CAR-T Cell Therapy in Nephrology: Evidence Across Immune-Mediated Kidney Diseases and Plasma Cell Dyscrasias, Renal Toxicity, and Patient Monitoring

Abstract

In many immune-mediated kidney diseases, tissue injury is driven by dysregulated B-cell immunity, with autoantibodies and complement acting as key effectors at the glomerulus. Corticosteroids and conventional immunosuppressants control these diseases only in part, and they do so at the price of cumulative toxicity and frequent relapse. Anti-CD20 antibodies deplete circulating B cells but spare plasmablasts and CD19+ plasma cells that sustain autoantibody production, leaving a residual autoreactive compartment that may contribute to refractory disease and relapse. Anti-CD19 chimeric antigen receptor (CAR) T cells target a broader spectrum of B-cell populations, and early clinical studies suggest that this deeper depletion extends into secondary lymphoid tissues. The clinical evidence, however, is uneven. It is strongest in systemic lupus erythematosus and refractory lupus nephritis, where case series and early-phase trials report clinical and serological remission together with discontinuation of immunosuppression and treatment-free remission. In multiple myeloma and immunoglobulin light-chain (AL) amyloidosis with renal involvement, anti-B-cell maturation antigen (anti-BCMA) CAR-T products are increasingly used in real-world cohorts of patients with reduced estimated glomerular filtration rate (eGFR) or on dialysis, while bispecific T-cell engagers such as teclistamab offer an off-the-shelf alternative. The toxicity of these agents concerns the nephrologist directly. Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, tumor lysis syndrome, and the immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) (IEC-HS) can each involve the kidney, as can the newly defined local immune effector cell-associated toxicity syndrome (LICATS). This review explores the immunological basis of CAR-T constructs, the evidence by disease, the renal toxicity profile, and the criteria for candidate selection and nephrological monitoring.

1. Introduction

In immune-mediated kidney diseases, tissue damage is driven by a complex interaction between innate and adaptive immunity [1]. Contributing to this process, in varying proportions, are the innate component of the immune system, with neutrophils and macrophages alongside complement [2,3], and the adaptive component with T and B lymphocytes [4,5]. B lymphocytes produce autoantibodies that form circulating immune complexes with soluble antigens, which in turn are destined to deposit in the glomerulus, as in the case of systemic lupus erythematosus (SLE) with anti-double-stranded DNA (anti-dsDNA). In other scenarios, the antibody reacts directly with glomerular antigens and generates immune complexes “in situ”, as occurs with anti-M-type phospholipase A2 receptor (PLA2R) antibodies in primary membranous nephropathy [5]. When this aberrant activity of B lymphocytes evolves into single clonal proliferation, a monoclonal component can become harmful to the kidney. This is the case of monoclonal gammopathies of renal significance (MGRS). In these manifestations, the B-cell or plasma cell clone, by definition, does not satisfy the criteria for multiple myeloma or another hematological malignancy, despite secreting an immunoglobulin capable of damaging the kidney. The same damage from a monoclonal component appears in fully expressed plasma cell dyscrasias, such as multiple myeloma and AL amyloidosis [6,7]. ANCA-associated vasculitis follows a distinct mechanism: the damage is predominantly pauci-immune, and ANCAs activate neutrophils, the origin of the vascular and glomerular lesions.

The standard of care relies on corticosteroids and conventional immunosuppressants, but these treatments often show inconsistent efficacy and carry cumulative toxicity, with a heightened risk of infection [8]. Even anti-CD20 B-cell depleting therapies, such as rituximab, fail to fully eliminate the autoreactive B-cell compartment. For example, in the randomized Lupus Nephritis Assessment with Rituximab (LUNAR) trial of proliferative lupus nephritis, adding rituximab to mycophenolate and corticosteroids did not meet the primary endpoint despite numerical improvements in several secondary outcomes [9]. Similarly, in ANCA-associated vasculitis, maintenance therapy with rituximab does not fully prevent relapses, and serious adverse events still occur [10]. These findings have prompted interest in cellular immunotherapy, and in chimeric antigen receptor (CAR) T cellsin particular, first developed in onco-hematology against well-defined antigens [11].

Anti-CD19 CAR-T cells achieve broader depletion of B-cell populations than anti-CD20 therapies, as CD19 is expressed across a wider range of B-cell maturation stages, including early pre-B cells, plasmablasts, and CD19+ plasma cells, cell types not targeted by rituximab [12,13]. Serial lymph node biopsies in patients with SLE and systemic sclerosis have demonstrated complete B-cell depletion even in secondary lymphoid tissues [13]. After B-cell aplasia resolves, the compartment is repopulated from naïve progenitors, a process some describe as an “immunological reset.” Its durability as genuine immune tolerance, rather than prolonged immune reconstitution, remains unproven [14]. Standardized criteria for selecting candidates for this therapy are still lacking [15]. These unresolved issues have been addressed at the level of expert consensus and research prioritization rather than formal guideline recommendations. The Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on therapies targeting B cells in immune-mediated kidney diseases convened experts in June 2025 to review the available evidence across glomerular diseases and define key research needs. The report supports a relatively advanced evidence base for B-cell-targeted biologics in lupus nephritis and ANCA-associated vasculitis, while emphasizing that cell-therapy approaches remain early-stage, particularly outside lupus nephritis. For membranous nephropathy, established anti-CD20 therapy remains first-line for many patients, whereas deeper B-cell depletion strategies, including cell-based approaches, are still investigational. The report also calls for validated biomarkers to guide patient selection and monitoring and to define the appropriate depth of B-cell depletion for each disease, weighing potential benefits against risks such as cytokine release syndrome (CRS) and other serious toxicities [16]. This review will examine the immunological basis and clinical data for CAR-T cell therapies in immune-mediated kidney diseases, with particular attention to renal toxicities and the potential of next-generation cellular platforms.

