Successful Renal Retransplantation after Post-Transplant Lymphoproliferative Disease
Abstract
Post-transplant lymphoproliferative disease (PTLD) is a rare but severe complication of renal transplantation. Reduction of immunosuppression is essential for controlling PTLD but may induce graft loss. Retransplantation after PTLD is considered dangerous, because immunosuppressive treatment resumption may trigger hematological relapse. We retrospectively report six patients (five adults, one child) who underwent a second renal transplantation after successfully treated PTLD.
Epstein-Barr virus (EBV) serology was positive before the first transplantation in all patients except the child. Post-transplant lymphoproliferative disease was detected 6.6 months (range 4.5–9.4) after transplantation. Lymphoproliferation was always monomorphic, B-cell, and EBV-related. Post-transplant lymphoproliferative disease was confined to the renal allograft (n = 4), multilocular (n = 1) or cerebral (n = 1). Immunosuppression tapering (6/6) and transplantectomy (5/6) led to hematological remission in all patients.
Retransplantation was performed 77 months (range 50–128) after PTLD diagnosis. Immunosuppression included steroids (n = 6), ATG (n = 2), anti-CD25 (n = 2), cyclosporine (n = 4), tacrolimus (n = 2), mycophenolate mofetil (n = 4) and azathioprine (n = 1). After a median follow up of 30 months (range 24–47) patient survival was 100%, with no recurrence of PTLD.
In conclusion, renal retransplantation can be considered in patients with monomorphic PTLD history, without major risk of hematological recurrence.
Introduction
Post-transplant lymphoproliferative disease (PTLD) is a rare complication of renal transplantation, as it occurs in up to 1.5% of patients receiving a kidney allograft (1–3). However, the risk of lymphoma in these patients is approximately 20-fold greater than that observed in the general population. Most cases of PTLD are of B-cell origin, contain the Epstein-Barr virus (EBV) genome, and express viral proteins on the cell surface. Because primary infection with EBV following organ transplantation is the main risk factor for the development of EBV-induced PTLD in organ transplant recipients, this disease is especially frequent in children who have negative EBV serology before transplantation and receive an organ from an EBV seropositive donor (2). Another major risk factor for PTLD after solid organ transplantation is the degree of immunosuppression, and this risk is probably much increased after antilymphocyte therapy.
The term PTLD encompasses a wide variety of lymphoproliferative disorders (3). It includes reactive, usually benign, lymphoid hyperplasia resembling infectious mononucleosis, polymorphic PTLD ranging from polymorphic B-cell hyperplasia to polymorphic lymphoma, and monomorphic lymphomatous PTLD, which has the worst prognosis.
Treatment of PTLD is one of the most controversial topics in solid organ transplantation (4). However, guidelines have been suggested and four major forms of treatment need to be considered: reduction of immunosuppression, chemotherapy, anti-B-cell monoclonal antibodies, and cell-based therapies. All these approaches must start with drastic tapering of immunosuppressive drugs (5), because it is well known that the reduction or elimination of these drugs can result in complete and lasting regression of PTLD. The aim of this reduction is to stimulate both the innate and acquired immune responses to viral or tumoral antigens, and to target these responses at EBV-infected lymphoma cells. On the other hand, this reduction of immunosuppression may also enhance the allo-immune response and lead to allograft rejection. In addition, in renal transplantation, graft nephrectomy is sometimes required to reduce the tumoral mass, as lymphoma is frequently located within the allograft. The frequent need for graft nephrectomy and the increased risk of allograft rejection explain why almost 50% of kidney transplant recipients who survive monomorphic PTLD will loose their allograft within a few months. As PTLD occurs more frequently in children, patients who survive may require a second transplantation. To our knowledge, very few reports have been published about the results of such retransplantation in patients with a history of PTLD (6–8) and the risk of hematological recurrence has rarely been evaluated to date. We report here the initial evolution of renal retransplantation in six patients who had developed monomorphic post-transplant lymphoproliferative disease during their initial transplantation.
