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Background and objectives: 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. Design, setting, participants, & measurements: 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 123patients 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. Results: 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 interstitialfibrosis/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. Conclusions: 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.

Introduction: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. Methods: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. Results: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and −0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = −0.83 and −0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = −0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = −0.57, p = 0.0021). Conclusion: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan–Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2–15 (median, 9; interquartile range, 7–11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13–8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

Kidney international 100(4), 753-779 (2021). doi:10.1016/j.kint.2021.05.015, Published by Elsevier, New York, NY

IgA nephropathy pathogenesis is incompletely understood, and this limits the development of disease-specific biomarkers and effective therapies. Evidence of complement activity in IgA nephropathy is well established. However, a growing body of research indicates complement activity is an important contributor to IgA nephropathy pathology. In particular, multiple associations have been identified between complement alternative, lectin and terminal pathway proteins and IgA nephropathy severity. Recently, we have also gained insight into possible mechanisms that could link glomerular IgA deposition, complement activity, glomerular inflammation and disease severity. Ongoing clinical trials of therapeutic complement inhibitors will provide insight into the importance of complement activity to IgA nephropathy pathogenesis. Further research into mechanisms of complement activity is essential to improving our understanding and management of patients with IgA nephropathy.

Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

Purpose of review In this review, we discuss recent studies showing the importance of the complement pathway in kidney disease. Recent findings Recent findings in C3 glomerulopathy (C3G) include: acute postinfectious glomerulonephritis is characterised by the presence of antifactor B antibodies; human leukocyte antigen type, but not rare complement gene variation, is associated with primary immunoglobulin-associated membranoproliferative GN and C3G. Immunohistochemistry in C3G shows that factor H related protein 5 (FHR5) is the most prevalent complement protein and correlates with kidney function. A multicentre study supported the use of mycophenolate mofetil (MMF) in C3G even after a propensity matching analysis. In immunoglobulin A nephropathy (IgAN) several studies have emphasised the importance of complement. Imbalances of circulating FH and FHR1 and FHR5, which interfere with the regulatory functions of FH, associate with IgAN. Immunohistochemistry has shown associations between glomerular FHR5 deposition and C3 activation; glomerular FHR5 associated with clinical markers of IgAN severity. Data also suggest the lectin complement pathway contributes to IgAN severity. We also discuss complement activation in thrombotic microangiopathy and other kidney diseases. Summary Complement activity can be detected in a wide range of kidney diseases and this provides pathogenic insight and potential for therapy with the ongoing development of several drugs directed at complement activation.

P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved.

Background Immune complexes within glomerular capillary walls cause crescentic GN (CrGN). Monocytes and macrophages are important in mediating CrGN, but little work has been done to phenotype the subpopulations involved and determine their respective contributions to glomerular inflammation. Methods Live glomerular imaging using confocal microscopy monitored intravascular monocyte subset behavior during nephrotoxic nephritis (NTN) in a novel WKY-hCD68-GFP monocyte/macrophage reporter rat strain. Flow cytometry and qPCR further analyzed ex vivo the glomerular leukocyte infiltrate during NTN. Results Non-classical monocytes surveyed the glomerular endothelium via lymphocyte function-associated antigen 1 (LFA-1) in the steady state. During NTN, non-classical monocytes were recruited first, but subsequent recruitment and retention of classical monocytes was associated with glomerular damage. Monocytes recruited to the glomerular vasculature did not undergo transendothelial migration. This finding suggests that inflammation in immune complex-mediated CrGN is predominantly intravascular, driven by dynamic interactions between intravascular blood monocytes and the endothelium. Glomerular endothelium and non-classical monocytes overexpressed a distinct chemokine axis, which may orchestrate inflammatory myeloid cell recruitment and expression of damage mediators. Reduced classical monocyte recruitment in Lewis rats during NTN confirmed a role for CD16 in mediating glomerular damage. Conclusions Monocyte subsets with distinct phenotypes and effector functions may be important in driving inflammation in experimental CrGN resulting from immune complexes formed within the glomerular capillary wall. LFA-1-dependent endothelial surveillance by non-classical monocytes may detect immune complexes through CD16, orchestrating the inflammatory response through intravascular retention of classical monocytes, which results in glomerular damage and proteinuria.

