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Immune complex-mediated glomerulonephritis. The glomerular capillary wall is composed of three layers: a fenestrated endothelial layer, a glomerular basement membrane (GBM), and an epithelial layer (podocytes). A) Immune complexes can form in the capillary wall when: 1) circulating antigen becomes trapped in the capillary wall, 2) pre-formed circulating immune complexes become trapped in the capillary wall, or 3) circulating immuno-globulin binds to antigens expressed within the capillary wall. B) Immune complexes can deposit: 1) in the subendothelial space, 2) within the GBM, and 3) in the subepithelial space. They can also form within the mesangium (not shown). The location of the immune complexes affects the histologic and clinical patterns of injury.
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It has long been known that the complement cascade is activated in various forms of glomerulonephritis. In many of these diseases, immune-complexes deposit in the glomeruli and activate the classical pathway. Researchers have also identified additional mechanisms by which complement is activated in the kidney, including diseases in which the altern...
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Citations
... The kidney is known to be sensitive to protein deposition as a result of the high blood flow relative to the mass of the kidney, its anatomic structure, and its unique role in filtering blood and concentrating urine. The kidney has previously been shown to be predisposed to the deposition of complement and immunoglobulin proteins with disease [17]. We hypothesized that the large increase in immunoglobulins in the plasma with age may result in an increased deposition of immunoglobulins in the kidney with age. ...
One of the main hallmarks of aging is aging-associated inflammation, also known as inflammaging. In this study, by comparing plasma and kidney proteome profiling of young and old mice using LC–MS profiling, we discovered that immunoglobulins are the proteins that exhibit the highest increase with age. This observation seems to have been disregarded because conventional proteome profiling experiments typically overlook the expression of high-abundance proteins or employ depletion methods to remove them before LC–MS analysis. We show that proteome profiling of immunoglobulins will likely be a useful biomarker of aging. Spatial profiling using immunofluorescence staining of kidney sections indicates that the main increases in immunoglobulins with age are localized in the glomeruli of the kidney. Using laser capture microdissection coupled with LC–MS, we show an increase in multiple immune-related proteins in glomeruli from aged mice. Increased deposition of immunoglobulins, immune complexes, and complement proteins in the kidney glomeruli may be a factor leading to reduced filtering capacity of the kidney with age. Therapeutic strategies to reduce the deposition of immunoglobulins in the kidney may be an attractive strategy for healthy aging.
... The complement system plays a central role in the pathogenesis of many immune-mediated kidney diseases (1)(2)(3)(4). All parts of the complement system, including dysfunction of the complement regulator proteins, have been implicated in complement mediated kidney injury (5). ...
... We will also discuss the limitations of these urinary biomarkers and the future for developing commercial assays for these diseases. 2 The pathways of complement activation ...
The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement system including the classical, alternative, and mannose-binding lectin pathways have been implicated in complement-mediated kidney injury. Although complement components are thought to be mainly synthesized in the liver and activated in the circulation, emerging data suggest that complement is synthesized and activated inside the kidney leading to direct injury. Urinary complement biomarkers are likely a better reflection of inflammation within the kidneys as compared to traditional serum complement biomarkers which may be influenced by systemic inflammation. In addition, urinary complement biomarkers have the advantage of being non-invasive and easily accessible. With the rise of therapies targeting the complement pathways, there is a critical need to better understand the role of complement in kidney diseases and to develop reliable and non-invasive biomarkers to assess disease activity, predict treatment response and guide therapeutic interventions. In this review, we summarized the current knowledge on urinary complement biomarkers of kidney diseases due to immune complex deposition (lupus nephritis, primary membranous nephropathy, IgA nephropathy) and due to activation of the alternative pathway (C3 glomerulopathy, thrombotic microangiography, ANCA-associated vasculitis). We also address the limitations of current research and propose future directions for the discovery of urinary complement biomarkers.
... This concept can be understood by analyzing the example of SLE due to deficiency in C1q, which plays a primary role in the classical pathway of the complement system (6). The main functions of the complement system include the clearance of immune complexes, so when C1q is deficient, it could lead to the deposition of immune complexes resulting in autoimmunity (21). This could further lead to C3 glomerulonephritis (21). ...
... The main functions of the complement system include the clearance of immune complexes, so when C1q is deficient, it could lead to the deposition of immune complexes resulting in autoimmunity (21). This could further lead to C3 glomerulonephritis (21). Since C3 is produced from C1q in the subsequent steps, deficiency in C3 causes C3 glomerulonephritis. ...
... When these complexes are deposited in tissue, they activate the complement system, leading to the destruction of antigens and tissue damage due to mast cell degranulation and neutrophil extravasation, causing inflammation in the tissue (57). This mechanism is seen in the case of glomerular nephritis (21). Here, immune complexes are formed in the blood and are deposited in the basement membrane of the glomerulus. ...
