Perioperative Use of Efgartigimod Alfa, a Neonatal Fc Receptor Antagonist, to Reduce Antiphospholipid Antibody Titers and Thrombotic Risk in a Kidney Transplant Recipient

Abstract

Antiphospholipid syndrome (APS) is associated with an increased risk of thrombotic complications after kidney transplantation, particularly in patients with persistently elevated and triple-positive antiphospholipid antibodies (aPLs). Management of APS in kidney transplantation relies primarily on perioperative anticoagulation; however, thrombotic events may still occur despite appropriate therapy in patients with high-risk aPLs. We report the case of a 49-year-old woman with systemic lupus erythematosus–associated APS and persistently triple-positive aPLs who underwent living donor kidney transplantation. Because of her high thrombotic risk, perioperative immunoglobulin G--lowering therapy with the neonatal Fc receptor antagonist efgartigimod alfa was administered in addition to therapeutic anticoagulation. Treatment with efgartigimod alfa was associated with marked reductions in anticardiolipin and anti–β2-glycoprotein I antibody levels before transplantation, conversion of lupus anticoagulant to negative after transplantation, and sustained suppression of aPLs during the early posttransplant period. Kidney transplantation was successful with stable graft function during follow-up. To our knowledge, this represents the first reported use of efgartigimod alfa to reduce aPLs in the perioperative management of APS in kidney transplantation.

Introduction

Antiphospholipid syndrome (APS) confers an increased risk of arterial and venous thrombotic events after kidney transplantation, particularly in patients with persistently elevated and triple-positive antiphospholipid antibodies (aPLs). Systemic anticoagulation remains the principal perioperative strategy used to reduce thrombotic risk in transplant candidates with APS; however, thrombotic events may still occur despite appropriate therapy, especially in those at highest immunologic risk.¹

Adjunctive strategies to reduce circulating aPL levels have been reported infrequently. Limited case reports describe perioperative plasmapheresis, often followed by rapid antibody rebound.² In addition, a single report described the use of eculizumab in 3 kidney transplant recipients to mitigate the risk of APS and enable successful kidney transplantation.³

In this study, we describe the perioperative use of efgartigimod alfa, a neonatal Fc receptor (FcRn) antagonist, to reduce aPL levels in a high-risk kidney transplant recipient with APS, resulting in sustained antibody suppression during the early posttransplant period. To our knowledge, this represents the first reported use of efgartigimod alfa for the perioperative management of APS in a kidney transplant recipient.

Case Report

A 49-year-old woman with kidney failure receiving kidney replacement therapy secondary to lupus nephritis and systemic lupus erythematosus–associated APS underwent evaluation for living donor kidney transplantation from her mother. APS had been diagnosed in 1994 following an embolic cerebrovascular accident caused by an intracardiac thrombus that required open-heart surgery, after which she was maintained on long-term warfarin anticoagulation. She subsequently developed kidney failure, requiring hemodialysis in 2022. At evaluation, she demonstrated triple-positive aPLs, including lupus anticoagulant (LA), anticardiolipin (aCL), and anti–β2-glycoprotein I (aβ2GPI), with moderate-to-high aCL and aβ2GPI titers. aPL titer results at the time of APS diagnosis were not available. The earliest available comprehensive testing, obtained approximately 5.5 months before transplantation while the patient was receiving warfarin (international normalized ratio 3.1), demonstrated positive LA and elevated aPL titers, including an aCL titer of 70 IgG phospholipid units (GPL) and an aβ2GPI titer of 92.8 standard IgG units (SGU).

Her mother, the only available donor, was 73 years old with no significant medical history. The 4-hour iohexol plasma clearance–measured glomerular filtration rate (GFR) was 67 mL/min/1.73 m². The donor was mismatched with the recipient at 2 human leukocyte antigen (HLA)-DR, 1 HLA-DQ, and 1 HLA-DP loci, with no HLA class I mismatches. The recipient had no donor-specific antibodies, and both B-cell and T-cell flow cytometry crossmatches were negative. Panel reactive antibody levels were 11% for class I and 15% for class II. Both the donor and the recipient were cytomegalovirus and Epstein-Barr virus seropositive.