ObjectiveThe International Society of Nephrology/Renal Pathology Society classification is the gold standard for the characterisation of lupus nephritis (LN) on renal biopsy, with therapeutic repercussions. Its recent revision simplified the current class subdivisions, eliminating the S/G forms of class IV, although data on a possible pathogenetic/clinical value of this subdivision are still contradictory.Methods353 renal biopsies from Belimumab International Study in LN were assessed through central pathology review. Univariate logistic models and a decision tree were performed on 314 adequate biopsies to evaluate the impact of histological features on focal/diffuse classes. Removing class I/II (n=6) and ‘pure’ class V (n=34), principal component analysis (PCA) and heatmap were used to explore similarities among III, IVS and IVG biopsies either incorporating or not the mixed classes (+V, n=274). Finally, a method aimed at partitioning the cases into k clusters based on their similarity (KMeans), was used to study features from the cohort of ‘pure’ class III/IVS/IVG cases (n=214) to determine alternative subdivisions based on phenotypic data.ResultsSegmental endocapillary hypercellularity (EH) was prevalent in class III, global EH, wire loops, hyaline thrombi and double contours were hallmarks of class IVG, with IVS cases showing intermediate characteristics. Heatmap and PCA confirmed the segregation of these features among classes, showing better segregation for focal/diffuse LN as compared with the mixed classes (+V). KMeans revealed the presence of two main clusters, membranoproliferative-like (n=83) or vasculitis-like (n=131).ConclusionsThis study reveals new phenotypic forms of LN surpassing the traditional classes as determined by the current classification. Future validation and confirmation are required to confirm these findings.

Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.

Kidney international 100(4, Supplement) S1-S276 (2021). doi:10.1016/j.kint.2021.05.021 special issue: "KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases", Published by Elsevier, New York, NY

Background IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. Methods To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. Results Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. Conclusions Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.

Background The diagnosis of antibody-mediated rejection (AMR) is reached using the Banff Classification for Allograft Pathology, which now includes gene expression analysis. In this study, we investigate the application of ‘increased expression of thoroughly validated gene transcripts/classifiers strongly associated with AMR’ as diagnostic criteria. Method We used quantitative real-time polymerase chain reaction for 10 genes associated with AMR in a retrospective cohort of 297 transplant biopsies, including biopsies that met the full diagnostic criteria for AMR, even without molecular data (AMR, n = 27), biopsies that showed features of AMR, but that would only meet criteria for AMR with increased transcripts [suspicious for AMR (AMRsusp), n = 49] and biopsies that would never meet criteria for AMR (No-AMR, n = 221). Results A 10-gene AMR score trained by a receiver-operating characteristic to identify AMR found 16 cases with a high score among the AMRsusp cases (AMRsusp-high) that had significantly worse graft survival than those with a low score (AMRsusp-low; n = 33). In both univariate and multivariate Cox regression analysis, the AMR 10-gene score was significantly associated with an increased hazard ratio (HR) for graft loss (GL) in the AMRsusp group (HR = 1.109, P = 0.004 and HR = 1.138, P = 0.012, respectively), but not in the whole cohort. Net reclassification index and integrated discrimination improvement analyses demonstrated improved risk classification and superior discrimination, respectively, for GL when considering the gene score in addition to histological and serological data, but only in the AMRsusp group, not the whole cohort. Conclusions This study provides evidence that a gene score strongly associated with AMR helps identify cases at higher risk of GL in biopsies that are suspicious for AMR but do not meet full criteria.

