Low Serum C3 Levels Research Articles

Poststreptococcal acute glomerulonephritis with 22F pneumococcal bacteremia.

Pneumococcal vaccines have been available worldwide since the early 2000s; consequently, few reports exist of poststreptococcal acute glomerulonephritis (PSAGN) or complications of pneumococcal infection. We describe a patient with PSAGN and bacteremia with Streptococcus pneumoniae serotype 22F (not covered by the 13-valent pneumococcal vaccine (PCV 13)). A 5-year-old boy received the PCV13 vaccine and was admitted to our hospital with a fever and gross hematuria. A throat swab was positive for a streptococcal antigen, and his serum anti-streptolysin O and creatinine levels were increased. Low serum C3 levels suggested PSAGN, with an infiltrating shadow on chest X-ray. His blood culture isolated S. pneumoniae serotype 22F, and he was administered intravenous ceftriaxone for 10days. His kidney function, pneumonia, and bacteremia improved. Children with PSAGN should be evaluated for pneumococcal bacteremia due to strains not covered by the vaccine.

Serum IgA/C3 ratio: a useful marker of disease activity in patients with IgA nephropathy.

High serum IgA and low serum C3 levels resulting from lectin and alternative pathway activation might be related to IgA nephropathy (IgAN) progression and exacerbation. This study examined whether the serum IgA/C3 ratio can serve as an IgAN progression marker. (1) This nationwide multicenter retrospective study in Japan included 718 patients with biopsy-confirmed IgAN. The patients whose serum creatinine levels at the time of renal biopsy had doubled were defined as having disease progression. (2) Furthermore, to investigate the pathological significance of a reduction in serum IgA/C3 ratio, we reviewed 63 patients whose serum IgA and C3 data at the end of the observation period were obtained. (1) A Kaplan-Meier analysis of the patients with IgAN revealed that the group with a high serum IgA/C3 (≥ 3.3) had a significantly worse renal outcome. In a multivariate analysis of eGFR ≥ 60mL/min per 1.73m2 at the time of biopsy, poor renal outcome was significantly predicted by a serum IgA/C3 ratio of ≥ 3.3. (2) A 15% reduction in the change of serum IgA/C3 ratio was associated with a significantly higher percentage of complete remission of proteinuria. Among the four groups divided by treatment, both the serum IgA/C3 ratio and proteinuria were reduced only in the tonsillectomy and steroid pulse group. The serum IgA/C3 level might reflect the disease activity and be a potent surrogate marker of therapeutic efficacy in patients with IgAN.

#1793 Association of low serum complement C3 with reduced renal survival in ANCA associated vasculitis

Abstract Background and Aims ANCA-associated vasculitis (AAV) is a condition that remains poorly understood. Recent data suggest the existence of a complement alternative pathway activation in the pathogenesis of this disease. And recent studies have correlated low complement levels to unfavourable outcomes. Our study aimed to determine whether low serum C3 levels could be used to estimate the severity of AAV and predict renal survival. Method Our study enrolled 26 patients diagnosed with AAV between January 2013 and January 2023. C3 levels were assessed at the time of diagnosis, and patients were categorized into two groups: those with low serum C3 levels and those with normal serum C3 levels (0.9–1.8 g/l). We examined the correlation between serum C3 levels and the severity of AAV at the time of diagnosis, as well as renal survival. Results The average age at diagnosis was 52.5 years, with 15 male patients (57.69%). All patients had kidney involvement, 30% of patients had respiratory symptoms (mostly due to diffuse alveolar hemorrhage) 42% had Ear Nose Throat system involvement 15% had nervous symptoms and 38% had skin signs. The mean Birmingham Vasculitis Activity Score (BVAS) at presentation was 20, and the average serum creatinine level was 360 µmol/l. The mean serum C3 and C4 levels were 108.3 and 24.5 mg/dL, respectively. Forty-two percent of the patients (eleven patients) had a low serum C3 level at presentation. Low C3 level was significantly correlated with poor renal survival (p: 0.031) and relapse after 6 months of immunosuppressive treatment (p: 0.02). Furthermore, remission at 6 months was significantly more frequent in patients with normal C3 levels. Conclusion The assessment of C3 level in AAV can be a valuable tool to predict the disease severity. Hypocomplementemia can predict worse renal outcome. This phenotype may confer a poor response to usual immunosuppressive approaches. Corresponding patients may greatly benefit from complement-targeting therapy.

