The scientific rationale is compelling. IgA nephropathy follows a multi-hit pathogenic sequence that begins with the production of galactose-deficient IgA1, an abnormally glycosylated antibody. Anti-glycan antibodies bind this molecule to form circulating immune complexes that deposit in the mesangium, the connective tissue scaffolding of the glomerulus. There they trigger local inflammation, predominantly by activating the alternative and lectin complement pathways, with limited evidence for classical pathway involvement. The alternative pathway is considered the dominant amplifier: it is constantly active at low levels in the circulation and can be enhanced by the deposited immune complexes. The lectin pathway, driven by pattern-recognition molecules such as mannan-binding lectin and ficolins that bind directly to the deposits, activates MASP-2 and downstream cleavage of complement components, adding a second engine of glomerular injury.

Both pathways converge at C3, generating the effector molecules C3a and C5a, which recruit inflammatory cells and promote cytokine release, and the membrane attack complex C5b-9, which drives mesangial cell proliferation, oxidative stress and extracellular matrix expansion. Persistent complement activation may also damage the endothelium: several studies have found histological evidence of thrombotic microangiopathy in a subset of patients, particularly severe cases, suggesting an additional injury mechanism that could explain the clinical heterogeneity of the disease. Precisely because complement sits at the center of this pathology, its proteins have become the most closely watched candidate biomarkers in nephrology, especially now that drugs designed to shut down specific complement pathways have reached the clinic.

Among tissue markers, mesangial C4d has emerged as the most extensively studied. Deposits of lectin pathway components are found in roughly 25 to 50 percent of IgA nephropathy biopsies, usually without C1q, supporting lectin pathway involvement. A meta-analysis of 12 studies including 1,251 participants reported an overall prevalence of glomerular C4d deposition of 34 percent. Multiple investigations have shown that C4d-positive patients have greater proteinuria, lower kidney function and adverse Oxford MEST lesions, including mesangial hypercellularity and segmental sclerosis, and deposition has been reported as an independent predictor of progression. Yet C4d has not entered standard risk models, and because lectin pathway activation occurs only in a subset of patients, its relevance to the global population remains unclear.

In the circulation, the factor H-related protein family has attracted particular attention. These proteins, encoded at the complement factor H gene locus, can compete with factor H, the major negative regulator of C3 activation. Plasma FHR-1 is elevated in patients even when kidney function is normal, and the FHR-1 to factor H ratio, proposed as a better measure of the balance between complement control and dysregulation, is significantly raised in patients with progressive disease. FHR-5 tells a different story: it does not track progression but correlates with more severe histological features and a reduced response to immunosuppression, hinting at a role in predicting treatment response. Alternative pathway cleavage products Bb and Ba also carry prognostic weight, with higher Bb linked to vascular and tubular lesions and worse long-term outcomes, while plasma Ba falls after immunosuppression. Low circulating MASP-3, meanwhile, has consistently marked severe, progressive disease.

Conventional serum measures are finding new life as well. In a study of 1,356 Chinese patients, serum C4 correlated with proteinuria, kidney function and the extent of chronic damage, and elevated levels were an independent risk factor for progression. The C3/C4 ratio outperformed either protein alone in predicting poor clinical and pathological features, and in a recent report the addition of serum C3 and C4 improved the predictive performance of both the CKD progression model and the International IgAN Risk Prediction Tool. The IgA/C3 ratio has shown strong diagnostic and prognostic associations in Asian cohorts, but inconsistent results elsewhere mean its generalizability remains unresolved.

Urine offers a non-invasive window onto intrarenal inflammation. Elevated urinary C4d has been associated with greater proteinuria, more severe histopathological injury and increased progression risk, independent of conventional factors, and with poorer response to steroids. Urinary factor H and soluble C5b-9 correlate with proteinuria, interstitial fibrosis and glomerulosclerosis, and a Swedish cohort found that urinary pentraxin 3 and mannan-binding lectin tracked active proliferative lesions while C4c marked chronic fibrosis and faster function decline. A caution remains: most studies lacked proteinuria-matched control groups, so urinary complement may partly reflect nonspecific leakage across a damaged filtration barrier rather than disease-specific activation.

The therapeutic stakes of these measurements are now enormous. The oral factor B inhibitor iptacopan, which suppresses the alternative pathway, reduced proteinuria and slowed kidney function loss in phase 2 and 3 trials, with the final 24-month APPLAUSE-IgAN data showing an annualized total eGFR slope of minus 3.10 versus minus 6.12 ml/min/1.73 m² per year compared with placebo and a kidney-failure endpoint hazard ratio of 0.57. Iptacopan received accelerated FDA approval in 2024 and traditional approval in 2026. The antisense oligonucleotide sefaxersen cut factor B, Bb and urinary Ba while reducing proteinuria by roughly 43 percent in phase 2 and now advances in a phase 3 program. Terminal pathway blockade also works: ravulizumab reduced proteinuria by 30.1 percent versus placebo at week 26, and the siRNA agent cemdisiran achieved a placebo-adjusted 37.4 percent reduction, although it has not progressed to phase 3. By contrast, the MASP-2 inhibitor narsoplimab failed its phase 3 program, a result that highlights the heterogeneity of complement activation and the potential need for biomarker-guided patient selection.

Despite this momentum, the review is candid about the gaps. The KDIGO 2025 guideline states that apart from proteinuria and eGFR there are no validated prognostic serum or urine biomarkers for IgA nephropathy, even while flagging biomarker discovery as a high-priority research recommendation. Most candidate markers have been evaluated in single-center studies with differing assays, non-standardized cut-offs and heterogeneous outcome definitions, yielding moderate and inconsistent performance. Each compartment has inherent limitations: biopsies provide the most direct evidence of complement activation but are invasive and unsuited to repeated monitoring; circulating markers are accessible but may reflect systemic rather than kidney-specific activation; urinary markers are promising but remain largely unvalidated. Complement activation also differs across ethnic populations and may shift over the course of disease.

The authors argue that the field’s priority should now shift from proving that complement matters to identifying which patients benefit most from which inhibitor, guided by pathway-specific biomarkers. The principle they invoke is straightforward: right pathway, right drug, right patient, right time. Biomarker-driven stratification could match pathway activity to targeted therapy, minimize unnecessary immunosuppression and reduce adverse effects, and may eventually reveal whether patients with complement-mediated thrombotic microangiopathy, a phenotype so far studied only in case reports, derive special benefit from complement inhibition. Large, multiethnic, longitudinal studies will be needed before complement biomarkers can move from research tool to routine clinical practice, but with effective complement drugs already approved, the incentive to validate them has never been greater.

Subject of Research: Complement biomarkers for diagnosis, prognosis and complement-targeted therapy in IgA nephropathy

Article Title: Complement biomarkers in IgA nephropathy: current insights and clinical relevance

Article References: Complement biomarkers in IgA nephropathy: current insights and clinical relevance. (n.d.). https://doi.org/10.3389/fneph.2026.1918450

Image Credits: AI Generated

DOI: 10.3389/fneph.2026.1918450

Keywords: IgA nephropathy, complement system, biomarkers, C4d, alternative pathway, lectin pathway, iptacopan, kidney disease, glomerulonephritis, precision medicine, proteinuria, nephrology