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Cryoglobulins (CGs) are immunoglobulins that precipitate at temperatures below 37 °C and dissolve again after rewarming. Cryoglobulinemia may be asymptomatic or cause end-organ damage by CG precipitation in small- to medium-sized blood vessels.1 In their seminal work, Brouet et al.2 classify cryoglobulinemias into 3 subgroups according to CG composition and clonality. In type II cryoglobulinemia there is a mixture of monoclonal IgM with rheumatoid factor activity and polyclonal IgG. In type III, CGs consist of polyclonal IgM and IgG.1 Type II and III cryoglobulinemias are also referred to as mixed cryoglobulinemias and are often caused by chronic hepatitis C infection and less frequently by autoimmune diseases or other viral infections (hepatitis B infection, HIV).3 CGs in type I cryoglobulinemia are monoclonal Igs (MIg), also known as paraproteins, commonly IgG, IgM subtypes, or free light chains. The underlying pathological process is a plasma cell or B-cell lymphoproliferative disease, such as multiple myeloma (MM), Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, or other B-cell non-Hodgkin lymphoma. However, in approximately 40% of symptomatic cases, the plasma cell or B-cell clone is too small to fulfill the diagnostic criteria of MM or overt lymphoma. The term monoclonal gammopathy of undetermined significance (MGUS) used for these cases is a misnomer, as the MIg causes disease regardless of the size and tumor burden.4 For cases with renal involvement, the International Kidney and Monoclonal Gammopathy Research Group introduced the term monoclonal gammopathies of renal significance (MGRS).5 The updated MGRS definition includes monoclonal gammopathies that cause renal disease but have low tumor burden and thus treatment from the hematological standpoint is not imminently indicated.6 These patients may have fewer than 10% plasma cells in bone marrow biopsy, smoldering myeloma, or low-grade lymphomas.7 MGRSs are not of undetermined significance, and their relevance to renal pathology has opened the use of clone-directed therapies targeting the nephrotoxic MIg-producing clone, with an aim to preserve renal function.8 Retrospective studies to date suggest that clone-directed therapy improves renal outcomes.9 MGRS encompasses a wide spectrum of renal histopathological entities caused by a nephrotoxic MIg, including ever rarer subtypes such as type I cryoglobulinemic glomerulonephritis.S1,S2 Historically, MGRS may have gone underdiagnosed and patients not offered optimal treatment, unlike their counterparts fulfilling consensus myeloma or lymphoma diagnostic criteria.S3 Here, we report a case of severe type I crystal cryoglobulinemic glomerulonephritis caused by MGRS, for which treatment with myeloma induction therapy and autologous stem cell transplantation (ASCT) induced long-lasting complete hematological response and renal function preservation.

Summary Iron is an essential metal that fine-tunes the innate immune response by regulating macrophage function, but an integrative view of transcriptional and metabolic responses to iron perturbation in macrophages is lacking. Here, we induced acute iron chelation in primary human macrophages and measured their transcriptional and metabolic responses. Acute iron deprivation causes an anti-proliferative Warburg transcriptome, characterized by an ATF4-dependent signature. Iron-deprived human macrophages show an inhibition of oxidative phosphorylation and a concomitant increase in glycolysis, a large increase in glucose-derived citrate pools associated with lipid droplet accumulation, and modest levels of itaconate production. LPS polarization increases the itaconate:succinate ratio and decreases pro-inflammatory cytokine production. In rats, acute iron deprivation reduces the severity of macrophage-dependent crescentic glomerulonephritis by limiting glomerular cell proliferation and inducing lipid accumulation in the renal cortex. These results suggest that acute iron deprivation has in vivo protective effects mediated by an anti-inflammatory immunometabolic switch in macrophages., Graphical Abstract, Highlights • Acute iron deprivation causes an atypical Warburg effect in human macrophages • Iron controls citrate and lipid pools and is essential for an intact TCA cycle • LPS polarization is limited in iron-deprived human macrophages • Acute iron deprivation reduces the severity of macrophage-driven glomerulonephritis, Iron is a crucial regulator of cell function, but its role in human macrophage immunometabolism is only partially understood. Pereira et al. show that acute iron deprivation in human macrophages causes anti-inflammatory immune and metabolic responses, and acute iron deprivation in rats reduces the severity of macrophage-driven renal inflammation.

Item does not contain fulltext The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.

Contains fulltext : 203024.pdf (Publisher’s version ) (Open Access) In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complement-mediated kidney diseases, and monoclonal gammopathies of renal significance.

Monoclonal Gammopathy of Renal Significance (MGRS) encompasses a wide spectrum of histopathology. Characterizing rare forms of MGRS-related renal pathology remains work in progress. Light chain crystalline podocytopathy in the context of MGRS, either in isolation or combined with proximal tubulopathy (LCPT) has rarely been described. Unravelling MGRS pathologies is critical for patient management and often requires ancillary techniques for antigen retrieval to demonstrate light chain (LC) restriction on immunofluorescence (IF).