This narrative review draws on a search of PubMed/MEDLINE covering publications through July 2026, in which the terms chimeric antigen receptor, CAR-T, CAR-natural killer (CAR-NK), bispecific T-cell engager, and teclistamab were combined with lupus nephritis, systemic lupus erythematosus, membranous nephropathy, podocytopathy, anti-nephrin, ANCA-associated vasculitis, monoclonal gammopathy of renal significance, multiple myeloma, AL amyloidosis, acute kidney injury, and dialysis. The reference lists of the retrieved articles, the ClinicalTrials.gov registry, and the consensus documents of KDIGO, European Society for Blood and Marrow Transplantation (EBMT)and American Society for Transplantation and Cellular Therapy (ASTCT) were screened for additional sources. Priority was given to primary clinical reports, early-phase trials, real-world cohorts, regulatory documents, and consensus statements published in English, and preclinical work was retained where it supplied the mechanistic basis of a clinical application. A total of 109 references were included in the final narrative synthesis.

2. Biological Principles of CAR-T Cells

CAR-T cells are autologous T lymphocytes reprogrammed to express a synthetic receptor that recognizes surface antigens without major histocompatibility complex (MHC) restriction [17]. Manufacturing follows mandatory steps: leukapheresis, transduction with lentiviral or retroviral vectors, expansion, quality control, and cryopreservation. Prior to reinfusion, the patient receives lymphodepleting chemotherapy, usually with infusion of fludarabine and cyclophosphamide, which creates the homeostatic space necessary for the expansion and persistence of the CAR-T [17].

CAR-T cells have evolved through successive generations of increasing signalling complexity. The first chimeric antigen receptor constructs emerged in the late 1980s [18]. Subsequently, first-generation CARs incorporated a single intracellular signalling domain, CD3ζ. Second-generation CARs added a costimulatory domain, most commonly CD28 or 4-1BB, alongside CD3ζ, resulting in improved expansion and in vivo persistence [19]. Third-generation CARs combine two costimulatory domains with CD3ζ, further enhancing T-cell proliferation and survival [20]. Fourth-generation CARs, known as TRUCKs (T cells Redirected for Universal Cytokine Killing), are engineered to express pro-inflammatory or immunomodulatory cytokines such as interleukin (IL)-12, IL-15, or IL-18 upon activation, thereby remodelling the local immune microenvironment and recruiting host innate immune cells [21]. The most recent iterations aim to overcome the constraints linked to the use of autologous cells. Off-the-shelf allogeneic CAR-T cells, obtained from healthy donors or induced pluripotent stem cells, require genomic editing of the T-cell receptor (TCR) and class I human leukocyte antigen (HLA) molecules. Removal of the TCR lowers the risk of Graft-versus-Host Disease (GvHD); modifying class I HLA mitigates host T-lymphocyte-mediated rejection, although susceptibility to lysis by Natural Killer (NK) cells persists [22]. In vivo generation of CAR-T cells using lipid nanoparticles (LNPs) targeted to CD8+ T lymphocytes, in preclinical models, showed deep B-cell depletion and the reconstitution of naïve cells without preemptive chemotherapy-induced lymphodepletion [23]; an initial use in humans has been reported in refractory SLE [24]. Finally, SUPRA-CAR (Split, Universal, and Programmable) modular systems allow for the reprogramming of antigenic specificity and activation through bipartite soluble adapters [25].

In autoimmune diseases, the efficacy and safety of these platforms remain under clinical evaluation. Translating CAR-T cells from onco-hematology to renal immunopathology requires specific revisions, because the immunological and inflammatory microenvironment of autoimmune nephropathies differs from that of hematological malignancies [26].

3. CAR-T Cells as a Treatment for Immune-Mediated Renal and Systemic Diseases

3.1. Lupus Nephritis and SLE

SLE is characterized by the production of anti-nuclear autoantibodies, primarily anti-dsDNA, and by the intrarenal deposition of immune complexes with complement activation. The occurrence of lupus nephritis increases morbidity and mortality [27]. Belimumab, anifrolumab, and next-generation calcineurin inhibitors such as voclosporin have expanded the available therapeutic options. However, none of these treatments fully eliminates the autoreactive B-cell compartment, and refractory cases and relapses remain possible [28].

The first reported use of anti-CD19 CAR-T cells in lupus nephritis was in 2021, when Mougiakakos et al. described a 20-year-old female with class IIIA lupus nephritis and nephrotic syndrome who achieved rapid clinical and serological remission, including anti-dsDNA seroconversion and normalization of serum complement, following CAR-T cell infusion [29]. Shortly thereafter, Mackensen et al. treated five patients with active, refractory SLE, achieving DORIS (Definition of Remission in SLE) remission and enabling discontinuation of immunosuppression within three months [30]. Subsequent evidence from larger cohorts further supported these findings. Müller et al. treated 15 patients with severe autoimmune disease, 8 of whom had SLE. All eight reached DORIS remission at six months, with seroconversion of anti-dsDNA and disappearance of proteinuria sustained thereafter. The three patients with idiopathic inflammatory myositis reached an ACR-EULAR (American College of Rheumatology and European League Against Rheumatism) major clinical response, and the four with systemic sclerosis showed reduced skin and lung disease severity. All 15 discontinued glucocorticoids and every other immunosuppressant over a median follow-up of 15 months [12]. Sequential lymph node biopsies by Tur et al. provided the histological correlation and showed that deep B-cell depletion extends to secondary lymphoid tissues, which may contribute to the maintenance of remission even after the return of peripheral B lymphocytes [13].

In the paediatric field, Krickau et al. followed a 15-year-old female adolescent with rapidly progressive lupus nephritis who was already on hemodialysis. In this case, after anti-CD19 CAR-T cell therapy, renal function recovered sufficiently to allow discontinuation of renal replacement therapy in this single case [31]. Also in the paediatric population, Mao et al. employed a dual-target bicistronic anti-CD19/CD22 CAR-T construct in a single case of childhood refractory lupus nephritis [32].

