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Department of Pharmacy Practice1 College of Pharmaceutical sciences Govt.medical college, Thiruvananthapuram, Kerala, India.
Immune-mediated glomerular diseases represent a major cause of chronic kidney disease and are characterized by abnormal immune responses involving autoantibody production, immune complex deposition, complement activation, and inflammatory injury to the glomerular filtration barrier. Conventional immunosuppressive therapies such as corticosteroids, cytotoxic agents, and calcineurin inhibitors have been widely used; however, their non-specific immune suppression and associated adverse effects highlight the need for more precise therapeutic strategies. Recent advances in molecular immunology have led to the development of novel biologic therapies that selectively target disease-driving immune pathways, including B-cell activation, plasma cell survival, cytokine signaling, and complement pathways. Agents such as rituximab, belimumab, daratumumab, eculizumab, and emerging complement inhibitors have demonstrated promising efficacy in conditions including membranous nephropathy, lupus nephritis, IgA nephropathy, ANCA-associated vasculitis, and other immune-mediated glomerulopathies. These therapies provide improved disease control, steroid-sparing effects, and the potential for personalized treatment approaches. However, challenges remain regarding patient selection, predictive biomarkers, long-term safety, optimal dosing strategies, treatment duration, accessibility, and evidence from large-scale clinical trials. This review summarizes current evidence on novel biologic therapies in immune-mediated glomerular diseases, evaluates their therapeutic benefits and limitations, and discusses future perspectives in precision nephrology and biomarker-guided management.
Glomerular diseases are group of kidney disorders that damage the filtering units in the kidney, that is glomeruli which filter the blood ,they hold back the necessary blood constituents and remove the waste products from blood .(1)There are 2 groups of glomerular diseases.
Most people with glomerulardiseases are asymptomatic unless they reach the advanced state of diseases. Major signs and symptoms include hematuria , foamy urine , swelling ,less urine made (Oliguria) , Fatigue. The causes include many from infection to autoimmune diseases that damage glomeruli.(1)
Different types of glomerulardiseases are
CKD is a public health problem there are many diseases that eventually progress to CKD, prevalence of each disease varies from country to country. Most of the glomerular diseases like FSGS , glomerulosclerosis,IgA nephropathy and membranous nephropathy shows edema as the most affecting clinical burden that has impact on health related quality of life of patients.(2)
The primary drawback of traditional immunosuppressive therapy in glomerulardiseases is its broad spectrum nature which indiscriminately dampens the entire immune system instead of neutralising the specific molecular drivers of illness. Although drugs like corticosteroides, cyclophosphamides, and calcineurin inhibitors triggers off target complications like life threatening infections and malignancy to permanent metabolic disorders like osteoporosis. Additionally these treatments often fail to produce lasting results frequently leading to relapses during dosage tapering and requiring rigorous invasive monitoring due to their narrow safety margin.(3) The lack of precision compromises both patient wellbeing and longterm kidney function,which indicates a need for targeted biologics. Most drugs have different adverse drug reactions due to low therapeutic index, to avoid toxicity the drug should be dosed correctly and monitored frequently.
Biologics therapies have marked a phenomenal transition from traditional immunosuppressive agents to targeted treatments guided by understanding of diseases mechanism, unlike conventional small molecules drug, bilogics are produced from living systems and specifically targeted components of immune system such as cytokines, b-cells and complement pathway . Progress in molecular biology, cytokine studies and monoclonal antibody development has facilitated the creation of these therapies, enabling more precise control of immune responses. In the context of glomerulardiseases, biologics have significantly improved treatment approaches by activity on critical process like Auto antibody production, immune complex deposition and inflammation resulting in better outcome with fewer side effects than conventional treatment(4).