#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.

#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.

C3 Hypocomplementemia Predicts the Progression of CKD towards End-Stage Kidney Disease in IgA Nephropathy, Irrespective of Histological Evidence of Thrombotic Microangiopathy.

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN causes end-stage kidney disease (ESKD) in 30-40% of all cases. The activation of the complement system by pathological circulating IgAs, which is often associated with low serum C3 levels (LowC3), seems to play a crucial role. Previous studies have shown an association between histological evidence of TMA, which is the result of alternative complement activation, and poor outcomes. However, it is not known to what extent the decrease in serum C3 levels reflects ongoing TMA injury. Our study aimed at assessing the association between LowC3 and ESKD and whether this association reflects ongoing TMA. Methods: We enrolled all patients with biopsy-proven IgAN and followed-up patients until their last visit, ESKD, or death. Results: Of the 56 patients included in the study, 12 (21%) presented low serum C3 (LowC3) at the time of renal biopsy. TMA was significantly more frequent in the LowC3 group [7/12 (58%) vs. 9/44 (20%), p = 0.02]. After adjusting for potential confounders, LowC3 was strongly associated with an increased hazard of ESKD (hazard ratio [HR]: 5.84 [95%CI: 1.69, 20.15; p = 0.005). The association was not affected by adjusting for TMA. The estimated overall proportion of the relation between C3 and ESKD mediated by TMA was low and not statistically significant. Conclusions: Our study provides evidence that C3 hypocomplementemia is associated with an increased risk of ESKD through mechanisms that are largely independent from TMA.

Low C3 in a 4-month-old baby: is it a problem?

A 4-month-old male baby was admitted because his father and uncles had chronic kidney disease. His father was diagnosed with membranoproliferative glomerulonephritis at the age of 5, underwent a kidney transplant at the age of 22, and lost the graft due to recurrence of the disease. In contrast, the young uncle was diagnosed with C3 glomerulopathy and mycophenolate mofetil and eculizumab were initiated early. It was remarkable that our patient had normal kidney function and urine analyses but low serum C3 level (0.56g/L; N, 0.9-1.8g/L). In the disease-associated clinical exome analysis, a heterozygous change in theCFH gene was found. The same mutation was found homozygous in the uncle. In genetically inherited diseases, findings may occur sequentially; early screening of at-risk individuals contributes to kidney survival.

#6035 PREDICTORS OF MORTALITY IN ANCA-ASSOCIATED VASCULITIS: WHAT IS THE ROLE OF SERUM BIOMARKERS?

