Lupus nephritis and kidney transplantation: A narrative review of patient and graft outcomes

Abstract

Lupus nephritis (LN), a serious manifestation of systemic lupus erythematosus, continues to be a major cause of morbidity and mortality. Despite significant advances in immunosuppressive therapy, many patients progress to end-stage kidney disease (ESKD), for which kidney transplantation (KT) remains the treatment of choice. However, the survival advantage of KT in LN-related ESKD is not yet clearly defined. This narrative review synthesizes current guidelines and recent evidence to address the distinctive challenges of transplantation in patients with autoimmune conditions such as LN, particularly regarding the optimal timing of KT. While existing recommendations emphasize achieving disease quiescence prior to transplantation, emerging data support the benefits of preemptive KT and individualized immunosuppressive regimens in improving both patient and graft outcomes. Advances in immunosuppressive therapies, including newly approved agents such as voclosporin and belimumab, have further enhanced LN management. In addition, novel biomarkers such as urinary monocyte chemoattractant protein-1, B-cell activating factor and matrix metalloproteinase-7 show promise for monitoring disease activity and predicting post-transplant recurrence risk. A comprehensive appraisal of guidelines and contemporary studies is essential to refine management strategies and optimize long-term outcomes for patients with LN undergoing KT.

Key Words: End-stage kidney disease; Graft survival; Immunosuppressive therapy; Kidney transplantation; Lupus nephritis; Outcomes

Core Tip: Kidney transplantation is the preferred treatment for lupus nephritis progressing to end-stage kidney disease, though its survival benefit in lupus nephritis end-stage kidney disease remains uncertain. Achieving disease quiescence before transplantation is critical, yet emerging evidence supports preemptive transplantation and personalized immunosuppressive regimens to enhance outcomes. New therapies such as voclosporin and belimumab, together with biomarkers like urinary monocyte chemoattractant protein-1, matrix metalloproteinase-7, and B-cell activating factor, show promise for improving patient selection, monitoring disease activity, and predicting recurrence. Careful integration of updated guidelines and recent evidence is essential to optimize both patient and graft survival.

INTRODUCTION

Systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disorder that primarily affects women of childbearing age[1,2]. Its variable clinical course, ranging from mild to life-threatening, presents major challenges for clinicians. Lupus nephritis (LN), one of the most severe complications of SLE, occurs in 40%-50% of patients[3,4] and represents the most common form of secondary glomerular disease[5]. In nearly one-third of cases, LN is the initial manifestation leading to an SLE diagnosis[6]. Despite advances in therapy, 10%-30% of patients progress to end-stage kidney disease (ESKD) within 15 years of their LN diagnosis[7,8].

Kidney transplantation (KT) is an effective treatment for LN-related ESKD[9]. Some studies report graft and patient survival rates comparable to those with ESKD from other causes, whereas others highlight increased risks of rejection, graft loss, and mortality[10-13]. For example, a review and meta-analysis by Kim et al[14], which included 17 studies, found similar 1- and 5-year graft survival between LN and non-LN recipients, suggesting that short-term outcomes may be comparable. In contrast, a recent systematic review and meta-analysis by Jiang et al[15] in 2024, encompassing 15 studies, demonstrated that longer-term outcomes diverge, with LN patients experiencing significantly worse results: A higher risk of graft loss [hazard ratio (HR): 1.06, 95% confidence interval (CI): 1.01-1.11] and lower patient survival (HR: 1.15, 95%CI: 1.01-1.31) compared with non-LN counterparts. This suggests that while early post-transplant survival may be reassuring, the long-term trajectory is less favorable for LN recipients. These findings underscore the complex interplay between lupus-related immune dysregulation and post-transplant immunosuppression, which complicates management in this population. Although advances in therapies and surgical techniques have improved overall outcomes, LN recipients remain at increased risk for adverse events, necessitating tailored strategies to optimize long-term survival.

This narrative review explores the current evidence on KT in LN, focusing on immunological challenges, graft survival trends, and the influence of transplant timing, disease recurrence, and immunosuppressive regimens. It also identifies gaps in existing research and emphasizes the need for long-term, multi-center studies to optimize care in this high-risk population.

LITERATURE SEARCH

This study was conducted as a narrative mini-review. A comprehensive literature search was carried out using electronic databases, including PubMed, MEDLINE, Scopus, and Web of Science. The search covered publications from January 1990 to May 2025 to incorporate both foundational and recent studies. A wide range of keywords and Medical Subject Headings terms were used to identify relevant literature, such as “Systemic lupus erythematosus”, “Lupus nephritis”, “pathophysiology”, “chronic kidney disease”, “end-stage kidney disease”, “Kidney transplantation”, “Preemptive Kidney Transplantation”, “Optimal Timing of Kidney Transplantation”, “Monitoring Disease Quiescence and Flare Risk”, “Key Indicators for Transplant Matching”, “updated management”, “kidney biopsy”, “Antiphospholipid antibodies”, “Immunosuppressive Agents”, and “ outcomes following transplantation”. Boolean operators (AND, OR) were applied strategically to refine and optimize the search results.

Inclusion criteria were: (1) Peer-reviewed original research articles, systematic reviews, or meta-analyses; (2) Studies involving human subjects who underwent KT; (3) Publications addressing the pathophysiology, diagnosis, biomarkers, or patient and graft outcomes following KT in LN; and (4) Articles published in English. Exclusion criteria were: (1) Conference abstracts without full text, case reports with insufficient detail, editorials, and commentaries; and (2) Studies focusing solely on non-renal organ transplantation without relevant kidney transplant data.

Two reviewers independently screened titles and abstracts to identify potentially relevant studies, followed by a full-text review (Figure 1). Any discrepancies were resolved through discussion or, when necessary, consultation with a third reviewer. The reference lists of all included studies were manually searched to identify additional eligible articles. Data extraction was performed to synthesize evidence for this descriptive review, focusing on study design, population characteristics, diagnostic criteria, interventions, outcomes, and key findings. The methodological quality of included studies was not formally appraised, consistent with the narrative review design.