The purpose of the review article 'Novel biologics therapies in immune mediated glomerulardiseases; current evidences and future perspectives' is to critically summarise and analyse emerging role of biologics and targeted therapies in the management of immune mediated glomerulardiseases. The review aims to evaluate current clinical evidence regarding efficacy safety and therapeutic potential of these agents in diseases such as membranous nephropathy, Lupus nephritis,IgA nephropathy etc , additionally the review intends to identify existing limitations,unmet clinical needs , challenges in biologics therapy implementation and gaps in current research. These are personalized medicines , biomarkers guided therapy, precision nephrology and ongoing clinical trials that may shape the future management of immune mediated glomerular diseases.
ANCA associated vasculiis
The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA)(5).The pathogenesis of AAV is complex and includes genetic, environmental, and infectious factors. Genome-wide association studies (GWAS) identified several genetic associations that include major histocompatibility complex (MHC) and non-MHC genetic loci. The clinical manifestations of AAV largely depend on the vascular bed affected, though the lungs and kidneys are the most common sites of involvement . Involvement of the upper respiratory tract can cause symptoms of rhinitis, sinusitis, deafness or epistaxis(6).
Atypical haemolytic uremic syndrome
The hemolytic–uremic syndrome, which is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment, occurs most frequently in young children. Most cases are secondary to infection with Escherichia coli and other Shiga-toxin–producing strains(7).One or several abnormalities of the complement system are presently demonstrated in 70% of children and adults with aHUS, and 30% of aHUS remain unexplained today(8).
Focal segmental glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) is the leading glomerular cause of ESRD in the United States. It present with proteinuria, podocyte injury, and minimal immune deposits. For the biopsy to exclude FSGS as a cause of nephrotic syndrome and assess the degree of cortical involvement, adequate renal cortical sampling is required(9).
Lupus nephritis
Lupus nephritis (LN) is a form of glomerulonephritis that constitutes one of the most severe organ manifestations of the autoimmune disease systemic lupus erythematosus (SLE). Most patients with SLE who develop LN do so within 5 years of an SLE diagnosis and, in many cases, LN is the presenting manifestation resulting in the diagnosis of SLE. Genetic polymorphisms and incessant activation by endogenous chromatin or microbial DNA seem to hyperactivate nucleic acid sensors in endosomes (such as TLR7, TLR8 and TLR9) and the cytosol (such as RIG1/MDA5–MAVS and CGAS–STING) in SLE(10).
Membranous nephropathy
Membranous nephropathy (MN) is a pathologically defined disorder of the kidney glomerulus. The specific lesion is an apparent thickening of the glomerular capillary walls, which results from immune complex formation on the outer aspect of the basement membrane1. The immune deposits consist of immunoglobulin G (IgG), the relevant antigens and complement components, including the membrane attack complex (MAC). The consequence of the immunological conflict is the loss of large amounts of proteins in the urine (proteinuria), which is predominantly mediated by the pathophysiological disturbance of the podocyte structure caused by immune complex deposition and MAC formation(11).
Pathophysiology of Glomerular diseases
Immune mediated glomerulardiseases develop as a consequence of abnormal immune response directed against various components of glomerulas , including podocyte mesangial cells , endothelial cells and glomerular basement membrane. These conditions are characterized by immune complex deposition,auto antibody production, complement activation and inflammatory cell infiltration , all of which contributes to the structural and functional damage to glomerular filtration barrier(12).
Pathogenic process commonly involves , formation of circulating immune complexes or Auto antibodies against intrinsic or extrinsic antigen. These immune deposits accumulate within the glomerulas and trigger activation of complement cascade leading to release of inflammatory mediators, such as cytokines and chemokines.The resulting inflammatory response promote recruitment leukocytes, oxidative stress and cellular injury, ultimately impairing glomerular permiability and renal function(13).
In membranous nephropathy immune complexes are deposited along the sub epithelial surface of glomerular basement membrane. Autoantibodies particularly those directed against PLAR2 expressd on podocytes , Activate complement pathway and promote formation of membranous attack complexes. This process cause podocyte detachment and deterioration of filtration barrier, leading to nephrotic range proteinuria. Continuous immune mediated inflammation eventually promote glomerulosclerosis, interstitial fibrosis and tubular atrophy. These chronic structural alteration progressively reduce renal function and may ultimately culminates in end stage renal disease(13).