Abstract Background and Aims ANCA-Associated vasculitis (AAV) is an autoimmune disease with necrotizing inflammation of small vessels as the main manifestation. AAV is a severe disease with high level of mortality. Severity markers are needed to better tailor treatment. ANCA titers have not always been correlated with disease severity and mortality. Other inflammation markers have also been used such as C3 and C-reactive protein (CRP). The aim of this study is to correlate ANCA titers, C3 and CPR values ​​with mortality in patients with renal vasculitis. Method We retrospectively analyzed all adult patients between June 2006 and December 2022 with a renal AAV in the nephrology department of São Bernardo Hospital. Demographic, clinical and laboratory findings of all patients were recorded. ANCA titers at the time of diagnosis (ANCAd), remission (ANCArm), relapse (ANCArl) and last follow-up (ANCAf) dates were registered. C3 levels were measured at diagnosis (dC3) and at the last follow-up (fC3) dates. CRP was measured at diagnosis (CRPd), remission (CRPrm) and last follow-up (CRPf). ANCA titers was analysed as continuous and categorical variables. C3 and CRP were used as continuous variables. We analyse the association between ANCA titers, C3, CPR values and mortality with univariate analysis. Multivariable adjusted cox regression analysis was performed for assessing predictive variables associated with mortality. Results We included 58 AAV patients with kidney involvement, with mean age of 69±10 years old, 54.4% were male (n = 31), 82.7% (n = 48) MPO-ANCA+, 12.1% (n = 7) PR3-ANCA+ and 5.2% (n = 3) seronegative. Median follow-up was 32.2 months. 20 (34.5%) patients died. At admission, categorization by ANCA titer revealed 5.2% (3) 0-19 UI/mL, 10.3% (6) 20-39, 8.6% (5) 40-59, 17.2% (10) 60-99, 8.6% (5) 100-134 and 38% >134 (22). C3 median was 109 UI/L at admission, 96.5 UI/L at last follow-up, CPR median was 7.9 mg/dL at admission, 2.4 mg/dL at last follow-up. Univariate analysis did not reveal a difference between patients who survived and those who died, in relation to ANCAd (p = 0.221), ANCArm (p = 0.346), ANCArl (p = 0.180) and ANCAf (p = 0.072). However, it did show that dC3 where significantly lower in those patients who died (p = 0.023) and CRPf higher (p = 0.012), but not for fC3 (p = 0.372), CRPd (p = 0.408) and CRPrm (p = 0.384). Used as categorical variable, ANCAd did not correlate to patients’ death occurrence (p = 0.788). In multivariate analysis including age, gender, dC3 and CRPf, only CRPf was almost significantly (p = 0,06, model p = 0,05). In univariate cox regression analysis to evaluate factors related to survival, none where statistic significant to predict dead – ANCA d (p = 0,349), ANCAf (p = 0.136), dC3 (p = 0.082) and CRPf (p = 0.066). In multivariate cox regression analysis, including age (p = 0.039), gender (p = 0.658), dC3 (p = 0.227) and CRPf (p = 0.639), none factor predict dead (model p = 0,08). Conclusion In our cohort of patients with AAV, we did not found a serologic marker to predict dead. However, it appears to have a relationship with low serum C3 levels at the time of diagnosis. We also found that could be a relationship with CRP at the last follow-up, but that could be a bias due to higher levels in those how died from infection causes. The diagnostic value of the PR3- and MPO ANCA test is well established, however the relationship between mortality and titer levels in the various stages of the disease is not well established. In our study, there was no association between them. Further research should determine whether C3 levels and CPR are indeed an independent predictor of AAV outcome.

#6517 CLINICOHISTOLOGICAL CHARACTERISTICS, THERAPEUTIC APPROACH AND RENAL OUTCOME IN PATIENTS WITH C3 GLOMERULOPATHY: A SINGLE-CENTER EXPERIENCE

