone dose.

#145 Subgroup and secondary endpoint evaluation of a phase 2 randomized placebo-controlled trial of ravulizumab in IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) involves immune complex deposition and activation of the complement system, causing formation of the terminal pathway components C5a and C5b-9, leading to inflammation and glomerular damage. Elevated levels of activated C3 in plasma are associated with proteinuria and renal function decline in patients with IgAN [1]; mesangial C3 deposition is also associated with progression of disease [2]. Ravulizumab is a humanized monoclonal antibody that immediately and completely inhibits complement component C5. Primary endpoint (week 26) data from the phase 2 randomized controlled trial (RCT) (NCT04564339) were previously reported and demonstrated a 30% and 33% treatment effect of ravulizumab compared to placebo on 24-hour urine protein and 24-hour urine protein-to-creatinine ratio (UPCR) reduction, respectively [3]. This analysis reports prespecified subgroup and secondary endpoints as well as post hoc exploration of treatment response by baseline serum C3 and C4 quartiles through week 26. Method The SANCTUARY RCT evaluated ravulizumab (IV; weight-based dosing Q8W) vs placebo in adults with primary IgA nephropathy. Randomized patients (2:1) were stratified by mean proteinuria (1–2 vs &amp;gt;2 g/day). Patients (18–75 years) with biopsy-confirmed IgA nephropathy, proteinuria ≥1g/day, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, and on stable maximally tolerated renin angiotensin inhibition were enrolled. The primary endpoint was proteinuria reduction at week 26 based on 24-hour urine collection. Secondary endpoints at week 26 included the proportion of patients with &amp;gt;50% reduction in proteinuria (absolute urine protein) and the percentage with &amp;lt;1g/day proteinuria. The percentage change in proteinuria (absolute urine protein) among subgroups of sex, race, duration of disease, baseline proteinuria and eGFR, and baseline serum C3 and C4 levels were also evaluated, as were safety data. Results 66 patients entered the 26-week initial evaluation period (n = 43, ravulizumab arm; n = 23, placebo arm); 71.2% were White and 21.2% were Asian. Overall, 41.5% and 18.2% of ravulizumab- and placebo-treated patients, respectively, achieved &amp;gt;50% proteinuria reduction (Fig. 1). Proteinuria reduction to &amp;lt;1g/day was achieved in 26.8% and 18.2% in the ravulizumab and placebo arms, respectively. Subgroup analysis indicated a treatment effect across subgroups of sex, race, disease duration, and baseline proteinuria and eGFR (Fig. 2). With ravulizumab, there were reductions of 41.9% and 41.0% in proteinuria for those with the lowest quartile of baseline serum C3 and C4, respectively. Similarly, reductions of 40.4% and 40.8% were observed in those with baseline serum C3 and C4 levels above the lowest quartile. In the ravulizumab arm, two patients had low serum C3 at baseline and there were no patients with low serum C4 at baseline; there was no change in mean serum C3 and C4 levels over time. Treatment with ravulizumab was well-tolerated. Conclusion In this phase 2 trial of ravulizumab in IgAN, proteinuria was significantly reduced with ravulizumab vs placebo through week 26. A reduction in proteinuria was also observed across subgroups of patients. As is typical in IgAN, serum C3 and C4 levels at baseline were normal, and there was no difference in proteinuria reduction by baseline serum C3 and C4 levels with ravulizumab through 6 months.

Autoimmunity and epithelial dysplasia in patients with oral lichenoid diseases.

The primary objective of this study was to explore relationship between autoimmunity and epithelial dysplasia in patients with oral lichenoid diseases. A total of 66 patients with oral lichen planus (OLP), 35 with oral lichenoid lesion (OLL), and 85 with oral lichenoid drug reaction (OLDR) were enrolled. OLP, OLL, and OLDR were diagnosed following the definitions of the modified World Health Organization criteria, except for the absence of epithelial dysplasia. All patients underwent diagnostic incisional biopsy and adjunctive direct immunofluorescence assays. An indirect immunofluorescence assay was conducted to determine the antinuclear antibody (ANA) positivity. OLP and OLDR patients with epithelial dysplasia demonstrated higher prevalence of serum ANA positivity compared to those without epithelial dysplasia. Elevated serum levels of high sensitivity-C reactive proteins were observed in the OLP, OLL, and OLDR patients with epithelial dysplasia. In the DIF analysis, patients with epithelial dysplasia in the OLP exhibited a higher prevalence of C3 deposition in the basement membrane zone. This study proposed that autoimmunity may contribute to elevating levels of focal and chronic systemic inflammation, potentially influencing abnormal wound healing and development of dysplastic changes in the oral epithelium among patients with oral lichenoid disease.