A second approach has targeted the autoreactive plasma cell directly. Hu et al. gave anti-BCMA (B-cell maturation antigen) CAR-T cells to 7 patients with refractory lupus nephritis: the SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index 2000) fell from a median of 18 to 0, complete DORIS remission was reached in 5 out of 7 patients, and the only safety signal was a single grade 1 CRS [33]. A dual-target anti-BCMA/CD19 CAR-T construct was then tested by Wang et al. in a single-arm, open-label, multicentre phase 1 study of 13 patients with SLE, enrolled on the basis of biopsy-confirmed class III–V lupus nephritis. Two patients had concomitant lymphoma, and one was underdosed because of insufficient lymphocyte counts. The mean SLEDAI-2K went from 10.6 to 2.7 at three months; all autoantibodies including those attributed to long-lived plasma cells became undetectable by three months, and complement normalised. Renal function improved in 10 patients with lupus nephritis within 90 days, B cells recovered fully within 2 to 6 months, and symptom- and medication-free remission was maintained with follow-up extending to 46 months. CRS was mild [34]. Extended follow-up of the same trial has since been reported separately. Among 12 evaluable patients followed for a median of 30 months, 10 reached stringent complete remission, defined as medication-free DORIS remission with complete serological normalisation and complete renal response. Of the 10 patients with lupus nephritis, 9 achieved a complete renal response with stable estimated glomerular filtration rate (eGFR) and resolution of proteinuria, and repeat biopsies at approximately one year in 9 patients showed resolution of cellular crescents and of mesangial and endothelial proliferation, with clearance of immune-complex deposits on immunofluorescence. One patient retained proteinuria attributable to chronic damage rather than to active disease, which illustrates the difficulty of interpreting residual proteinuria after deep B-cell depletion [35]. Feng et al. chose instead to co-infuse two separate products, anti-CD19 and anti-BCMA CAR-T cells, in 15 patients with severe refractory SLE: Lupus Low Disease Activity State (LLDAS) and DORIS remission within 12 weeks in 80% of cases, grade 1 CRS in 86.7%, and cytopenias among the commonest adverse events [36]. Finally, the phase 1/2a CASTLE basket trial evaluated the autologous anti-CD19 product zorpocabtagene autoleucel across several systemic autoimmune diseases, SLE included, with grade 1 CRS in 70.8% of cases and no neurotoxicity [37]. Even in SLE, where the data are most consistent, the evidence consists of single-arm studies without a comparator arm and of series that each enrolled fewer than 30 patients, so that estimates of efficacy and of the durability of treatment-free remission remain provisional.

In refractory SLE, two questions remain open: the duration of the response and long-term safety, along with the positioning of the therapy relative to bispecific T-cell engagers (Section 3.6) [14]. An initial Chinese series explored off-the-shelf allogeneic anti-CD19 CAR-NK cells in SLE [38], and a recent systematic review aggregated the evidence on CAR cellular therapies in refractory SLE [39].

3.2. Membranous Nephropathy

Membranous nephropathy (MN) is among the leading causes of nephrotic syndrome in adults. In the primary form (pMN), the targets are autoantibodies against podocyte antigens: PLA2R in 70–80% of cases, and thrombospondin type-1 domain-containing 7A protein (THSD7A) in 2–5% [40,41]. Immune complexes deposit in the subepithelial space and activate complement in situ, leading to podocyte injury. Corticosteroids, alkylating agents such as cyclophosphamide, calcineurin inhibitors, and anti-CD20 therapies have improved the prognosis. However, some patients remain refractory or relapse after drug discontinuation [42].

The rationale for investigating anti-CD19 CAR-T cell therapy in pMN lies in its potential to deplete the CD19+/CD20− plasmablasts and early plasma cells that may secrete anti-PLA2R, populations that lie beyond rituximab’s reach and may sustain antibody positivity in tissue and circulation [43]. This rationale is biologically coherent, yet no clinical results in pMN appear to have been published to date. Two early studies, both registered trials that are still recruiting or have not yet reported, are probing feasibility, one with anti-CD19 CAR-T cells in refractory pMN [44], the other with the CAR-T construct IM19 in immunoglobulin A (IgA) nephropathyand in medium-to-high-risk pMN [45].

CAAR (Chimeric AutoAntibody Receptor) cells offer a more selective approach. They display the target autoantigen on their surface and target only the B and plasma cell clones producing the pathogenic autoantibody, without affecting the rest of the B compartment and without global aplasia. Similarly, Seifert et al. showed that NK cells armed with immunogenic fragments of PLA2R1 and THSD7A selectively eliminate cells secreting the respective autoantibodies without touching non-autoreactive populations [46]. Before clinical use, however, this approach must undergo validation.

3.3. Podocytopathies and Anti-Nephrin Variants

Minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS) are the podocytopathies that most frequently cause nephrotic syndrome, the former primarily in children, the latter in adults. For a long time, both were attributed to a primary T-lymphocyte dysregulation involving circulating permeability factors [47,48]. Molecular nephrology has partially redefined this interpretation. The finding of anti-nephrin autoantibodies in a significant proportion of active MCD, and to a lesser extent in primary FSGS, together with the reproduction of podocyte injury in mice immunized with the nephrin antigen, has outlined a subtype of antibody-mediated podocytopathy [49]. The hypothesis of T-cell dysregulation with circulating permeability factors retains a role in a subset of MCD and FSGS cases, especially in forms seronegative for anti-nephrin.

Deep B-cell depletion thus finds a rationale primarily in anti-nephrin-seropositive variants, whereas in seronegative forms, the benefit remains to be demonstrated. For this population, clinical trials or structured case series on CAR-T cells are lacking so far [15]. A recent review outlines the possible role of B-cell depletion strategies, including antigen-specific ones, in anti-nephrin podocytopathies [50].

3.4. ANCA-Associated Vasculitis

ANCA-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), which are unified by heterogeneous organ involvement and renal involvement. B lymphocytes sustain the synthesis of autoantibodies against neutrophil cytoplasmic granules (ANCA) and the consequent inflammatory amplification. Compared to SLE, however, the T component and the microbicidal activation of neutrophils also weigh heavily in vascular and parenchymal injury, especially in phenotypes with granulomatous features [51].