Figure 1  Flow diagram showing study methodology for selecting the articles for inclusion in the study.

EPIDEMIOLOGY OF LN

The incidence and prevalence of SLE and LN vary across populations and genders, with notably higher rates among certain ethnic groups[3]. Globally, the incidence of SLE is estimated at 5.14 per 100000 person-years, while the prevalence is approximately 43.7 per 100000 individuals, affecting an estimated 3.41 million people. Despite this burden, epidemiological data on SLE remain unavailable for nearly 79.8% of countries[16]. LN occurs more frequently in Hispanic (49.3%), African American (39.9%), and Asian (36.8%) patients, compared with only 20.3% of Caucasians[17]. In North America, Black patients are at a disproportionately higher risk of progressing to ESKD compared with other ethnic groups[18]. These disparities underscore the complex interplay between genetic predisposition and socioeconomic factors in disease progression. SLE is more common in women, particularly those of reproductive age, with a female-to-male ratio of approximately 9:1. Interestingly, during the first decade of life, males are at relatively higher risk, with a female-to-male ratio of 4:3 in the prepubertal period[19]. The incidence of ESKD in high-income countries declined significantly from the 1970s to the mid-1990s and has since stabilized[8]. Conversely, poverty remains a major risk factor for LN progression, independent of race or ethnicity, and contributes substantially to the global burden of chronic kidney disease due to limited access to early diagnosis and treatment[20].

PATHOGENESIS OF LN

The pathogenesis of LN is complex and multifactorial, involving both extra-renal and intra-renal mechanisms. It arises from a combination of genetic predisposition, environmental triggers, and hormonal influences[21]. Environmental factors such as ultraviolet light exposure and infectious agents can initiate autoimmune activity in genetically susceptible individuals. Genetic variations, including polymorphisms, further disrupt immune regulation. Hormonal influences most notably estrogen, play a significant role, as evidenced by the markedly higher incidence of SLE in women. This intricate interplay drives immune dysregulation, leading to widespread inflammation and organ-specific manifestations such as LN[22]. The central pathogenic process is characterized by the deposition of immune complexes within renal tissue, activation of autoreactive B and T lymphocytes, and prominent involvement of non-classical complement pathways[21]. Activation of these alternative complement cascades amplifies kidney injury, contributing to the progressive nature of LN.

PATHOPHYSIOLOGY OF LN

A defining feature of SLE is the production of autoantibodies, particularly anti-double-stranded DNA (anti-dsDNA) antibodies, which form circulating immune complexes. These complexes preferentially deposit in renal tissues, especially within the glomeruli, triggering a cascade of inflammatory events. Once deposited, immune complexes activate the complement system, leading to recruitment of inflammatory cells and amplification of tissue injury. Clinically, this process manifests as hypocomplementemia, with reduced serum levels of C3 and C4 serving as biomarkers of active disease. Immune complex deposition in the glomeruli initiates mesangial proliferation (expansion of mesangial cells and matrix), endothelial injury (disruption of capillary lumina and impaired filtration), and podocyte damage (loss of slit diaphragm integrity, resulting in proteinuria). These pathological changes present clinically as hematuria, proteinuria, and progressive kidney dysfunction. Beyond immune complex-mediated injury, cytokine dysregulation plays a critical role. Elevated levels of interferon-α, interleukin-6 (IL-6), and B-cell activating factor perpetuate B-cell hyperactivity, sustaining autoantibody production and chronic inflammation. This maladaptive immune response establishes a vicious cycle of ongoing renal injury[23].

Kidney biopsy remains the gold standard for diagnosis, providing histological confirmation and guiding therapeutic decisions. The International Society of Nephrology/Renal Pathology Society classification, revised in 2018, stratifies LN into six distinct classes based on the distribution and severity of immune complex deposition and inflammatory changes, ranging from mild mesangial involvement (class I) to advanced sclerosing nephritis (class VI)[24]. The 2018 revision emphasized the importance of activity and chronicity indices, distinguishing active inflammation (potentially reversible with therapy) from chronic damage (irreversible scarring). It also underscored the prognostic significance of segmental vs global lesions, as well as tubulointerstitial and vascular involvement, which are now recognized as critical determinants of long-term kidney outcomes. A large study validated this new classification in a Chinese population in 2020, showing that fibrous crescents, tubular atrophy/interstitial fibrosis and this chronicity index reliably predicted a composite renal outcome[25]. Table 1 summarizes the classification, updates from the 2018 revision, and their clinical implications.

Table 1 International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis (2018 revision) and its clinical implications.

Class	Key histological features	2018 revision updates	Clinical implications
Class I	Minimal mesangial LN; immune complex deposition confined to mesangium	Emphasis on subtle mesangial deposits	Usually asymptomatic; normal urinalysis; excellent prognosis
Class II	Mesangial proliferative LN; mesangial hypercellularity and matrix expansion	Clarified distinction between mesangial hypercellularity vs deposits only	Mild disease; hematuria/proteinuria; generally favorable outcomes
Class III	Focal LN; < 50% of glomeruli affected with segmental/global endocapillary or extracapillary proliferation	Activity/chronicity indices introduced; segmental vs global lesions highlighted	Variable course; risk of progression; requires immunosuppression
Class IV	Diffuse LN; ≥ 50% of glomeruli affected; extensive endocapillary/extracapillary proliferation	Activity/chronicity scoring; segmental vs global lesions emphasized	Most severe and common form; high risk of renal failure; aggressive therapy needed
Class V	Membranous LN; diffuse thickening of glomerular capillary walls due to subepithelial deposits	Recognition of mixed class V + III/IV lesions	Presents with nephrotic syndrome; risk of progression if mixed lesions present
Class VI	Advanced sclerosing LN; ≥ 90% of glomeruli globally sclerosed	Highlighted as irreversible stage	Poor prognosis; progression to ESKD; supportive care or renal replacement therapy

LN: Lupus nephritis; ESKD: End-stage kidney disease.