Abstract Background and Aims C3 glomerulopathy has been identified as a distinct disease in the last decade but it has already been associated with a high burden of end stage renal disease (ESRD). Due to the rarity and heterogeneity of the disease, data regarding the prognosis and optimal treatment are still lacking. We aimed to describe the clinical and histological phenotype of patients with C3 glomerulopathy followed at our center, the treatment regimens applied and their long-term renal outcome. Method We conducted a retrospective medical chart review of 19 patients with C3 glomerulopathy followed at our center and we reported clinical, histological and therapeutic parameters as well as their long-term renal outcome. Results Median age of patients at the time of diagnosis was 23 years (IQR 28), median proteinuria 2.6 g/d (IQR 2.8) and median eGFR 63ml/min (IQR 63). 26% of patients (5/19) presented with an eGFR <30ml/min. Low serum C3 levels were reported in 11/19 patients (58%). Α monoclonal paraprotein was detected in three patients and pathogenous mutations of CFH/CFI genes in 4 out of 10 patients who underwent genetic testing. 41% of patients (7/17) were treated with RAAS inhibitors only, while 59% (10/17) received immunosuppressive treatment. Immunosuppressive treatment consisted of different combinations of steroids with mycophenolic acid, cyclophosphamide, cyclosporine or rituximab and steroid monotherapy in one patient. Treatment data were not available for two patients. There was a significant difference in baseline proteinuria between patients treated with RAAS inhibitors only (median 1.5g/d, IQR 1.14) and those who were treated with immunosuppressants (median 3.95g/d, IQR 4.8) (p = 0.003). Remission (complete or partial) was achieved by 43% of patients at 6 months and by 50% at 12 months. Median follow up time was 45 months (IQR 66). Eight patients (42%) reached ESRD in a median time of 58.5 months (IQR 62.5) while other three patients (16%) ended up with a GFR decline >30%. Among patients with adverse renal outcome (ESRD, GFR decline >30%), 54.5% (6/11) had baseline proteinuria >3g/d, 73% (8/11) had low serum C3 and 54.5% (6/11) had interstitial fibrosis/tubular atrophy >25%, while the median percentage of glomerulosclerosis was 33% (IQR 58). On the contrary, in the group of patients with favorable renal outcome, baseline proteinuria >3g/d was reported in only 25% (2/8), low serum C3 in 37.5% (3/8), interstitial fibrosis/tubular atrophy >25% in 25% (2/8), while median glomerulosclerosis was only 8% (IQR 15). Attainment of complete remission was associated with favorable renal outcome (p = 0.001). Five of eight patients who reached ESRD underwent kidney transplantation from a living related donor. All of them received basiliximab, mycophenolic acid, tacrolimus and steroids. Recurrence of C3 glomerulopathy was reported in four of these patients and eculizumab was given in two of them. Graft loss due to disease recurrence was observed in one patient. Conclusion The present case series of patients with C3 glomerulopathy highlights the great heterogeneity in the clinical phenotype, therapeutic approach and renal prognosis of the disease. It also underscores the importance of attainment of complete remission regarding the long-term renal survival. Large studies are needed in order to better define clinical and histological predictors of adverse renal outcome as well as the optimal treatment regimens.

#6470 PATIENT SURVIVAL IN AN ASSOCIATED VASCULITIS COHORT – DATA FROM A REFFERAL CENTER

Abstract Background and Aims Patients with ANCA associated vasculitis (AAV) have variable survival rates depending on disease activity, complications and sometimes the choice of treatment. Still today there are a lot of differencies between various cohorts regardless of similarities in clinical presentation, serology or histology. Understanding risk factors for various outcomes in cohorts from different geographical areas might help build better and more uniform prediction models. We present data on patient survival from our refferal center. Method This study included 106 consecutive AAV patients with biopsy proven renal involvement in the period from 2007-2017. We analyzed clinical, laboratory and pathohistological data as predictors for death of the patients. Survival univariate analysis was performed using Kaplan-Meier method and log-rank (Mantel-Cox) test. Variables that had p<0,1 in univariate analysis were alongside age and gender included in multivariate Cox proportional hazard model. Results The study included 106 AAV patients with renal involvement: 66 (61,1%) MPA, 20 (18,5%) GPA, 20 (18,5%) RLV. There were 14 (13%) PR3-ANCA positive patients, 57 (52,8%) MPO ANCA positive, 5 (4,6%) PR3-ANCA+MPO-ANCA and 32 (29,6%) ANCA negative patients. Average SCr was 316,5 μmol/l (IQR 207,0-548,5), 24-hour proteinuria median was 1,7g/24h (IQR 0,8-2,8). Histologicaly (Berden classification) 43 (39,8%) patients had crescentic, 19 (17,6%) focal, 34 (31,5%) mixed and 12 (11,1%) sclerotic class. Follow up time was 1 to 127 months with median 21 months (IQR = 7 - 44) and medium follow up time of 28,6 months (SD = 26,6). All the patients recieved the same induction treatment (cyclophosphamide and glucocorticoids +/- acute haemodialysis and plasma exchange treatment) and remission maintenance treatment (azathioprine). During the follow up 21 patient (19,8%) died. Out of those 13 were females. Main causes of death were either infections or cardiovascular diseases. In follow up period patient survival was 83,9-81,2-79-74,7% at 12-24-36-60 months. There were no differences in survival rates between clinical, histological or serological phenotypes. In univariate analysis significant predictors for death of patients were: age (>68 years; p = 0,002), anaemia (Haemoglobin <96 g/l; p = 0,001), increased CRP levels (CRP > 63mg/l; p = 0,001), lower serum C3 levels (p = 0,001), BVAS > 18 (p = 0,003) and the need for dialysis (p = 0,06). In multivariate analysis however significant predictors for the death of patients were age (HR = 1,059, 95% CI = 1,001-1,120; p = 0,046), anaemia (HR = 0,952, 95% CI = 0,908-0,998; p = 0,040) and BVAS (HR = 1,093, 95% CI = 1,030-1,159; p = 0,003). Interestingly in additional analysis PLEX was, alongside acute haemodialysis, significant predictor in combined ESRD/death outcome (as well as for ESRD and relapse rate) but not for death alone. Conclusion In our data disease activity as defined by BVAS and anaemia alongside the patient age are predictors for the patient survival. Anaemia is not included either in BVAS or in other disease activity scores or prediction models. Considering its potential impact on multiple organ functions perhaps anaemia levels should be included either in BVAS or perhaps in VDI though anaemia itself is mostly not autoimmune phenomenon in AAV patients. Also in our cohort PLEX wasn't a significant predictor for patient survival.