In a mouse model of AAV, anti-CD19 CAR-T cells were associated with durable B-cell depletion, a decrease in antibody, and reduced histological damage from crescentic glomerulonephritis [52]. In humans, the literature is currently limited to single case reports, from which no estimate of efficacy or safety in AAV can be derived. Minopoulou et al. reported clinical remission and a marked reduction in proteinase 3 (PR3)-ANCA in a refractory PR3-ANCA-positive GPA [53]. Uhlmann et al. reported a clinical response to anti-CD19 CAR-T cells in a single case of GPA resistant to conventional therapies [54]. In a single case of refractory MPA, Schultze-Florey et al. observed a reduction in anti- myeloperoxidase (MPO) titers and improvement in proteinuria [55]. Prospective studies are needed before any conclusion on safety, tolerability, or efficacy can be drawn in severe AAV resistant to the standard of care. A dedicated review has recently systematized the rationale and evidence for anti-CD19 CAR-T cells in AAV [56].

3.5. Monoclonal Gammopathies of Renal Significance and AL Amyloidosis

In plasma cell dyscrasias, CAR-T cells pose clinical and management problems that closely concern the nephrologist. The KarMMa and CARTITUDE-1 trials demonstrated the efficacy of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Both drugs were directed against BCMA and approved in relapsed or refractory multiple myeloma (MM) [57,58]. However, the two registration studies excluded patients with impaired renal function (in KarMMa, creatinine clearance below 45 mL/min) and those on renal replacement therapy, although acute or chronic kidney injury ranks among the most frequent organ complications of MM, such as in cast nephropathy.

AL amyloidosis is more insidious due to the frequent multi-organ involvement, particularly cardiac and renal. Preliminary data, so far limited to case reports, suggest that forms associated with myeloma may be treatable with anti-BCMA CAR-T cells. In two patients with concurrent myeloma and severe cardiac or renal dysfunction, ide-cel or cilta-cel led to minimal residual disease negativity (MRD-negativity), with toxicity manageable through rigorous CRS prophylaxis and surveillance of hemodynamic and cardio-renal stability [59]. A recent review summarizes the emerging evidence for anti-BCMA therapies in isolated AL, without overt MM, and recommends stringent selection criteria, such as excluding patients with severe autonomic dysfunction or irreversible end-stage organ damage [60].

For MGRS, dedicated trials are still lacking, and no published clinical experience with CAR-T cells appears to be available, so that the use of these products in MGRS remains a hypothesis. The pathophysiological rationale is that the selective elimination of the B or plasma cell clone responsible for the nephrotoxic light chain could remove the cause of glomerular or tubular damage before progression to chronic kidney disease (CKD); this rationale awaits clinical testing.

3.6. Beyond Autologous CAR-T Cells: Off-the-Shelf Platforms and Bispecific T-Cell Engagers

Bispecific T-cell engagers (TCEs) are currently the most mature off-the-shelf alternative to CAR-T cells. They avoid the manufacturing times of the autologous product and spare the patient leukapheresis and chemotherapy-induced lymphodepletion; they can also be discontinued if acute toxicity arises. However, the short circulating half-life necessitates repeated or prolonged administration, and the optimal duration of treatment and the risk of relapse after discontinuation remain to be defined. When to prefer a TCE over a CAR-T cell, and with what timing, is still a matter of discussion [14].

Teclistamab, an anti-BCMA/CD3 bispecific approved in multiple myeloma, has recently also been used in severe and refractory autoimmune diseases, with early clinical signals that derive from single cases and small uncontrolled series. Alexander et al. documented a complete and sustained treatment-free remission in a single patient with severe refractory SLE after a short course of teclistamab [61]. Hagen et al. treated four patients with different systemic diseases (systemic sclerosis, primary Sjögren’s syndrome, idiopathic inflammatory myopathy, rheumatoid arthritis), with clinical improvement and toxicity limited to grade 1–2 CRS [62]. In the series by Bucci et al., 10 patients with six different autoimmune diseases showed deep and simultaneous depletion of B lymphocytes and plasma cells, with clinical benefit in most of the cohort [63]. The evidence has since widened while retaining the same observational character. A multicenter case series reported responses to teclistamab across several refractory autoimmune diseases [64], and both blinatumomab and teclistamab showed activity in severe treatment-resistant connective tissue disease, reducing target cells in tissue and lowering autoantibody titers [65]. The mechanisms and prospects of bispecific T-cell engagers in autoimmunity have been reviewed in detail [66]. None of these reports included a control group, and the dose, schedule, and duration of TCE treatment in autoimmunity remain undefined.

3.7. Limitations of the Available Evidence

Table 1 also displays the limits of the current evidence. Outside SLE, every entry consists of a case report, a case series, or a registered trial without published results, and even in SLE the largest experiences are single-arm studies of fewer than 30 patients, conducted in a small number of highly specialised centres and, for the anti-BCMA and dual-target constructs, almost exclusively in China. No randomised comparison with standard immunosuppression or with anti-CD20 therapy appears to have been reported in any renal indication. Efficacy endpoints differ from study to study (DORIS remission, LLDAS, change in SLEDAI-2K, renal response), which limits comparison across reports, and follow-up seldom exceeds three years. Publication bias is likely, since single cases with a favourable course are more readily reported than treatment failures, and the retrospective real-world cohorts in plasma cell dyscrasias carry the selection and confounding inherent to that design (Section 4.3). The enrolment of patients with refractory disease and preserved organ function further restricts the generalisability of the findings to the broader nephrological population, in which advanced CKD and dialysis dependence are common.

Table 1. Studies on cellular therapies (CAR-T and bispecific T-cell engagers) in immune-mediated diseases with renal relevance.