Significance The complement system is integral to innate immunity and host defense. However, inappropriate activation causes host tissue damage and disease. In health, this is prevented by a complex protein network that includes the factor H proteins. Understanding control of complement is critical to treat complement-mediated disease. We demonstrate that a gain-of-function mutant factor H–related 5 protein (FHR5) results in glomerular damage. The mutant interfered with complement regulation within the kidney, resulting in complement accumulation within glomeruli and kidney damage. Administration of a complement regulator with enhanced surface regulatory activity reduced mutant-associated glomerular complement. FHR5 can disrupt the homeostatic regulation of complement within the kidney, and targeting FHR5 represents a way to treat some types of complement-mediated kidney injury., Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury.

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh-/-) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH1-5) linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-P-FH1-5). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH1-5 to alter C3 activation in either plasma or glomeruli. Following IgG-FH1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh-/- mice IgG-FH1-5 reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH1-5 restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh-/- mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH1-5 protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy., Graphical abstract

Anti-double stranded DNA antibodies (anti-dsDNA) are a hallmark of SLE but their role in disease pathogenesis is not fully resolved. Anti-dsDNA in serum are highly heterogeneous therefore in this study, we aimed to dissect the functional specificities of anti-dsDNA using a panel of human monoclonal antibodies (humAbs) generated from patients with active lupus nephritis. A total of 46 ANA reactive humAbs were isolated and divided into four broad classes based on their reactivity to histones, DNA and Crithidia. Functional analysis indicated that one subclass of antibodies bound strongly to decondensed DNA areas in neutrophil extracellular traps (NETs) and protected NETs from nuclease digestion, similar to the sera from active SLE patients. In addition, these anti-dsDNA antibodies could stimulate type I interferon responses in mononuclear phagocytic cells, or NF-kB activity in endothelial cells, by uptake of NETs-anti-NETs immune complexes and subsequently trigging inflammatory responses in an Fc-gamma receptor (Fcg-R)-dependant manner. Together our data suggest that only a subset of anti-dsDNA antibodies is capable to amplify inflammatory responses by deposit in the nephritic kidney in vivo, protecting NETs digestion as well as uptake of NETs immune complexes into Fcg-R-expressing cells in vitro.

Introduction: Membranous glomerulonephritis (MGN) is rarely associated with necrotizing and crescentic glomerulonephritis (NCGN). Methods: We report the clinical and pathologic findings in 15 patients with MGN and NCGN associated with anti-neutrophil cytoplasm antibodies (ANCAs), anti–glomerular basement membrane (GBM), or anti–phospholipase A2 receptor (PLA2R) antibodies. Results: The cohort consisted of 15 patients: 7 males and 8 females with a median age of 63 years (range: 18–79). In 12 of 15 patients, MGN and NCGN were diagnosed at the time of the biopsy, and in 3 cases, MGN predated the NCGN. ANCA was positive in 7 cases (6 MPO myeloperoxidase (MPO)-ANCA and 1 PR3–ANCA), anti-GBM antibodies were detected in 5 cases, and anti-PLA2R antibodies were found in 2 cases. One case was negative for all antibodies. Microscopic hematuria was present in all but one patient who was anuric, and median urinary protein-to-creatinine ratio was 819.5 mg/mmol (range: 88–5600). Pathologic evaluation revealed MGN and NCGN with crescents involving 28% of glomeruli (median; range: 5%–100%). Follow-up was available for all 15 patients; all were treated with steroids; 10 with cyclophosphamide, and 6 also received rituximab. At a median follow-up of 72 months, 9 had stabilization or improvement of renal function, 6 had progressed to end-stage renal disease, and 4 died during the follow-up period. Conclusion: MGN with crescents associated with ANCAs or anti-GBM antibodies is a rare dual glomerulopathy. Patients present with heavy proteinuria, microscopic hematuria, and acute kidney injury and should be treated for a rapidly progressive glomerulonephritis. Prognosis is variable, and 40% of patients progress to end-stage renal disease. Keywords: anti-GBM disease, anti-neutrophil cytoplasm antibodies, anti-PLA2R antibody, crescentic glomerulonephritis, membranous glomerulonephritis