Pembrolizumab induced-C3 glomerulonephritis and RBC cast nephropathy: a case report

BackgroundImmune checkpoint inhibitors (ICIs) are increasingly being used in the treatment of several cancers. Pembrolizumab is an anti-programmed cell death-1 (anti-PD-1) monoclonal antibody that is approved for the treatment of metastatic non-small cell lung cancer (NSCLC). Pembrolizumab-associated renal toxicity is relatively rare, even in pembrolizumab-associated glomerulonephritis. In this study, we report a rare case of pembrolizumab-induced C3 glomerulonephritis (C3GN) and RBC cast nephropathy.Case presentationA 68-year-old man with NSCLC was receiving treatment with pembrolizumab. After 19 cycles of pembrolizumab therapy, he presented with gross hematuria, severe lower-limb edema and oliguria. Laboratory tests revealed hypoalbuminemia, increased serum creatinine and low serum C3 level. Renal biopsy revealed a typical membranoproliferative glomerulonephritis accompanied by remarkable RBC casts in tubular cavities and tubulointerstitial infiltration of CD8-positive lymphocytes. Based on C3-only immunofluorescence deposit on glomeruli, a diagnosis of C3GN was made. Pembrolizumab was considered the cause of C3GN. Pembrolizumab was discontinued immediately, and 60 mg/day of prednisone was initiated. One dose of cyclophosphamide (400 mg, IV) was also administered. Upon treatment, his symptoms improved rapidly and serum creatinine decreased a lot. However, the patient became dialysis dependent eventually.ConclusionThis is the first case of C3GN with RBC cast nephropathy caused by ICIs. This rare case caused by the prolonged use of pembrolizumab further strengthens the relationship between ICIs and C3GN. Thus, periodic evaluation of urine and renal function is recommended in patients receiving pembrolizumab and other ICIs.

MO231: Comparison of Dominant and Non-Dominant C3 Deposition in Primary Glomerulonephritis

Abstract BACKGROUND AND AIMS Alternative complement pathway (AP) dysregulation plays a key role in glomerulonephritis (GN) and is associated with C3 deposition. Herein, we examined pathological and clinical differences between cases of primary GN with C3-dominant (C3D-GN) and non-dominant (C3ND-GN) deposition. METHOD We extracted primary GN data from the Korean GlomeruloNEphritis sTudy (KoGNET). C3D-GN was defined as C3 staining two grades greater than C1q, C4 and immunoglobulin via immunofluorescence analysis. Data between groups were age- and sex-matched (each group, n = 61). RESULTS The C3D-GN group exhibited higher serum creatinine (P = .027), greater prevalence of estimated glomerular filtration rates < 60 mL/min/1.72 m2 (P = .009), higher C-reactive protein levels (P = .003) and lower serum C3 levels (P = .018). Serum albumin, urine protein/creatinine ratio, number of patients who progressed to end-stage renal disease and mortality were comparable between groups. Interstitial fibrosis and tubular atrophy were greater in the C3D-GN group (P = .0027 and .005, respectively) than in the non-C3GN group. C3 deposition was dominant in the former group (P < .001), in parallel with increased subendothelial deposition (P = .003). CONCLUSION Greater progression of renal injury and inflammation occurred in patients with C3D-GN than with C3ND-GN, potentially owing to AP dysregulation.