Prognostic limitations and therapeutic transition in LN

Despite advances in immunosuppressive therapy, the long-term prognosis of LN has remained largely unchanged since the early 2000s[8]. A major clinical challenge is progression to ESKD, which necessitates kidney replacement therapy, typically beginning with dialysis and, when feasible, followed by KT. This highlights the persistent burden of LN and the limitations of current treatments in preventing irreversible kidney damage. Once ESKD develops, dialysis serves as a stabilizing measure, but KT offers superior survival and quality of life compared to dialysis alone, making it the preferred long-term option for eligible patients[26,27]. Determining the optimal timing for transplantation is complex and requires careful consideration of disease trajectory, systemic involvement, and overall health status. Factors such as immunologic activity, comorbidities, and prior treatment response must be weighed to maximize outcomes.

Lupus activity in ESKD

The onset of ESKD in many patients often leads to partial or complete resolution of extrarenal manifestations of SLE[28-30]. One review reported that active clinical SLE (such as arthritis, rash, or serositis) decreased from 55% at the initiation of dialysis to 6.5% after five years, and in some cases disappeared entirely after ten years[31]. Similarly, serologic activity (abnormal antinuclear antibody, anti-dsDNA, 50% hemolytic complement, or complement 3) declined from 80% to 22% over the same period, possibly reflecting immune system changes associated with prolonged ESKD. Most patients with persistent disease exhibit only mild to moderate symptoms. For example, severe extrarenal activity (defined by a SLE Disease Activity Index > 10) decreased from 17 cases at dialysis initiation to 3, and none after transplantation[32]. However, some studies suggest that lupus quiescence in ESKD may be overstated, noting that up to one-quarter of dialysis patients continue to experience manifestations such as alopecia, arthritis, myositis, pleuritis, pericarditis, fever, cytopenias, and vasculitis[33,34]. Variations in patient populations and the examining physician’s specialty may account for these conflicting observations.

PRE-TRANSPLANT EVALUATION

Optimal timing of KT in LN patients

Patients with LN-related ESKD generally achieve favorable outcomes with KT, but timing depends on achieving disease quiescence to reduce peri-transplant complications and recurrence risk.

Monitoring disease quiescence and flare risk in LN

Quiescence in LN is generally defined as a state of clinical and serological stability lasting at least six months. However, no universally accepted definition exists, and criteria vary across studies and guidelines. Beyond traditional serum markers, urinary biomarkers extending beyond proteinuria such as monocyte chemoattractant protein-1, B-cell activating factor and matrix metalloproteinase-7 are increasingly recognized for their ability to provide a more comprehensive assessment of LN activity[35-38]. Commonly used markers include dsDNA antibodies, serum creatinine, and complement components C3 and C4. Yet, these markers often lack specificity and sensitivity, particularly following immunosuppressive therapy[39]. To address these limitations, additional markers such as anti-complement component C1q, anti-chromatin, anti-Smith, anti-ribosomal P autoantibodies, and serum type I interferon levels have been linked to disease activity, with significant reductions observed in patients achieving remission[40,41]. Transcriptomic changes in kidney biopsies, especially among patients resistant to conventional therapies, have also been associated with more severe disease courses. Achieving quiescence or remission prior to KT requires normalization or stabilization of clinical and serological markers, proteinuria levels below 0.5 g/24 hours (or < 300 mg/m²/day), and the absence of active inflammation on biopsy characterized by minimal immune deposits and quiescent glomerular changes. Both the Kidney Disease: Improving Global Outcomes (KDIGO) 2024 and European Renal Association-European Dialysis and Transplant Association 2019 guidelines emphasize the importance of achieving disease quiescence before transplantation to reduce recurrence risk[42,43]. Table 2 summarizes the clinical, serological, urinary, and histological markers of LN, highlighting their relevance for disease activity and clinical outcomes.

Table 2 Markers of disease activity in lupus nephritis.

Marker	Type	Significance for disease activity	Clinical implications
Anti-dsDNA antibodies	Serological	Correlate with disease activity and renal involvement	Rising titers often precede LN flares; useful for monitoring
Serum creatinine	Clinical	Reflects renal function and progression	Elevated levels indicate impaired kidney function and possible ESKD
Complement C3 and C4	Serological	Low levels indicate complement consumption due to active immune complex disease	Hypocomplementemia is a marker of active LN and flare risk
Anti-C1q antibodies	Serological	Associated with immune complex deposition and LN activity	Predictive of renal involvement and poor prognosis
Anti-chromatin antibodies	Serological	Linked to active nephritis and systemic disease	May serve as adjunct marker for LN activity
Anti-Sm antibodies	Serological	Specific for SLE, associated with severe disease	Presence indicates higher risk of multi-organ involvement
Anti-ribosomal P autoantibodies	Serological	Associated with neuropsychiatric lupus and systemic activity	May complicate LN with extra-renal manifestations
Serum IFN-I	Serological	Reflects immune dysregulation and ongoing inflammation	Elevated levels linked to refractory disease and poor outcomes
MCP-1	Urinary	Marker of renal inflammation and monocyte recruitment	Elevated levels predict LN activity and progression
BAFF	Urinary	Promotes B-cell survival and autoantibody production	High levels associated with LN activity and relapse risk
MMP-7	Urinary	Reflects tissue remodeling and renal injury	Elevated levels linked to chronic damage and poor prognosis
IgG, IgA, IgM deposits	Histological (biopsy)	Indicate immune complex-mediated glomerular injury	Presence confirms LN diagnosis and activity
C1q, C3 deposits	Histological (biopsy)	Evidence of complement activation in renal tissue	Associated with active LN and severity of disease
Tissue ANA	Histological (biopsy)	Nuclear antigen deposition in kidney tissue	Supports diagnosis of LN and immune-mediated injury
Extraglomerular immune deposits	Histological (biopsy)	Indicate widespread immune complex deposition	Associated with severe LN and poor prognosis
Endothelial tubular reticulum inclusion bodies	Histological (biopsy)	Reflect interferon activity and immune activation	Linked to active LN and systemic disease burden

