The complement system, an ancient and highly conserved branch of innate immunity, serves as a frontline defense against pathogens and a scavenger of cellular debris. However, its potent effector functions—including inflammation, opsonization, and direct membrane lysis—must be tightly controlled to prevent collateral damage to host tissues. A growing body of evidence now implicates dysregulated complement activation in the pathogenesis of various forms of nephropathy. From glomerular diseases to tubulointerstitial injury, complement components and activation fragments are increasingly recognized as both biomarkers and drivers of kidney damage. Recent advances in molecular immunology have uncovered specific genetic variants, autoantibodies, and tissue-level interactions that explain why the kidney is especially vulnerable. This article provides a comprehensive overview of emerging data on complement system activation in nephropathy, exploring underlying mechanisms, recent research findings, and therapeutic implications that may reshape the management of kidney disease.

The Complement System: An Overview

The complement system comprises more than 50 soluble and membrane-bound proteins that interact in a tightly regulated cascade. Activation proceeds through three distinct pathways, all converging at the central component C3:

  • Classical pathway: Triggered by antigen-antibody complexes (IgG or IgM) binding to C1q. This pathway is critical in autoimmune diseases such as lupus nephritis and is also involved in membranous nephropathy.
  • Lectin pathway: Initiated by mannose-binding lectin (MBL) or ficolins recognizing carbohydrate patterns on microbial surfaces or damaged host cells. This pathway may contribute to IgA nephropathy and ischemia-reperfusion injury after transplantation.
  • Alternative pathway: Continuously ticked over at low levels (“tick-over”) but amplified by properdin and suppressed by regulators like factor H and factor I. Uncontrolled activation of the alternative pathway underlies atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy.

All three pathways generate C3 convertases, which cleave C3 into the anaphylatoxin C3a and opsonin C3b. C3b tags surfaces for phagocytosis and also binds with other fragments to form C5 convertases, leading to cleavage of C5 into C5a (a potent chemoattractant) and C5b. The terminal pathway then assembles the C5b-9 membrane attack complex (MAC), which inserts into cell membranes, causing lysis or sublytic injury. Host protection is ensured by regulatory proteins such as CD46 (membrane cofactor protein), CD55 (decay-accelerating factor), CD59 (protectin), and fluid-phase regulators like factor H, factor I, and C4b-binding protein. When these regulators are deficient, overwhelmed, or genetically impaired, complement overactivation can drive tissue injury.

Complement Activation in Kidney Disease: General Mechanisms

The kidney is particularly vulnerable to complement-mediated injury. Glomeruli are exposed to circulating immune complexes and complement proteins, while the tubulointerstitium can be damaged by complement fragments filtered or produced locally. Emerging data highlight several common mechanisms:

  • Immune complex deposition: In diseases like lupus nephritis and membranous nephropathy, immune complexes activate the classical pathway, leading to C3 and C4 deposition on glomerular basement membranes. The local density and composition of these deposits influence the extent of complement activation.
  • Alternative pathway dysregulation: Genetic variants or autoantibodies against factor H, factor I, or C3 convertase components lead to uncontrolled alternative pathway activation, as seen in aHUS and C3 glomerulopathy. This dysregulation can also occur secondary to other conditions, such as post-streptococcal glomerulonephritis.
  • Anaphylatoxin-mediated inflammation: C5a recruits neutrophils and macrophages via C5a receptors (C5aR1 and C5aR2), while C3a promotes mast cell degranulation and proinflammatory cytokine release. These actions contribute to glomerular hypercellularity, crescent formation, and tubular atrophy. Recent work has shown that C5a can directly activate podocytes to produce matrix metalloproteinases.
  • Sublytic MAC injury: Sublytic amounts of C5b-9 can activate intracellular signaling pathways in podocytes and tubular epithelial cells, inducing apoptosis, matrix production, and epithelial–mesenchymal transition—key processes in proteinuria and fibrosis. Sublytic MAC also triggers release of extracellular vesicles that propagate complement activation to neighboring cells.
  • Endothelial activation: Complement activation on the endothelial surface promotes expression of adhesion molecules (e.g., P-selectin, VCAM-1) and release of von Willebrand factor, microthrombi formation, and loss of barrier integrity—critical in thrombotic microangiopathies.