Given prior arterial thrombosis, triple-positive aPLs, and elevated titers, she was considered at high risk for perioperative and early posttransplant thrombotic complications. Accordingly, a perioperative strategy to reduce circulating aPLs was pursued in addition to therapeutic anticoagulation. An FcRn antagonist was selected to achieve targeted antibody reduction because her aPLs were exclusively of the immunoglobulin (Ig)G isotype.⁴

The patient was admitted 8 days before transplantation (day -8). Warfarin was discontinued, and bridging anticoagulation with intravenous heparin was initiated once the international normalized ratio decreased below the therapeutic range. Heparin was held before surgery and restarted after transplantation, with subsequent transition back to warfarin. Efgartigimod alfa (10 mg/kg) was administered on day -8 and day -1, with an additional dose on posttransplant day +6. Induction immunosuppression consisted of methylprednisolone and rabbit antithymocyte globulin (Thymoglobulin [Sanofi]) at a cumulative dose of 4.5 mg/kg over 4 days. Maintenance immunosuppression consisted of tacrolimus (target trough 8-10 ng/mL), mycophenolate mofetil 1,000 mg twice daily, and a corticosteroid taper; belatacept (5 mg/kg intravenously) was initiated approximately 1 week after transplantation and continued monthly thereafter. The transplant procedure and immediate postoperative course were uncomplicated. At discharge, serum creatinine was 1.63 mg/dL (estimated GFR 38 mL/min/1.73 m²). One week later, she was readmitted with a urinary tract infection; urine culture grew Enterococcus faecalis and Escherichia coli. The patient received appropriate antibiotic therapy, and the ureteral stent was removed during that admission. At the most recent follow-up approximately 90 days after transplantation, serum creatinine was 1.32 mg/dL (estimated GFR 49 mL/min/1.73 m²). The urine protein-creatinine ratio was 151 mg/g creatinine. Serum IgG decreased to <300 mg/dL approximately 3 weeks after transplantation and gradually recovered without intervention to 740 mg/dL by week 9.

Serial aPL measurements demonstrated a marked reduction in antibody levels. aCL declined from 71 GPL approximately 2 weeks before transplantation to 18 GPL immediately before surgery, and aβ2GPI decreased from 128 SGU to 31.4 SGU over the same interval. LA was positive before transplantation but was first reassessed 1 week afterward, at which time it was negative. Antibody levels remained suppressed throughout the early posttransplant period. At the last follow-up (approximately 90 days posttransplant), aβ2GPI was 38.6 SGU (≈30% of baseline) and aCL was 29 GPL (≈41% of baseline), and LA remained negative. The timing of immunomodulatory therapy and corresponding changes in aPL titers relative to transplant are shown in Fig 1.

Figure 1.

Peritransplant antiphospholipid antibody trends and immunomodulatory therapy. Anticardiolipin immunoglobulin G (IgG) and anti--β2-glycoprotein I IgG levels are plotted according to days relative to transplant (day 0). Light-shaded bands indicate moderate (≥40) and high (≥80) antiphospholipid antibody titers. Horizontal dashed and dotted lines denote the upper limits of normal for anticardiolipin IgG (14 GPL) and anti--β2-glycoprotein I IgG (20 SGU), respectively. Lupus anticoagulant results are shown along the bottom row as filled circles (positive) and open circles (negative); the international normalized ratio at the time of each lupus anticoagulant assessment is shown below the corresponding marker. Blue downward arrows indicate efgartigimod alfa administration, and red downward arrows indicate belatacept administration. The pretransplant measurement shown corresponds to the assessment obtained approximately 2 weeks before transplantation; earlier pretreatment values are described in the text. Abbreviations: aCL, anticardiolipin; anti-β2GPI, anti--β2-glycoprotein I; aPL, antiphospholipid antibody; GPL, IgG phospholipid units; INR, international normalized ratio; LA, lupus anticoagulant; SGU, standard IgG units; ULN, upper limit of normal.