Anti-dsDNA: Anti-double-stranded deoxyribonucleic acid; LN: Lupus nephritis; ESKD: End-stage kidney disease; anti-C1q: Anti-complement component 1q; anti-Sm: Anti-Smith; SLE: Systemic lupus erythematosus; IFN-I: Type I interferon; MCP-1: Monocyte chemoattractant protein-1; BAFF: B-cell activating factor; MMP-7: Matrix metalloproteinase-7; Ig: Immunoglobulin; C3: Complement component 3; C1q: Complement component 1q; ANA: Antinuclear antibody.

Preemptive KT

Preemptive KT (PKT), performed before the initiation of long-term dialysis, is associated with improved patient and graft survival[44]. By minimizing dialysis exposure, this approach reduces cardiovascular morbidity, infection risk, and dialysisrelated complications, thereby enhancing long-term survival and quality of life. More recent evidence from Contreras et al[43] demonstrated that PKT utilization steadily increased between 1985 and 2019 among patients with LN and other primary kidney diseases. In lupus recipients, PKT rates rose from 3.02% to 4.65% (P = 0.001). Importantly, the incidence of kidney allograft failure per 100 patient-years remained comparably low in lupus recipients (4.40), and all-cause mortality rates were similarly favorable. Furthermore, lupus patients undergoing PKT exhibited a lower risk of kidney allograft failure and mortality compared with recipients transplanted for other primary kidney diseases[45].

Multidisciplinary collaboration between nephrologists and rheumatologists is essential for assessing disease activity, immunological markers (e.g., anti-dsDNA, complement levels), and overall patient health. Shared decision-making ensures that reduced dialysis exposure is balanced against risks from residual disease activity or comorbidities. Patient concerns regarding surgical risks, lifelong immunosuppression, and complications such as infection or malignancy must also be addressed. Cultural, psychological, and socioeconomic factors further influence attitudes toward transplantation, underscoring the importance of patient education and counseling[46].

Impact of dialysis duration before transplantation

Dialysis vintage significantly influences outcomes in LN-related ESKD. Evidence suggests that shorter dialysis exposure or preemptive transplantation is associated with improved survival and graft function, whereas prolonged waiting time - particularly during dialysis - is linked to poorer graft outcomes after transplantation, increased cardiovascular morbidity, higher infection risk, and reduced quality of life[46]. For example, in an analysis of 4743 patients with ESKD secondary to LN, White recipients who underwent transplantation after a longer dialysis duration, compared with those transplanted within three months, demonstrated a trend toward a higher risk of graft failure (adjusted HR: 1.23, 95%CI: 0.93-1.63)[47]. Notably, this association was not observed among African American recipients. Furthermore, Ntatsaki et al[48] reported that longer pre-transplant dialysis duration was associated with poorer survival, underscoring the importance of minimizing dialysis exposure.

Balancing disease quiescence and dialysis exposure

Transplant timing in LN hinges on achieving disease remission. Many experts recommend at least 6 months of quiescence, with some preferring 12 months without flares or serologic activity (stable/Low anti-dsDNA, normal complement) before listing for KT. Transplantation should be deferred in cases of active extra-renal SLE (e.g., vasculitis, serositis, central nervous system involvement) or ongoing high-dose immunosuppressive therapy. However, extending dialysis beyond this period does not improve outcomes and instead increases complications. A 40-year retrospective study showed that each additional month on dialysis prior to KT increased mortality risk, with survival particularly affected when dialysis exceeded 24 months[48]. Thus, optimal timing requires balancing the need for disease remission against the risks of prolonged dialysis exposure.

Determinants and key indicators for transplant matching in LN

Successful donor-recipient matching in LN necessitates a thorough assessment of both human leukocyte antigen (HLA) and non-HLA immunological parameters, disease activity, and individualized clinical considerations. Critical determinants include HLA compatibility particularly at the HLA-DR and HLA-C loci - and the presence of donor-specific antibodies, which are strong predictors of rejection risk[49,50]. Modern crossmatch methodologies, such as flow cytometry crossmatch[51], combined with high-resolution HLA typing[52], offer superior sensitivity and accuracy compared with the traditional complement-dependent cytotoxicity crossmatch. However, complement-dependent cytotoxicity crossmatch may produce false-positive results in patients with autoimmune conditions due to factors such as non-specific donor lymphocyte binding, the prozone effect, incomplete donor typing, and interference from non-HLA antibodies[53]. To enhance specificity, pronase digestion is frequently incorporated into flow cytometry crossmatch, as it removes Fc receptors from the cell surface, thereby improving the reliability of B-cell crossmatching[54]. Non-HLA antibodies including major histocompatibility complex class I chain-related molecule A, angiotensin II type 1 receptor, endothelin type A receptor antibody, vimentin antibody, anti-endothelial cell antibodies, poikilodulin, myocardin, microtubulin antibody (anti-Ka1 tubulin), and collagen antibodies, also contribute significantly to graft loss through immune-mediated injury and fibrosis[55]. Beyond immunological profiling, evaluation of disease quiescence, comorbidities, and donor characteristics remains essential, with living donors generally associated with superior outcomes[15]. Collectively, these determinants establish a structured framework for optimizing transplant success and minimizing rejection risk in LN patients, as outlined in Table 3.

