Cieniawski, Dominik

Giza, Agnieszka

Ignacak, Ewa

Kuźniewski, Marek

Sułowicz, Joanna

Sułowicz, Władysław

Transplantation Proceedings

English

Jagiellonian Univeristy Repository

Post-transplant Lymphoproliferative Disorder in a Patient After KidneyTransplant, 5-Year Follow-up: A Case ReportEwa Ignacaka, Joanna Sułowiczb,*, Agnieszka Gizac, Dominik Cieniawskia,Marek Kuzniewskia, and Władysław SułowiczaaDepartment of Nephrology, Jagiellonian University Medical College, Krakow, Poland; bDepartment of Dermatology, JagiellonianUniversity Medical College, Krakow, Poland; and cDepartment of Hematology, Jagiellonian University Medical College, Krakow, Polandª 2020 Theaccess articcreativecom230 Park AvTransplantatABSTRACTIntroduction. Post-transplant lymphoproliferative disorder (PTLD) is a serious,life-threatening complication in organ transplant patients receiving immunosuppressivetherapy. The risk factors include Epstein-Barr virus infection and a cumulative dose ofthe immunosuppression.Case Report. We present a 5-year follow-up case of a 28-year-old patient with PTLD inthe gastrointestinal tract. In the ninth month after kidney transplant, the patient washospitalized for pain in the abdomen and diarrhea. Physical examination demonstratedtenderness in the area of the cecum, and colonoscopy revealed ulcerations in the largeintestine. Polymorphic lymphoma (PTLD) was found in the collected samples. Thepatient received monotherapy treatment with anti-CD20 antibodies, resulting incomplete remission of disease, confirmed by computed tomography scan and colonoscopy.Conclusion. PTLD may have a different clinical course and should be considered in thedifferential diagnosis of patients after organ transplant.*Address correspondence to Joanna Sułowicz, Department ofDermatology, Jagiellonian University Medical College, Skawinska8, 31-066 Krakow, Poland. Tel: þ48 668462002. E-mail:sulowiczj@interia.plPOST-TRANSPLANT lymphoproliferative disorder(PTLD) is a serious, life-threatening complication inorgan transplant patients receiving immunosuppressivetherapy [1]. Epstein-Barr virus (EBV) plays an importantrole in the etiology of PTLD and is found in more than 90%of patients with PTLD, usually as a consequence of theimmunosuppressive treatment. The stronger the immuno-suppression and the higher its cumulative dose, the greaterrisk the patient has of developing lymphoproliferativedisorders [2,3].PTLD may have a varied clinical course, resembling in-fectious mononucleosis with manifestation such as fever,pharyngitis, tonsil enlargement, lymphadenopathy, or maytake on fulminant forms characterized by severe metabolicacidosis, graft and other internal organs dysfunction, whereinfiltrates may take the form of a tumor [4,5]. This paperpresents a 5-year follow-up of a patient with PTLD in thegastrointestinal tract.A CASE REPORTA 28-year old patient with tubulointerstitial nephritis (chronicself-catheterization due to the posterior urethral valve) who hadAuthors. Published by Elsevier Inc. This is an openle under the CC BY-NC-ND license (http://mons.org/licenses/by-nc-nd/4.0/).enue, New York, NY 10169ion Proceedings, 52, 2517e2519 (2020)been hemodialyzed since September 2012 and received a kidneytransplant from a deceased donor in July 2013. He obtainedimmunosuppressive treatment: tacrolimus, mycophenolate mofetil,and prednisone. After kidney transplant, the patient manifestedrecurrent urinary tract infections (UTIs) caused by multiresistantstrains, requiring antibiotic therapy (meropenem, imipenem andcilastatin), and experienced repeated relapses of Clostridium difficileinfection treated with metronidazole, vancomycin, and then fidax-omicin. Because of the high risk of cytomegalovirus (CMV) infec-tion (CMV donor þ CMV recipient -), valganciclovir prophylaxiswas used, and early conversion from mycophenolate mofetil toeverolimus was performed.In March 2014, the patient was hospitalized for pain in theabdomen and diarrhea. Physical examination demonstratedtenderness in the area of the cecum. In biochemical tests, hemo-globin was 11.2 g/dL, white blood count was 4390/mL, creatinine was138 mmol/L, lactate dehydrogenase increased up to 1002 U/L(normal values 240-480), and in a hybridization