Autoimmunity and its associated diseases have been the primary area of focus in research in the past decade; however, several mechanisms are still left unclear. Autoimmune diseases are idiopathic and currently, there are hardly any genetic tools available to predict who is at risk of developing them. With the advancement of artificial intelligence, it could be possible to predict the potential emergence of autoimmune disorders. This review article discusses the disease classification and relevant causes, including environmental, biological, and genetic factors. Additionally, it explores certain mechanisms where the T-regulatory cells fail and lead to disease development. The article delves into the etiology to illustrate how autoimmune diseases could develop in a person as well as therapeutic approaches are also discussed. With the development of multiplex technologies, it is easier to detect autoantibodies in blood while cytokines and chemokines can give a breakthrough in diagnosis and novel therapeutics for these diseases.
... Tubular deposition of C5a has also been shown to correlate with the severity of DKD and blocking the C5a-C5a1R axis ameliorated interstitial fibrosis in a murine diabetic (db/db) model (Yiu et al., 2017). Notably, uncontrolled complement activation is a crucial driving force in kidney diseases, including complement 3 glomerulopathy (C3G) and IgA nephropathy, caused by excessive activation of the alternative complement pathway (Poppelaars & Thurman, 2020). In summary, hyperactivation of complement components and their breakdown products (C3, C5a, and MAC) manifests in glomerular inflammation and injury that include endocapillary hypercellularity, mesangial hypercellularity, focal segmental sclerosis, interstitial fibrosis, tubular atrophy, crescent formation and all leading to proteinuria and CKD (Schena, Esposito, & Rossini, 2020;Xie et al., 2023). ...
Chronic diabetes leads to various complications including diabetic kidney disease (DKD). DKD is a major microvascular complication and the leading cause of morbidity and mortality in diabetic patients. Varying degrees of proteinuria and reduced glomerular filtration rate are the cardinal clinical manifestations of DKD that eventually progress into end-stage renal disease. Histopathologically, DKD is characterized by renal hypertrophy, mesangial expansion, podocyte injury, glomerulosclerosis, and tubulointerstitial fibrosis, ultimately leading to renal replacement therapy. Amongst the many mechanisms, hyperglycemia contributes to the pathogenesis of DKD via a mechanism known as non-enzymatic glycation (NEG). NEG is the irreversible conjugation of reducing sugars onto a free amino group of proteins by a series of events, resulting in the formation of initial Schiff's base and an Amadori product and to a variety of advanced glycation end products (AGEs). AGEs interact with cognate receptors and evoke aberrant signaling cascades that execute adverse events such as oxidative stress, inflammation, phenotypic switch, complement activation, and cell death in different kidney cells. Elevated levels of AGEs and their receptors were associated with clinical and morphological manifestations of DKD. In this chapter, we discussed the mechanism of AGEs accumulation, AGEs-induced cellular and molecular events in the kidney and their impact on the pathogenesis of DKD. We have also reflected upon the possible options to curtail the AGEs accumulation and approaches to prevent AGEs mediated adverse renal outcomes.
... Their inappropriate activation leads to deleterious effects causing tissue damage. Genetic or acquired defects of the alternate complement pathway can lead to TMA, complement deposition in the kidneys, inflammation, and kidney damage [32]. ...
... A possible role of complement-induced ET-1 and ETB receptor expression, within the glomerulus and proximal tubules, has also been suggested [36]. Thus, activation of the complement cascade can accentuate both complement-mediated kidney damage and HTN (Fig. 2) [32,34]. ...
... Rights reserved. mediated inflammation and elevation of BP [32]. Furthermore, several BP-related genetic polymorphisms have been suggested to worsen progression of GD [6]. ...
Purpose of Review
This review aims to explore the underlying mechanisms that lead to hypertension in glomerular diseases and the advancements in treatment strategies and to provide clinicians with valuable insights into the pathophysiological mechanisms and evidence-based therapeutic approaches for managing hypertension in patients with glomerular diseases.
Recent Findings
In recent years, there have been remarkable advancements in our understanding of the immune and non-immune mechanisms that are involved in the pathogenesis of hypertension in glomerular diseases. Furthermore, this review will encompass the latest data on management strategies, including RAAS inhibition, endothelin receptor blockers, SGLT2 inhibitors, and immune-based therapies.
Summary
Hypertension (HTN) and cardiovascular diseases are leading causes of mortality in glomerular diseases. The latter are intricately related with hypertension and share common pathophysiological mechanisms. Hypertension in glomerular disease represents a complex and multifaceted interplay between kidney dysfunction, immune-mediated, and non-immune-mediated pathology. Understanding the complex mechanisms involved in this relationship has evolved significantly over the years, shedding light on the pathophysiological processes underlying the development and progression of glomerular disease-associated HTN, and is crucial for developing effective therapeutic strategies and improving patients’ outcomes.