Patients and Methods
We retrospectively included in this study all the reported cases of retransplanted patients, with a history of monomorphic PTLD. Accordingly, a questionnaire was sent to 10 French renal transplantation centers. We were able to single out six patients treated in four of these centers. Monomorphic PTLD was defined as the presence of a biopsy-proven lymphoid tumor according to standard morphologic criteria, with a monoclonal B-cell population determined on immunohistochemical analysis of tissue samples by the presence of kappa or lambda light-chain restriction. In all cases, EBV was detected inside the tumoral cells, by either immunohistologic staining or in situ hybridization with the EBER-1 probe.
We excluded from this study all patients with a medical history of polyclonal or benign lymphoproliferation, such as infectious mononucleosis, in order to obtain a homogeneous group with monomorphic high-grade B-cell lymphoma.
Remission of PTLD was defined as the absence of all clinical, laboratory or morphologic signs of lymphoproliferation for a minimum period of 2 years after the end of PTLD treatment.
Cumulative data on our four renal transplantation centers found 22 cases of PTLD during this 6-year period. Five of these patients had a rapidly fatal outcome and five experienced rapid improvement of PTLD after immunosuppression tapering without significant deterioration of the allograft function. Twelve patients had their PTLD contained by immunosuppression discontinuation and/or surgical treatment but lost their kidney allograft and returned to dialysis. Only six of them (50%) were considered for retransplantation and subsequently retransplanted, two were excluded from retransplantation because of their age and four remained on hemodialysis treatment. In these latter patients, retransplantation was not considered.
Results (Table 1)
| no. | Age | Sex | First transplantation | Time to PTLD (months) | PTLD site | PTLD treatment | Time (mo) from PTLD to dialysis | Time (mo) from PTLD to waiting list | Time (mo) from PTLD to 2nd transpl. | Second transplantation | Follow up (months) | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Immunosuppression | Rejection episodes | Immunosuppression | Rejection episodes | ||||||||||
| 1 | 54 | M | ATG, S, CsA, Aza | 1 | 4.5 | G | IST, S | 0 | 40 | 90 | aCD25, S, CsA, MMF | 0 | 24 |
| 2 | 17 | F | ATG, S, CsA, Aza | 2 | 6.5 | B | IST | 27 | 89 | 128 | S, T, Aza | 0 | 31 |
| 3 | 3 | M | ATG, S, CsA, Aza | 1 | 9.4 | G, L, N. | IST, S | 0.3 | 50 | 65 | aCD25, S, CsA, MMF | 0 | 30 |
| 4 | 44 | F | ATG, S, CsA | 0 | 6.6 | G | IST, S | 0.5 | 29 | 50 | ATG, S, T | 1 | 47 |
| 5 | 28 | M | ATG, S, CsA, Aza | 1 | 7.0 | G | IST, S | 0.5 | 42 | 53 | S, CsA, MMF | 1 | 31 |
| 6 | 44 | F | ATG, S, CsA, Aza | 0 | 4.5 | G | IST, S, Ch | 5.3 | 97 | 98 | ATG, S, CsA, MMF | 0 | 26 |
- Immunosuppression: ATG, thymoglobulin; S, steroids; CsA, cyclosporine A; Aza, azathioprine; MMF, mycophenolate mofetil; aCD25, basiliximab; T, tacrolimus.
- Post-transplant lymphoproliferative disease (PTLD) site: G, graft; B, brain; L, liver; N, lymph node.
- PTLD treatment: IST, immunosuppression tapering; S, surgery; Ch, chemotherapy.
First transplantation
We began by analyzing the characteristics of our six patients at their first kidney transplantation. Five patients were adults, whose mean age was 37 years (range: 17–54). The remaining patient (no. 3) was a 3-year-old child. As regards EBV status, all patients but the pediatric recipient were EBV-positive before transplantation.
For all six patients, the immunosuppressive regimen for the first graft combined antithymocytes polyclonal antibodies (Thymoglobulin®, Sangstat, France), steroids and cyclosporine. Five of them received azathioprine as part of the initial immunosuppressive therapy. Note that none of the recipients was treated with mycophenolate mofetil (MMF) during their first transplantation.