Background and objectives Minimal change disease is an important cause of nephrotic syndrome in adults. Corticosteroids are first-line therapy for minimal change disease, but a prolonged course of treatment is often required and relapse rates are high. Patients with minimal change disease are therefore often exposed to high cumulative corticosteroid doses and are at risk of associated adverse effects. This study investigated whether tacrolimus monotherapy without corticosteroids would be effective for the treatment of de novo minimal change disease. Design, setting, participants, & measurements This was a multicenter, prospective, open-label, randomized, controlled trial involving six nephrology units across the United Kingdom. Adult patients with first presentation of minimal change disease and nephrotic syndrome were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily, or prednisolone at 1 mg/kg daily up to 60 mg daily. The primary outcome was complete remission of nephrotic syndrome after 8 weeks of therapy. Secondary outcomes included remission of nephrotic syndrome at 16 and 26 weeks, rates of relapse of nephrotic syndrome, and changes from baseline kidney function. Results There were no significant differences between the tacrolimus and prednisolone treatment cohorts in the proportion of patients in complete remission at 8 weeks (21 out of 25 [84%] for prednisolone and 17 out of 25 [68%] for tacrolimus cohorts; P=0.32; difference in remission rates was 16%; 95% confidence interval [95% CI], −11% to 40%), 16 weeks (23 out of 25 [92%] for prednisolone and 19 out of 25 [76%] for tacrolimus cohorts; P=0.25; difference in remission rates was 16%; 95% CI, −8% to 38%), or 26 weeks (23 out of 25 [92%] for prednisolone and 22 out of 25 [88%] for tacrolimus cohorts; P=0.99; difference in remission rates was 4%; 95% CI, −17% to 25%). There was no significant difference in relapse rates (17 out of 23 [74%] for prednisolone and 16 out of 22 [73%] for tacrolimus cohorts) for patients in each group who achieved complete remission (P=0.99), or in the time from complete remission to relapse. Conclusions Tacrolimus monotherapy can be effective alternative treatment for patients wishing to avoid steroid therapy for minimal change disease. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_01_16_CJN06180519.mp3

Introduction: Immunohistochemical staining for C4d in peritubular capillaries has been part of antibody-mediated rejection (AbMR) definition in the Banff Classification for Allograft Pathology since 2003. However, it has limited sensitivity and specificity, therefore the clinical significance of C4d-positive biopsies without evidence of rejection (C4d+ WER) is unknown. We investigated the transcript levels of genes associated with AbMR in C4d+ WER biopsies from both ABO-compatible and incompatible renal transplant patients. Methods: RNA was extracted from formalin-fixed paraffin-embedded renal transplant biopsies (n = 125) and gene expression analysis of 35 AbMR-associated transcripts carried out using the NanoString nCounter system. Results: AbMR-associated transcripts were significantly increased in samples with AbMR or suspicious AbMR. A subgroup of 17 of 35 transcripts that best distinguished AbMR from C4d-negative biopsies without evidence of rejection was used to study C4d+ WER samples. There was no differential expression between C4d-negative and C4d+ WER from both ABO-incompatible and -compatible transplants. The geometric mean of 17 differentially expressed genes was used to assign the C4d+ WER biopsies a high- or low-AbMR transcript score. Follow-up biopsies showed AbMR within 1 year of initial biopsy in 5 of 7 high-AbMR transcript patients but only 2 of 46 low-AbMR transcript patients. In multivariate logistic regression analysis, elevated transcript levels in a C4d+ WER biopsy were associated with increased odds for biopsy-proven AbMR on follow-up (P = 0.032, odds ratio 16.318), whereas factors including donor-specific antibody (DSA) status and time since transplantation were not. Conclusion: Gene expression analysis in C4d+ WER samples has the potential to identify patients at higher risk of developing AbMR. Keywords: antibody mediated rejection, C4d, kidney, molecular, transplant rejection