Table 3 Determinants and key indicators for transplant matching in lupus nephritis and its clinical implications.

Indicator	Type	Significance	Implications in LN
HLA matching	Genetic/immunological	Cornerstone of transplant success; closer matching reduces rejection and improves graft survival	Mismatches, especially at HLA-DR and HLA-C loci, increase rejection risk; careful prioritization of typing is critical
PRA and DSA	Immunological	Elevated PRA and DSAs indicate heightened sensitization from transfusions, pregnancies, or disease activity	High titers are strongly associated with graft rejection, including hyperacute rejection; pre-transplant interventions (plasma exchange, IVIG, rituximab, proteasome inhibitors) can reduce risk
Disease quiescence and serological activity	Clinical/serological	Active disease increases recurrence and systemic complications	Anti-dsDNA, complement (C3, C4), and anti-C1q must be monitored to confirm remission before transplantation
CDC-XM	Laboratory test	Detects HLA and non-HLA antibodies but is prone to false positives in autoimmune patients	May misinterpret sensitization due to non-specific binding, prozone effect, incomplete typing, or non-HLA antibodies
FCXM	Laboratory test	More sensitive than CDC; detects pre-formed antibodies against donor lymphocytes	Preferred method; pronase digestion enhances the accuracy of B-cell cross-matching
High-Resolution HLA typing (sequencing-based)	Genetic/Laboratory	Provides precise identification of donor-specific HLA antibodies	Improves matching accuracy; limited feasibility in deceased donor transplantation due to time constraints
Non-HLA Antibodies (MICA, AT1R, poikilodulin, myocardin, microtubulin, collagen)	Immunological	Account for approximately 38% of graft losses vs 18% from HLA mismatches	Contribute to fibrosis, immune modulation, and graft failure; must be considered in risk stratification
Crossmatch testing (general)	Laboratory test	Negative crossmatch essential to prevent hyperacute rejection	Provides safeguard against unforeseen immunological incompatibilities in autoimmune background
Comorbid conditions and systemic involvement	Clinical	LN often coexists with cardiovascular disease, neuropsychiatric lupus, or vasculitis	Extra-renal involvement must be controlled before transplantation to avoid poor outcomes
Donor characteristics	Clinical	Donor age, health, and source (living vs deceased) influence graft survival	Living donor transplantation is preferred; it allows better timing, reduces dialysis exposure, and improves prognosis
Immunological risk stratification	Clinical/immunological	Helps tailor immunosuppressive regimens post-transplant	LN recipients require vigilant balancing to prevent rejection and recurrence while minimizing infection/malignancy risks

LN: Lupus nephritis; HLA: Human Leukocyte Antigen; PRA: Panel reactive antibody; DSAs: Donor-specific antibodies; IVIG: Intravenous immunoglobulin; Anti-dsDNA: Anti-double-stranded deoxyribonucleic acid; anti-C1q: Anti-complement component 1q; C3: Complement component 3; C4: Complement component 4; CDC-XM: Complement-dependent cytotoxicity crossmatch; FCXM: Flow cytometry crossmatch; CDC: Complement-dependent cytotoxicity; MICA: Major histocompatibility complex class I chain-related molecule A; AT1R: Angiotensin II type 1 receptor.

Antiphospholipid antibodies in LN and transplantation

Antiphospholipid antibodies (aPL) are present in up to 40 percent of individuals with SLE[56], though progression to overt antiphospholipid syndrome (APS) is considerably less frequent. Nevertheless, the coexistence of aPL in SLE confers a heightened risk of thrombotic complications, including the occurrence of thrombotic microangiopathy within the renal allograft[57-59]. Consequently, universal screening for aPL is recommended prior to KT. Patients who meet criteria for APS should be managed with long-term anticoagulation. In contrast, the optimal therapeutic approach for aPL-positive patients without a prior thrombotic history remains uncertain, and practices differ across transplant centers. Some institutions adopt a prophylactic strategy by initiating low-dose aspirin (81 mg daily), while others rely on individualized risk assessment. Evidence from several studies suggests that oral vitamin K antagonists may reduce the incidence of allograft thrombosis in aPL-positive recipients[57,58]. Importantly, the decision to initiate anticoagulation must balance the protective benefits against thrombotic events with the potential hazards of bleeding, underscoring the need for patient-specific tailoring of therapy. The role of sirolimus in mitigating recurrent coagulation or preventing graft loss in this subset of lupus patients remains unclear, with current data insufficient to support routine use[60].

PRE-TRANSPLANT MEDICATION IN LN

Pre-transplant management in patients with LN aims to achieve sustained disease remission, optimize immunosuppressive therapy, and minimize risks prior to KT. Therapeutic regimens typically incorporate immunosuppressive, antimetabolic, and biologic agents to induce and maintain remission, stabilize kidney function, and prepare patients for the heightened immunosuppressive burden required after transplantation.

Immunosuppressive agents

Immunosuppressive drugs form the cornerstone of induction therapy in LN. Cyclophosphamide (CYC), an alkylating agent, in combination with corticosteroids such as prednisolone, has historically been the standard approach for proliferative LN. The National Institutes of Health regimen of high-dose intravenous CYC demonstrated efficacy in reducing renal flares; however, its toxicity profile including ovarian failure, infection risk, and malignancy prompted investigation into lower-dose strategies[61]. The Euro-LN trial[62] established that low-dose IV CYC (500 mg every two weeks for six doses) was equally effective in achieving remission, with fewer adverse events, and is now widely adopted. Calcineurin inhibitors (CNIs) such as tacrolimus and cyclosporine have also shown benefit, particularly in resistant LN. The multitarget therapy trial[63] demonstrated that a regimen combining tacrolimus, mycophenolate mofetil (MMF), and steroids was superior to IV CYC in inducing remission among Chinese patients, underscoring the role of CNIs in combination therapy.