IgA Nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by mesangial deposition of galactose-deficient IgA1 (Gd-IgA1) with accompanying C3 and often properdin. Research has shown that the alternative and lectin pathways are predominant in IgAN. In particular, MBL binds to abnormal IgA1 glycoforms and initiates the lectin pathway, while properdin stabilizes the alternative pathway C3 convertase. Elevated levels of C5a and C5b-9 in urine correlate with disease activity and progression. Recent studies have also identified that glomerular endothelial cells express C5aR in response to Gd-IgA1, amplifying local inflammation. These findings have spurred interest in complement inhibition as a therapeutic strategy, with trials of C5 inhibitors (e.g., eculizumab) and factor B inhibitors (e.g., iptacopan) showing early promise. The phase II APPLAUSE trial reported a 40% reduction in proteinuria with iptacopan over 6 months, and phase III results are expected in 2025.

Membranous Nephropathy

Membranous nephropathy (MN) is an autoimmune disease in which antibodies target podocyte antigens (primarily PLA2R and THSD7A). Subepithelial immune complex deposition activates the classical complement pathway via C1q, leading to MAC assembly on podocyte foot processes. Sublytic MAC disrupts the slit diaphragm and cytoskeleton, causing proteinuria. Recent work from Beck et al. (2021) demonstrated that elevated urinary C5b-9 levels predict poor outcome and that complement inhibition might protect podocytes before irreversible scarring occurs. Successful targeting of C5 with eculizumab has been reported in some refractory cases, although controlled trials are pending. Newer approaches focus on blocking C5aR1 on podocytes to mitigate the pro-fibrotic signaling that occurs downstream of complement activation, as shown in single-cell RNA sequencing studies.

Lupus Nephritis

Systemic lupus erythematosus (SLE) frequently involves the kidneys, and complement activation is a hallmark. Classical pathway consumption leads to low serum C3 and C4 levels—a classic marker of disease activity. Glomerular deposits of C1q, C4, C3, and C5b-9 are common. Additionally, genetic deficiencies of classical pathway components (e.g., C1q, C4) paradoxically predispose to SLE and severe lupus nephritis, suggesting a dual role of complement in clearing apoptotic debris versus causing inflammatory tissue injury. Newer approaches aim to inhibit C5a–C5aR1 signaling to reduce neutrophil and macrophage infiltration, with the monoclonal antibody vilobelimab showing potential in phase II studies. Furthermore, blockade of the alternative pathway at the level of factor B with iptacopan is being evaluated in lupus nephritis to prevent amplification of complement activation driven by autoantibodies.

Atypical Hemolytic Uremic Syndrome

aHUS is a prototypical complement-mediated thrombotic microangiopathy (TMA). Mutations in complement regulators (factor H, factor I, CD46, thrombomodulin) or gain-of-function mutations in C3 and factor B lead to unchecked alternative pathway activation on endothelial surfaces. This results in endothelial injury, platelet thrombosis, microangiopathic hemolytic anemia, and acute kidney injury. The introduction of eculizumab, a C5 inhibitor, revolutionized aHUS treatment, providing rapid hematologic and renal recovery. Long-term outcomes and the potential for treatment withdrawal remain areas of active investigation, as highlighted in a recent review in Nature Reviews Nephrology. Ravulizumab, a long-acting C5 inhibitor, now offers less frequent dosing, and oral factor D inhibitors (e.g., danicopan) show potential for oral maintenance therapy.

C3 Glomerulopathy

C3 glomerulopathy (C3G) is a rare but devastating kidney disease driven by uncontrolled alternative pathway activation on the glomerular basement membrane. It encompasses dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). In both subtypes, the primary defect involves a failure to regulate the alternative pathway C3 convertase, leading to deposition of C3 fragments (C3c, C3d) without significant immunoglobulin staining. Genetic mutations in factor H, factor I, or C3, as well as autoantibodies such as C3 nephritic factor, are found in the majority of cases. Recent studies have shown that complement activation products like C3a and C5a drive podocyte injury and mesangial proliferation. The phase II trial of danicopan (factor D inhibitor) demonstrated reduced proteinuria and stabilized eGFR out to 52 weeks (Kidney International, 2023). Iptacopan, a factor B inhibitor, showed promise in the APPAREIL phase II trial, and phase III studies are ongoing.