study in situ for0041-1345/20https://doi.org/10.1016/j.transproceed.2020.02.08325172518 IGNACAK, SUŁOWICZ, GIZA ET ALEBV infection, numerous positive cells were shown. Colonoscopyrevealed ulcerations in the large intestine and polymorphic lym-phoma (PTLD) was found in the collected samples. In order toassess the stage of the disease, positron emissiontomographyecomputed tomography (PET-CT) examination wasperformed, which demonstrated metabolically active areas withinthe large intestine and especially in the rectum in the form ofthickening of the posterior and right-sided wall up to 25 mm in thearea of 38  21  90 mm. Clinical stage IVA, according to the AnnArbor classification, was determined.Because of the diagnosis of PTLD, the existing immunosup-pressive treatment was modified by gradually reducing tacrolimus(to a blood concentration of 3-4 ng/mL) and then discontinuing it,while continuing the administration of everolimus (concentrationsfrom 5.4-10.2 ng/mL) and methyloprednisolone.In the Department of Hematology, the patient received mono-therapy treatment with anti-CD20 antibodies according to theprotocol of the Polish Lymphoma Research Group. At the begin-ning, 4 doses of rituximab (375 mg/m2 every 1 week) were given, andthen maintenance treatment with rituximab (4 doses every 3 weeks)was administered. After a few weeks of treatment, a completeremission was achieved. The patient was carefully followed up by ahematologist under the following schedule: every 3 months for1 year, every 6 months for 2 years, and then once a year.Complete remission of disease was confirmed in CT scan andcolonoscopy. In the following years (2016 and 2017), 2 episodes ofsymptomatic UTI were observed (Klebsiella pneumoniae extendedspectrum beta-lactamase positiveetreated with good clinicalresponse to broad-spectrum antibiotics). Currently, more than 5years from the onset of PTLD symptoms, the patient is in fullremission with a very good general condition, sterile urine cul-tures, stable graft function, and the following laboratory values:creatinine levels 137 mmol/L, estimated glomerular filtration rate57 mL/min/1.73 m2, uric acid 271 mmol/L, sodium 138 mmol/L,potassium 3.82 mmol/L, magnesium 0.80 mmol/L, calcium 2.34mmol/L, alanine transaminase 31 U/L, cholesterol 5.9 mmol/L,leukocytes 5820/mL, erythrocytes 5,080,000/mL, hemoglobin 14 g/dL, and platelets 218,000/mL. Five to 10 leukocytes were observedin urine sediment at the last testing. Currently, the patient re-ceives the following treatment: everolimus 2 mg twice daily,methyloprednisolone 4 mg once daily, potassium chloride 391 mgtwice daily, betaxolol 20 mg in the morning, atorvastatin 20 mg atnight, vitamin B6 and magnesium twice daily one tablet, andfosfomycin 3 g every 2 weeks (as prevention of UTI).DISCUSSIONPTLD is a heterogeneous group in which uncontrolledlymphocyte proliferation is observed in transplant recipientsundergoing chronic immunosuppression [5,6]. Proliferationaffects B lymphocytes in more than 85% of cases and isassociated with EBV infection. In 15% of cases, hyperplasiainvolves T lymphocytes, and it affects NK (natural killer)cells extremely rarely. PTLD occurs after both bone marrowand solid organ transplantation, and the type of trans-planted organ and the type of the employed immunosup-pression appear to have a significant impact on theoccurrence of the disease. PTLD occurs most often afterheart-lung transplant (5%-10%); occurs less often afterheart (3.9%-5%), liver (2.3%), and kidney (0.3-3%) trans-plant; and occurs the least frequently after bone marrowtransplant [3,7,8]. A low 5-year cumulative incidence ofPTLD after solid organ transplantation (0.96%) wasobserved in a Swiss transplant cohort study [9].As mentioned in the introduction, an infection with EBVusually plays a crucial role in the etiology of PTLD as aconsequence of the immunosuppressive treatment. Ourpatient's infection with this virus has been documentedduring the diagnosis of PTLD. EBV is a DNA virus thatbelongs to the Herpes family. A decreased cytotoxic activityof T lymphocytes following immunosuppression allows forreactivation and replication of the virus and tumor trans-formation of B lymphocytes. Particularly, increased prolif-eration of