POS-501 COMPLEMENT LEVELS IN ANCA ASSOCIATED VASCULITIS AS PREDECTOR OF RENAL SURVIVAL

During the last few years, novel findings have suggested that activation of the complement system, in particular the alternative complement system, has a significant role in ANCA associated vasculitis pathogenesis. We investigated whether low serum C3 levels can cross sectionally estimate severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and estimate the renal servival.

Long-term follow-up including extensive complement analysis of a pediatric C3 glomerulopathy cohort

BackgroundC3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G.MethodsTwenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood.ResultsDDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m2 at last follow-up.ConclusionsWe extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics.Graphical abstract

C3 Glomerulonephritis associated with Anti-complement Factor H Autoantibodies in an Adolescent Male: A Case Report

C3 glomerulonephritis (C3GN), a rare condition associated with dysregulation of the alternative pathway of the complement system, is histopathologically characterized by isolated or dominant C3 deposition in the renal glomeruli. We report a case of C3GN associated with anti-complement factor H (CFH) autoantibodies and CHF-related protein deficiency in an adolescent male. A 16-year-old adolescent male was admitted to a hospital with a 1-month history of generalized edema prior to presentation. Persistent microscopic hematuria and low serum C3 levels were incidentally detected at 7 and 10 years of age, respectively. Laboratory test results revealed hypoalbuminemia, nephrotic-range proteinuria, microscopic hematuria, and normal serum creatinine levels. The serum C3 and C4 levels were 17 mg/dL (normal 80–150 mg/dL) and 22 mg/mL (17–40 mg/mL), respectively. Renal biopsy showed typical features of C3GN. Further investigations revealed positive results on plasma anti-CFH autoantibody testing and a homozygous deletion of CFHR1 and CFHR3, which encode CFH-related proteins 1 and 3, respectively. Proteinuria persisted despite treatment with intravenous methylprednisolone, mycophenolate mofetil, and angiotensin-receptor blocker; however, his renal function remained stable. In conclusion, anti-CFH autoantibodies serve as important contributors to C3GN. This is the first case report that describes C3GN in an adolescent Korean male with anti-CFH autoantibodies and homozygous CFHR1 and CFHR3 deletion. Key words: C3 glomerulonephritis, Hypocomplementemia, Anti-complement factor H autoantibodies, Complement factor H related proteins

Relationship of complement activation pathway to clinical and pathological characteristics and renal outcome in patients with lupus nephritis.

Involvement of the complement system in the pathogenesis of lupus nephritis (LN) is well accepted, but its exact role remains unclear. The aim of this study was to investigate the relationship of complement activation pathway to clinical and pathological characteristics and renal outcome in patients with LN. Patients with LN were divided into two groups: those in whom the complement system was mainly activated through the classical pathway (low serum C3 and C4 levels; CP group); and those in whom the complement system was solely activated through the alternative pathway (low serum C3 with normal C4 levels; AP group). Clinical and pathological data and renal outcomes were compared between the two groups. Atotal of 102 LN patients were enrolled in this study, 63patients (61.8%) in the CP group and 39patients (38.2%) in the AP group. LN patients in the CP group had significantly higher SLEDAI (p < 0.001), more anti-dsDNA (p = 0.001), higher renal activity index (p < 0.001), and more classIV LN (p = 0.008) than LN patients in the AP group. Mean length of follow-up was 50.6 ± 26.4months. Renal outcome in the form of progression of kidney disease was significantly poorer in the CP group in the AP group (p = 0.037). Our findings suggest that evaluation of the complement activation pattern may be useful for evaluating disease activity and predicting the prognosis of LN.