Discussion

APS is an autoimmune disorder characterized by arterial, venous, or microvascular thrombosis and pregnancy morbidity occurring in individuals with persistently detectable aPLs, together with a spectrum of associated nonthrombotic manifestations.⁵ APS may present as a primary disorder occurring in isolation or as a secondary condition associated with another autoimmune disease, most commonly systemic lupus erythematosus.⁵ APS testing includes 2 immunoassays—IgG and/or IgM aCL and aβ2GPI using enzyme-linked immunosorbent assay—and 1 functional coagulation assay for LA.⁶ A persistently positive LA is the aPL most predictive of adverse obstetric and thrombotic outcomes and therefore carries a weight of 5 points in the American College of Rheumatology/European League Against Rheumatism classification criteria. Patients who are triple positive for all aPLs carry the highest risk for thrombotic and obstetric complications. In contrast, isolated low-positive aCL or aβ2GPI antibody results are of uncertain clinical significance and are not included in the American College of Rheumatology/European League Against Rheumatism classification criteria. In addition, IgG aCL and aβ2GPI antibodies are considered more clinically relevant than IgM isotypes. Based on standardized enzyme-linked immunosorbent assay testing, aCL and aβ2GPI antibody levels are categorized as moderate at 40-79 units and high at ≥80 units.⁵

The kidney is a major target organ in both primary and secondary APS. Renal manifestations are detailed in Table 1,^7,8 primarily as defined by pathologic criteria.

Table 1.

Renal Manifestations of APS

Category	Renal Manifestations in APS7,8
Macrovascular complications	Large-vessel involvement: renal artery thrombosis; renal vein thrombosis; renal infarction; renal artery stenosis.
Microvascular (aPL nephropathy)	Renal microvasculature involvement, pathology defined: (a) acute renal vascular or glomerular thrombotic microangiopathy lesions (fibrin thrombi in arterioles or glomeruli without inflammatory cells or immune complexes); and/or (b) chronic vascular or glomerular lesions including arterial or arteriolar organized microthrombi ± recanalization, fibrous or fibrocellular (arterial or arteriolar) occlusions, focal cortical atrophy ± thyroidization, fibrous intimal hyperplasia, or chronic/organized glomerular thrombi.

Note: Macrovascular disease involves large vessels, whereas aPL nephropathy affects the renal microvasculature and is defined by characteristic acute and/or chronic vascular and glomerular pathology.

Abbreviations: aPL, antiphospholipid antibody; APS, antiphospholipid syndrome.

Kidney transplantation remains the optimal therapy for kidney failure requiring kidney replacement therapy; however, recipients with APS—or with aPLs not meeting APS criteria—are at increased risk of graft vessel thrombosis, anticoagulation-related perioperative bleeding, surgery-triggered catastrophic APS, and recurrence or development of aPL nephropathy. In a retrospective cohort of 37 kidney transplant recipients with aPLs (all LA positive), 12 met APS criteria. Mortality after transplantation was higher in patients with APS or aPLs compared with controls, with most APS-related deaths occurring within 3 months. Graft loss occurred in 12 recipients and thrombotic complications were markedly more frequent in aPL-positive patients than controls (59.5% vs 20.3%), including allograft thrombosis and cortical necrosis. Protocol biopsies demonstrated aPL-associated nephropathy in ∼70% of aPL-positive recipients, and the measured GFR among those with functioning grafts was significantly lower than that in controls.¹

The cornerstone of perioperative management in kidney transplant recipients with aPLs or APS is anticoagulation to reduce allograft and arterial thrombosis risk. To date, no studies have shown that pretransplant reduction in aPL titers improves transplant outcomes. Evidence is limited to isolated case reports describing prophylactic plasmapheresis for antibody reduction, lacking controlled comparisons and unable to distinguish the effect of antibody lowering from concomitant anticoagulation.² The task force report from the 16th International Congress on Antiphospholipid Antibodies suggested that anti-FcRn–targeted therapies may represent a promising therapeutic strategy in IgG-mediated diseases and could potentially be useful in APS. Efgartigimod blocks FcRn-mediated IgG recycling, promoting IgG degradation and reducing circulating IgG levels.⁹

