Global perspectives on lupus nephritis: a review of clinical trials and therapeutic innovations.

Introduction

Lupus nephritis (LN) is the most common and severe renal complication associated with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by widespread inflammation and tissue damage ( Figure 1A ). It affects more than 30%-60% of patients with SLE, and renal biopsy reveals evidence of renal involvement in nearly 100% of cases, underscoring the critical role of renal manifestations in the disease progression ( 2 ). Clinical manifestations of renal damage can vary widely among patients, ranging from mild proteinuria and hematuria to severe nephritis, which can lead to renal failure ( 3 , 4 ). Currently, there is no standardized treatment protocol for LN. The primary goals are to control lupus activity, prevent the progression of renal damage, and minimize the side effects associated with drug therapy.

The 2025 update to the EULAR recommendations for managing LN represents a significant refinement of the therapeutic framework ( 5 ). It consolidates a more proactive and goal-oriented strategy, with complete renal remission, defined by specific thresholds of proteinuria and stable renal function, serving as the paramount treatment objective. The standard protocol consists of an induction of remission phase followed by maintenance therapy, with rigorous supportive care integrated throughout ( 6 ). For induction therapy, mycophenolate mofetil (MMF) or low-dose cyclophosphamide (CTX), each combined with glucocorticoids, remains foundational. Notably, the update elevates the role of calcineurin inhibitor-based regimens, particularly the combination of voclosporin with MMF, for high-risk or proliferative disease. Maintenance therapy continues to prioritize MMF or azathioprine, with an emphasis on adequate treatment duration. The guidance also clarifies the additive benefit of belimumab to standard therapy and suggests a broader potential role for rituximab in refractory cases. Throughout, stringent supportive care, including hydroxychloroquine use, blood pressure control, and regular monitoring via renal activity indices, is underscored as integral to management.

However, despite these advances, a significant proportion of patients fail to achieve complete renal response. This review analyzes global clinical trial data since 2000 to evaluate the evolution of treatment strategies, assess the efficacy of emerging targeted therapies, and identify critical unmet needs in LN management.

Methods

To provide a data-driven perspective on the evolution of LN therapy, we conducted a systematic search of global clinical trial registries.

Search strategy and data sources

We queried four major international registries: ClinicalTrials.gov , Chinadrugtrials.org , and the UK’s Clinical Study Registry (ISRCTN), among others. The search was performed for interventional trials registered from January 1, 2001, to 2026. The primary search term used was “lupus nephritis”.

Inclusion and exclusion criteria

Trails were included if they met the following criteria:

Study type: interventional drug trials;

Phase: trials ranging from Phase I to IV.

We excluded:

Observational studies and diagnostic/biomarker validation trials;

Non-pharmacological interventions (e.g., dietary or lifestyle-based studies);

Trials with a status of “Withdrawn” or “Unknown”.

Data extraction and categorization

A total of 200 trials were retrieved and indexed by their unique registration numbers (e.g., NCT, CTR, or ISRCTN). In this analysis, each registration number was treated as an independent entry to reflect the total volume of registered clinical activity, including multi-center extensions or platform-specific registrations. Extracted data included the trials phase, start year, intervention/treatment name, geographic region of the study sites, and LN class (see Table 1 ). To ensure scientific rigor, the therapeutic mechanism of action was cross-referenced using Pharmacodia ( mdata.pharmacodia.com ) and BCPM ( pharma.bcpmdata.com ) databases, with detailed target classifications summarized in Table 2 .

The landscape of clinical trials

Temporal and geographic trends

The early 2000s were characterized by pivotal trials aiming to optimize cytotoxic regimens, establishing MMF and low-dose CTX as standard induction therapies ( 7 , 8 ). Subsequently, the late 2000s and post-2010 era witnessed a paradigm shift towards novel mechanism-based therapies, with a surge in industry-sponsored trials focusing on biologics (e.g., B-cell and T-cell costimulation modulators) and small molecules ( 9 – 11 ). Geographically, while North America and Europe have historically led trial recruitment, there has been a significant shift over the past decade with increasing contributions from the Asia-Pacific region, particularly China. This diversification is crucial, given the well-documented ethnic disparities in LN severity and treatment responses ( 12 ).

Analysis of target populations: the “missing” classes

A critical analysis of the enrolled patient populations reveals a distinct polarization based on histological classification. Consistent with the data in Table 1 , many interventional trials have exclusively recruited patients with active proliferative LN (Class III/IV), with or without co-existing membranous features. This focus is driven by the aggressive clinical course of proliferative nephritis, which offers quantifiable endpoints (e.g., reduction in proteinuria and active sediment) suitable for efficacy assessment.