MO274EVALUATION OF SERUM C3 LEVELS AND C3 IMMUNOFLUORESCENCE IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS: A RETROSPECTIVE COHORT STUDY

Abstract Background and Aims The role of complement activation, mainly alternative system, has been recently proposed to play an important role in the pathogenesis of ANCA associated vasculitis (AAV). Real life data assessing its predictive role in renal outcomes are limited. In this study, we evaluated the value of serum and kidney deposited C3 in predicting renal outcomes in patients with AAV. Method In this retrospective study, patients with AAV were categorized according to their baseline serum C3 levels as hypo- or normo-complementemic and to those with positive or negative kidney biopsy immunofluorescence (IF) for C3. Clinical, serologic, treatment and histopathologic characteristics, as well as prognosis between the 2 groups were compared. Results: Forty-seven patients (51% men) were enrolled with a mean age at diagnosis of 65 years and were followed up for a median period of 56 months. At baseline, 23% (11/47) of the patients were hypocomplementemic (C3 &amp;lt;75 mg/dL). These patients were older (74 vs. 65 years,p=0.013), had higher creatinine levels (4.9 vs. 2.2 mg/dL, p=0.006), were more often hemodialysis dependent (64% vs. 19%, p=0.009) and progressed more often to ESRD (55% vs .11%,p=0.01) compared to normo-complementemic patients (n=36). On multivariate analysis, serum Cr at diagnosis (HR=16.8, 95%CI: 1.354-208.62,p=0.028) and low serum C3 (HR=2.492; 95% CI: 1.537-11.567,p=0.044) were independent predictors for ESRD. Among 25 patients with kidney biopsy data, those with positive IF staining for C3 (56%, n=14) had more often a mixed histological pattern (72% vs. 27%,p=0.033), low serum C3 levels (42% vs. 18%,p&amp;lt;0.001) and serious infections during follow-up (57% vs. 18%,p=0.047) compared to those with negative (n=11) IF staining. Conclusion Low serum C3 levels at diagnosis may be an independent prognostic factor for ESRD progression in patients with AAV. This should be taken into account in therapeutic and monitoring strategies.

Disparities between IgG4-related kidney disease and extrarenal IgG4-related disease in a case\u2013control study based on 450 patients

We aimed to compare the demographic, clinical and laboratory characteristics between IgG4-related kidney disease (IgG4-RKD+) and extrarenal IgG4-related disease (IgG4-RKD−) in a large Chinese cohort, as well as describing the radiological and pathological features of IgG4-RKD+. We retrospectively analyzed the medical records of 470 IgG4-related disease (IgG4-RD) patients at Peking University People’s Hospital from January 2004 to January 2020. The demographic, clinical, laboratory, radiological and pathological characteristics between IgG4-RKD+ and IgG4-RKD− were compared. Twenty IgG4-RD patients who had definite etiology of renal impairment including diabetes, hypertension and etc. were excluded. Among the remained 450 IgG4-RD patients, 53 were diagnosed with IgG4-RKD+ . IgG4-RKD+ patients had older age at onset and at diagnosis. Male to female ratio of IgG4-RKD+ patients is significantly higher. In the IgG4-RKD+ group, the most commonly involved organs were salivary gland, lymph nodes and pancreas. It was found that renal function was impaired in approximately 40% of IgG4-RKD+ patients. The most common imaging finding is multiple, often bilateral, hypodense lesions. Male sex, more than three organs involved, and low serum C3 level were risk factors for IgG4-RKD+ in IgG4-RD patients. These findings indicate potential differences in pathogenesis of these two phenotypes.

Clinical characteristics and outcome of IgG4-related disease with hypocomplementemia: a prospective cohort study

BackgroundImmunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic, immune-mediated, and fibro-inflammatory disease. Hypocomplementemia was found in part of IgG4-RD patients especially in the setting of active disease.ObjectivesThis study aimed to clarify the clinical features, treatment efficacy, and outcome in IgG4-RD patients with hypocomplementemia.Methods312 IgG4-RD patients were recruited in our prospective cohort conducted in Peking Union Medical College Hospital. Patients were divided into hypocomplementemia group and normal complement group according to serum C3 and C4 levels measured at baseline before treatment. Low serum C3 levels (< 0.73 g/L) and/or C4 levels (< 0.10 g/L) were defined as hypocomplementemia. Demographic data, clinical characteristics, laboratory parameters, treatment, and outcome of two groups were analyzed and compared.ResultsHypocomplementemia was identified in 65 (20.8%) cases of untreated IgG4-RD patients at baseline. The average age of hypocomplementemia group was 55.85 ± 10.89 years, with male predominance (72.3%). Compared with normal complement group, patients with hypocomplementemia were likely to have more involved organs, higher IgG4-RD responder index (IgG4-RD RI), and higher laboratory parameters such as counts of eosinophils, inflammatory markers, immunoglobulin G (IgG), IgG1, IgG3, IgG4, and IgE. In addition, lymph nodes, lacrimal gland, submandibular gland, parotid gland, paranasal sinus, bile ducts, and prostate gland were more commonly affected (p < 0.05). Serum C3 and C4 showed a significant positively correlation with each other. Both C3 and C4 were negatively correlated with the number of involved organs, IgG, IgG3, IgG4, and IgG4-RD RI, as well as positively correlated with IgA and hypersensitive C reactive protein (hsCRP). 64 (98.5%) patients responded quickly to initial therapy at a 3-month follow-up. Fifteen (23.1%) patients relapsed during follow-up with mean recurrence time of 14.2 ± 13.8 months. Compared with normal complement group, there was no significant difference of relapse rate in two groups (P = 0.401).ConclusionsClinical characteristics of IgG4-related disease with hypocomplementemia differ from normal complement group. Serum C3 and C4 at baseline before treatment could be biological markers for disease activity. IgG4-RD with hypocomplementemia responded well to treatment and had no significant difference of relapse rate in IgG4-RD with normal complement.

P0455CLINICAL PROFILE OF C3 GLOMERULOPATHY AT A TERTIARY CARE CENTRE

Abstract Background and Aims To study the clinico-pathological profile of patients with C3 glomerulonephritis at a tertiary care entre. Method A prospective observational study of all cases of C3 glomerulonephritis was done between August 2016 and December 2017. C3 glomerulonephritis was defined by predominant glomerular C3 fragment deposition with electron-dense deposits on EM Results Total of the 1190 patients under went biopsy during the study period. C3 glomerulonephritis was present in 32 cases (2.68%). The mean age was 35±2 years. Out of the 32 patients, 18 were male ( 56.25% ) and 14 were female (43.75% ). Hypertension was present in 30 out of 32 patients (93.7%) while diabetes was present in 7 patients (21.8%). Most common presentation was with RPGN (72%). 100% patients had active urinary sediments. The mean serum creatinine at admission was 5.15mg/dl while it was 3.18mg/dl at discharge. The mean serum C3 was 83.8 mg/dl with 18 patients (56.25%) having low serum C3 levels in our study. All patients had normal serum C4 levels with mean being 29.34 mg/dl. Anti CFH antibody titres were measured in 6 patients of with it was elevated in 2 patients (33.3%). On LM, 14 out of 32 had crescentic GN (43.75%), 12 had diffuse exudative pattern (37.5%), 4 had diffuse mesangioproliferative pattern (12.5%), 3 had MPGN pattern (9.37%), 3 had focal exudative pattern (9.37%), 1 patient had glomerular TMA (3.15%) and 1had chronic sclerosing pattern ( 3.15%). On IF, all patients had dominant C3 staining. Also 3 (9.37%) patients had IgG staining of 1+ intensity. EM study was done in two patients and was suggestive of DDD in one patient (3.15%). All patients were managed with pulse steroids followed by oral steroids. IV Cyclophosphamide was used monthly for 6 doses in 14 patients ( 43.7%) while oral cyclophosphamide was used in 2 patients (6.25%). Plasmapharesis was done in 11 patients (34.37%) and 11 patients required haemodialysis (34.37%) Conclusion C3 glomerulonephritis has emerged as a new entity in the recent past with significant percentage of our patients presenting with RPGN. Hypertension was present in most patients. On light microscopy, the most common presentation was crescentic glomerulonephritis, One third of our patients had advanced renal failure requiring haemodialysis. Plasmapharesis was done in one third of patients.