Key Mediators and Biomarkers of Complement Activation

Identifying specific complement activation products in blood or urine provides diagnostic and prognostic information. Commonly measured biomarkers include:

  • C3 and C4: Low serum levels suggest classical pathway consumption (e.g., SLE, postinfectious glomerulonephritis). However, normal levels do not rule out local complement activation in tissues.
  • C3a, C5a: Anaphylatoxins that reflect upstream activation; elevated in active IgAN, lupus nephritis, and aHUS. Urine C5a has been shown to correlate with disease activity in ANCA vasculitis as well.
  • C5b-9 (sMAC): Terminal complement activation product; increased in MN, IgAN, C3 glomerulopathy, and aHUS. Urinary C5b-9 is a noninvasive marker of podocyte injury in MN.
  • Factor H, factor I, and autoantibodies: Key for diagnosing aHUS and C3 glomerulopathy. Anti-factor H antibodies are associated with a subtype of aHUS that responds well to immunosuppression.
  • Properdin: Elevated in IgAN and C3G, reflecting alternative pathway amplification. Properdin stabilizes the C3 convertase and may serve as a therapeutic target.
  • Factor H-related proteins (FHRs): FHR-1, -2, -3, and -5 compete with factor H for C3b binding, acting as enhancers of alternative pathway activation. Polymorphisms in CFHR genes modify risk in IgAN and C3G.

Recent proteomic analyses have identified over 30 complement-related proteins in kidney tissue, reinforcing the complexity of local complement regulation. Multiplex assays and advanced imaging techniques (e.g., mass spectrometry imaging) are now enabling precise mapping of complement deposits within glomerular compartments, offering new insights into disease mechanisms. A promising approach is the use of urinary complement activation fragments combined with circulating markers to non-invasively diagnose and monitor disease activity, reducing the need for repeated biopsies.

Recent Research Advances

Significant progress has been made in understanding how complement activation contributes to nephropathy progression. Several key studies published between 2021 and 2024 deserve attention:

  • A genome-wide association study (GWAS) by Kiryluk et al. (2023) confirmed that variants in complement factor H-related genes (CFHR3, CFHR1) modify risk for IgAN, independent of circulating Gd-IgA1 levels. This suggests that genetically determined complement regulation influences susceptibility to complement-mediated injury in the glomerulus and may guide prophylactic therapy in high-risk individuals.
  • In membranous nephropathy, single-cell RNA sequencing of kidney biopsies from patients revealed that podocytes upregulate complement receptor C5aR1 and C3aR in response to sublytic attack, driving a pro-fibrotic program involving TGF-β and CTGF. This finding points to potential therapeutic targets beyond MAC formation, such as antagonists of these receptors.
  • For C3 glomerulopathy, a phase II trial of the factor D inhibitor danicopan demonstrated reduced proteinuria and stabilized renal function in patients with dense deposit disease (DDD) and C3GN. The results, reported at the American Society of Nephrology (ASN) Kidney Week 2023, support the feasibility of upstream alternative pathway blockade and provided validation for targeting the amplification loop.
  • In lupus nephritis, a study using a novel C3a receptor antagonist in murine models showed significant attenuation of glomerular crescent formation and reduced renal expression of inflammatory cytokines (TNF-α, IL-1β). Human trials are expected to begin soon, and this approach offers the advantage of preserving MAC function needed for pathogen defense.
  • A study on post-transplant complement activation demonstrated that pre-transplant donor-specific antibodies (DSAs) trigger classical pathway activation in the peritubular capillaries, leading to antibody-mediated rejection. Inhibition of C1s with a monoclonal antibody (e.g., sutimlimab) is being evaluated to prevent early rejection episodes.

These advances underscore the shift from a “one-size-fits-all” approach toward targeted complement inhibition tailored to the specific pathway and disease subtype involved. Precision medicine in nephrology will increasingly rely on complement biomarkers and genetic profiling to select the optimal therapeutic strategy.

Therapeutic Targeting of the Complement System

The growing understanding of complement's role in nephropathy has catalyzed development of several complement inhibitors. Broadly, these agents target the initiation, amplification, or terminal phases of the cascade.

C5 Inhibitors

Eculizumab (Soliris) and its long-acting derivative ravulizumab (Ultomiris) are monoclonal antibodies that bind C5, preventing its cleavage into C5a and C5b and thus blocking MAC formation. Approved for aHUS, these drugs have also been used off-label in severe IgAN, MN, and lupus nephritis with variable success. The high cost and requirement for meningococcal vaccination remain barriers. Novel oral C5 inhibitors (e.g., nomacopan, a C5a/LTB4 inhibitor) are under development and could offer greater convenience. Small interfering RNA (siRNA) approaches that reduce hepatic production of C5 (e.g., cemdisiran) have shown safety in early trials and may provide quarterly dosing.