In contrast, other histological classes remain significantly underrepresented in the clinical trial landscape.

Class I and II (Mesangial LN): Specific interventional trials for these classes are virtually non-existent in our dataset. This gap is likely attributable to their relatively indolent clinical course and subtle pathological features, which typically respond well to background SLE therapy without requiring aggressive renal-specific immunosuppression. However, the lack of data leaves uncertainty regarding the optimal management of low-grade proteinuria in these patients.

Class VI (Advanced Sclerotic LN): Similarly, patients with advanced sclerosis (Class VI) are systematically excluded. The irreversible nature of the renal damage in this group raises ethical challenges for testing novel immunosuppressants, as the therapeutic window for recovering renal function is largely closed. Consequently, management for this subgroup remains focused on renal replacement therapy rather than immunomodulation.

Pure Membranous LN (Class V): While often included as a subset in mixed cohorts (Class III/IV + V), trials specifically designing primary endpoints for “pure” Class V LN are rare (only 3 trials identified in our dataset focused solely on Class V). Given its distinct pathophysiology (podocyte injury vs. inflammation) and slower progression, it may require different therapeutic strategies than proliferative disease.

Evolution of therapeutic mechanisms

To comprehensively evaluate the evolving landscape of drug development, we used data from mdata.pharmacodia.com and pharma.bcpmdata.com to investigate both approved and novel therapeutic agents for LN ( Table 2 ). The survey results reveal a clear paradigm shift from broad-spectrum immunosuppression to precision medicine. As illustrated in Figure 1C , the therapeutic targets have diversified significantly. While traditional protocols relied heavily on non-specific inhibition, the current pipeline focuses on specific immunological pathways, predominantly including B cells (35.3%), cytokines (19.1%), and intracellular signaling pathways (8.8%).

Notably, recent years have witnessed the rise of novel mechanisms such as complement inhibition (13.2%) and immunoproteasome modulation (16.2%), reflecting a deeper understanding of LN pathogenesis beyond simple autoimmunity. Furthermore, the mode of action is evolving; as shown in Figure 1D , most agents exert reversible inhibitory effects (89.71%), allowing for flexible management of immune suppression, whereas irreversible inhibitors (e.g., certain Bruton’s tyrosine kinase inhibitors) represent a smaller but potent niche. This evolution highlights a strategic pivot towards balancing high efficacy with reduced systemic toxicity.

Emerging therapeutic targets and clinical evidence

Based on the mechanistic evolution outlined above, we critically assess the clinical potential of key emerging targets, focusing on those that address the limitations of conventional broad-spectrum immunosuppression.

B-cell directed therapies

CD20 depletion

Historically, the use of rituximab (a chimeric Type I anti-CD20 antibody) in LN was met with disappointment in the pivotal Phase III LUNAR trial, which failed to meet its primary endpoint of superior renal response compared to placebo ( 13 , 14 ). Critics have attributed this failure not to a lack of biological efficacy, as serological improvements were observed, but to limitations in trial design, particularly the confounding effect of high-dose background corticosteroids and incomplete B-cell depletion in tissue niches ( 15 , 16 ).

Addressing these shortcomings, obinutuzumab, a novel humanized Type II anti-CD20 antibody, has recently demonstrated superior efficacy ( 17 ). Unlike rituximab, obinutuzumab is glycoengineered to enhance antibody-dependent cellular cytotoxicity (ADCC) and induce direct cell death, resulting in more profound B-cell depletion ( 18 ). The Phase III REGENCY trial recently reported positive top-line results, meeting its primary endpoint of Complete Renal Response (CRR) at Week 76 ( 19 ). This success validates the hypothesis that deeper and more sustained B-cell depletion is required to translate biological activity into clinical renal remission in LN.

B-cell survival factors (BAFF/APRIL)

While CD20 antibodies target circulating B cells, they spare long-lived plasma cells. Targeting B-cell survival factors offers a complementary approach.

The success of the BLISS-LN trial established belimumab as the first FDA-approved biologic for LN ( 20 , 21 ). In the pivotal Phase III BLISS-LN trial, belimumab significantly improved the Primary Efficacy Renal Response (PERR) rate compared to placebo and reduced the risk of renal-related events or death, with a safety profile comparable to standard therapy alone. Inhibiting B-lymphocyte stimulator (BLyS), it effectively reduces the transition of naive B cells to autoreactive plasma cells ( 22 ). Its inclusion in the 2024 KDIGO guidelines as an add-on therapy underscores its role in enhancing renal response rates and sparing glucocorticoids ( 23 ).