Figure no -1 : pathogenesis of membranous nephropathy and focal segmental glomerulosclerosis( anti- glomerular basement membrane disease)(13)
Complement activation
There are 3 complement pathways in glomerulardiseases
For acquired and innate immunity proper functioning of these pathways are essential. These pathways converge C3 to generate an enzyme complex C3 convertase, which cleave C3 to C3a and C3b . The association of C3b with C3 convertase resulting in C5 convertase generation. Which produces C5a and C5b from C5 . The clevage triggers terminal complement cascade,and the membrane attack complex.(C5-9) produced followed by cellular injury(14).
Glomerulonephritis is a classical complement pathway mediated disease.In lupus nephritis deposition of immune complexes of anti double strand DNA antibodies directed against nucloesomal antigen. In primary membranous nephropathy phospholipase A2 receptor are main site for podocyte antigen.There are C3 glomerulopathies which occurs due to alternate complement pathway.
As in the other autoimmune diseases,there are B cell involvement in the glomerular auto immune diseases. Other than the pathological action, the B cells involved in other areas like antigen presentation to T cells , cytokines production etc. regular B cells involved in maintainance of immune tolerance,its deficiency seen in several autoimmune diseases like LN , ANCA etc(15). From the site of glomerular injury cytokines are released. Which further attack leukocytes to specific site of injury. There are different types of cytokine expression in Glomerulonephritis(16).Biologics or biologicals are those class of drugs that cultured in large scale culture of bacteria or yeast or plant or animal cell. That include vaccines, growth factors, immune modulators , monoclonal antibodies as well as product derrived from human blood and plasma. Rituxumab is the commonly used biologics agent to treat immune modulated glomerulopathies(17).
Indicated mostly for
Alemtuzumab ( Anti CD52 antibody targeting B cells , activated T cells etc) used to treat refractory renal transplant rejection. Milatuzumab , which is tested in Lupus nephritis. Belimumab , monoclonal antibody approved to treat SLE .Eculizumab , first class agent to inhibit complement compund C5 , used in treating glomerulardiseases with alternate pathway activation. Abatacept inhibit co stimulation of T cells and evaluated in patients with Lupus nephritis(18).
Table no-1 : targeted therapy in glomerular disease(19)
|
Sl no |
Pathway |
Drug |
|
1 |
B Cell depletion , AntiCD20 |
Rituximab |
|
2 |
BAFF/APRIL pathway |
Belimumab , Tabalimab ,Blisibimod,Atracicept |
|
3 |
Plasma cell depletion |
Daratumumab |
|
5 |
complement activation terminal pathway |
Eculizumab |
|
6 |
Alternate pathway |
iptacopan |
|
7 |
Lectin pathway |
Narsoplimab |
|
8 |
Chemokine /cytokine signaling |
Adalimumab |
Clinical evidence and major trials
Historically ,kidney research has fallen far behind other medical fields in both number and quality of its clinical trials. In fact studies testing new kidney treatment make up only 2.6% of reviewed medical trials. FDA approved novel drugs specifically for glomerular disease over half a centuary following 1962 drug ethics amendments. This is mainly due to slow approval by IRB and protracted contract negotiation. Also it faces different cultural barrier(20).culturally an uncertainty regarding treatment uniformity makes many nephrologists backward regarding clinical trials. The inadequate classification of diseases due to their pathophysiological charecteristics mainly rely on histopathology rather than underlying molecular mechanisms. This leads to difficulty in innovations like targeted therapy and identification of biological markers(20). These shortages overcame by development of infrastructure , collaborative network and innovative trial methodologies.These are large observational cohorts funded by national institute of diabetes and kidney disease (NIDDK) such as NEPTUNE and Cure GN . which analyse tissue , genomic and clinical data to better map and the natural history of these condition(21).
