Glomerular C3 Research Articles

Glomerular Injury and Differences in Colocalization of Glomerular IgA, IgG, and Complement C3 in Patients with IgA Vasculitis with Nephritis

Glomerular Injury and Differences in Colocalization of Glomerular IgA, IgG, and Complement C3 in Patients with IgA Vasculitis with Nephritis

Prediction model for treatment response of primary membranous nephropathy with nephrotic syndrome.

To investigate the predictors and establish a nomogram model for the prediction of the response to treatment in primary membranous nephropathy (PMN) with nephrotic syndrome (NS). The clinical, laboratory, pathological and follow-up data ofpatients withbiopsy-proven membranous nephropathy at the Affiliated Hospital of QingdaoUniversity were collected. A total of 373 patients were randomly assigned into development group (n = 262) and validation group (n = 111). Logistic regression analysis was performed in the development group to determine the predictors of treatment response. A nomogram model was established based on the multivariate logistic regression analysis and validated in the validation group. The C-index and calibration plots were used for the evaluation of the discrimination and calibration performance, respectively. Serum albumin levels (OR = 1.151, 95% CI 1.078-1.229, P < 0.001) and glomerular C3 deposition (OR = 0.407, 95% CI 0.213-0.775, P = 0.004) were identified as independent predictive factors for treatment response in PMN with NS, then a nomogram was established combining the above indicators and treatment regimen. The C-indices of this model were 0.718 (95% CI 0.654-0.782) and 0.789 (95% CI 0.705-0.873) in the development and validation groups, respectively. The calibration plots showed that the predicted probabilities of the model were consistent with the actual probabilities (P > 0.05), which indicated favorable performance of this model in predicting the treatment response probability. Serum albumin levels and glomerular C3 deposition were predictors for treatment response of PMN with NS. A novel nomogram model with good discrimination and calibration was constructed to predict treatment response probability at an early stage.

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.

#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.

Apolipoprotein E is enriched in dense deposits and is a marker for dense deposit disease in C3 glomerulopathy

C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative pathway of complement. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), both of which are characterized by bright glomerular C3 staining on immunofluorescence studies. However, on electron microscopy (EM), DDD is characterized by dense osmiophilic mesangial and intramembranous deposits along the glomerular basement membranes (GBM), while the deposits of C3GN are not dense. Why the deposits appear dense in DDD and not in C3GN is not known. We performed laser microdissection (LCM) of glomeruli followed by mass spectrometry (MS) in 12 cases each of DDD, C3GN, and pretransplant kidney control biopsies. LCM/MS showed marked accumulation of complement proteins C3, C5, C6, C7, C8, C9 and complement regulating proteins CFHR5, CFHR1, and CFH in C3GN and DDD compared to controls. C3, CFH and CFHR proteins were comparable in C3GN and DDD. Yet, there were significant differences. First, there was a six-to-nine-fold increase of C5-9 in DDD compared to C3GN. Secondly, an unexpected finding was a nine-fold increase in apolipoprotein E (ApoE) in DDD compared to C3GN. Most importantly, immunohistochemical and confocal staining for ApoE mirrored the dense deposit staining in the GBM in DDD but not in C3GN or control cases. Validation studies using 31 C3G cases confirmed the diagnosis of C3GN and DDD in 80.6 % based on ApoE staining. Overall, there is a higher burden of terminal complement pathway proteins in DDD compared to C3GN. Thus, our study shows that dense deposits in DDD are enriched with ApoE compared to C3GN and control cases. Hence, ApoE staining may be used as an adjunct to EM for the diagnosis of DDD and might be valuable when EM is not available.

Combined Effects of the Serum IgA/C3 Ratio and Glomerular C3 Staining on the Renal Outcome in Adult Immunoglobulin A Nephropathy

