Kidney transplantation after chronic active Epstein-Barr virus infection remission

Abstract

Chronic active Epstein-Barr virus is a rare but severe condition characterized by persistent Epstein-Barr virus activation, leading to chronic lymphoproliferation, significant morbidity, and mortality. We report the case of a 34-year-old male with autosomal dominant polycystic kidney disease who achieved chronic active Epstein-Barr virus remission through hematopoietic stem cell transplantation in childhood. Despite long-term remission, the patient developed end-stage renal disease and underwent ABO-incompatible living-donor kidney transplantation. Post-transplant monitoring over 7 months revealed no major complications, including post-transplant lymphoproliferative disorder or rejection, despite transient Epstein-Barr virus-DNA positivity. This case underscores the feasibility of kidney transplantation in chronic active Epstein-Barr virus survivors with careful immunosuppressive management. It also highlights the critical need for vigilant long-term surveillance to mitigate the risks of malignancies and viral reactivation.

Introduction

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that primarily infects B-cell lymphocytes, typically causing asymptomatic infection or mild infectious mononucleosis. In rare cases, EBV leads to severe immune dysfunction characterized by persistent fever, systemic inflammation, and lymphoproliferation [1]. Chronic active EBV infection (CAEBV), which involves clonal expansion of EBV-infected T or natural killer (NK) cells, represents a particularly severe manifestation of EBV [2]. Predominantly reported in China, Japan, and other East Asian regions, CAEBV is associated with a poor prognosis and a high risk of malignant transformation [3].

In the context of kidney transplantation, EBV poses significant risks [4]. Primary infection, particularly in EBV-naive recipients, and reactivation under immunosuppression are major concerns, as both can lead to post-transplant lymphoproliferative disorder (PTLD), a life-threatening complication. Despite advancements in CAEBV treatment, including allogeneic hematopoietic stem cell transplantation (allo-HSCT), no documented cases of kidney transplantation (KTx) in CAEBV survivors exist, leaving the safety and feasibility of KTx in this population unclear.

This report describes the long-term follow-up of a patient previously reported by Hanafusa et al., who achieved CAEBV remission through allo-HSCT and subsequently underwent ABO-incompatible living-donor kidney transplantation for ESKD secondary to autosomal dominant polycystic kidney disease (ADPKD) [5]. This case highlights the challenges of managing immunosuppression to prevent rejection while minimizing the risks of EBV reactivation and PTLD, emphasizing the importance of long-term monitoring and further research.

Case report

A 34-year-old male patient with autosomal dominant polycystic kidney disease (ADPKD) visited our department for a preemptive living-donor kidney transplant (PEKT). The patient was diagnosed with chronic active Epstein-Barr virus infection (CAEBV) at age 5 after presenting with recurrent fevers. He underwent immunotherapy, including interferon, interleukin, and steroids, for 2 years without improvement, followed by multiple courses of chemotherapy, which also failed to achieve remission. At age 9, remission was achieved through allo-HSCT using his HLA-half-matched father as a donor, following myeloablative conditioning with total body irradiation and high-dose chemotherapy. Post-HSCT complications included graft-versus-host disease (GVHD), tacrolimus-related encephalopathy with clonic seizures, and cytomegalovirus (CMV) infection. GVHD was initially controlled by increasing the tacrolimus trough level. However, the patient developed tacrolimus-related encephalopathy post-transplant day 25, which required switching tacrolimus to cyclosporine. CMV infection, which developed 4 months after HSCT, did not improve with ganciclovir treatment and was eventually controlled only after cyclosporine was discontinued 2 weeks later.

