Daratumumab as rescue therapy in refractory recurrent FSGS after kidney transplantation: a case series

Abstract

Recurrent focal segmental glomerulosclerosis (FSGS) remains one of the most challenging complications after kidney transplantation, frequently leading to early graft dysfunction and premature graft loss¹ -³. Despite advances in immunosuppressive therapy, treatment options remain limited, particularly in patients who do not respondrefractory to standard approaches such astherapies including plasmapheresis and B-cell-depleting strategies. In this context, plasma celltargeted therapies such as daratumumab have recently emerged as a promising therapeutic strategy in refractory cases⁴ -⁷. However, current evidence remains is limited to small case series and heterogeneous cohorts, and the effectiveness of daratumumab across different clinical scenarios is not yet well definedremains unclear.We report a consecutive single-center case series of six kidney transplant recipients with biopsyproven recurrent FSGS who were refractory to conventional treatment and subsequently received daratumumab as rescue therapy. All patients had kidney failure due to primary FSGS and experiencedwith biopsy-confirmed recurrence after transplantation. Electron microscopy demonstrated a podocytopathy with diffuse podocyte foot process effacement in all cases. Genetic testing using a targeted NGS panel was performed in four patients and did not reveal a genetic cause of FSGS.All patients received induction therapy with basiliximab followed by standard triple maintenance immunosuppression consisting of tacrolimus, mycophenolate mofetil, and corticosteroids. All patients were dialysis-dependent and anuric prior to transplantation, no pre-emptive transplantations were performed; one patient had previously undergone kidney transplantation. Following biopsy-confirmed recurrence of FSGS, five patients were switched from tacrolimus to cyclosporine. All patients received anti-proteinuric therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at maximally tolerated doses. One patient additionally received an SGLT2-inhibitor.Prior to daratumumab, all patients underwent treatment were treated with plasmapheresis and anti-CD20 therapy (rituximab in all cases with escalation to obinutuzumab in one patientand obinutuzumab in one case), reflecting current standard approaches in this setting, but failed to achieve sustained remission. The timing of treatment Treatment timing initiation varied between patients, reflecting real-world clinical practice. The interval between initiation of anti-CD20 therapy and the first daratumumab administration was a median of 110 days (IQR 72-133).Daratumumab was administered subcutaneously at a fixed dose of 1800 mg, with patients receiving between three and six administrations. MThe median follow-up after the last daratumumab administration was 12.3 months (IQR 11.0-14.7).Following daratumumab treatment, four patients achieved complete remission and two achieved partial remission, accompanied by stabilization or improvement of graft function. These responses were observed despite prior failure of multimodal therapy and may therefore represent reflect clinically meaningful treatment effects in a highly refractory population., likely driven by a synergistic effect of B-cell and plasma cell depletion. One patient experienced a relapse 12 months after treatment but regained complete remission after a single additional dose of daratumumab, suggesting that retreatment may be effective in selected cases. Infectious complications, including cytomegalovirus infection, hepatitis E virus infection, herpes zoster, and bacterial infections, occurred in three patients. All infections were mild to moderate, managed on anas outpatients basis, and resolved without sequelae, indicating an acceptable safety profile despite intensive immunosuppression.Importantly, our cohort reflects a broad spectrum of clinical presentations and disease trajectories. Recurrence occurred early within days after of transplantation in most patients, consistent with previous reports, but included one patient with delayed clinical progression requiring treatment escalation more than four years postafter -transplantation. Notably, this patient had an early histological recurrence shortly after transplantation but remained clinically stable for severalfour years before developing overt nephrotic syndrome with subsequent graft dysfunction requiring dialysis. This observation highlights the dynamic and heterogeneous nature of recurrent FSGS and suggests that disease activity may evolve over time before manifesting clinically. It also underscores the potential effectiveness of plasma cell-targeted therapy even in advanced and long-standing disease. The longitudinal course of proteinuria and graft function following daratumumab therapy is illustrated in Figure 1.In contrast to previously reported case series, our observations emphasize that daratumumab may be effectivehave potential across a broader range of clinical scenarios than