The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening multi-system diseases characterized by necrotising inflammation of small blood vessels and crescentic glomerulonephritis. ANCA are thought to play a direct pathogenic role. Previous studies have shown that spleen tyrosine kinase (SYK) is phosphorylated during ANCA-induced neutrophil activation in vitro. However, the role of SYK in vivo is unknown. Here, we studied its role in the pathogenesis of experimental autoimmune vasculitis, a pre-clinical model of myeloperoxidase-ANCA-induced pauci-immune systemic vasculitis in the Wistar Kyoto rat. Up-regulation of SYK expression in inflamed renal and pulmonary tissue during early autoimmune vasculitis was confirmed by immunohistochemical and transcript analysis. R406, the active metabolite of fostamatinib, a small molecule kinase inhibitor with high selectivity for SYK, inhibited ANCA-induced pro-inflammatory responses in rat leucocytes in vitro. In an in vivo study, treatment with fostamatinib for 14 days after disease onset resulted in rapid resolution of urinary abnormalities, significantly improved renal and pulmonary pathology, and preserved renal function. Short-term exposure to fostamatinib did not significantly affect circulating myeloperoxidase-ANCA levels, suggesting inhibition of ANCA-induced inflammatory mechanisms in vivo. Finally, SYK expression was demonstrated within inflammatory glomerular lesions in ANCA-associated glomerulonephritis in patients, particularly within CD68+ve monocytes/macrophages. Thus, our data indicate that SYK inhibition warrants clinical investigation in the treatment of AAV., Graphical abstract

Introduction: IgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.Methods: To elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.Results: M-ficolin, L-ficolin, mannan-binding lectin (MBL)-associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H-related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.Conclusion: Our data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.

IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

Class IV-S lupus nephritis is often associated with more necrosis and fewer subendothelial immune deposits compared to class IV-G lupus nephritis, suggestive of necrotising glomerular inflammation found in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. ANCAs are present in a significant proportion of patients with lupus nephritis. Here we determine whether ANCAs are associated with distinct clinical and histopathologic features of lupus nephritis. Thirty-two ANCA-positive biopsies were compared to 222 ANCA-negative biopsies from patients with lupus nephritis. The majority (82%) of ANCA-positive patients had antimyeloperoxidase antibodies. Class IV-S lupus nephritis and glomerular necrosis were significantly more common (36% vs. 16% and 35% vs. 15%, respectively) and isolated Class V lupus nephritis significantly less common (10% vs. 29%) in the ANCA-positive group. ANCA-positive patients had significantly higher dsDNA titers (335u/ml vs. 52u/ml), significantly lower serum C4 concentrations (0.125g/L vs. 0.15g/L) and significantly higher serum creatinine (130μmol/L vs. 84μmol/L) at the time of biopsy. Hence ANCAs appear to influence the histological pattern of lupus nephritis and are associated with worse baseline renal function and more active lupus serology. There was no significant difference in outcome between groups when matched for severity of disease and treatment using propensity scoring. Thus, further studies are needed to examine whether ANCAs in patients with lupus nephritis have a pathogenic role and whether they are associated with worse renal outcomes or are simply a marker of more severe disease.

Background Endocapillary hypercellularity independently predicts renal outcome in immunoglobulin A nephropathy (IgAN). Mycophenolate mofetil (MMF) treatment is offered to patients presenting to the Imperial College Renal and Transplant Centre with IgAN and histological evidence of endocapillary hypercellularity. Clinical trials of MMF in IgAN have been inconclusive and have been limited by a lack of specific histological inclusion and exclusion criteria when recruiting patients. Evidence of histological improvement following MMF treatment would support its therapeutic use. We therefore reviewed histological changes after MMF therapy in a cohort of IgAN patients. Method Eighteen IgAN patients with native renal biopsies before and after repeated MMF treatment were identified. Patients were excluded if they had received any other immunosuppressive therapy, including corticosteroids. On the basis of the Oxford Classification of IgAN, we reviewed histological changes after MMF treatment. Results Nine patients (50%) were male. At diagnostic renal biopsy, the median age was 35 years [interquartile range (IQR) 30-41], serum creatinine was 97 µmol/L (IQR 79-153) and urine protein creatinine ratio (UPCR) was 146 mg/mmol (IQR 98-212). The median time between biopsies was 24 months (range 9-41). Following MMF treatment, repeat biopsy demonstrated statistically significant improvement in the mean percentage of glomeruli showing endocapillary hypercellularity and cellular/fibrocellular crescents. There was no change in mesangial hypercellularity, segmental sclerosis or tubular atrophy scores. Mesangial IgA deposition was also significantly reduced. Histopathological improvement persisted after the cessation of MMF therapy, suggesting that 2 years of treatment is adequate for benefit. The median serum creatinine remained stable at 3 years follow-up at 104 µmol/L (IQR 79-147). Conclusion MMF treatment is associated with histopathological improvement in IgAN.