Introduction: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy. Methods: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining. Results: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival. Conclusions: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Targeting complement in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent years have witnessed significant improvements in the understanding of the pathogenesis of IgAN and particularly, the pathogenic role of complement activation. The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression. In addition, several studies have provided insight into the pathogenic role of factor H-related proteins -1 and -5 in IgAN, as independent players in complement dysregulation. The lectin pathway has also been shown to be associated with the severity of IgAN. Glomerular deposition of C4d has been associated with increased histologic disease activity, faster decline in estimated glomerular filtration rate and higher risk of kidney failure. On the other hand, although overlooked in the Oxford classification, numerous studies have shown that the coexistence of thrombotic microangiopathy in IgAN is a significant indicator of a poorer prognosis. All the breakthroughs in the understanding of the contributing role of complement in IgAN have paved the way for the development of new complement-targeted therapies in this disease. Several ongoing trials are evaluating the efficacy of new agents against factor B (iptacopan, Ionis-FB-LRX), C3 (pegcetacoplan), factor D (vemircopan, pelecopan), C5 (ravulizumab, cemdisiran) and C5a receptor 1 (avacopan). In this study, we provide a comprehensive review of the role of complement in IgAN, including the emerging mechanisms of complement activation and the promising potential of complement inhibitors as a viable treatment option for IgAN.

Liver factor B silencing to cure C3 glomerulopathy: Evidence from a mouse model of complement dysregulation

Uncontrolled activation of the alternative pathway (AP) of complement, due to genetic and/or acquired defects, plays a primary pathogenetic role in C3 glomerulopathy (C3G), a rare and heterogeneous disease characterised by predominant C3 fragment deposition within the glomerulus, as well as glomerular damage. There are currently no approved disease-specific treatments for C3G, but new drugs that directly counteract AP dysregulation, targeting components of the pathway, have opened promising new perspectives for managing the disease.Complement factor B (FB), which is primarily synthesised by hepatocytes, is a key component of the AP, as it drives the central amplification loop of the complement system. In this study we used a GalNAc (N-Acetylgalactosamine)-conjugated siRNA to selectively target and suppress liver FB expression in two mouse models characterised by the complete (Cfh-/- mice) or partial (Cfh+/-) loss of function of complement factor H (FH). Homozygous deletion of FH induced a severe C3G phenotype, with strong dysregulation of the AP of complement, glomerular C3 deposition and almost complete C3 consumption. Mice with a heterozygous deletion of FH had intermediate C3 levels and exhibited slower disease progression, resembling human C3G more closely.Here we showed that FB siRNA treatment did not improve serum C3 levels, nor limit glomerular C3 deposition in Cfh-/- mice, while it did normalise circulating C3 levels, reduce glomerular C3 deposits, and limit mesangial electron-dense deposits in Cfh+/- mice. The present data provide important insights into the potential benefits and limitations of FB-targeted inhibition strategies and suggest RNA interference-mediated FB silencing in the liver as a possible therapeutic approach for treating C3G patients with FH haploinsufficiency.

#3418 DISAPPEARANCE OF GLOMERULAR C3 DEPOSITION MIGHT BE A PROGNOSTIC MARKER IN MEMBRANOUS NEPHROPATHY AFTER TREATMENT

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults. In about 80% is primary and remaining 20% are secondary due to medications or other diseases. Treatment of primary MN remains controversial, and the prognosis is still difficult to predict despite the introduction of anti phospholipase A2 receptor (PLA2R) antibody. We evaluated pathological changes for predicting prognosis in patients of MN after methyprednisolone (MPD) pulse therapy. Method We performed 1,649 renal biopsies at the OPD during last 9 years, of which 31 subjects were MN. We performed follow up biopsy who showed normal urinary findings after treatment with MPD pulse therapy in 11 subjects of MN. Indications of the initial biopsy in MN were oral steroid resistant NS (9 subjects), massive proteinuria associated with hematuria (2 subjects). Among the 11 subjects of MN, 3 subjects were lupus nephritis (LN), 8 subjects were primary MN. One cycle of MPD consist of 10-20 mg/kg (max 1.0 g)/day for 3 consecutive days, performing every 10 to 14 days. Mean MPD pulse therapy were done 13 cycles Results Among the 11 cases of MN, male to female ratio was 6 to 5. Age distribution from 1 year old to 61years old (mean 40.8 y/o), Mean spot urine protein to creatinine before treatment was 4,182.5 mg/g and 189.4 mg/g after treatment. 9 subjects showed glomerular C3 deposition were noted at the initial biopsy and 2 subjects showed no C3 deposition. After treatment glomerular C3 deposition were disappeared in 8 subjects, and showed no relapse during 5.3 years follow up. However, 3 subjects who showed glomerular C3 deposition were lupus nephritis, relapsed during follow up period. Conclusion MPD pulse therapy might be still promising therapeutic modality in conventional oral steroid resistant MN. Although further larger number of studies are mandatory, disappearance of glomerular C3 deposition might be a prognostic marker for treatment response, instead of disappearance of proteinuria in MN.

