Subcutaneous ofatumumab in recurrent focal segmental glomerulosclerosis after kidney transplantation

ABSTRACT

Background

Recurrent focal segmental glomerulosclerosis (rFSGS) is a severe condition occurring after kidney transplantation (KT) and has a high graft loss rate. Its incidence is reported as up to 55% of KTs, typically diagnosed within 1.5 months post-transplant. Treatment typically involves plasmapheresis, with adjunctive rituximab therapy, achieving partial or complete remission in up to 57% of patients. We report the case of a paediatric patient who experienced two episodes of rFSGS post-KT, presenting with acute kidney injury (AKI). The second episode was treated with subcutaneous ofatumumab with complete remission.

Methods

The treatment protocol included four weekly plasmapheresis treatments, with Kesimpta administered subcutaneously at a dose of 20 mg twice weekly, given at the end of the plasmapheresis session. Plasmapheresis was then discontinued for 48–72 h following Kesimpta administration. CD20 levels were followed.

Results

A KT patient experienced a second rFSGS, presenting with massive proteinuria of 13 g/day, 3 years post-transplant. Due to severe allergic reaction to rituximab during the first recurrence, she was treated with a combination of plasmapheresis and Kesimpta during the second episode. CD20 levels were undetected within two doses of Kesimpta treatment. Full remission and AKI resolved 1 month after initiation of this treatment. There were no severe adverse effects of the combined protocol.

Conclusions

We propose a combination treatment of subcutaneous ofatumumab and intensive plasmapheresis, with CD19 and CD20 levels monitored regularly, might be safe and effective in rFSGS in KT patients.

Graphical Abstract

Graphical Abstract.

KEY LEARNING POINTS.

What was known:

• Recurrent FSGS (rFSGS) occurs in >50% of kidney transplant patients with primary FSGS.

• The recurrence of FSGS carries a high rate of graft loss.

This study adds:

• Currently there are no guidelines to treatment for rFSGS.

• The combination of plasmapheresis with rituximab is widely used.

Potential impact:

• Subcutaneous ofatumumab in combination with high-dose plasmapheresis showed complete remission and no adverse effects in our patient.

INTRODUCTION

Primary focal segmental glomerulosclerosis (FSGS) manifests as idiopathic nephrotic syndrome, necessitating the exclusion of secondary causes such as genetic factors, viral infections or drug-related adverse effects. In paediatric patients, primary FSGS is treated with immunomodulatory drugs, including glucocorticoids, calcineurin inhibitors (CNIs), anti-metabolites like mycophenolate mofetil (MMF) and rituximab [1].

Recurrent FSGS (rFSGS) is a devastating disease with high rates of graft loss. The incidence of rFSGS is challenging to assess and varies significantly, with estimates ranging from 17 to 55%. This wide variability is due to the rarity of cases and the small sample sizes reported [1, 2]. The most reliable data derives from the multicentre Post-Transplant Glomerular Disease (TANGO) cohort study [3], which included 11 742 adult kidney transplant recipients, 176 of whom had biopsy-confirmed primary FSGS. Among these, 57 patients (32%) experienced FSGS recurrence, typically within a median time of 1.5 months post-transplantation.

Risk factors for post-transplant FSGS recurrence include younger age at primary disease onset, rapid progression to end-stage kidney disease (ESKD), Caucasian ethnicity, previous native kidney nephrectomy, lower body mass index (BMI) at the time of transplantation and a history of recurrence in a previous allograft [1, 2]. Notably, the histologic subtype of FSGS in the native kidney, human leucocyte antigen mismatch and the choice of immunosuppressive therapy for transplantation have not been shown to significantly influence recurrence risk [2].

rFSGS often leads to graft loss, with rates as high as 50% [2, 3]. Treatment most commonly involves plasmapheresis, and in some reports, adjunctive therapy with rituximab has been utilized, with partial or complete remission in up to 57% of patients [3].