The evolution of the first transplantation was associated with at least one episode of acute rejection in four patients, but only one of these episodes was considered as steroid-resistant and required two courses of anti-CD3 monoclonal antibodies (OKT3®, Muromonab, Orthobiotech, France).
Post-transplant lymphoproliferative disease
Lymphoproliferative disease was diagnosed after a mean period of 190 ± 53 days after transplantation. The disease was first suspected because of fever in four patients, acute renal failure in one and seizures in one. A definite diagnosis was made on the basis of standard morphologic criteria and immunohistochemical analysis of lymphoma tissue samples. The primary site of PTLD was the renal allograft in five cases, with distant lymphadenopathies in one patient. In the case of patient no. 2, the diagnosis of primary brain lymphoma was confirmed by stereotaxic needle biopsy. Among standard laboratory tests, anemia was constantly noted, a monoclonal gammapathy was present in two cases and elevated serum LDH level was only found in three patients.
Management of PTLD combined drastic tapering of immunosuppressive regimen in all patients. As anti-B monoclonal antibody treatment was not available at the time, cytotoxic chemotherapy was used in one case (patient no. 6).
Graft nephrectomy was performed in five cases. For patient no. 1, nephrectomy was performed after irreversible graft failure secondary to a severe acute rejection episode. Post-transplant lymphoproliferative disease was diagnosed on routine pathological examination of the explanted allograft. In the case of patient no. 2, immunosuppression reduction permitted PTLD remission, but chronic rejection led to nephrectomy 2 years later, after definitive graft loss. In the three remaining cases, graft nephrectomy was performed in order to reduce the tumoral mass.
Second transplantation
Patients were considered for a second renal transplant when they had been followed up for at least 2 years after complete remission of PTLD. They were put on the waiting list with a median delay of 45.8 months (range: 29–97) after graft nephrectomy. The second renal transplantation was performed with a median delay of 77.3 months after PTLD diagnosis (range: 50–128). All patients received a graft from a cadaveric donor. Although none of the patients was highly sensitized to HLA antigens, induction immunosuppressive therapy was used in four cases to avoid allograft rejection. Two patients received a short course of polyclonal antibodies and two received a humanized anti-IL2R monoclonal antibody (basiliximab). All patients were given steroids and calcineurin inhibitors, either cyclosporine (n = 4) or tacrolimus (n = 2), with the standard trough level required. Mycophenolate mofetil was used in four patients and azathioprine in one. Rapamycin, although considered by many authors as an interesting immunosuppressive drug with potential antiproliferative properties, has not been used in any of these six patients.
Cytomegalovirus (CMV) prophylaxis was given to only two of these patients. In both cases valacyclovir was used at the dose of 4500 mg per day, during the 4-month initial period that followed their second graft. One patient who had not received antiviral prophylaxis developed CMV disease and was subsequently treated by a 3-week course of i.v. ganciclovir.
The evolution after retransplantation was uneventful in four patients. Two patients experienced an acute rejection episode a few weeks after transplantation. In patient no. 5, the episode was considered steroid-resistant. This patient was subsequently successfully treated with intravenous polyvalent immunoglobulins, plasmapheresis and a switch from cyclosporine to tacrolimus.
Regarding PTLD, no clinical recurrence has been noted to date (March 2004) among these six transplant recipients. The median follow up since the second renal transplantation is 30 months (range: 24–47). All patients have been regularly assessed for both clinical and radiological signs of PTLD, but there has been no sign of any recurrence to date. Furthermore, the renal graft biopsy performed in three patients did not show any monomorphic infiltration suggestive of malignant lymphoproliferation. Lastly, the EBV viral load has been regularly measured by real-time quantitative polymerase chain reaction (PCR) using peripheral blood mononuclear cells. Until now, no patient has exhibited significant positivity of EBV viral load.
Discussion
Post-transplant lymphoproliferative disease was first described by Starzl in 1968. Its incidence varies according to the transplanted organ and the immunosuppressive regimen used. After kidney transplantation, the reported prevalence ranges from 0.6 to 1.4% (1–3).