Study (Ref.)	Design	Disease/Renal Context	Target/Construct	n	Key Efficacy Outcomes	Safety (CRS/ICANS)	Level of Evidence; Main Limitations
Systemic lupus erythematosus and lupus nephritis
Mougiakakos et al. [29]	Case report	Class IIIA lupus nephritis with nephrotic syndrome	Anti-CD19 CAR-T	1	Clinical and serological remission; seroconversion of anti-dsDNA; complement normalization	NR	Single case; no comparator
Mackensen et al. [30]	Case series	Active refractory SLE	Anti-CD19 CAR-T	5	DORIS remission in all 5 patients at 3 months, with discontinuation of immunosuppression; drug-free remission maintained over longer follow-up	Grade 1 CRS in 3/5; no ICANS	Uncontrolled series; single centre
Müller et al. [12]	Case series	Severe autoimmune diseases (8 with SLE)	Anti-CD19 CAR-T	15 (8 SLE)	DORIS remission in all patients with SLE, with seroconversion of anti-dsDNA (median follow-up 15 months, range 4–29)	Grade 1 CRS in 10/15; 1 grade 2 CRS; 1 grade 1 ICANS	Uncontrolled series; single centre; mixed diseases
Krickau et al. [31]	Case report	Rapidly progressive lupus nephritis, adolescent on hemodialysis	Anti-CD19 CAR-T	1	Recovery of renal function and discontinuation of replacement therapy	NR	Single paediatric case
Hu et al. [33]	Single-arm trial	Refractory lupus nephritis	Anti-BCMA CAR-T	7	SLEDAI-2K from median 18 (range 10–22) to 0 (range 0–4) at last follow-up; DORIS complete remission in 5/7	Grade 1 CRS in 1 patient; no ICANS; no severe infection	Single-arm trial; single centre; small sample
Wang et al. [34]	Phase 1 trial	SLE, class III–V lupus nephritis	Dual anti-BCMA/CD19 CAR-T (compound)	13 (10 with LN)	Mean SLEDAI-2K from 10.6 to 2.7 at 3 months; all autoantibodies undetectable and complement normalised at 3 months; renal function improved in 10 patients with LN within 90 days; symptom- and medication-free remission, follow-up to 46 months	Mild CRS; ICANS NR	Single-arm phase 1; no comparator; heterogeneous cohort (2 with lymphoma, 1 underdosed)
Feng et al. [36]	Phase 1 trial	Severe refractory SLE	Co-infusion anti-CD19 + anti-BCMA CAR-T	15	LLDAS and DORIS remission in 12/15 (80%) by week 12	Grade 1 CRS in 86.7%; no ICANS; grade ≥ 3 neutropenia in 100%, thrombocytopenia in 40%, anaemia in 13.3%, all reversible	Single-arm phase 1; no comparator; 12-week primary endpoint
CASTLE [37]	Phase 1/2 basket trial	Systemic autoimmune diseases, including SLE	Anti-CD19 CAR-T (zorpocabtagene autoleucel)	24 (10 SLE, 9 SSc, 5 IIM)	Predefined efficacy endpoints met in 22/24; DORIS remission in 9/10 patients with SLE at 24 weeks; all patients free of glucocorticoids and immunosuppression over the observation period	Grade 1 CRS in 17/24 (70.8%), 1 grade 2, none higher; no ICANS; LICATS mild in all; one grade 3 kidney injury with biopsy-proven TMA during CMV reactivation	Single-arm basket trial; mixed diseases; early data
ANCA-associated vasculitis
Minopoulou et al. [53]	Case report	Refractory PR3-ANCA-positive GPA	Anti-CD19 CAR-T	1	Clinical remission with BVAS 0 at day 132; PR3-ANCA undetectable at day 28; no CD19+ B cells in bone marrow at day 48	Grade 1 CRS (tocilizumab); grade 3 neutropenia; no ICANS	Single case; no comparator
Uhlmann et al. [54]	Case report	GPA resistant to conventional therapies	Anti-CD19 CAR-T	1	Almost complete resolution of pulmonary inflammatory activity at 4 months; prednisolone reduced from 10 to 2 mg/day; B-cell aplasia persisting at 300 days	No CRS or ICANS; transient leukopenia for 14 days	Single case; no comparator
Schultze-Florey et al. [55]	Case report	Refractory MPA	Anti-CD19 CAR-T	1	MPO-ANCA decline, stable kidney function, 87% reduction in proteinuria, resolution of haematuria and BVAS from 10 to 0 over 6 weeks of follow-up	Well tolerated; no CRS or ICANS reported	Single case; no comparator
Membranous nephropathy
NCT07266181 Preliminary study [44]	Registered trial (ongoing)	Refractory pMN	Anti-CD19 CAR-T	NR	Ongoing: feasibility and safety	NR	Registered trial; no results published
NCT06690359 Preliminary study [45]	Registered trial (ongoing)	IgA nephropathy or pMN	IM19 CAR-T	NR	Ongoing	NR	Registered trial; no results published
Multiple myeloma and AL amyloidosis with renal relevance
Sidana et al. [67]	Real-world cohort	MM with reduced renal function	ide-cel (anti-BCMA)	28 RI/214	Efficacy comparable to patients with preserved renal function; renal function did not worsen after infusion	CRS 89% vs. 84% (grade ≥ 3: 7% vs. 2%) and ICANS 23% vs. 20% in patients with and without RI; more short-term grade ≥ 3 cytopenias with RI	Retrospective real-world cohort; selection bias
Atanackovic et al. [68]	Comparative cohort	MM (cilta-cel vs. ide-cel)	anti-BCMA	39	Higher response rates with cilta-cel; higher peak CAR-T counts, driven by CD4+ expansion	cilta-cel: more frequent atypical neurotoxicities and infections	Retrospective comparison; product choice not randomised
Pak et al. [69]	Case series	MM on chronic hemodialysis	cilta-cel (anti-BCMA)	2	Complete haematological response in one patient and very good partial response in the other; fludarabine dose reduced or omitted	No CRS or ICANS	Two cases; no comparator
Swamy et al. [70]	Case series	Dialysis-dependent MM	Anti-BCMA CAR-T	5	Case series in dialysis-dependent patients	NR	Case series; no comparator
Wood et al. [71]	Cohort	Large B-cell lymphoma, including reduced renal function and dialysis	Anti-CD19 CAR-T	166 (17 with eGFR < 60 mL/min/1.73 m2, 2 on dialysis)	Baseline renal function did not affect renal or efficacy outcomes; AKI associated with worse PFS and OS; feasible in the 2 patients on dialysis with adapted lymphodepletion	AKI related to CRS and to higher peak inflammatory cytokine levels	Retrospective cohort; lymphoma setting, not autoimmune disease
Das et al. [59]	Case series	AL amyloidosis with cardiac/renal dysfunction and concurrent MM	anti-BCMA (ide-cel/cilta-cel)	2	MRD-negativity	Toxicity manageable with rigorous CRS prophylaxis	Two cases with concurrent MM; no comparator
Bispecific T-cell engagers
Alexander et al. [61]	Case report	Severe refractory SLE	Teclistamab (anti-BCMA/CD3)	1	Complete, stable, treatment-free remission	NR	Single case; no comparator
Hagen et al. [62]	Case series	Different systemic diseases (SSc, Sjögren, inflammatory myopathy, RA)	Teclistamab	4	Clear clinical improvement	Grade 1–2 CRS	Case series; mixed diseases; no comparator
Bucci et al. [63]	Case series	Six different refractory autoimmune diseases	Teclistamab	10	Deep B-cell and plasma cell depletion with clinical and serological improvement in most patients; drug-free remission in 6/10, follow-up to 15 months	Low-grade CRS; infections	Case series; mixed diseases; no comparator

CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; DORIS, Definition of Remission in SLE; LLDAS, Lupus Low Disease Activity State; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; MRD, minimal residual disease; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MM, multiple myeloma; pMN, primary membranous nephropathy; SSc, systemic sclerosis; RA, rheumatoid arthritis; ide-cel, idecabtagene vicleucel; cilta-cel, ciltacabtagene autoleucel; LN, lupus nephritis; n, number of patients; NR, not reported; LICATS, local immune effector cell-associated toxicity syndrome; TMA, thrombotic microangiopathy; CMV, cytomegalovirus.

4. The Kidney in the CAR-T Cell-Treated Patient

The most frequent adverse events of CAR-T cells are CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). Prolonged cytopenias, infections, hypogammaglobulinemia, and hemophagocytic lymphohistiocytosis-like (HLH-like) conditions appear with more variable incidence [72]. In autoimmune diseases, overall toxicity has so far appeared milder than in onco-hematology, although this comparison rests on small series. In the cohort by Müller et al., only grade 1 CRS was observed in 10 out of 15 patients, a single grade 2, and a single grade 1 ICANS, all resolving without sequelae [12].

4.1. Systemic Toxicity Syndromes with Renal Impact: CRS, ICANS, TLS, IEC-HS

CRS is an acute systemic inflammation characterized by high fever, hypotension, and hypoxia, up to multi-organ dysfunction. It typically occurs within a few days of infusion and is driven by increased serum concentrations of pro-inflammatory cytokines such as IL-6, interferon (IFN)-γ, tumor necrosis factor (TNF)-α [73]. It is regarded as one of the principal mechanisms associated with acute kidney injury (AKI) after infusion. The prevailing interpretation, inferred largely from the clinical course and from the pathophysiology of other inflammatory states, is that systemic vasodilation and increased capillary permeability reduce effective blood volume and cause a pre-renal AKI from hypoperfusion, which, if prolonged, may evolve toward acute tubular necrosis (ATN) [74]. More broadly, cytokine-driven endothelial activation and disruption of vascular barrier integrity are recognized mechanisms of vascular leakage and tissue injury across severe inflammatory conditions [75]. This network-based view is consistent with the broader concept that inflammatory pathology emerges from interactions among cytokine signaling, intracellular regulatory pathways, and inflammasome activity rather than from the action of individual mediators alone [76]. Histological confirmation is available in a minority of cases, and concurrent nephrotoxins, sepsis, and cytokine-mediated tubular injury may contribute in proportions that have not been quantified.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). ICANS covers a broad neurological spectrum, from encephalopathy to seizures, focal deficits to altered consciousness, up to fatal cerebral edema in the most severe forms [77]. The proposed mechanism involves an endothelial hyperactivation that compromises the blood–brain barrier and allows pro-inflammatory cytokines such as IFN-γ, IL-6, IL-1, and granulocyte-macrophage colony-stimulating factor (GM-CSF)to enter the central nervous system [78]. The delayed neurotoxicity of the anti-BCMA construct cilta-cel warrants attention, presenting with parkinsonian-like movement disorders and neurocognitive deficits via a mechanism that is not fully understood; hypotheses include the expression of BCMA in the central nervous system, particularly in the basal ganglia [79]; however, this remains an unconfirmed hypothesis.

Tumor Lysis Syndrome (TLS). More frequent in hematological malignancies with a high proliferative fraction, TLS results from the rapid and massive destruction of neoplastic cells, releasing potassium, phosphate, and nucleic acids into the circulation [80]. AKI is attributed mainly to the precipitation of uric acid and calcium phosphate crystals in the tubules with obstruction of their lumen, with a possible contribution from renal vasoconstriction; the relative weight of these pathways has been inferred from TLS in other settings and has not been studied directly after CAR-T infusion [80]. Zhang et al., in 105 patients with relapsed/refractory multiple myeloma on anti-BCMA immunotherapy, recorded TLS in 17.1% (18 patients) at a median of 8 days post-infusion. The entire TLS sub-cohort had concomitant CRS, which was grade 3–4 in 72.2% of cases, an aggressive phenotype associated with worse progression-free survival and overall survival [81]. The risk of AKI during TLS or CRS increases when a recent or concurrent nephrotoxic insult is superimposed, such as iodinated contrast media or nephrotoxic antimicrobials [82].

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS). The post-CAR-T HLH-like form, codified as IEC-HS in the ASTCT consensus, is characterized by uncontrolled macrophage hyperactivation, which is thought to be sustained by a transactivation loop between T lymphocytes and macrophages with the protracted release of IFN-γ, IL-18, and IL-6; it typically emerges as CRS is resolving [83]. Renal involvement in IEC-HS has been described mainly as part of multi-organ dysfunction, and its specific mechanisms remain to be defined. Distinguishing it from severe CRS is difficult, because high fever, deep cytopenias, coagulopathy, hyperferritinemia, and multi-organ dysfunction overlap [84]. A very high ferritin level, marked hypofibrinogenemia, hepatosplenomegaly, and the finding of bone marrow hemophagocytosis on biopsy point toward IEC-HS. Treatment is based on high-dose corticosteroids and early administration of anakinra (anti-IL-1), with further immunosuppressive lines in refractory forms [85].