More recently, voclosporin, a novel CNI, received approval in 2021[64]. Pharmacologically, voclosporin enhances podocyte stability and reduces proteinuria while offering fixed dosing without routine trough-level monitoring, though it remains subject to cytochrome P-450 3A4-mediated drug interactions and requires surveillance for CNI-related adverse effects[65]. The AURORA-1 trial[66] confirmed that voclosporin combined with MMF and steroids significantly improved renal response rates compared with placebo, with an acceptable safety profile. In a phase 2 study of KT recipients, voclosporin showed comparable efficacy to tacrolimus in reducing acute rejection, but with a markedly lower incidence of new-onset diabetes (1.6% vs 16.4%)[67].

Antimetabolic agents

Antimetabolites are central to both induction and maintenance therapy. MMF has become the preferred agent in many centers due to its favorable safety profile and comparable efficacy to CYC. The Aspreva Lupus Management Study Induction trial[68] compared MMF with IV CYC and found MMF to be non-inferior, with better tolerability and fewer discontinuations. For maintenance therapy, the Aspreva Lupus Management Study Maintenance trial[69] showed that MMF was superior to azathioprine (AZA) in preventing treatment failure and relapse. AZA, however, remains an important option, particularly in women planning pregnancy, as MMF is teratogenic. While less potent, AZA is safer in reproductive settings and continues to be used in maintenance regimens. Methotrexate is rarely used in LN due to nephrotoxicity risk and is not considered standard in transplant preparation.

Hydroxychloroquine (HCQ) remains a fundamental therapy in the management of SLE and LN, owing to its immunomodulatory, anti-inflammatory, and antithrombotic properties[70]. Determining the optimal dosage of HCQ in patients with advanced LN, particularly those with impaired kidney function, continues to be a subject of ongoing discussion. Current guidelines recommend reducing the HCQ dose by 50% in individuals with a glomerular filtration rate below 30 mL/minute to minimize the risk of toxicity[43]. However, several studies argue in favor of maintaining standard dosing, highlighting the drug’s protective role in slowing disease progression[71].

Biologic agents

Biologic therapies have emerged as valuable options in refractory LN, targeting specific immune pathways while reducing adverse effects, and are increasingly incorporated into pre-transplant regimens. IL-2 plays a pivotal role in immune tolerance by promoting regulatory T-cell proliferation and function. Low-dose IL-2 therapy has been shown to restore Treg activity and ameliorate disease manifestations in SLE[72]. Agents targeting B-cell activity such as rituximab, belimumab, and obinutuzumab have also demonstrated efficacy. Rituximab, an anti-CD20 monoclonal antibody, is used off-label in patients unresponsive to conventional therapy. The LN assessment with rituximab trial[73] compared rituximab plus MMF with MMF alone; although primary endpoints were not met, rituximab improved serological markers and remains a rescue option in refractory LN. The KDIGO 2024 guidelines recommend considering rituximab in patients with inadequate response to initial therapy[42]. Belimumab, an anti-B lymphocyte stimulator monoclonal antibody, became the first biologic approved for LN in 2020. The BLISS-LN trial[74] demonstrated that belimumab added to standard therapy significantly improved renal response compared with standard therapy alone. Subsequent studies confirmed its ability to reduce LN flares and slow epidermal growth factor receptor decline[75,76]. Accordingly, KDIGO 2024 guidelines endorse belimumab as an adjunct to standard immunosuppressive therapy in active LN[42]. Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody engineered for enhanced B-cell depletion, showed promise in the phase III REGENCY trial, where its addition to standard therapy resulted in higher renal response rates[77]. In this randomized, controlled trial among adults with active LN, obinutuzumab plus standard therapy was more efficacious than standard therapy alone in providing a complete renal response. Although not yet incorporated into KDIGO 2024 guidelines, obinutuzumab represents a promising therapeutic candidate pending further validation.

POST-TRANSPLANT MEDICATION IN LN

In patients with ESKD secondary to LN, post-transplant immunosuppressive regimens generally parallel those used in other etiologies of kidney failure, though additional vigilance is required to mitigate the risk of LN recurrence. The standard therapeutic backbone typically combines a CNI, an antimetabolite such as MMF or mycophenolic acid (MPA), and glucocorticoids[78]. Glucocorticoid-free strategies are not routinely employed in LN-related ESKD due to concerns about disease relapse. Furthermore, prior exposure to agents such as CYC or other immunosuppressants may predispose patients to marrow suppression and opportunistic infections, including progressive multifocal leukoencephalopathy.

Induction therapy

Induction immunosuppression is tailored according to the recipient’s immunologic risk profile. In standard-risk patients, non-depleting agents such as anti-CD25 monoclonal antibodies (e.g., basiliximab) are frequently utilized. In contrast, lymphocyte-depleting agents such as antithymocyte globulin are preferred in sensitized or high-risk recipients to reduce the likelihood of early acute rejection. The overarching objective is to balance effective rejection prophylaxis with minimization of infection and cardiovascular complications[78]. Achieving disease quiescence prior to transplantation, as emphasized by the KDIGO 2024 guidelines, is essential to lowering recurrence risk, after which conventional induction protocols are generally applied[42].

Maintenance therapy

Maintenance immunosuppression most often consists of a CNI (typically tacrolimus or cyclosporine), an antimetabolite (MMF or MPA), and low-dose corticosteroids[42]. Tacrolimus-based regimens are favored in many centers due to superior rejection prophylaxis and graft survival compared with cyclosporine. MMF remains the antimetabolite of choice owing to its selective inhibition of lymphocyte proliferation, efficacy in reducing proteinuria, and favorable tolerability profile[42]. For patients unable to tolerate or access MPA, AZA serves as an alternative, particularly in women planning pregnancy, given MMF’s teratogenicity. Prednisone is generally continued long term, with tapering individualized according to rejection risk, infection history, and LN activity.