infected B lymphocytes can be observed inseronegative recipients in whom primary EBV infectiondeveloped after transplantation [2,5,10]. A patient with aprimary EBV infection is therefore at a much higher risk ofdeveloping PTLD than an individual demonstrating reac-tivation of persistent infection [8]. The highest risk ismanifested by seronegative recipients who have received aseropositive donor organ (Dþ/R-). The risk of developingPTLD may be further increased in the presence ofco-infection with an immunomodulatory virus such as CMV[1,2,8].At the time of dual immunosuppressive regimens(azathioprine and oral steroids in the 1990s), PTLD was anextremely rare complication. Its incidence began to increasesince the introduction of cyclosporin A, tacrolimus, andmedications used in induction and treatment of acutetransplant rejection such as antithymocyte globulin andmonoclonal antibody for CD3 receptor (OKT3) [11,12].An increased risk of PTLD development occurs mainly inthe first year after transplantation [4,7]. Opelz et al [6]evaluated more than 50,000 patients after heart or kidneytransplant found a significantly higher incidence of B-cellPTLD in the first year after transplantation, while T-cellPTLD should be expected 5 years after transplant. Inanother report based on the analysis of data of 1176 kidneyrecipients, the average time of PTLD occurrence was 72.8 56.3 months after transplant [5].PTLD can have a variable clinical course and location.The lymph nodes are most often affected, followed by theabdominal cavity (gastrointestinal tract, liver, transplantedorgan) and the central nervous system, as well as bonemarrow and skin. Lymphoproliferative disorders may alsomanifest as isolated fever without associated local symp-toms. PTLD can occur in the form of a tumor mass orinfiltrate as in our patient in the intestine [13]. Gastroin-testinal involvement can cause life-threatening ulcers andperforations [14]. Extra-node localization is very common,especially in lymphoproliferative disorders originating fromT cells, which are generally aggressive, demonstrate poorresponse to treatment, and are therefore burdened with apoor prognosis [4,11].The diagnosis of PTLD requires a great deal of insightbecause the disease is often insidious and occurs in anextranodal location. The diagnosis is determined by thehistopathology of the removed lymph node or specimenPOST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER 2519taken from the affected organ through biopsy. It is alsohelpful to demonstrate the immunoreactivity of EBVprotein in lymphocytes [10,11,15].In the treatment of PTLD, the reduction of immuno-suppression is important because immunosuppressiveagents impair the function of, among others, cytotoxic Tlymphocytes, favoring EBV infection [3,11]. The key role inthe treatment of patients with PTLD is played by thechimeric monoclonal antibody directed against the CD20antigen, rituximab. The administration of rituximab causesrapid elimination of B lymphocytes from the circulation.This is due to complement activation and antibody-dependent cellular cytotoxicity. In addition, rituximab actssynergistically with conventional chemotherapy, sensitizingcells to apoptosis, by inhibiting BCL-2 protein expression,which improves the effectiveness of chemotherapy. Theoverall response to rituximab used as monotherapy as thefirst-line treatment is estimated to be around 45% to 50%.It is usually used at a dose of 375 mg/m2 once a week for4 weeks, provided that CD20 þ (> 90% PTLD) is present[16]. Rituximab is also used as a pretreatment to prevent thedevelopment of PTLD in patients infected with EBV [17].The prognosis in PTLD depends on the type, malignancyfeatures, and stage of the disease. Mortality in monoclonalmalignant forms of PTLD is high and can be up to 80%.Polymorphic forms have a better prognosis than mono-morphic ones. Adverse prognostic factors are high-gradelymphoma histology and advanced disease in the Ann Ar-bor classification, central nervous system and bone marrowinvolvement, disseminated form of the disease (at least 2extra-node locations), hypoalbuminemia, hepatitis B or Cinfection, late PTLD, age older than 60 years, and positivitytoward cancer before transplant [3,4]. A multicenter studyin a group of 80 solid organ transplant recipients diagnosedwith PTLD found a 3-year progression-free survival andoverall survival of 57% and 62%, respectively. Anotherprospective study in a group of 230 patients diagnosed withPTLD after kidney transplant found that 73% of thepatients survived 1 year after the diagnosis and 61% sur-vived 5 years [4,5].REFERENCES[1] Abe T, Ichimaru N, Kokado Y, Maeda T, Kakuta Y,Okumi M, et al. Post-transplant lymphoproliferative disorderfollowing renal transplantation: a single center experience over 40years. Int J Urol 2010;17:48e54.