Local Immune Effector Cell-Associated Toxicity Syndrome (LICATS). Beyond the systemic syndromes, a local and self-limited toxicity specific to the autoimmune setting has been described. LICATS consists of transient, organ-specific inflammation that arises during B-cell aplasia and is confined to organs already affected by the underlying autoimmune disease; it is distinct from CRS and does not represent a disease flare [86]. In an observational cohort of 39 patients, LICATS affected 30 (77%), with the skin and the kidneys among the most involved organs; renal manifestations included a rise in serum creatinine or proteinuria, and nearly all events were mild (grade 1–2) and resolved without sequelae [86]. Its recognition is relevant to nephrological monitoring, since LICATS should not by itself prompt reintroduction of immunosuppression.

4.2. Acute Kidney Injury Associated with CAR-T Cells: Epidemiology and Mechanisms

Post-CAR-T AKI is reported with a frequency ranging between 5% and 33%. Much of this variability comes from how AKI is defined; the underlying malignancy and the CAR-T construct also contribute [87]. The damage is multifactorial and, in most reported series, appears to primarily reflect the systemic manifestations of CRS and TLS, with possible additional contributions from sepsis, nephrotoxic drugs and, less often, direct immune-mediated glomerular injury [74,88]. In addition to pre-renal forms and acute tubular necrosis, individual case reports describe a collapsing glomerulopathy close to the infusion, whose immunopathological mechanisms remain unclear [89]. Lymphodepletion with fludarabine and cyclophosphamide is not inherently nephrotoxic. However, fludarabine requires dosage adjustment in renal impairment, where reduced clearance favors its accumulation and can accentuate systemic toxicity [90,91].

The risk of AKI increases with reduced baseline eGFR, advanced age, preexisting CKD, poor performance status, and advanced neoplastic disease [88,91]. In 111 patients with relapsed/refractory multiple myeloma, AKI occurred in 12.1% within 30 days of infusion, with baseline tumor burden as an independent risk factor; short-term renal prognosis nevertheless remained good, with complete resolution in 84.6% of cases (11 out of 13 patients) within one month [92]. In the single-center analysis by Boardman et al., involving 399 patients with non-Hodgkin lymphoma treated with anti-CD19 constructs, AKI of any grade affected 10% of patients and KDIGO grade ≥ 2 affected 5%. Pre-renal etiology also prevailed in this cohort (72%), and the primary prognostic finding is the link between post-infusion AKI and reduced overall survival [93]. More recent series confirm the picture: a prospective study documented a transient increase in proteinuria after infusion, with AKI in 19% of patients [94]; a retrospective analysis reaffirmed the weight of renal comorbidities and electrolyte disorders among the factors associated with AKI [95].

4.3. Anti-CD19 and Anti-BCMA CAR-T Cells in Patients with Impaired Renal Function or on Dialysis

The underrepresentation of patients with impaired renal function in registration trials has been partially filled by real-world studies in severe or end-stage renal failure. Sidana et al. evaluated ide-cel in cohorts with MM and reduced renal function, with results and tolerability in line with controls with preserved renal function [67]. Independently of renal function, product choice also matters: in the real-world comparison by Atanackovic et al., involving 39 patients with MM, cilta-cel was more effective hematologically, at the cost of more infections and atypical neurotoxicities [68]. Pak et al. treated two patients on chronic hemodialysis with cilta-cel, both with a hematological response and without CRS or ICANS [69]; Swamy et al. reported five dialysis-dependent patients with MM [70]. The feasibility of anti-CD19 CAR-T cells even with impaired renal function had already been shown by Wood et al. in B-cell-mediated lymphoproliferative malignancies [71]. To these are added larger real-world studies: in the US Multiple Myeloma Immunotherapy Research Consortium (USMIRC). multicenter study on 223 patients, anti-BCMA therapy maintained comparable efficacy in the presence of baseline renal impairment with a creatinine clearance below 45 mL/min, despite higher neurotoxicity and infections [96]; a propensity-matched database analysis extended the observation to patients with severe renal dysfunction or who were dialysis-dependent [97]. These findings should be read with the limitations of retrospective and real-world evidence in mind. Patients with renal impairment who reached infusion had already passed the selection of the treating centre, so that referral and survivorship bias are likely; renal function was defined with heterogeneous thresholds and estimating equations; dialysis-dependent patients remain few; outcome ascertainment, toxicity grading, and follow-up duration varied among centres; and propensity matching can balance only the covariates that were measured. Comparable efficacy in these cohorts therefore indicates feasibility in selected patients and does not establish equivalence with the trial population.

4.4. Delayed Toxicity: Cytopenias, Infections, and Secondary Malignancies

Immune Effector Cell-Associated Hematotoxicity (ICAHT) usually manifests as prolonged cytopenia in the weeks or months after infusion. The consensus classification of the EHA (European Hematology Association)/EBMT distinguishes early ICAHT, within the first 30 days, from delayed ICAHT, beyond the 30th day; this temporal threshold guides hematological monitoring and antimicrobial prophylaxis [98]. Infections are favored by prolonged lymphopenia, persistent B-cell aplasia, and hypogammaglobulinemia.

In the long term, between 2023 and 2024, suspicion of secondary T-cell malignancies after anti-CD19 and anti-BCMA CAR-T cell therapies emerged. The US Food and Drug Administration (FDA) responded with a boxed warning extended to the entire class of commercial products [99]. The analysis by Elsallab et al. on the FAERS (FDA Adverse Event Reporting System) database places secondary malignancies at 4.3% of adverse event reports (536 cases out of 12,394 reports), with an excess of T-cell lymphoproliferative disorders and myeloid malignancies [100]. In immune-mediated patients, who are young and have a long life expectancy, this risk necessitates dedicated pre-treatment counseling and prolonged clinical-laboratory surveillance [14]. At the European regulatory level, the European Medicines Agency (EMA) evaluated 38 suspected cases of T-cell malignancy following CAR-T therapy, with a reporting rate on the order of one case per 1000 treated patients [101].

4.5. Candidate Selection, Management, and Prevention of AKI

Faced with the rapid spread of these therapies, the EBMT formalized indications for autoimmune diseases in a position statement dedicated to Practice Harmonization, which sets candidate selection criteria, center requirements, and the follow-up structure [102]. These recommendations currently guide prescriptive appropriateness in onco-hematology as well as in multi-organ autoimmune diseases [103].