#5012 THE EFFECT OF GLOMERULAR C3 DEPOSITION ON RENAL OUTCOME IN PATIENTS WITH MEMBRANOUS NEPHROPATHY: DATA OF THE TSN-GOLD STUDY

Abstract Background and Aims We aimed to evaluate the effect of glomerular C3 deposits on clinical and laboratory findings and outcome in patients with idiopathic membranous nephropathy (MN) included in the Primary Glomerular Diseases Study of Turkish Society of Nephrology Glomerular Diseases Study Group (TSN-GOLD). Method The data of 1595 patients with MN in the database has been evaluated. 114 patients were excluded due to lack of data about C3 staining, 54 patients due to secondary MN and 523 due to lack of data about the follow-up. Patients with glomerular C3 deposits were compared with those with no C3 staining. Results Glomerular C3 deposits were detected in kidney biopsy specimens of 601 patients of the 888 patients analysed. The demographic data, clinical and laboratory findings at the time of diagnosis of C3 (+) and C3 (-) groups are presented in Table 1. They were similar except serum albumin level that was lower in C3 (+) group. Subepithelial deposits and interstitial fibrosis was more prominent, IgG, Kappa and Lambda staining more intense, positivity for C1q and IgA was more frequent in C3 (+) group (Table 2). The study groups were similar regarding remission rates after the first imuunosuppressive treatment (p = 0.582). 155 patients (25.8%) had partial, 152 (25.3%) had complete remission while no remission was detected in 92 patients (15.3%) in C3 (+) group. 69 patients (24.0%) had partial and 81 patients (28.2%) had complete remission; 40 patients (13.9%) had no remission in C3 (-) group. The relapse rates were 17.6% and 19.9% in C3 (+) and C3 (-) groups (p = 0.360). The percentage of patients who died or needed renal replacement therapy (RRT) were higher C3 (+) group (p = 0.013) (Figure 1). Conclusion Need for RRT and mortality is higher in patients with C3 deposition showing the importance of C3 deposition in the prognosis of MN. More prominent interstitial fibrosis may be related with the worse outcome.

O043 Evaluation of minimal factor H therapy administered to kidneys during ex vivo normothermic perfusion as a treatment to improve ischaemia reperfusion injury

Abstract Introduction Complement activation is a key mechanism of Ischaemia reperfusion injury, with the alternative pathway driving damage in particular. The main regulator of the alternative pathway is factor H. We hypothesised that homodimeric mini-factor H (HDM-FH; PMID:29588430) may protect transplanted kidneys from complement mediated damage when administered during normothermic perfusion machine perfusion. Methods Kidneys were retrieved from female white landrace pigs following an optimised protocol. One kidney from each pair was randomised to receive 5mg of HDM-FH (∼8μg/mL). Kidneys were perfused at 37°C with autologous blood for 6 hours. HDM-FH binding was measured using ELISA and immunofluorescence. Complement activation was measured by quantifying Bb deposition in tissue. The ability of HDM-FH to inhibit complement in serum was measured using haemolytic assays. Results 4mgs of HDM-FH bound from perfusate during perfusion, with &amp;lt;10% lost in urine suggesting saturation was achieved. HDM-FH binding within the kidneys was confirmed using immunofluorescence. HDM-FH localised to glomeruli with deposition increasing over the time of the perfusion. Alternative pathway activation was reduced in kidneys receiving HDM-FH as demonstrated by reduced Bb deposition. Fibrinogen deposition was also reduced and found to colocalise with C3 in glomeruli. HDM-FH inhibits complement activity in serum in a dose-dependent manor. Conclusion Infusion with HDM-FH prior to simulated kidney transplant conditions reduced complement activation and other secondary negative outcomes to the organ. Therefore, organ perfusion with HDM-FH is highly likely to help prolong graft survival after transplant and this will be assessed in future studies.

Lectin Complement Pathway Activation is Associated with Massive Proteinuria in PLA2R-Positive Membranous Nephropathy: A Retrospective Study.