Alternative and adjunctive approaches

Several adjunctive or alternative agents have been explored. Everolimus, when used as a replacement for CNIs, has been associated with improved and stabilized graft function without significantly increasing biopsy-proven rejection[79]. Belatacept, a selective T-cell co-stimulation blocker, has been investigated as a CNI substitute. However, the BENEFIT trial demonstrated higher rates and severity of acute rejection compared with cyclosporine[80]. Combination regimens of belatacept with MMF and corticosteroids have since been Food and Drug Administration-approved for adult KT recipients[81,82]. Anti-CD25 monoclonal antibodies such as basiliximab and daclizumab have demonstrated efficacy in reducing acute rejection episodes in solid-organ transplantation[83]. In LN patients with thrombotic microangiopathy or atypical hemolytic uremic syndrome, complement inhibitors such as eculizumab may be considered[84].

Novel agents

While voclosporin, belimumab, and obinutuzumab have been extensively evaluated in the pre-transplant setting for LN, their role after KT remains undefined. Post-transplant immunosuppression is typically guided by CNIs, antimetabolites, and corticosteroids, with biologics reserved for specific complications such as antibody-mediated rejection. Continuation of voclosporin post-transplant is theoretically redundant given the standard use of tacrolimus or cyclosporine, and no data currently support its use in this context. Belimumab, its use in KT recipients remains limited, with little information available regarding potential interactions with conventional immunosuppressive regimens. Importantly, few clinical cases have recently reported the use of belimumab in kidney transplant recipients with LN to manage systemic disease activity. These cases highlight belimumab’s potential as an effective and safe therapeutic option for controlling extrarenal SLE manifestations and reducing glucocorticoid dependence in transplant recipients. Although data are scarce, these findings align with prior evidence supporting belimumab’s safety and efficacy in LN, suggesting that its addition may be considered in patients with recurrent LN after KT[85,86]. Obinutuzumab, has not been studied as maintenance therapy for LN post-transplant but has shown promise in desensitization and rejection protocols. Its unique mechanism of action effectively depletes B-cell counts in sensitized kidney transplant candidates and, unlike rituximab, does not affect complement-dependent cytotoxicity crossmatch results[87]. Considering the specific characteristics of SLE and LN, obinutuzumab may favor the development of integrated anti-CD20 and anti-complement strategies. Current literature supports the potential future use of obinutuzumab in kidney transplant recipients with aggressive or refractory LN, though its role remains investigational[88]. Overall, initiation or continuation of these agents after transplantation should be individualized, balancing lupus activity against infection risk and graft outcomes. At present, their use post-transplant remains experimental, and further studies are needed to clarify whether voclosporin, belimumab, or obinutuzumab can safely complement conventional immunosuppression or whether their role should remain restricted to pre-transplant disease control.

Special considerations in LN

Beyond rejection prophylaxis, LN patients require ongoing surveillance for lupus activity to prevent recurrence. HCQ may be continued post-transplant to support systemic lupus control, with dosing adjusted for kidney function. In women with childbearing potential, HCQ is recommended alongside low-dose aspirin initiated before 16 weeks of gestation to reduce risks of pre-eclampsia and intrauterine growth restriction[42].

OUTCOMES FOLLOWING TRANSPLANTATION

Patient and graft survival

KT has been shown to enhance life expectancy in individuals with ESKD resulting from LN[89-91]. In a cohort of 20974 patients diagnosed with ESKD due to LN, 9659 were placed on the transplant waiting list and 5738 ultimately received a KT. Compared with patients who did not undergo transplantation, those who received a transplant experienced a 70% reduction in overall mortality[90,91]. This survival advantage was primarily attributed to a lower incidence of cardiovascular-related deaths (HR = 0.26) and infection-related deaths (HR = 0.41). These benefits were consistent across racial and ethnic groups, including African American, Asian, Hispanic, and White populations. Comparisons of transplant outcomes between patients with LN-related ESKD and those with ESKD from other causes have yielded mixed findings. Some investigations reported higher mortality in LN patients relative to individuals with other kidney diseases[10,13]. Recent meta-analysis showed that LN patients had lower graft survival rate (HR = 1.15) and patient survival rate (HR = 1.06) when compared with patients underwent transplantation due to other causes[15]. However, the majority of studies have demonstrated that 5- and 10-year graft survival rates are broadly comparable between LN patients and those with other glomerular disorders[13,92-94]. For instance, in a long-term study involving 77 adults with LN and 154 matched controls with non-LN glomerulonephritis, death-censored graft survival at 1, 5, and 10 years was nearly equivalent: 88%, 81%, and 71% in LN patients vs 91%, 83%, and 74% in controls, respectively.

Malignancy risk

Recipients of solid organ transplants face a greater likelihood of developing cancer compared with the general population. This risk is particularly elevated in individuals who have been exposed to immunosuppressive therapy prior to transplantation, such as patients with SLE[95,96]. Even outside the transplant setting, people with SLE have been shown to carry an increased overall risk of malignancies[97]. Among KT recipients, however, the incidence of most cancers (with the exception of melanoma) appears comparable between those with SLE and those without the condition[98]. Current recommendations suggest that cancer screening and monitoring in SLE transplant recipients should follow the same protocols as for other transplant patients.

Cardiovascular risk

Individuals with SLE are predisposed to cardiovascular disease including heart attacks, strokes, and peripheral vascular disease at rates higher than those seen in the general population. Patients with ESKD caused by LN also demonstrate an elevated risk of cardiovascular complications (such as myocardial infarction, ischemic stroke, or death from cardiovascular or cerebrovascular causes) compared with patients whose ESKD stems from other etiologies, except for diabetic kidney disease. KT has been linked to a reduction in these risks. In one cohort of 5963 patients with LN-related ESKD, 3209 (54%) underwent transplantation. Compared with patients maintained on dialysis, those who received a transplant had a significantly lower risk of heart attack (HR = 0.13) and stroke (HR = 0.30)[99].