Despite these early interventions, the patient developed intractable epilepsy at age 11, progressing to parkinsonism and severe motor disability by age 32. Meanwhile, polycystic kidney disease (PKD) had already been identified by ultrasound prior to HSCT, and proteinuria emerged by age 14, worsening by age 21. Due to worsening proteinuria, an open renal biopsy was performed at the previous hospital, which revealed only sclerotic lesions without active glomerulonephritis, immune or complement deposition, calcineurin inhibitor toxicity, or endothelial injury. Kidney function declined more rapidly than typically observed in ADPKD, leading to ESKD by age 34 (eGFR, 10.0 mL/min/1.73 m²); abdominal CT confirmed bilateral PKD (Fig. 1). Genetic testing revealed a low-frequency mosaic mutation in the PKD1 gene, and the previous report [5], which described the same patient, suggested that chemoradiation therapy for CAEBV may have accelerated renal decline.

Fig. 1.

CT image of bilateral polycystic kidney disease

Although peritoneal dialysis was initially planned after ESKD, he was referred to our hospital for PEKT. Because his father, the HSCT donor, had rectal cancer, we performed ABO-incompatible PEKT with his mother as the donor after confirming negative EBV-PCR and the absence of malignancies over 20 years post-HSCT. The surgical procedure was uneventful, with immediate urine output and no acute rejection observed. Induction immunosuppression included basiliximab. Although tacrolimus is typically used as both the induction and maintenance calcineurin inhibitor (CNI) at our hospital, prior tacrolimus-related encephalopathy necessitated the use of cyclosporine instead, in combination with methylprednisolone and mycophenolate mofetil (MMF). Cyclosporine trough levels were maintained at 300 ng/mL during the first 2 weeks postoperatively and then tapered to 150–250 ng/mL thereafter (Fig. 2). Methylprednisolone pulse therapy was administered intraoperatively, followed by a taper to 4 mg/day within 4 weeks postoperatively. MMF was administered at a dose of 1000 mg (25 mg/kg) daily. Serum creatinine (sCr) improved from 7.50 mg/dL preoperatively to 0.81 mg/dL within 4 weeks. A urinary tract infection developed on postoperative day 14, resolving after a 2-week course of ceftazidime. Dysphagia related to parkinsonism was managed with enteral nutrition and swallowing therapy, enabling oral intake 1 month after surgery.

Fig. 2.

Immunosuppressive therapy and serum creatinine trends in kidney transplantation. sCr serum creatinine

Post-transplant monitoring revealed transient EBV-DNA positivity, peaking within the first 3 months before declining without clinical signs of PTLD (Table 1). Notably, EBV-related treatment was not administered, as the viral load remained low and EBV-DNA became undetectable at 6 months, and the patient showed no symptoms of active EBV-related complications. Anti-VCA-IgG antibody titers showed a slight increase, but no EBV-related complications have been observed to date. At 7 months post-transplant, the patient remains stable with a serum creatinine of 0.93 mg/dL, no evidence of rejection, and regular follow-up visits. This case demonstrates that kidney transplantation in CAEBV survivors can be successful with careful monitoring and management of immunosuppression.

Table 1.

Transition of EBV-DNA levels and EBV-specific antibodies before and after kidney transplantation

	Time relative to kidney transplantation
	Prior	1 Mo after	2 Mo after	3 Mo after	4 Mo after	5 Mo after	6 Mo after	Reference range
Anti-EA-DR IgG, titer	< 10	< 10	< 10	< 10	< 10	< 10	< 10	< 10
Anti-EBNA IgG, titer	< 10	10	< 10	< 10	< 10	< 10	< 10	< 10
Anti-VCA IgM, titer		< 10	< 10	< 10	< 10	< 10	< 10	< 10
Anti-VCA IgG, titer	< 10	20	40	40	40	20	40	< 10
EBV-DNA, log IU/mL	ND	2.81	2.50	< 2.18	< 2.18	2.47	ND	ND

Mo month, EA-DR early antigen, diffuse type and restricted type, EBNA Epstein-Barr virus nuclear antigen, VCA viral capsid antigen, ND not detected

Discussion

In this case, chemotherapy for CAEBV failed to achieve remission, but sustained remission was successfully attained through allo-HSCT. The patient also had ADPKD, which progressed to ESKD at the age of 34, a relatively young age for ADPKD, and required renal replacement therapy and ultimately underwent a preemptive living-donor kidney transplantation. This case is a valuable example that shows the long-term complications of CAEBV and its treatment, particularly in monitoring for EBV reactivation and adjusting immunosuppressive therapy. To our knowledge, this is the first report of solid organ transplantation following remission from CAEBV.