Taking this mechanism a step further, telitacicept (RC18) targets both BLyS and a proliferation-inducing ligand (APRIL) ( 24 ). Since APRIL is crucial for the survival of long-lived plasma cells, which produce autoantibodies, telitacicept theoretically offers broader suppression of the pathogenic humoral response than BLyS inhibition alone. Clinical data from Phase IIb and recent Phase III studies in China have shown promising renal recovery rates and significant reductions in proteinuria, positioning it as a potent alternative for refractory cases ( 25 , 26 ).

The evolution of B-cell therapies highlights a fundamental shift in philosophy. Early trials simply aimed to “remove” B cells, often failing because pathogenic clones persisted in protected tissue niches. The current trend is moving toward “immune reset”. Strategies like obinutuzumab aim for absolute depletion, while emerging CAR-T therapies (discussed in Section 3.4.2) seek to completely purge the immunological memory. However, the next leap forward must address B-cell repopulation: rather than continuous suppression, future trials should investigate how to guide the immune system to repopulate with a “tolerant” B-cell repertoire, potentially through the integration of pharmacogenomic markers such as FCGR3A variants to predict individual response.

Complement inhibition

Complement activation, evidenced by hypocomplementemia and glomerular deposition of C3/C4, is a hallmark of active LN ( 27 ). However, targeting the complement system remains a “double-edged sword”, as excessive inhibition may hinder the clearance of immune complexes and increase infection risks.

Terminal pathway blockade (C5 inhibitors)

Agents like ravulizumab and crovalimab prevent the formation of the membrane attack complex (MAC) (C5b-9) ( 28 – 33 ). While effective in managing LN-associated thrombotic microangiopathy (TMA), blocking the terminal pathway alone may be “too downstream” to fully suppress C3b-mediated opsonization and inflammatory cell recruitment. Critically, the loss of MAC function introduces a persistent risk of encapsulated bacterial infections (e.g., Neisseria meningitidis), necessitating strict vaccination protocols ( 34 ). It’s a significant clinical burden for patients already on complex immunosuppressive regimens.

Alternative pathway blockade (factor B inhibitors)

The oral Factor B inhibitor iptacopan ( NCT05268289 ) offers a more proximal intervention by blocking Factor B and halting the amplification loop of the alternative pathway ( 35 ). This approach theoretically provides superior control over glomerular inflammation compared to terminal blockade alone ( 36 , 37 ). However, the critical concern remains that proximal inhibition more broadly impairs the body’s natural “clearing” mechanism and anti-bacterial defense, potentially magnifying the infection risks seen with terminal blockade ( 38 ). Early classical pathway components (C1q, C4) are protective by facilitating the clearance of apoptotic debris ( 39 ). Current trials often struggle to selectively block the “inflammatory” pathways that damage the kidney, while sparing the “protective” pathways that help the body clear metabolic waste. Future success may hinge on temporally specific modulation rather than continuous broad inhibition.

Intracellular signaling

While biologic agents target cell surface receptors or circulating cytokines, small molecule inhibitors capable of penetrating the cell membrane offer a unique advantage: the ability to block downstream signaling cascades shared by multiple pathogenic receptors.

BTK inhibition: dual targeting of B cells and myeloid cells

Bruton’s tyrosine kinase (BTK) is a critical node in B-cell receptor (BCR) signaling. However, unlike CD20 antibodies that primarily deplete B cells, BTK inhibitors (BTKi) offer a dual mechanism of action ( 40 ). They block BCR signaling in B cells and, crucially, inhibit Fc gamma receptor (FcγR) signaling in myeloid cells (macrophages and monocytes), which are key effectors of renal tissue injury ( 41 , 42 ). Our dataset highlights zanubrutinib, a highly selective second-generation BTK inhibitor, which is currently under evaluation in a Phase II trial for active proliferative LN (CTR20202662). Owing to its optimized molecular structure, zanubrutinib demonstrates greater selectivity for BTK and a reduced off-target toxicity profile compared to first-generation agents such as ibrutinib ( 43 , 44 ). The theoretical advantage of BTKi lies in its potential to suppress autoantibody production while simultaneously dampening the intrarenal inflammatory milieu driven by macrophages ( 45 , 46 ). However, the efficacy signal in SLE/LN has been mixed in the broader class (e.g., failures of other BTKi in SLE phase II trials), suggesting that patient selection based on molecular signatures (e.g., high BTK/myeloid gene expression) may be necessary to unlock their full potential ( 47 – 49 ).