RECURRENT LN AFTER KT

Recurrence of LN following KT remains an important clinical concern for patients with ESKD secondary to SLE. Reported recurrence rates vary considerably across studies, ranging from 2% to 11%[94,100-102], while recurrent systemic manifestations of SLE occur in only about 6% of cases[31]. These relatively low figures are thought to reflect the suppressive effects of long-term immunosuppressive therapy. The largest analysis, based on United Network for Organ Sharing data, included 6850 patients with LN-related ESKD who underwent transplantation between 1987 and 2006[94]. Of these, 167 (2.4%) experienced recurrent LN, whereas rejection was far more frequent, affecting 1770 patients (26%). Risk factors for recurrence included younger age (≤ 33 years), female sex, and non-Hispanic Black ethnicity, with odds ratios of 1.69, 1.70, and 1.88, respectively[103]. Other studies have reported higher recurrence rates (30%-54%), largely due to surveillance biopsies that detect subclinical disease, typically classified as class I or II LN[104,105]. Recurrence may occur as early as one week or as late as 16 years post-transplant, with a median onset of 4.3 years, and most cases present within the first decade[94]. Clinically, patients often develop elevated serum creatinine, new or worsening proteinuria, and hematuria detected on routine screening. Serologic markers such as hypocomplementemia, elevated anti-dsDNA titers, and occasional extrarenal SLE manifestations are unreliable indicators of graft disease activity[27,106,107]. In cases of unexplained graft dysfunction, biopsy is essential for diagnosis. Histologic findings in the allograft are frequently milder than those in native kidneys, often showing class I or II lesions, likely due to ongoing immunosuppression. This correlates with generally favorable long-term outcomes in recurrent LN. Importantly, no specific immunosuppressive regimen has been shown to alter recurrence risk[108]. Treatment strategies depend on biopsy findings and clinical severity. At present, no studies have directly evaluated the impact of different immunosuppressive agents on LN recurrence in KT recipients. Management of recurrent LN in transplanted kidneys generally follows the same therapeutic principles used for native kidney disease[42,109]. For patients with mild lesions (class I or II LN) on allograft biopsy, no adjustment to baseline immunosuppression is required. In contrast, those with moderate to severe lesions (class III or IV LN) typically require escalation of therapy, most often involving high-dose corticosteroids combined with either an increased dose of MMF 2-3 g/day or CYC for induction. The optimal CYC dose in transplant recipients remains undefined, and regimens generally mirror those used for native kidney LN. Response to therapy is monitored through serial assessments of serum creatinine, proteinuria, and hematuria, with many centers performing repeat biopsies at six months to confirm histologic improvement. For patients who are refractory to conventional therapy, anti-CD20 monoclonal antibodies such as rituximab may be considered, although optimal dosing in the transplant setting has not been established[73]. Current evidence is insufficient to support the use of belimumab or voclosporin in recurrent LN after transplantation. In severe cases, plasmapheresis may be employed as an adjunctive therapy to remove circulating autoantibodies and reduce immune-mediated injury.

MANAGING PREGNANCY AFTER KT

Pregnancy in women who have undergone KT requires careful planning, close monitoring, and individualized management to ensure both maternal and fetal well-being[110,111]. The timing of conception is crucial; it is generally recommended to delay pregnancy for at least one year after transplantation, as the risk of acute rejection is greatest during the period of intensive immunosuppression[112,113]. Immunosuppressive therapy must be tailored to balance graft preservation with maternal and fetal safety. CNIs such as tacrolimus and cyclosporine are considered safe during pregnancy and should be continued to maintain graft function[114]. HCQ is another cornerstone of therapy, as it reduces lupus activity and prevents disease flares without compromising fetal health[115]. In contrast, teratogenic agents such as MMF must be discontinued prior to conception and replaced with AZA, which is safer during pregnancy[116]. Rituximab should also be avoided for at least one year before conception due to its potential effects on fetal B-cell development[117]. Women with concomitant APS require special attention, as aPL increases the risk of thrombosis and pregnancy loss. Preventive measures often include low-dose aspirin and prophylactic heparin to reduce these risks[118]. Tacrolimus is generally preferred over cyclosporine because of its lower impact on blood pressure, thereby supporting maternal cardiovascular stability[119]. Despite advances in pharmacologic therapy, ongoing surveillance remains essential. A renal biopsy before the 20^th week of gestation may be performed to confirm disease quiescence, while regular placental Doppler ultrasound examinations are recommended to monitor fetal growth and well-being throughout pregnancy[120].

FUTURE PERSPECTIVES

Advancing the understanding of LN and KT requires more rigorous and standardized research. Future studies should include larger, well-characterized patient cohorts with extended follow-up periods to ensure adequate statistical power and reliable conclusions. Reducing biases inherent in retrospective designs and harmonizing outcome definitions and assessment methods across studies are essential to enable meaningful comparisons and global applicability of findings. Personalized transplant strategies such as tailored immunosuppression, biomarker monitoring, and holistic patient care are crucial to address the unique challenges of systemic autoimmune disease. Collaborative multicenter trials and international registries will be key to improving long-term patient and graft outcomes.

CONCLUSION

KT offers the best treatment option for patients with LN progressing to ESKD, yet outcomes are shaped by factors such as timing, disease quiescence, demographics, and prior treatment history. Early evaluation and timely referral to transplant centers are critical for success. Advances in immunosuppressive therapies, personalized regimens, emerging biomarkers, and transplant matching hold promise for improving patient selection, enhancing survival, and reducing recurrence.