Most cases of PTLD are related to EBV infection. This ubiquitous herpes virus has a particular propensity to infect human B lymphocytes. Epstein-Barr virus primary infection, which mostly occurs in healthy children, is either asymptomatic or associated with infectious mononucleosis, usually a benign disorder. Primary infection or reactivation of this virus in immunocompromised hosts such as HIV-infected patients or organ recipients may lead to lymphoproliferation. Although EBV-related PTLD of T- or NK-cell origin can occur, as well as EBV-negative lymphomas, the great majority of PTLD have a B-cell origin. Lymphoproliferative disorders can be polymorphic and polyclonal, or have characteristics of typical monoclonal aggressive lymphomas. Their classification, based on histologic examination and immunohistologic analyses, is crucial for defining the prognosis and management of PTLD (4). Clinically, PTLD often manifests itself as a febrile illness with leukopenia or pancytopenia, allograft invasion or dysfunction, but can also be a disseminated disease with distant lymph nodes enlargement or central nervous system involvement.
Tapering or cessation of certain immunosuppresive drugs may allow the recovery of natural immune surveillance mechanisms and subsequently the control of EBV-infected cell proliferation. This approach has been widely adopted as the initial step in PTLD management, although it increases the risk of allograft rejection. The regression, not only of polyclonal lymphoproliferation but also of monoclonal EBV-related PTLD after the reduction of immunosuppression, alone or combined with other strategies, has been reported in up to 80% of patients (5).
The use of new therapeutic agents such as monoclonal B-cell-specific antibodies has greatly improved the survival of patients with PTLD (9–11). As graft loss remains frequent after PTLD treatment, the question may arise of whether a second renal transplantation can be performed. The hypothetical risk of PTLD recurrence after the reintroduction of immunosuppression has prevented many physicians from proposing a second transplantation in such cases. To date, this question has not been precisely answered, as very few reports in the literature have dealt with the risk of renal retransplantation in patients with a history of PTLD.
Our series comprises a homogeneous group of transplanted patients with biopsy-proven monoclonality of B-cell lymphoproliferation as well as EBV involvement. Our results, together with nine previously reported cases (Table 2), seem to indicate that renal retransplantation can safely be proposed for patients who have previously experienced monoclonal B-cell PTLD, especially if the lymphoma was located in the kidney allograft. Interestingly, organ retransplantation has been successfully achieved in PTLD following liver and intestinal transplantation (12–15).
| Reference | no. | Age | PTLD pathology | PTLD clonality | Time (mo) to PTLD | PTLD site | PTLD treatment | Time (mo) from PTLD to 2nd transpl. | Second transplantation immunosuppression | Follow up (months) | Patient survival |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Hickey (6) | 1 | 58 | histiocytic | nd | 6 | ileum, prostate | IST, S, Ch | 40 | S + CsA | 1 | Y (graft loss) |
| 2 | 30 | plasmocytic | mono | 4.5 | ileum | IST, S, Ch | 42 | S + CsA | 26 | Y | |
| 3 | 12 | histiocytic | poly | 4.5 | graft | IST, S | 9 | S + CsA | 18 | Y | |
| Demircin (7) | 4 | 15 | B-cell | mono | 4 | graft | IST, S | 24 | ATG + S + CsA + Aza | 36 | Y |
| Birkeland (8) | 5 | NA | B-cell | poly | 50 | neck | IST | 69 | S + CsA + MMF | 9 | Y |
| 6 | NA | B-cell | mono | 3.5 | neck | IST | 60 | ATG + S + CsA + MMF | 15 | Y | |
| 7 | NA | B-cell | mono | 65 | neck | IST | 43 | ATG + T + MMF | 14 | Y | |
| 8 | NA | B-cell | poly | 2 | graft, lung | IST, S | 85 | aCD25 + S + CsA + MMF | 5 | Y | |
| 9 | NA | Hodgkin Dis. | 58 | neck | R | 31 | ATG + CsA + MMF | 30 | Y |
- NA, not available.
- Immunosuppression: ATG, thymoglobulin; S, steroids; Cs, cyclosporine; Aza, azathioprine; MMF, mycophenolate mofetil; aCD25, daclizumab; T, tacrolimus.