Ofatumumab is a human monoclonal antibody that targets CD20 on B lymphocytes, leading to selective B cell depletion. Unlike rituximab, ofatumumab binds to a distinct CD20 epitope with higher affinity and induces stronger antibody-dependent cell-mediated cytotoxicity. Ofatumumab has been approved by the US Food and Drug Administration for treating relapsing forms of multiple sclerosis (MS) and chronic lymphocytic leukaemia (CLL) in adults and is contraindicated in patients with active hepatitis B virus infection. Intravenous use of ofatumumab has been reported in small case series for treating rFSGS [4–9]. Subcutaneous (SC) administration of ofatumumab has been evaluated in several clinical trials for MS [10–12], demonstrating both efficacy and a favourable safety profile, even in patients previously treated with rituximab. The SC route offers the advantage of self-administration at home by patients or their caregivers, potentially reducing the need for hospital admissions.

We report the case of a paediatric patient who experienced two episodes of rFSGS after kidney transplantation, both accompanied by severe acute kidney injury (AKI). The patient was treated with plasmapheresis and SC ofatumumab (Kesimpta), due to a previous severe serum sickness reaction to rituximab. Kesimpta treatment resulted in complete remission, thereby forming the basis of our proposed protocol.

MATERIALS AND METHODS

Ofatumumab was chosen for its humanized nature, thus reducing the risk for allergic reactions. Our treatment protocol included four weekly plasmapheresis treatments, with Kesimpta administered subcutaneously at a dose of 20 mg twice weekly, given at the end of the scheduled plasmapheresis session. Plasmapheresis was then discontinued for 48–72 h following Kesimpta administration. CD20 levels were tested after two doses of Kesimpta. Subsequently, Kesimpta dosing frequency was reduced to once weekly, overall completing a 6-week treatment course.

CLINICAL CASE

Our patient, a 19-year-old female kidney transplant recipient, was diagnosed with primary idiopathic steroid-resistant nephrotic syndrome at 22 months of age. Initially steroid-dependent, she required second- and third-line immunomodulatory treatments. An initial kidney biopsy was consistent with minimal change disease. Ultimately she developed resistance to immunosuppressive treatments, including high-dose steroids, cyclophosphamide, CNIs, MMF and rituximab. Treatment with rituximab led to life-threatening serum sickness reactions, characterized by high fever, urticarial rash and hypotension, occurring 2 weeks after the initial dose. At the age of 14 years she progressed to ESKD, undergoing haemodialysis for 2 years before receiving a deceased-donor kidney transplant. Induction therapy included basiliximab and high-dose glucocorticoids, while maintenance therapy consisted of low-dose oral glucocorticoids, steroids, tacrolimus and MMF. At 48 h post-transplantation she rapidly developed a recurrence of nephrotic syndrome, complicated by AKI with oliguria and deteriorating glomerular filtration rate (GFR), which was unresponsive to high-dose steroid pulse therapy and daily plasmapheresis. She experienced severe oedema and massive proteinuria, ranging from 30 to 40 g/day. A transplant kidney biopsy confirmed recurrence of FSGS.

Due to plasmapheresis dependence, she received two doses of rituximab with a desensitization protocol. However, serum sickness recurred. Subsequently she achieved prolonged complete remission from FSGS and the AKI subsided, allowing for gradual weaning from plasmapheresis.

Three years later she experienced a second recurrence of FSGS, presenting with massive proteinuria of 13 g/day, but with no GFR compromise. Plasmapheresis treatment was rapidly initiated. However, following temporary cessation of plasmapheresis secondary to a central venous catheter bacterial infection, she developed persistent massive proteinuria, oedema and worsening GFR. Donor-specific antibodies tested negative. Urine polymerase chain reaction for BK virus was also negative. A transplant biopsy showed no evidence of humoral or cell-mediated rejection, as it was C4D negative, with no tubulitis or glomerulitis, and immunofluorescence was negative. Electron microscopy revealed podocyte effacement, compatible with FSGS recurrence. Intensified plasmapheresis at four sessions per week was resumed, with no improvement in proteinuria or GFR. Kesimpta was initiated at a dose of 20 mg, administered twice weekly for the first 2 weeks, following a modified protocol, based on the standard MS regimen. Of note, the usual MS protocol prescribes Kesimpta at 20 mg once weekly; however, due to concerns regarding potentially reduced blood levels caused by plasmapheresis, which was being performed four times weekly, the dosing interval was shortened during the initial 2 weeks. Starting from the third week of treatment, the dosing of Kesimpta was adjusted to 20 mg once weekly, as CD20 levels decreased and eventually became undetectable.