... As a major part of innate immunity, the complement system is essential in the defence against pathogens, while dysregulation can lead to inapprioate activation thereby inducing tissue damage. 1 In peritoneal dialysis (PD), this system has been proposed to be an important mediator of peritoneal membrane damage and inflammation. 2,3 Furthermore, complement activation in dialysis has also been linked to relevant clinical implications such as cardiovascular disease, vasculopathy, peritoneal fibrosis and peritonitis. ...
Background:
Despite several advantages compared to haemodialysis (HD), peritoneal dialysis (PD) remains an underused dialysis technique due to its high technique failure rate related to membrane fibrosis and peritonitis events. Previous work has suggested a harmful role for the complement system in these processes, highlighting the need for a more comprehensive examination in PD.
Methods:
Plasma levels of C1q, mannose-binding lectin (MBL), Properdin, Factor D, C3d/C3-ratio and soluble membrane attack complex (sC5b-9) were determined in PD patients ( n = 55), HD patients ( n = 41), non-dialysis chronic kidney disease (CKD) patients ( n = 15) and healthy controls ( n = 14). Additionally, C1q, MBL, Properdin, Factor D and sC5b-9 levels were assessed in the peritoneal dialysis fluid (PDF). In a subgroup, interleukin-6, matrix metalloproteinase-2 (MMP-2), myeloperoxidase (MPO) and elastase were measured in the PDF.
Results:
PD patients had significantly higher systemic levels of sC5b-9 compared to healthy controls, CKD and HD patients ( p < 0.001). Plasma levels of C1q and C3d/C3-ratios were significantly associated with systemic sC5b-9 levels ( p < 0.001). Locally, sC5b-9 was detected in the PDF of all PD patients, and levels were approximately 33% of those in matched plasma, but they did not correlate. In the PDF, only Properdin levels remained significantly associated with PDF sC5b-9 levels in multivariate analysis ( p < 0.001). Additionally, PDF levels of sC5b-9 positively correlated with elastase, MPO and MMP-2 levels in the PDF ( p < 0.01).
Conclusions:
Our data reveal both systemic and local complement activation in PD patients. Furthermore, these two processes seem independent considering the involvement of different pathways and the lack of correlation.
... Dysregulation of the complement system is implicated in the pathogenesis of many rare diseases, including immunoglobulin A nephropathy (IgAN), complement 3 glomerulopathy (C3G), atypical hemolytic uremic syndrome (aHUS), lupus nephritis (LN), and paroxysmal nocturnal hemoglobinuria (PNH) (Morgan and Harris, 2015); apart from PNH, these are all kidney diseases. Both the structural and functional aspects of the kidneys make them uniquely susceptible to complement-mediated damage (Poppelaars and Thurman, 2020). Iptacopan (LNP023) is an oral, small-molecule, first-in-class, highly potent proximal complement inhibitor that specifically binds factor B and inhibits the alternative complement pathway (Schubart et al., 2019;Mainolfi et al., 2020). ...
Iptacopan (LNP023) is an oral, small-molecule, first-in-class, highly potent proximal complement inhibitor that specifically binds factor B and inhibits the alternative complement pathway. Iptacopan is currently in development as a targeted treatment for PNH and multiple other complement-mediated diseases. In this study, the absorption, distribution, metabolism, and excretion (ADME) of iptacopan was characterized in six healthy volunteers after a single 100 mg oral dose of [14C]iptacopan. This was supplemented with an in vivo rat ADME study and metabolite exposure comparisons between human, rat and dog, in addition to in vitro assays, to better understand the clearance pathways and enzymes involved in the metabolism of iptacopan. The fraction of [14C]iptacopan absorbed was estimated to be about 71%, with a time to maximum concentration (Tmax) of 1.5 h and elimination half-life from plasma of 12.3 h. Following a single dose of [14C]iptacopan, 71.5% of the radioactivity was recovered in feces and 24.8% in urine. [14C]iptacopan was primarily eliminated by hepatic metabolism. The main biotransformation pathways were oxidative metabolism via CYP2C8, with M2 being the major oxidative metabolite, and acyl glucuronidation via UGT1A1. The two acyl glucuronide metabolites in human plasma, M8 and M9, each accounted for {less than or equal to}10% of the total circulating drug-related material; systemic exposure was also observed in toxicology studies in rat and dog, suggesting a low risk associated with these metabolites. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan. Significance Statement We characterized the pharmacokinetics, excretion, metabolism and elimination of [14C]iptacopan (an oral, selective small-molecule inhibitor of factor B) - in healthy human subjects. [14C]iptacopan was primarily eliminated by metabolism. The primary biotransformation pathways were oxidative metabolism via CYP2C8 and acyl glucuronidation via UGT1A1. Direct secretion of iptacopan into urine and potentially bile represented additional elimination mechanisms. Binding of iptacopan to its target, factor B, in the bloodstream led to a concentration-dependent blood:plasma distribution and plasma protein binding of [14C]iptacopan.