Biologic therapies offer a distinct advantage over conventional immune suppression in glomerular disease by shifting treatment from broad non specific immune destruction to targeted molecular precision , while conventional agents like cyclophosphamide and calcineurin inhibitors carry heavy burden of systemic steroids toxicity , permenant gonadal failure , increased malignancy risks and direct nephrotoxicities. Biologics acts as molecular scalpels that specifically depletes pathogenic cells or block exact cascade pathways. This high specificity enables robust steroid sparing regimen , preserves overall immune competence and renal hemodynamics , eliminate cytotoxic organ damage and utilises intermittent dosing schedule improve patient adherence and long term quality of life(22).
Novel biologics to treat glomerular diseases
Telitacicept
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and a leading cause of end-stage renal disease for young adults. Telitacicept, a novel recombinant fusion protein that dual-targets BAFF and APRIL, exhibits considerable therapeutic potential by inhibiting the production of Gd-IgA1 and its autoantibodies. Stage A results of the Phase 3 clinical trial demonstrated that patients in the telitacicept group achieved a 55% reduction in 24-h urinary protein-to-creatinine ratio and stable estimated glomerular filtration rate at Week 39 versus the placebo group, with favorable tolerability and safety.(18)
Belimumab
At the FDA?approved dose of 10 mg/kg, belimumab was shown to improve some benefits compared to placebo in people with SLE, while evidence related to harms was inconclusive. Specifically, belimumab 10 mg/kg was associated with a higher likelihood of achieving at least a 4?point improvement (reduction) in SELENA?SLEDAI score, a validated SLE disease activity score(23).
Iptacopan
Overactivation of the alternative complement pathway contributes to IgA nephropathy and glomerular inflammation.there is a significant improvement in eGFR decline in patient receiving iptacopan than placebo in a phase 3 clinical trial conducted in patients with IgA nephropathy(24).
Rituximab and Ofatumumab
Rituximab, a monoclonal anti-CD20 antibody is currently the third-line therapy of frequently relapsing or resistant minimal change disease. Recent pediatric case series has proposed the use of a novel humanized anti-CD20 antibody ofatumumab, reporting superior efficacy due to its ability to bind a membrane-proximal epitope, and dissociates from its target at a slower rate compared to rituximab.conventional immunosuppressive therapy with cortecosteroids may be insufficient for disease control and is associated with number of side effects. The humanized Anti CD monoclonal antibody ofatumumab may be alternate drug for patient intolerant to Rituximab(25).
Research gap
Despite the rapid advancement of novel biologic therapies in immune-mediated glomerular diseases, several research gaps remain unresolved. Although targeted agents acting on B cells, plasma cells, and complement pathways have demonstrated promising outcomes, the identification of reliable biomarkers to predict treatment response and guide personalized therapy is still limited. Long-term safety data regarding repeated biologic exposure, including risks of infections, immune suppression, and other adverse effects, require further evaluation. Additionally, evidence from large-scale, long-term, head-to-head clinical trials comparing different biologic agents is insufficient, making it difficult to determine optimal drug selection, dosing strategies, and treatment duration(26). The therapeutic role of biologics in rare and treatment-resistant glomerular disorders remains unclear, and further research is needed to understand disease-specific mechanisms, improve precision medicine approaches, evaluate combination therapies, and determine cost-effectiveness in real-world clinical practice.
Although biological therapies have transformed the management of immune-mediated glomerular diseases by targeting specific immune pathways, several limitations remain in this field. The clinical efficacy of newer biologics, including B-cell–depleting agents, BAFF/APRIL inhibitors, plasma cell–targeted therapies, and complement inhibitors, requires further validation through large-scale randomized controlled trials. There is still insufficient evidence regarding the selection of appropriate patients, optimal timing of initiation, dosing schedules, duration of treatment, and strategies to prevent relapse(19). The heterogeneity of glomerular diseases and variations in underlying immune mechanisms create challenges in predicting therapeutic response. Moreover, long-term safety concerns, including infection risk, immunological complications, and effects of prolonged immune modulation, remain incompletely understood. Limited data are available regarding the use of biologics in rare glomerular disorders, combination approaches with conventional therapies, real-world effectiveness, and cost-effectiveness. Future research should focus on biomarker-guided personalized biologic therapy to improve efficacy while minimizing adverse outcomes(27).