Alternative Pathway Inhibitors

Because the alternative pathway is the primary driver in many complement-mediated kidney diseases, upstream inhibition has attracted intense interest. Iptacopan (Novartis), an oral factor B inhibitor, has shown efficacy in C3 glomerulopathy (APPAREIL trial) and IgAN (APPLAUSE trial). A phase III trial in IgAN is underway. Another agent, ALXN2040 (factor D inhibitor), is being evaluated for aHUS and C3G. Pegylated therapies and siRNA approaches that reduce hepatic production of complement components (e.g., factor B siRNA with ALN-FB) are also in clinical testing. The potential advantage of alternative pathway blockade is the preservation of classical and lectin pathway functions, which are important for pathogen defense, while preventing the amplification loop that drives tissue injury.

C5a Receptor Antagonists

Avacopan (Tavneos), an oral C5a receptor (C5aR1) antagonist, is already approved for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and is being explored in lupus nephritis and IgAN. By selectively blocking proinflammatory signaling without inhibiting MAC, avacopan may reduce infections while preserving opsonization ability. Phase II data in lupus nephritis (NOBILITY trial) showed improved renal response rates compared to placebo, and a phase III trial is in planning. C5aR2 antagonists are also in preclinical development, offering a way to fine-tune the complement response.

Classical and Lectin Pathway Inhibitors

In diseases driven primarily by immune complexes, such as lupus nephritis and MN, blocking the classical pathway at C1s or C1q may be beneficial. Sutimlimab, a monoclonal antibody targeting C1s, has been approved for cold agglutinin disease and is being tested in kidney transplantation and lupus nephritis. Narsoplimab, an anti-MASP-2 antibody that blocks the lectin pathway, showed promise in IgAN but failed to meet primary endpoints in a phase III trial. Nevertheless, the approach remains of interest for ischemia-reperfusion injury.

Clinical Trial Landscape

Numerous clinical trials are evaluating complement inhibitors for nephropathy. Key ongoing or recently completed studies include:

  • APPLAUSE-IgAN (NCT04557462): Phase III trial of iptacopan in IgAN, with primary endpoint of proteinuria reduction at 9 months. Results are expected in 2025.
  • NEPTUNE (NCT04563819): Phase II trial of avacopan in lupus nephritis; expanded access studies continue.
  • ECULIZUMAB for thrombotic microangiopathy after kidney transplant: Several case series suggest benefit, but controlled data are lacking. A randomized trial (CURE-TMA) is recruiting.
  • NOBILITY trial (NCT03053193): Phase II trial of avacopan in lupus nephritis; showed improved renal response compared to placebo when added to standard therapy (odds ratio 2.6). Phase III is being planned.
  • Factor D inhibitor (danicopan) in C3G: Phase II data indicating dose-dependent reduction in proteinuria and stabilization of eGFR out to 52 weeks (Kidney International, 2023). A phase III trial (DANCE) is ongoing.
  • C5 siRNA (cemdisiran) in IgAN: Phase II data showed a 30% reduction in proteinuria. Phase III trials are expected to begin in 2025.

Despite these promising findings, challenges remain: identifying patients most likely to benefit, monitoring for potential complement deficiency-related infections (especially Neisseria meningitidis), and managing treatment costs. Long-term safety data are still accumulating, and biomarker-driven patient selection will be critical to maximizing therapeutic success. Pharmacoeconomic analyses are needed to justify the high cost of these biologics in the context of chronic kidney disease.

Future Directions and Conclusion

The complement system is no longer viewed solely as a helper of innate immunity but as a central mediator of tissue injury in many forms of nephropathy. From IgA nephropathy to aHUS, the evidence is clear: uncontrolled complement activation drives inflammation, podocyte damage, and fibrosis. The rapidly expanding arsenal of complement inhibitors—targeting C5, factor B, factor D, C5aR, and even specific anaphylatoxins—offers new hope for patients who have limited treatment options. As data from ongoing trials mature, clinicians will need to integrate complement biomarkers into routine diagnostic assessments and adopt a personalized approach to therapy. Emerging strategies such as CRISPR-based gene editing to correct mutations in complement regulators or to disrupt the alternative pathway in the liver are on the horizon. The journey from bench to bedside is accelerating, and the next decade promises to transform the management of complement-mediated kidney diseases through earlier detection, targeted therapy, and improved outcomes.