- Post-transplant lymphoproliferative disease (PTLD) treatment: IST, immunosuppression tapering; S, surgery; Ch, chemotherapy.
In the present series, five out of six lymphomas were primary located inside the allograft, suggesting that the lymphoma cells were of donor origin. This hypothesis was confirmed in one of our (patient no. 6), as previously published (11). The alloimmune response against these tumoral EBV-infected cells may improve after partial or complete withdrawal of immunosuppression and thus help to control the tumoral mass. The risk of hematological recurrence might even be smaller in polyclonal EBV-driven lymphoproliferation, as this condition is considered as more prone to respond to the immunosuppression tapering.
We strongly believe that several questions need to be addressed before kidney retransplantation can be envisaged in patients with history of PTLD. First, it is of the utmost importance to be sure that the initial PTLD is completely cured. As the graft is a common site of the lymphoproliferative disease, transplantectomy of the first kidney allograft may be required. Quantitative polymerase chain reaction (PCR) technology for EBV is now available and can be performed in lymphocytes. Patients willing to receive a second transplantation should be checked for a low level of EBV copies before new immunosuppressive drugs are given. Another approach is based on fine analysis of EBV serologic status. During PTLD, anti-VCA IgM associated with IgG antiVCA and anti-EA may be observed, together with the disappearance of anti-EBNA IgG. A patient should be positive for anti-EBNA IgG before retransplantation is considered, as this marker is associated with an effective cytotoxic response to EBV (16). Clonal rearrangements of B lymphocytes and plasma protein immunoelectrophoresis should also be performed, to confirm the absence of residual monoclonal lymphoproliferation.
The situation can be very different in nonrenal solid organ recipients. In such cases, PTLD can lead to life-threatening graft dysfunction and retransplantation may be required before PTLD is completely controlled. We have no data on the risk of hematological recurrence under these specific circumstances but retransplantation is sometimes the unique treatment that can be proposed.
The degree of immunosuppression to be used for retransplantation in these patients has not yet been studied. Although some of them may develop anti-HLA immunization after their first transplantation, we think that overimmunosuppression should be avoided. However, our data show that newer immunosuppressive drugs such as monoclonal antibodies, MMF or tacrolimus can be used without great risk of PTLD recurrence.
Another open question concerns antiviral prophylaxis after renal transplantation, to prevent PTLD recurrence. Recent results suggest that the use of antiviral agents, like ganciclovir, valganciclovir or acyclovir, mostly as CMV prophylaxis, may also provide some protection against EBV infection (17), even though controlled randomized trials have shown little benefit in this respect. One theoretical goal of these agents might be to reduce the transmission of replicative-lytic EBV from the allograft in D+R-transplantation, or to prevent EBV reactivation in EBV-positive recipients.
The last question concerns the modalities of virologic and hematological monitoring after re-transplantation. Epstein-Barr virus viral load monitoring in lymphocytes by quantitative PCR is the best technique available for the time being. Measuring the EBV viral load may allow early detection of EBV replication, and the identification of patients likely to develop PTLD (18). To date, none of our patients has exhibited strong or sustained positivity of the EBV viral load. We believe that weekly monitoring during the first month after retransplantation and monthly monitoring during the first year may be recommended for this population. Recent findings (19) suggest that the ratio of the EBV viral load over the EBV specific T-cell response is a highly specific diagnostic test, with a 100% positive predictive value for PTLD. Other diagnostic approaches may be useful, including EBNA serology, immunoelectrophoresis, and the monitoring of LDH and C-reactive protein levels, but these methods still require prospective studies.
In summary, we report here successful renal retransplantation after the occurrence of PTLD during the first transplantation. Even though it is difficult to formulate any firm conclusion from the small number of patients studied, retransplantation may be envisaged for patients who experienced a first PTLD episode. However, further studies are needed to ascertain the usefulness of EBV viral load monitoring for early detection of PTLD recurrence, the risks or advantages of the newest immunosuppressive drugs, and the role of active prophylactic antiviral treatment in this specific population.