Against this background, adjunctive aPL reduction was pursued in addition to standard anticoagulation as an individualized strategy in this high-risk case. Efgartigimod alfa was selected rather than plasmapheresis because it selectively lowers IgG while preserving other Ig classes, avoids an invasive procedure and plasma exposure, does not complicate perioperative heparin anticoagulation required in APS, and may produce slower IgG rebound.^2,10 In a pivotal study of intravenous efgartigimod alfa for generalized myasthenia gravis, acetylcholine receptor antibody levels decreased by 59.6% 7 days after the fourth weekly infusion, with parallel declines in total IgG that gradually returned toward baseline by approximately week 10.¹¹

Efgartigimod alfa was initiated 8 days before the planned transplant, with an additional dose administered the day before surgery. This timing reflected inability to obtain outpatient coverage and preclinical data demonstrating that FcRn antagonism can blunt tissue factor–driven procoagulant activity triggered by pathogenic IgG immune complexes, including complexes containing aβ2GPI.¹²Accordingly, this approach was intended to mitigate aPL-associated risk through complementary mechanisms—reduction of circulating antibodies and attenuation of tissue factor induction by residual antibodies.

We maintained the patient on a quadruple immunosuppressive regimen including belatacept to permit early tacrolimus minimization, with the long-term goal of withdrawal, given the use of an older donor kidney with a suboptimal measured GFR. Belatacept was additionally selected based on the hypothesis that costimulatory blockade might mitigate rebound in aPL titers, supported by prior data showing a lower incidence of de novo donor-specific HLA antibodies with belatacept-based immunosuppression compared with cyclosporine-based regimens.¹³

Both aCL and aβ2GPI levels declined by ∼75% immediately before transplant and remained suppressed thereafter. At the last follow-up (approximately 90 days posttransplant), aβ2GPI measured 38.6 SGU (≈30% of baseline) and aCL 29 GPL (≈41% of baseline), whereas LA remained negative. The magnitude and persistence of antibody suppression were unexpected, as IgG levels typically returned toward baseline about 10 weeks after the last dose of efgartigimod. Consistent with this pattern, non–donor-specific HLA antibodies also decreased but returned to baseline between 55 and 68 days posttransplantation (data not shown). One possible explanation is that a proportion of aPLs are sustained by short-lived plasma cells, whose generation depends on ongoing B-cell activation and differentiation; this process may have been suppressed by posttransplant immunosuppression, thereby limiting the conversion of B cells into antibody-secreting plasma cells. In contrast, HLA antibodies are more commonly sustained by long-lived plasma cells that are relatively resistant to conventional immunosuppressive therapy. This hypothesis is supported by a recent report demonstrating that blinatumomab, a CD19-directed bispecific T-cell engager, eliminated high titers of aCL and aβ2GPI in a patient with refractory immune thrombocytopenia and concomitant APS, whereas no reduction in HLA antibodies was observed in 4 patients who received CD19 chimeric antigen receptor T-cell therapy.^14,15

This report has several limitations. It describes a single case with a favorable outcome, and the magnitude and persistence of aPL antibody reduction may not be reproducible in all patients. Although the multiplicity and titer of aPLs correlate with thrombotic risk, it remains uncertain whether the favorable outcome was related to lowering of aPL levels, inhibition of tissue factor expression suggested by preclinical data, or anticoagulation alone; clarification of the relative contribution of these mechanisms will require randomized controlled studies. In addition, interpretation of the aPL profile should be considered in light of known laboratory limitations. LA testing in anticoagulated patients has recognized limitations because anticoagulants, including vitamin K antagonists such as warfarin, can interfere with clot-based assays and may result in occasional false-positive or false-negative results.¹⁶ However, in this case, LA remained positive both while the patient was receiving warfarin with a therapeutic international normalized ratio and after anticoagulation was withheld and the international normalized ratio normalized, supporting the presence of a true LA rather than an assay artifact.

Nonetheless, these preliminary observations support further evaluation of targeted IgG reduction in selected transplant recipients at high risk for APS/aPL-related complications. Because a substantial proportion of recipients with APS develop aPL nephropathy, as described in the study mentioned earlier in this article, and this condition is likely to reduce graft survival, it would also be of interest to evaluate this strategy in patients with established aPL nephropathy rather than limiting investigation to the perioperative setting for thrombotic risk reduction, in which it could potentially influence disease progression.