Background Tacrolimus (TAC) is effective in treating membranous nephropathy (MN); however relapses are frequent after treatment cessation. We conducted a randomised controlled trial to examine whether the addition of mycophenolate mofetil (MMF) to TAC would reduce relapse rate. Methods Forty patients with biopsy proven idiopathic MN and nephrotic syndrome were randomly assigned to receive either TAC monotherapy (n = 20) or TAC combined with MMF (n = 20) for 12 months. When patients had been in remission for 1 year on treatment the MMF was stopped and the TAC gradually withdrawn in both groups over 6 months. Patients also received supportive treatment with angiotensin blockade, statins, diuretics and anticoagulation as needed. Primary endpoint was relapse rate following treatment withdrawal. Secondary outcomes were remission rate, time to remission and change in renal function. Results 16/20 (80%) of patients in the TAC group achieved remission compared to 19/20 (95%) in the TAC/MMF group (p = 0.34). The median time to remission in the TAC group was 54 weeks compared to 40 weeks in the TAC/MMF group (p = 0.46). There was no difference in the relapse rate between the groups: 8/16 (50%) patients in the TAC group relapsed compared to 8/19 (42%) in the TAC/MMF group (p = 0.7). The addition of MMF to TAC did not adversely affect the safety of the treatment. Conclusions Addition of MMF to TAC does not alter the relapse rate of nephrotic syndrome in patients with MN. Trial registration This trial is registered with EudraCTN2008–001009-41. Trial registration date 2008-10-08.

Introduction: Therapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H–related protein 5 (FHR5) interacts with complement C3 and is considered to promote activation. Circulating and glomerular FHR5 associates with IgA nephropathy and abnormal FHR5 associates with familial C3 glomerulopathy (C3G). We characterized glomerular FHR5 staining in C3G and assessed its relationships with histological features of glomerular injury and clinical outcome. Methods: We developed FHR5 staining protocols for formalin-fixed paraffin-embedded (FFPE) renal tissue and applied them to surplus biopsy sections from a C3G cohort. Results: Glomerular FHR5 was highly prevalent in native and transplant C3G and correlated with glomerular C3 and C5b-9 staining. Glomerular FHR5 staining correlated negatively with estimated glomerular filtration rate (eGFR) (P = 0.04, difference of medians 19.7 ml/min per 1.73 m2; 95% confidence interval [CI] 1.1–43.0) and positively with a membranoproliferative glomerulonephritis pattern at diagnostic biopsy (odds ratio 18; 95% CI 1.6–201; P = 0.049). Glomerular FHR5 staining intensity positively correlated with glomerular complement C3b/iC3b/C3c (Pearson’s correlation coefficient [R] = 0.59; P = 0.0008), C3dg (R = 0.47; P = 0.02) and C5b9 (R = 0.44, P = 0.02). Conclusions: Glomerular FHR5 is highly prevalent in C3G, interacts with glomerular C3, and is associated with markers of disease severity. Glomerular FHR5 likely exacerbates complement-mediated glomerular damage in C3G and its interaction with glomerular complement might be exploited to target complement therapeutic agents. Keywords: complement, C3 glomerulopathy, glomerulonephritis

Contains fulltext : 202673.pdf (Publisher’s version ) (Open Access) The Kidney Disease: Improving Global Outcomes (KDIGO) initiative organized a Controversies Conference on glomerular diseases in November 2017. The conference focused on the 2012 KDIGO guideline with the aim of identifying new insights into nomenclature, pathogenesis, diagnostic work-up, and, in particular, therapy of glomerular diseases since the guideline's publication. It was the consensus of the group that most guideline recommendations, in particular those dealing with therapy, will need to be revisited by the guideline-updating Work Group. This report covers general management of glomerular disease, IgA nephropathy, and membranous nephropathy.