Complement activation is highly involved in membranous nephropathy. Identifying the mechanism of the complement activation pathway carries crucial therapeutic implications yet remains controversial. This study explored lectin complement pathway activation in PLA2R-associated membranous nephropathy (MN). One hundred and seventy-six patients with biopsy-proven PLA2R-associated MN were enrolled in the retrospective study and divided into the remission group (24-hour urine protein <0.75g and serum albumin >35 g/L) and the nephrotic syndrome group. The clinical manifestation and C3, C4d, C1q, MBL, and B factor in renal biopsy tissues and C3, C4, and immunoglobulins in serum were evaluated. Deposition of glomerular C3, C4d, and mannose-binding lectin (MBL) was significantly higher in the activated state than in the remission state in PLA2R-associated MN. MBL deposition was the risk factor for no remission. During follow-up, the persistent non-remission patients have significantly lower serum C3 levels. Activation of the lectin complement pathway in PLA2R-associated MN may contribute to proteinuria progression and disease activity.

A retrospective study on the characteristics of renal pathological grades in HSPN children with mild to moderate proteinuria.

To investigate the characteristics of renal pathological grades in Henoch-Schönlein purpura nephritis (HSPN) children with mild to moderate proteinuria and the correlation between pathological grade and severity of proteinuria among this population. HSPN children who were presented with mild (150 mg <24 h urinary protein <25 mg/kg) to moderate (25 mg/kg ≤24 h urinary protein <50 mg/kg) proteinuria and performed renal biopsy without steroid ± immunosuppressant treatment in the Second Xiangya Hospital between January 2010 and March 2021 were involved. We retrospectively analyzed the correlation between age, disease course, degree of proteinuria, type of immunoglobulin deposits, C3 deposits in glomeruli and renal pathological grade. (1) 72 HSPN children including 46 boys and 26 girls were included, with a mean age of onset of 9.01 ± 2.65 years old. The majority of these patients (62.5%) had a disease course between 1 week to 1 month. 51 patients presented with mild proteinuria and 21 patients with moderate proteinuria. (2) Renal biopsy results showed that ISKDC Grade IIIa were both predominant in mild proteinuria group (25, 49%) and moderate proteinuria group (11, 52.4%). 32 patients had grade II (44.4%), 2 had grade IIIb (2.8%), 1 had grade IV (1.4%), and 1 had grade VI (1.4%). There was no correlation between age, disease course and renal pathological grade (p > 0.05). (3) In patients with mild proteinuria (n = 51), 27 (52.9%) HSPN children had a pathological grade ≥ grade III. In patients with moderate proteinuria (n = 21), 13 (61.9%) HSPN children had grade ≥ III. There was no significant difference in the proportion of renal pathological grade between the 2 groups (p > 0.05). (4) There was no significant correlation between glomerular C3 deposits or immunoglobulin deposit types and renal pathological grade (p = 0.776 and p = 0.056 respectively). In HSPN children with mild to moderate proteinuria, longer disease course or heavier urinary protein level is not completely parallel with higher renal pathological grade. ISKDC grade IIIa is the most common pathological grade. Clinicians should pay great attention to the renal injury in patients with mild to moderate proteinuria.

THE IMPORTANCE OF GLOMERULAR C3 ACCUMULATION IN ELDERLY PATIENTS WITH PRIMARY MEMBRANOUS NEPHROPATHY

Objective: The purpose of this study was to investigate the impact of glomerular C3 accumulation density on clinical, histopathological parameters and outcomes in elderly (&gt;60 years) individuals with primary membranous nephropathy (PMN). Material and Methods: In this study, we examined the patients (n=105) in two groups according to the C3 staining density in kidney biopsy samples as low intensity (C3: 1+; LI group) and high intensity (C3: 2+ or C3: 3+; HI group). The primary endpoint of our study was the end-stage renal disease, and the secondary endpoints were the development of partial remission (PR) or complete remission (CR). Results: At the end of the follow-up (mean 30.6 months), more patients achieved the primary endpoint, and fewer patients achieved the secondary endpoints in the HI group compared to the LI group. (p=0.015 and p=0.016, respectively). Moreover, the glomerular filtration rate (eGFR) was lower (p&lt;0.001), and proteinuria was higher in the HI group (p=0.018). Kaplan-Meier survival analysis revealed that renal survival (p=0.031) was lower in the HI group compared to the LI group. In the multivariate logistic regression analyses, no predictive parameters could be detected for the endpoints.&nbsp;Conclusion: Intense glomerular C3 deposition in elderly (&gt;60 years) patients with PMN may be related to poor clinical outcomes.