EBV reactivation is a well-recognized complication after allo-HSCT, occurring in 67.9–73.3% of cases. Patients with CAEBV are potentially at even higher risk due to their history of severe EBV-related immune dysregulation [6, 7]. Additionally, PTLD, a life-threatening complication associated with EBV reactivation, has been reported in 1–10% of allo-HSCT recipients within the first 6 months [8]. Although an exact threshold remains controversial, PTLD risk increases markedly when EBV-DNA exceeds 3–4 log IU/mL [9, 10]. While MMF has not been strongly linked to PTLD development after KTx, overall immunosuppressive burden—especially CNI exposure—remains a critical determinant [11, 12].

In our case, immunosuppression was tailored according to EBV-DNA kinetics. EBV-DNA was monitored monthly during the first post-transplant year, and more frequently when levels approached 3 log IU/mL. When viral load increased, cyclosporine trough targets were reduced by 20–30%, aiming for approximately 150 ng/mL. If EBV-DNA had exceeded 3 log IU/mL, we planned to further reduce cyclosporine, decrease MMF to 15–20 mg/kg, and consider conversion to everolimus, with close monitoring for rejection. Steroid tapering followed our institutional protocol. In this case, EBV-DNA transiently increased but remained below 3 log IU/mL and normalized without intervention. Adherence to a structured EBV surveillance protocol and stepwise immunosuppression adjustment likely prevented PTLD development.

The long-term risks of secondary malignancies following allo-HSCT are significant, with malignancy rates reported at 3.5% at 10 years and 12.8% at 15 years [13]. Total body irradiation and multiple chemotherapy regimens are major contributing factors, increasing the likelihood of treatment-related bone marrow tumors. In the context of KTx after allo-HSCT, malignancy rates are even higher, with approximately 10% of patients developing malignancies within 3 years post-transplant [14]. This is notably greater than the 4–5% observed 5 years post-transplant in the general KTx population. Notably, in this case, no secondary malignancies were observed even 25 years after allo-HSCT. This may be attributable to the early discontinuation of cyclosporine, which could have mitigated long-term oncogenic risks. Nevertheless, the reintroduction of immunosuppressants following KTx necessitates continued vigilance to monitor for malignancies, including PTLD.

This case highlights the feasibility of KTx in CAEBV survivors while underscoring the need for individualized management strategies to minimize complications. The success of this case was achieved through stringent post-transplant monitoring, which included regular assessment of EBV-DNA levels and clinical surveillance for malignancies. Since the late 2000s, with the widespread recognition of allo-HSCT and the establishment of its treatment strategy, the prognosis of CAEBV has improved [15, 16]. However, there have also been reports that 4.4% of pediatric patients who underwent allo-HSCT progress to ESKD within 10.9 years [17]. Given the growing population of CAEBV survivors who may develop ESKD, further research is needed to establish standardized protocols for managing solid organ transplantation in this unique patient population.

In conclusion, this is the first reported case of KTx following CAEBV remission, demonstrating its feasibility with meticulous monitoring and individualized immunosuppressive management. This case highlights the need for ongoing vigilance in monitoring EBV reactivation and malignancies, as well as the importance of further research to guide clinical practice. Long-term surveillance remains crucial to ensuring favorable outcomes for similar patients in the future. By expanding our understanding of post-transplant management in CAEBV survivors, we can better address the challenges of balancing the risks of immunosuppression with the benefits of solid organ transplantation.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

This article does not involve any studies with human participants or animals conducted by any of the authors. And, the studies were in accordance with the Declaration of Istanbul.

Informed consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.