... Deficient clearance of such material could stimulate autoantibody responses, leading to autoimmunity. Sequence and copy number variations in genes that encode components of the alternative complement pathway (for example, complement-factor H related proteins) may also drive disease in C3 glomerulonephritis, lowering complement levels much as do the autoantibodies to these proteins 32,88 . ...
Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur widely and affect individuals of all ages, especially women. Among these diseases, the most prominent immunological manifestation is the production of autoantibodies, which provide valuable biomarkers for diagnosis, classification and disease activity. Although T cells have a key role in pathogenesis, they are technically more difficult to assay. In general, autoimmune disease results from an interplay between a genetic predisposition and environmental factors. Genetic predisposition to autoimmunity is complex and can involve multiple genes that regulate the function of immune cell populations. Less frequently, autoimmunity can result from single-gene mutations that affect key regulatory pathways. Infection seems to be a common trigger for autoimmune disease, although the microbiota can also influence pathogenesis. As shown in seminal studies, patients may express autoantibodies many years before the appearance of clinical or laboratory signs of disease - a period called pre-clinical autoimmunity. Monitoring autoantibody expression in at-risk populations may therefore enable early detection and the initiation of therapy to prevent or attenuate tissue damage. Autoimmunity may not be static, however, and remission can be achieved by some patients treated with current agents.
... Introduction Dysregulation or deficiency of the complement alternative pathway (AP) is implicated in several rare blood disorders and renal diseases 1,2 , and more broadly plays a role in progression of inflammatory conditions. 3 Nascently-generated C3b molecules (from any of the three initiation pathways) bind Factor B (FB) to form the proconvertase C3bB, which is cleaved by Factor D (FD) to form the active convertase C3bBb. ...
Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the inactive complement proteins present at high concentrations in plasma, which increases target-mediated drug disposition and necessitates high drug levels to sustain therapeutic inhibition. Furthermore, many efforts are aimed at inhibiting only terminal pathway activity, which leaves opsonin-mediated effector functions intact. We describe the discovery of SAR443809, a specific inhibitor of the active alternative pathway C3/C5 convertase C3bBb. SAR443809 selectively binds to the activated form of Factor B (Factor Bb), and inhibits alternative pathway activity by blocking cleavage of C3, leaving initiation of classical and lectin complement pathways unaffected. Ex vivo experiments with patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes show that, while terminal pathway inhibition via C5 blockade can effectively inhibit hemolysis, proximal complement inhibition with SAR443809 inhibits both hemolysis and C3b deposition, abrogating the propensity for extravascular hemolysis. Finally, intravenous and subcutaneous administration of the antibody in nonhuman primates demonstrated sustained inhibition of complement activity for several weeks following injection. Overall, SAR443809 shows strong potential for treatment of alternative pathway-mediated disorders.
... Many new drugs targeting various sites in the complement cascade are also in clinical trials for MPGN patients [11]. To understand the best treatment for each patient, it is important to study the complement abnormalities in detail. ...
Membranoproliferative glomerulonephritis (MPGN) is subdivided into immune-complex-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G). Classically, MPGN has a membranoproliferative-type pattern, but other morphologies have also been described depending on the time course and phase of the disease. Our aim was to explore whether the two diseases are truly different, or merely represent the same disease process. All 60 eligible adult MPGN patients diagnosed between 2006 and 2017 in the Helsinki University Hospital district, Finland, were reviewed retrospectively and asked for a follow-up outpatient visit for extensive laboratory analyses. Thirty-seven (62%) had IC-MPGN and 23 (38%) C3G (including one patient with dense deposit disease, DDD). EGFR was below normal (≤60 mL/min/1.73 m2) in 67% of the entire study population, 58% had nephrotic range proteinuria, and a significant proportion had paraproteins in their serum or urine. A classical MPGN-type pattern was seen in only 34% of the whole study population and histological features were similarly distributed. Treatments at baseline or during follow-up did not differ between the groups, nor were there significant differences observed in complement activity or component levels at the follow-up visit. The risk of end-stage kidney disease and survival probability were similar in the groups. IC-MPGN and C3G have surprisingly similar characteristics, kidney and overall survival, which suggests that the current subdivision of MPGN does not add substantial clinical value to the assessment of renal prognosis. The high proportion of paraproteins in patient sera or in urine suggests their involvement in disease development.