Predictive prognostic value of glomerular C3 deposition in IgA nephropathy.

IgAN is the most common primary glomerulonephritis worldwide. However, the pathogenesis of IgAN remains unknown. Currently, there is evidence that C3 deposition plays a role in disease development. This study aimed to investigate clinical, pathological features, and prognosis of adult IgAN patients with C3 deposition, as well as explore the role of complement activation in disease progression. A total of 821 patients with biopsy-proven IgAN were included in this study. Patients were divided into three different groups according to their C3 deposition intensity. Clinical and pathological characteristics were compared between groups. Logistic analysis was used to estimate the relationship between C3 deposition and the Oxford scoring system. Univariate and multivariate Cox proportional hazard regression models were used to analyze the effect of the presence ofC3 deposits on the prognosis of patients with IgA nephropathy. Kaplan-Meier survival analysis was used to evaluate the cumulative incidence of renal progression between groups. Patients with C3 deposition exhibited more severe clinical and pathological features and had a higher score according to the Oxford scoring system. With the increasing intensity of C3 deposition, patients present more hematuria, crescents, heavier interstitial inflammatory cell infiltration and a higher score on segmental sclerosis lesions. Logistic regression identified a positive relationship between C3 deposition and histopathology. Univariate and multivariate Cox regression indicated thatC3 deposition was an independent risk factor for IgANseverity. The Kaplan-Meier survival curves indicated that patients with positive C3 deposition had a worse prognosis compared to those without C3 deposition. Patients with positive glomerular C3 deposition presented with more severe clinical and histopathological characteristics and a higher score on the Oxford scoring system. With the increasing intensity of C3 deposition, IgAN patients were more likely to present with high level ofmicroscopic hematuria, fibrous crescents, interstitial inflammatory cell infiltration, and a higher score on segmental sclerosis lesions. C3 deposition at the time of renal biopsy is likely an independent risk factor for IgA nephropathyseverity and progression.

Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis.

C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

Characteristics and renal survival of patients with lupus nephritis with glomerular immunoglobulin G4 deposition: a single-centre retrospective analysis

ObjectiveRenal injury is common in SLE. Immune complex deposition plays an important role in the development of lupus nephritis (LN), while little is known about glomerular IgG4 deposition in patients...

Factor H-Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy.

C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear. Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant's association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population. Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome. Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.

Complement Deposition Predicts Worsening Kidney Function and Underlines the Clinical Significance of the 2010 Renal Pathology Society Classification of Diabetic Nephropathy.

ObjectivesConverging evidence points towards a role of the complement system in the pathogenesis of diabetic nephropathy (DN). The classification system of diabetic kidney lesions devised by the Renal Pathology Society (RPS) in 2010 are based on the pathogenic process of DN. Therefore, we investigated the correlation between glomerular C3 deposits and RPS DN classification and the combined deleterious effects thereof on kidney function.MethodsThe study analyzed data from 217 diabetic patients who underwent renal biopsy between 2010 and 2021 and were found to have DN as the only glomerular disease. C3 deposition was considered positive if the glomerular C3 immunofluorescence intensity was at the trace or ≥1+ level. We divided DN into five glomerular lesion classes and separately evaluated the degree of interstitial and vascular involvement. The primary outcome was the composite of a ≥50% decline from the initial estimated glomerular filtration rate, end-stage renal disease, and death.ResultsNone of the patients were classified into class I, and few were classified into classes IIa (7.8%) and IV (9.2%). Most patients were classified as IIb (30.9%) and III (52.1%). C3 deposition was detected in 53.9% of patients. Multivariate logistic regression analysis showed that DN class was significantly correlated with C3 deposits [odds ratio, 1.59; 95% confidence interval (CI), 1.08–2.36; p = 0.02). During a median follow-up of 22 months, 123 (56.7%) patients reached the composite outcome. The endpoints occurred more frequently in patients with C3 deposition (69.2 vs. 42%) compared with those without C3 deposition. Patients with C3 deposition in either class IIb [hazards ratio (HR), 3.9 (95% CI, 1.14–13.17) vs. 2.46 (95% CI, 0.68–8.89)] or III [HR, 4.98 (95% CI, 1.53–16.23) vs. 2.63 (95% CI, 0.77–9.0)] had a higher risk of adverse kidney outcomes than those without C3 deposition. The prognostic accuracy of the combination of DN class and C3 deposits at 1 and 3 years was higher than that for DN class only.ConclusionsComplement deposition together with DN class predicts more rapid deterioration of kidney function in DN, which underlines the clinical significance of the DN phenotype according to the RPS classification.