JAK inhibition: broad cytokine blockade

The pathogenesis of LN involves a complex storm of cytokines (Type I Interferons, IL-6, IL-12/23) ( 50 ). Targeting single cytokines often proves insufficient. Janus kinase (JAK) inhibitors can simultaneously interrupt signaling from multiple cytokine receptors, acting as “broad-spectrum” cytokine blockers ( 51 ). As shown in Table 1 , baricitinib (a JAK1/2 inhibitor) has advanced to Phase III clinical evaluation (e.g., NCT05432531 ). Early phase data suggested that baricitinib could significantly reduce proteinuria and improve resolution of renal flares ( 52 ). The oral bioavailability and rapid onset of action make JAK inhibitors attractive options. However, safety concerns, particularly regarding venous thromboembolism (VTE) and herpes zoster reactivation, require vigilant monitoring ( 53 – 55 ). Balancing the depth of immune suppression with infection risk remains the primary challenge for this class in the context of LN.

Novel approaches

Beyond established pathways, the LN pipeline is expanding into highly innovative modalities. These therapies represent high-risk, high-reward strategies targeting the fundamental machinery of autoimmunity and tissue repair.

Immunoproteasome inhibition

The immunoproteasome is highly expressed in immune effector cells and is crucial for cytokine production and plasma cell survival ( 56 ). Unlike broad proteasome inhibitors (e.g., bortezomib), which carry significant toxicity, selective immunoproteasome inhibitors aim to target pathogenic cells while sparing constitutive proteasomes in non-immune tissues ( 57 , 58 ). Our analysis identified zetomipzomib (KZR-616) as a first-in-class selective inhibitor of the immunoproteasome ( NCT03393013 ) ( 59 ). Results from the Phase Ib/II MISSION study demonstrated a favorable safety profile and clinically meaningful reductions in proteinuria and SLEDAI scores in patients with active LN, while avoiding the severe peripheral neuropathy and systemic toxicity associated with bortezomib ( 35 ). Simultaneously targeting cytokine release and plasma cell function, it offers a dual therapeutic effect distinct from standard immunosuppressants.

Chimeric antigen receptor-T cell therapy

The concept of “immune reset” in refractory LN is not entirely new, having been fundamentally established by Hematopoietic Stem Cell Transplantation (HSCT). For decades, HSCT has served as the most extensively studied strategy for systemic immune reconstitution in severe SLE/LN, demonstrating the potential for long-term, drug-free remission through the eradication of autoreactive immunological memory ( 60 ). However, the widespread clinical application of HSCT has been significantly hampered by its high treatment-related toxicity and the risks associated with non-selective lymphodepletion. Modern engineered cellular therapies, led by CAR-T, represent a precision evolution of this “reset” philosophy. By specifically targeting B-cell lineages (e.g., CD19 or BCMA) rather than the entire immune system, CAR-T aims to achieve the profound efficacy of HSCT while significantly mitigating systemic risks, thus marking a transition from broad-spectrum ablation to targeted immune-reconstitution ( 61 ).

Recent entries in the registry highlight the initiation of trials using CD19/BCMA bispecific CAR-T cells (e.g., NCT05030779 ) and fourth-generation CAR-T constructs (e.g., NCT06350110 , initiated in 2024) ( 62 ). While data are preliminary, early case reports suggest that CAR-T therapy can induce drug-free remission in severe, multidrug-resistant LN. However, the risks of cytokine release syndrome (CRS) and neurotoxicity require careful patient selection and specialized management ( 63 ).

Mesenchymal stem cell therapy

Shifting focus from suppression to repair, MSCs offer immunomodulatory and tissue-regenerative properties ( 64 ). Multiple trials in our dataset (e.g., NCT03174587 ) investigate allogenic MSCs derived from bone marrow or umbilical cord ( 65 ). These therapies aim to downregulate autoreactive T/B cells and promote renal tissue repair. While early phases indicate safety, consistent efficacy in large-scale randomized controlled trials (RCTs) remains to be firmly established, with standardization of cell preparation being a key hurdle.