[2] Dharnidharka VR, Araya CE. Post-transplant lymphoproli-ferative disease. Pediatr Nephrol 2009;24:731e6.[3] Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K.Posttransplant lymphoproliferative disorders after renal trans-plantation in the United States in era of modern immunosuppres-sion. Transplantation 2005;80:1233e43.[4] Caillard S, Lelong C, Pessione F, Moulin B, French PTLDWorking Group. Post-transplant lymphoproliferative disordersoccurring after renal transplantation in adults: report of 230 casesfrom the French Registry. Am J Transplant 2006;6:2735e42.[5] Pałka K, Ignacak E, Sułowicz W. [Post transplant lympho-proliferative disorder (PTLD) in patients after kidney trans-plantation e clinical manifestation, treatment and prognosis]. PrzeglLek 2012;69:695e9 [in Polish].[6] Opelz G, Döhler B. Lymphomas after solid organ trans-plantation: a collaborative transplant study report. Am J Transplant2004;4:222e30.[7] Lewin KJ. Post-transplant lymphoproliferative disorders.Pathol Oncol Res 1997;3:177e82.[8] Wasson S, Zafar MN, Best J, Reddy HK. Post-trans-plantation lymphoproliferative disorder in heart and kidney trans-plant patients: a single-center experience. J Cardiovasc PharmacolTher 2006;11:77e83.[9] Steiner R, Kridel R, Giostra E, McKee T, Achermann R,Mueller N, et al. Low 5-year cumulative incidence of post-transplant lymphoproliferative disorders after solid organ trans-plantation in Switzerland. Swiss Med Wkly 2018;148:w14596.[10] Sampaio MS, Cho YW, Shah T, Bummapradist S,Hutchinson IV. Impact of Epstein-Barr virus donor and recipientserostatus on the incidence of post-transplant lymphoproliferativedisorder in kidney transplant recipients. Nephrol Dial Transplant2012;27:2971e9.[11] Liu M, Husain S, Famure O, Li Y, Kim SJ. Incidence, riskfactors, clinical management, and outcomes of posttransplant lym-phoproliferative disorder in kidney transplant recipients. ProgTranspl 2019;29:185e93.[12] Morton M, Coupes B, Roberts SA, Klapper PE, Byers RJ,Vallely PJ, et al. Epidemiology of posttransplantation lymphopro-liferative disorder in adult renal transplant recipients. Trans-plantation 2013;95:470e8.[13] Inayat F, Hassan GU, Tayyab GUN, Saif MW. Post-trans-plantation lymphoproliferative disorder with gastrointestinalinvolvement. Ann Gastroenterol 2018;31:248e51.[14] Ignacak E, Bętkowska-Prokop A, Kuzniewski M, Rudzki Z,Okon K, Skotnicki A, et al. [Post transplant lymphoproliferativedisorder (PTLD) e 10 years follow-up]. Przegl Lek 2011;68:1202e3[in Polish].[15] Petrara MR, Serraino D, Di Bella C, Neri F, Del Bianco P,Brutti M, et al. Immune activation, immune senescence and levelsof Epstein Barr virus in kidney transplant patients: impact ofmTOR inhibitors. Cancer Lett 2020;469:323e31.[16] Oertel SHK, Verschuuren E, Reinke P, Zeidler K, Papp-Váry M, Babel N, et al. Effect of anti-CD20 antibody rituximab inpatients with post-transplant lymphoproliferative disorder (PTLD).Am J Transplant 2005;5:2901e6.[17] Stocker N, Labopin M, Boussen I, Paccoud O, Bonnin A,Malard F, et al. Pre-emptive rituximab treatment for Epstein-Barrvirus reactivation after allogenic hematopoietic stem cell trans-plantation in worthwhile strategy in high-risk recipients: acomparative study for immune recovery and clinical outcomes.Bone Marrow Transplant 2020;55:586e94.

Post-transplant lymphoproliferative disorder in a patient after kidney transplant, 5-year follow-up: a case report

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Post-transplant lymphoproliferative disorder in a patient after kidney transplant, 5-year follow-up: a case report

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