MO261: Sparsentan, The Dual Endothelin Angiotensin Receptor Antagonist (DEARA), Attenuates Albuminuria and Protects from the Development of Renal Injury to a Greater Extent Than Losartan in the GDDY Mouse Model of IGA Nephropathy: A 16-Week Study

Abstract BACKGROUND AND AIMS gddY mice are an IgA nephropathy (IgAN)-prone mouse model that develops albuminuria by 8 weeks (wks) of age with glomerular IgA, IgG and C3 deposits and progressive mesangioproliferative glomerulonephritis. We have previously shown that sparsentan (SP), a novel, highly selective, first-in-class, single-molecule dual endothelin angiotensin receptor antagonist (DEARA) being developed for the treatment of focal segmental glomerulosclerosis and IgAN, protected gddY mice from the development of albuminuria and glomerulosclerosis in an 8-week study. Here we compare the impact of SP and losartan (LS), an angiotensin II subtype 1 receptor antagonist (AT1R), on albuminuria, % of sclerotic glomeruli (GS), podocyte number, and glycocalyx damage in gddY mice treated for 16 weeks. METHOD gddY mice at 4 weeks of age were treated for 8 or 16 weeks either with chow as a control (C) (n = 10) or containing SP at 900 ppm (SP900) (n = 12) or with control chow and LS in drinking water to deliver 30 mg/kg of LS (LS30) (n = 12). Systolic blood pressure (BP) was measured by tail-cuff plethysmography at 8, 12 and 18 weeks of age. Albuminuria/creatinine ratio (ACR) was assessed every 2 weeks until 20 weeks of age. Kidney biopsies (n = 4–5 per group) were taken from a subset of mice sacrificed at age 12 weeks and at the end of the study at 20 weeks of age (5–7 per group) and processed for determination of GS, the number of podocytes assessed by immunohistochemistry using an anti-WT-1 antibody (30 glomeruli per animal), and measurement of the glycocalyx area using FITC-labeled lectin (10 glomeruli per animal). RESULTS gddY mice treated with SP900 or LS30 had an equivalent and significant (P &amp;lt; .01) reduction in BP compared with C mice at 12 and 18 weeks of age (18 weeks of age mean BP ± SD mmHg: C, 147 ± 28; SP900, 100 ± 6; LS30, 101 ± 8). Despite similar systemic hemodynamic effects, SP900 treatment resulted in a greater and more rapid reduction in ACR from baseline compared with either mice treated with C or LS30 during the first 4 weeks of treatment (Fig. 1). Development of GS was significantly attenuated in mice at 20 weeks of age treated with SP900 (P &amp;lt; .001) compared with C mice, but not in those treated with LS30 (mean sclerosis score ± SD: C, 28 ± 17; SP900, 3 ± 1; LS30, 19 ± 21). Compared with C mice at 20 weeks of age, SP900 (P &amp;lt; .0001) and LS30 (P &amp;lt; .05) significantly prevented the reduction in WT-1 immunoreactivity (WT-1 positive cells/glomerulus, mean ± SD: C, 7.3 ± 0.5; SP900, 10.0 ± 0.5; LS30 8.1 ± 0.8). Notably, SP900-treated mice had significantly greater WT-1 staining (P &amp;lt; .0001) and glycocalyx area (Fig. 2) than LS30 mice. CONCLUSION gddY mice treated from 4–20 weeks of age with sparsentan demonstrated a more rapid attenuation of ACR and greater protection from GS than mice treated with losartan. Sparsentan protected the glomeruli from loss of podocytes and glycocalyx to a greater extent than losartan despite equivalent lowering of BP. These results suggest that the ability of sparsentan to protect gddY mice from progression of IgAN nephropathy may go beyond effects mediated through reduction in blood pressure and antagonism of AT1R alone and may be attributed to its dual mechanism of action. If translated to the clinic, these data may support sparsentan as a new approach to the treatment of IgAN.