previously appreciated. While prior reports have primarily focused on early recurrence or highly selected refractory cases, our consecutive cohort captures both early and delayed treatment settings as well as and diverse disease trajectories within a clearly defined salvage setting after failure of standard therapies. This real-world cohort therefore provides additional insight into the potential role of plasma cell-targeted therapy in routine clinical practice.Recent multicenter analyses have reported encouraging remission rates with combined B-cell and plasma cell-targeted strategies⁷. Our findings are consistent with these observations but extend them by providing detailed longitudinal clinical data in a well-characterized cohort, allowing a more granular and clinically relevant assessment of treatment response. In particular, the inclusion of patients with delayed disease progression and prolonged disease courses prior to treatment initiation suggests that the therapeutic window for daratumumab may be broader than previously assumed.Circulating anti-nephrin autoantibodies have recently been proposed as potential biomarkers and possible mediators of recurrent podocytopathies⁸ , ⁹. In our cohort, aAnti-nephrin autoantibodies were serologically assessed in all patients at the time of recurrence during active nephrotic disease, and and all testedwere negative in all cases. These findings argue against a dominant role of antinephrin-mediated mechanisms in these cases and further underscore the biological heterogeneity of recurrent FSGS. They also suggest that additional, as yet unidentified circulating factors may contribute to disease pathogenesis in a subset of patients. However, additional podocyte-associated markers were not systematically assessed and therefore cannot be evaluated in this cohort.The mechanism of action of daratumumab in this setting likely extends beyond plasma cell depletion. CD38 is expressed on multiple immune cell subsets, including plasma cells, activated B cells, T cells, natural killer cells, and dendritic cells. Targeting CD38 may therefore exert broader immunomodulatory effects that influence influencing the production of circulating permeability factors implicated in disease pathogenesis¹⁰. While the precise mechanisms remain incompletely understood, the consistent clinical responses observed in our cohort support further investigation of CD38-directed therapies in recurrent FSGS.Our study has several limitations, including its retrospective design, small sample size, and relatively short follow-up, and lack of systematic B-cell and plasma cell count data, which precludinge conclusions regarding long-term durability of response and graft survivaloutcomes. In addition, treatment strategies were not standardized but reflected real-world clinical decision-makingpractice, and the. The absence of a control group limits attribution of treatment effects to daratumumab alonethe ability to isolate the specific contribution of daratumumab within a multimodal treatment approach. Nevertheless, the consistent clinical responses observed across a heterogeneous patient population provide clinically relevant insights into treatment effectiveness in a defined salvage setting.In conclusion, daratumumab may represent a promising rescue therapy in patients with recurrent FSGS after kidney transplantation who are refractory to standard treatment. Our findings suggest potential benefit across diverse clinical scenarios, including delayed treatment escalation and prolonged disease courses, and support further evaluation in prospective, multicenter studies. A) Urine protein-to-creatinine ratio (UPCR; g/g) values are shown at peak proteinuria at recurrence, after completion of treatment, and during follow-up. Peak values were obtained prior to daratumumab initiation, although some patients were already receiving plasmapheresis or rituximab, with escalation to /obinutuzumab in one patient. Post-treatment values were assessed at a median of 16 days (IQR 7-18) after the last daratumumab administration. Four patients achieved complete remission (<0.5 g/g creatinine), and two achieved partial remission (<2 g/g creatinine with ≥50% reduction in proteinuria). Patient 1 experienced a relapse 12 months after the last daratumumab dose and received a single additional administration. B) Serum creatinine (mg/dL) values are shown at peak levels at recurrence, after completion of treatment, and during follow-up. Treatment consisted of plasmapheresis, rituximab/obinutuzumab, and daratumumab. Follow-up time points at 1, 2, and 3 months and thereafter refer to the interval since the last daratumumab administration.B) Estimated glomerular filtration rate (eGFR; mL/min/1.73 m²) values are shown at recurrence, after completion of treatment, and during followup. eGFR was calculated using the CKD-EPI equation. Treatment consisted of plasmapheresis, rituximab/obinutuzumab, and daratumumab. Follow-up time points at 1, 2, and 3 months and thereafter refer to the interval since the last daratumumab administration.