Discussion and future perspectives

Despite the unprecedented expansion of the therapeutic armamentarium over the past two decades, a definitive “cure” for LN remains elusive. Our review of the global trial landscape reveals a paradox: while the number of targeted agents has surged, the “ceiling” of complete renal response (CRR) in pivotal Phase III trials remains stubbornly around 40-50% at one year ( 21 , 66 , 67 ). This stagnation suggests that simply adding more immunosuppressants to current protocols may yield diminishing returns. Based on the evidence synthesized, we propose three priority areas for future research.

Current trials largely treat active LN as a homogeneous entity, recruiting “all-comers” with proliferative histology. However, LN is biologically heterogeneous. For instance, a patient driven by a Type I Interferon signature (responsive to anifrolumab) may differ fundamentally from one driven by B-cell selection survival (responsive to belimumab/telitacicept) ( 68 ). Future trials must move beyond histological classification. We advocate for the integration of liquid biopsy (e.g., urine proteomics) and molecular stratification into trial inclusion criteria ( 69 ). For example, trials for BTK inhibitors could stratify patients based on myeloid signature expression ( 42 ). Only by matching the drug’s mechanism to the patient’s specific immunopathology can we break the 50% response barrier.

Most trials analyzed in this review employed an “add-on” design (Standard of Care + Experimental Drug vs. Standard of Care + Placebo). While ethical, this design often masks the efficacy of the novel agent due to the high potency of background high-dose corticosteroids and MMF. The failure of several biologically potent agents (e.g., ocrelizumab, abatacept) in LN may partly be attributed to this “noise”. The success of the recent voclosporin and belimumab trials, which enforced stricter steroid tapering, points the way forward. Future designs should prioritize superiority trials with rapid steroid withdrawal or even head-to-head comparisons against MMF, rather than simply piling new drugs on top of toxic backbones.

Proteinuria, the traditional primary endpoint, is a lagging indicator of renal inflammation. Persistent proteinuria can reflect chronic damage rather than active disease, potentially leading to overtreatment. Conversely, histological activity can persist despite clinical remission. There is an urgent need to validate non-invasive biomarkers (e.g., urinary CD163, ALCAM) as surrogate endpoints that can read out renal inflammation in real-time. Furthermore, as “drug-free remission” becomes a tangible goal with therapies like CAR-T, future trials must incorporate long-term follow-up (3–5 years) to assess not just response induction, but the durability of tolerance and the prevention of end-stage kidney disease (ESKD).

Beyond clinical and histological stratification, the integration of pharmacogenomics is essential for a truly precise approach to LN management. Genetic variations in drug-metabolizing enzymes and immune receptors significantly influence both therapeutic efficacy and systemic toxicity. For instance, screening for TPMT and NUDT15 polymorphisms is increasingly recognized as a clinical imperative to prevent severe bone marrow suppression in patients receiving azathioprine ( 70 , 71 ). Similarly, the metabolism of calcineurin inhibitors (CNIs), such as tacrolimus and the recently approved voclosporin, is heavily dictated by CYP3A5 genotypes, where “rapid metabolizers” may fail to reach therapeutic troughs despite standard dosing ( 72 ). Furthermore, polymorphisms in the FCGR3A gene, which encodes the FcγRIIIa receptor on effector cells, may modulate the intensity of antibody-dependent cellular cytotoxicity (ADCC), potentially explaining the heterogenous clinical response to B-cell depleting agents like rituximab and obinutuzumab ( 73 , 74 ). Identifying these single nucleotide polymorphisms (SNPs) before therapy initiation offers a transformative pathway to minimize trial-and-error prescribing and the “ceiling effects” currently observed in LN clinical trials.

The last 20 years of clinical trials have transformed LN from a disease managed by blunt immunosuppression to one treated with increasing precision. The approvals of belimumab and voclosporin mark the beginning of this new era. However, the next leap forward will not come from merely discovering new targets, but from revolutionizing how we select patients and design trials. By embracing precision medicine and prioritizing steroid-free remission, the next decade holds the promise of altering the natural history of this devastating disease.

Edited by: Charalampos Skarlis , University of Nicosia, Greece

Reviewed by: Arriel Makembi Bunkete , Centre Hospitalier de l’Ouest Guyanais, French Guiana

Faisal Parlindungan , University of Indonesia, Indonesia

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Author contributions

JX: Conceptualization, Writing – original draft, Data curation, Resources, Visualization. YZ: Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing. HH: Methodology, Visualization, Writing – original draft. YC: Data curation, Funding acquisition, Supervision, Writing – review & editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The author(s) declared that generative AI was not used in the creation of this manuscript.

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