Ten days after resuming plasmapheresis and starting Kesimpta, a 24-h urine collection showed a significant reduction of proteinuria to 1.6 g/day, with a protein:creatinine ratio of 2.5 mg/mg (Figs. 1 and 2). However, AKI showed no initial improvement, with creatinine levels remaining at ≈3.7–4 mg/dl (eGFR of 16–18 ml/min) (Fig. 3).

Figure 1:

Daily urinary protein extraction.

Figure 2:

Urine protein:creatinine ratio (mg/g).

As the CD20 level was undetectable after the first two doses of Kesimpta, dosing was tapered to once weekly, for a total period of 6 weeks. Unfortunately, CD19 levels were not available at the time. Side effects included nausea, vomiting and headaches, resolving spontaneously within 48 h. After 4 weeks from the initiation of Kesimpta therapy, the GFR improved to 70 ml/min/1.73 m² and 24-h urinary protein excretion decreased to 250 mg/day. Within 6  weeks of Kesimpta initiation, the patient exhibited complete remission of proteinuria, with further improvement of her GFR to 85 ml/min/1.73 m². Further improvement of the GFR occurred over the following 4 months, to a GFR of 100 ml/min/1.73 m². Prolonged remission is currently sustained after cessation of plasmapheresis therapy for the past 4 months.

DISCUSSION

rFSGS poses the highest risk of graft failure among glomerular diseases, with a relative risk of 2.25 [13]. Disease recurrence typically occurs within the first 2 years post-transplantation, with graft failure rates reaching 50% within 5 years [14]. There is no standardized treatment protocol for rFSGS after kidney transplantation. Various treatment protocols, including plasmapheresis, immunoadsorption and immunosuppression therapies have shown differing success rates. The latest consensus guidelines by Raina et al. [1] suggest prompt treatment with intensive plasmapheresis, with exchanges of 1–1.5 plasma volumes against albumin or haemofiltrate and using plasma only when fibrinogen in low. Most reported regimens show ≈50% remission on a combination of plasmapheresis and rituximab [15].

Ofatumumab, a humanized anti-CD20 monoclonal antibody, binds the CD20 target via the Fab domain at a distinct epitope located nearest to the cell surface, offering a more extensive binding site compared with other anti-CD20 antibodies [16]. Previous reports have described ofatumumab as a rescue treatment for rFSGS in patients who exhibited an allergic reaction to rituximab [4, 5]. In a mouse model, Torres et al. [17] demonstrated that SC delivery of ofatumumab enhances lymph node targeting compared with intravenous (IV) administration. This may improve drug efficacy, as lymph nodes are critical key sites where pathogenic B and T cells interact.

Our patient, who had a previous serum sickness reaction to rituximab, was treated with a desensitization protocol, without success. Ofatumumab was chosen due to its humanized nature, anticipating fewer allergic reactions. Thus far, reports on the use of ofatumumab for this indication have been restricted to IV administration, typically involving high doses [4–7]. To the best of our knowledge, this is the first case of rFSGS treated with SC ofatumumab.

We propose a protocol involving twice-weekly dosing of SC ofatumumab at a dose of 20 mg during intensive plasmapheresis, with CD20 and CD19 levels monitored regularly, as CD20 levels alone might be undetected after this treatment due to saturation of CD20 by ofatumumab. After 2 weeks of SC ofatumumab therapy, or once CD19 and CD20 reach undetectable levels, dosing is reduced to once weekly for a total of 6 weeks. Under this regimen, our patient experienced no severe adverse effects.

The SC administration of ofatumumab allows for outpatient treatment, eliminating the need for hospitalization. This approach also reduces the risk of a rapid increase in blood levels of the drug, which can occur with IV administration and potentially lead to severe allergic reactions, as the medication is absorbed more gradually.

Further clinical trials using this proposed protocol may help refine the appropriate dosage and provide data regarding the remission rates of rFSGS in response to ofatumumab therapy.

FUNDING

None declared.

AUTHORS’ CONTRIBUTIONS

S.P. is the author of the manuscript. D.M. edited the manuscript. All other authors cared for study patients.

DATA AVAILABILITY STATEMENT

The data underlying this article are available in the article.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.