Limitation and safety concern
Delayed response is the main limitation of biological therapy till now. Also there are high non response rate related to Rituximab treatment. Main safety concern include infectious complications,hypoglycaemia , almumenemmia , infusuion related hypersensitivity , neutropenia etc(20). similarly obinutuzumab a type 2 anti CD20 monoclonal antibodies with enhanced cytotoxicity , it causes severe neutropenia . evalizumab and ravulizumab gives warning of meningococcal infections(28).
Biological therapy has emerged as a prospective approach for glomerulonephritis management. Biological therapies involve drugs produced from living organisms or their products intended to focus immunologic mechanisms contributory to glomerulonephritis development and progression(29). Monoclonal antibodies represent one category of biological therapy exhibiting promise for glomerulonephritis management. Monoclonal antibodies comprise laboratory-formulated molecules able to target specific immune proteins. In glomerulonephritis management, monoclonal antibodies can home in on complement system proteins or other immunological elements linked to kidney injury(16). Immunomodulating agents constitute another classification of biological therapy displaying possibility for glomerulonephritis management. Immunomodulating drugs modify the immune system to avert or handle disease. In glomerulonephritis management, immunomodulating drugs can suppress the immune system and inhibit additional harm to the kidneys(18).
FUTURE PERSPECTIVE
There is a huge transition from conventional immunosuppressants to newer biologics which leads to targeted therapy and precision medicine(30). These are mainly based on invention of underlying mechanisms , based on biomarkers in the body. Novel biotherapies emerging towards specific pathway and they left behind the conventional b cell destruction like Rituximab. The different mechanisms involved are complement system inhibition , b cell costimulation blockadgeand dual BAFF/APRIL , specific modulator for IgA nephropathy. Also there are evoloving biotherapies which shields podocyte cells and leads to decreased scarring(31). Progression to ESRD also reduced. By combining all the mechanisms and newer pathway the biologics will make a higher remission rate in patients with glomerular diseases with low toxicities. Focal segmental glomerulosclerosis (FSGS) is not a single disease. Instead, it is a histopathological entity that is the manifestation of a wide range of clinical insults that injure the podocyte, a key structural element in the glomerular filtration barrier(18).
CONCLUSION
Novel biologic therapies have transformed the therapeutic landscape of immune-mediated glomerular diseases by enabling precise targeting of pathogenic immune pathways involved in disease initiation and progression. Agents directed against B cells, BAFF/APRIL signaling, plasma cells, cytokines, and complement pathways have demonstrated encouraging efficacy in conditions such as lupus nephritis, membranous nephropathy, IgA nephropathy, ANCA-associated vasculitis, and other glomerular disorders. Compared with conventional immunosuppressive therapies, biologics offer improved specificity, steroid-sparing benefits, and the potential to reduce treatment-related toxicities while preserving long-term renal function. Nevertheless, important challenges remain, including limited long-term safety data, high treatment costs, delayed therapeutic responses, variable patient outcomes, and the absence of reliable biomarkers for individualized treatment selection. Future advances in precision nephrology, biomarker-guided therapy, and well-designed multicenter clinical trials will be essential to optimize the use of these agents. Ultimately, the integration of novel biologics into personalized treatment strategies holds great promise for improving remission rates, minimizing adverse effects, and enhancing the quality of life of patients with immune-mediated glomerular diseases.
REFERENCES:
Aswathy Devadas, Sajitha G., Novel Biologic Therapies in Immune Mediated Glomerular Diseases; Current Evidences and Future Perspectives, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 7, 1207-1216. https://doi.org/ 10.5281/zenodo.21225620
10.5281/zenodo.21225620