Prior to treatment, the candidate must be evaluated from a nephrological standpoint: baseline renal function, screening for microalbuminuria or proteinuria, and biochemical markers of TLS risk [104,105]. During and after infusion, it is important to preserve volemia with intravenous hydration using isotonic crystalloids and close hemodynamic monitoring, which is associated with a lower risk of severe AKI [104]. Early recognition of CRS and timely treatment with tocilizumab and corticosteroids reduce capillary leak and limit renal damage [104]; in refractory forms, anakinra (anti-IL-1) represents an additional option [106]. The sequence of nephrological evaluation, peri-infusion prevention, syndrome-specific management, and follow-up is summarized in Figure 1.

Figure 1. Nephrological pathway of the patient treated with CAR-T cells. The diagram follows the clinical course in five steps. Abbreviations: AKI, acute kidney injury; ASTCT, American Society for Transplantation and Cellular Therapy; ATN, acute tubular necrosis; CKD, chronic kidney disease; CRS, cytokine release syndrome; EBMT, European Society for Blood and Marrow Transplantation; eGFR, estimated glomerular filtration rate; FDA, Food and Drug Administration; ICAHT, immune effector cell-associated hematotoxicity; ICANS, immune effector cell-associated neurotoxicity syndrome; IEC-HS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome; IgG, immunoglobulin G; KDIGO, Kidney Disease: Improving Global Outcomes; LDH, lactate dehydrogenase; LICATS, local immune effector cell-associated toxicity syndrome; RRT, renal replacement therapy; TLS, tumor lysis syndrome; TMA, thrombotic microangiopathy.

Once AKI is established, supportive care includes the discontinuation of nephrotoxic drugs, control of mean arterial pressure, and management of fluid balance [105]. Recourse to renal replacement therapy follows the criteria for critical AKI: refractory hyperkalemia, severe metabolic acidosis, and fluid overload non-responsive to diuretics [105]. In the case series by Gutgarts et al., 14 out of 46 patients (30%) developed AKI of any grade within 100 days; among patients alive at 30 days, almost all (10 out of 11, 91%) returned to baseline values [107]. Advanced stages, KDIGO grades 2 and 3, conversely remain independently associated with longer hospital stays, greater use of intensive care, and reduced overall survival [93]. Therefore, a prolonged and well-structured nephrological follow-up is needed, capable of detecting in a timely manner any progression of AKI CKD [108] Table 2.

Table 2. Management of AKI related to CAR-T therapy.

Etiology	Mechanism of Renal Injury	First-Line Management	Nephrological Monitoring/Notes
AKI associated with CRS	Systemic vasodilation and capillary leak reduce effective circulating volume, causing pre-renal AKI; prolonged hypoperfusion progresses to acute tubular necrosis	Crystalloids, vasopressors, tocilizumab (anti-IL-6), corticosteroids; anakinra in refractory cases [104,105,106]	Urine output and hemodynamic support; avoid concurrent nephrotoxins
AKI associated with TLS	Rapid tumor lysis releases potassium, phosphate and nucleic acids; uric acid and calcium-phosphate crystals precipitate in the tubules, with reflex renal vasoconstriction	Hydration, rasburicase, electrolyte correction, renal replacement therapy if indicated [80,81]	Serial potassium, phosphate and uric acid; predefined RRT threshold
AKI in IEC-HS (HLH-like)	Macrophage hyperactivation with sustained release of IFN-γ, IL-18 and IL-6 and multi-organ dysfunction	High-dose corticosteroids and early anakinra (anti-IL-1); further immunosuppression in refractory forms [83,85]	Ferritin, fibrinogen, cytopenias and hepatic function
Infectious/nephrotoxic AKI	Sepsis-related hemodynamic and tubular injury; direct nephrotoxicity from iodinated contrast or nephrotoxic antimicrobials	Targeted antibiotic therapy, volume resuscitation, withdrawal of nephrotoxic drugs [105,108]	Drug-level monitoring; minimize iodinated contrast exposure
Persistent AKI or transition to CKD	Incomplete recovery and maladaptive repair	Dedicated nephrological follow-up, cardio-renal optimization [93,108]	Longitudinal eGFR and proteinuria surveillance to detect AKI-to-CKD progression

AKI, acute kidney injury; CRS, cytokine release syndrome; TLS, tumor lysis syndrome; IEC-HS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome; HLH, hemophagocytic lymphohistiocytosis; IL, interleukin; IFN, interferon; RRT, renal replacement therapy; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.

5. Conclusions

For immune-mediated renal and systemic disease, CAR-T cells are a promising option, but the evidence remains uneven and, in most indications, preliminary. It is strongest in SLE and refractory lupus nephritis, where single-arm early-phase trials and structured series now converge, although without any randomised comparison [12,30,37]. In AAV, it is limited to single case reports [53,54,55]; in membranous nephropathy, direct clinical data are lacking despite a coherent rationale [46], and in MGRS, no clinical experience appears to have been published. The largest body of data concerns plasma cell dyscrasias with renal involvement, where retrospective real-world studies suggest that anti-BCMA CAR-T cells can be delivered to selected patients with low eGFR or on dialysis, with the selection and ascertainment biases inherent to that design [67,70,71].

The optimal positioning of autologous CAR-T cells relative to alternative platforms remains undefined. Bispecific T-cell engagers such as teclistamab [63] already offer an off-the-shelf route, so far on the basis of case series alone, while allogeneic products and in vivo engineering [23] may overcome the manufacturing constraints of the autologous product; the place of each in the treatment sequence is unresolved. These options must all be weighed against the FDA boxed warning on secondary T-cell malignancies [99,100]. In a young autoimmune population with a long life expectancy, this signal warrants careful clinical and ethical counseling before treatment.

Prospective, multicenter data in patients with established kidney disease, who were excluded from the registration trials, are now needed. Selection criteria and monitoring protocols should derive from such studies rather than be extrapolated from onco-hematology [109]. This will require close and continuous communication between nephrology units and the accredited cell-therapy centers that deliver the product [14,104].