Case Conference: Quiz and Questionnaire

Post-Transplant Lymphoproliferative Disorder in a Kidney Transplant Recipient

Gaurav Agarwal and Roslyn B. Mannon Clin J Am Soc Nephrol 14: 751–753, 2019. doi: https://doi.org/10.2215/CJN.00180119

Division of Introduction Discussion of Question 1 Nephrology, A 53-year-old man with ESKD underwent living donor The correct answer is E. There is no evidence to Department of Medicine, University kidney transplantation from his spouse who had a suggest early rejection (A or B), except perhaps the – of Alabama at positive serum PCR for Epstein Barr virus (EBV) at intentional reduction in . Tacro- Birmingham, thetimeofdonation.Hereceivedrabbitantithymo- limus toxicity (C) is unlikely. Without abdominal Birmingham, Alabama cyte globulin induction and rapid pain and urinary complaints, D is less likely. With taper with maintenance immunosuppressive ther- his poor appetite, weight loss, and glucosuria, E is Correspondence: apy of (target trough 8–12 ng/ml) and the best choice. Dr. Roslyn B. Mannon, – Division of (target trough 8 11 ng/ml). The pa- Nephrology, tient was seronegative for EBV. At 1 month post- Department of transplant, the patient had a serum of Clinical Course Medicine, University of 0.8 mg/dl, and serum EBV and cytomegalovirus Admission chest x-ray (Figure 1A) demonstrated Alabama at fi PCR were negative. mediastinal and paratracheal adenopathy con rmed Birmingham, 1900 on computerized tomography (Figure 1B). Head com- University Boulevard, At 3 months post-transplant, he presented with 4 kg THT 643, Birmingham, weight loss attributed to gastroparesis and serum puterized tomography showed no masses. Immuno- AL 35294. Email: creatinine of 1.5 mg/dl. His LDH was mildly elevated suppression was discontinued, because EBV PCR rose [email protected] 3 6 (338 IU/ml), but remaining liver enzymes were normal. to 15 10 copies per 1 ml. Because of a creatinine of His sirolimus dose was reduced to achieve a trough 2.6 mg/dl, a kidney biopsy was performed. This fi level of 6 ng/ml. Over the next 2 weeks, he lost an revealed interstitial lymphocytic in ltrates (Figure 1, additional 2 kg. Serum creatinine rose to 1.7 mg/dl, C and D), which stained positive for CD3 (Figure 1E), and LDH rose to 1005 IU/ml; tacrolimus and siroli- CD20 (Figure 1F), and EBV-encoded RNA (Figures 1, mus levels were stable. Serum EBV PCR was positive G and H). Lymph node and bone marrow biopsies fi at 73106 copies per 1 ml. were positive for monomorphic B cell in ltrates. fi He was admitted to the hospital for additional Positron emission tomography scan con rmed tumor management. On examination, he had a temperature in the liver, spleen, and sinuses. A diagnosis of post- of 37.8°C, normal heart rate, BP of 122/82 mm Hg transplant monomorphic (large B cell ) without orthostatsis, shotty cervical lymph nodes, lymphoproliferative disorder (PTLD) was made. clear lungs, normal cardiac examination, and mildly distended with a nontender but palpa- Question 2 ble kidney allograft. Laboratory testing showed Which of the following statements is true about serum creatinine of 1.7 mg/dl, blood glucose of PTLD? 357 mg/dl, LDH of 1500 IU/ml, tacrolimus trough level of 5.0 ng/ml, and sirolimus trough of 6.0 ng/ml. A. The greatest risk of EBV-PTLD is in kidney transplant fi 1 Urinalysis showed a speci c gravity of 1015, 1 recipients. 1 1 protein/3 glucose/2 ketones on dipstick, and B. It is more common in EBV-mismatched transplant negative microscopy. with donor positive and recipient negative for EBV immunity. Question 1 C. There is an increased risk when using T cell–depleting What is the most likely cause of the AKI in this induction therapy. patient? D. Risk of development is reduced with sirolimus therapy. A. Acute cellular rejection B. Antibody-mediated rejection C. Tacrolimus toxicity Discussion of Question 2 D. Urinary tract obstruction The correct answer is B. The risk of PTLD is lowest E. Volume depletion after kidney transplant (0.8%–2.5%) and highest in www.cjasn.org Vol 14 May, 2019 Copyright © 2019 by the American Society of Nephrology 751 752 Clinical Journal of the American Society of Nephrology

CD

A

EF

B

G H

Figure 1. | Radiographic and histological features of PTLD. Plain radiograph of the chest demonstrates enlarged paratracheal and para-aortic lymph nodes (A). Noncontrast computerized tomography of the chest confirms para-aortic lymphadenopathy (B). Hematoxylin and eosin staining of a kidneyallograft biopsy (C) exhibits a perivascular lymphocytic infiltrate (D). Immunohistochemical staining for CD3 (E) and B220 (F) indicating a B cell–predominant infiltrate. Epstein–Barr virus (EBV)–encoded RNA staining at 3100 (G) and 3200 (H) documents the presence of the EBV genome in the infiltrate consistent with EBV–post-transplant monomorphic (large B cell lymphoma) lymphoproliferative disorder. Original magnification, 3100 in B and G; 3200 in C and H. small bowel transplants (#20%) (1). C is incorrect, because but repeat bone marrow biopsy showed ongoing lym- both rabbit antithymocyte globulin and alemtuzumab have phoma and hemophagocytic syndrome. On hospital day 32, uncertain effects on PTLD risk (2). D is incorrect, because his family withdrew intensive support, and he died sirolimus has been associated with higher rather than lower 4.6 months post-transplant. risk for PTLD (3).

Discussion Additional Clinical Course Solid organ transplant recipients have a threefold higher The patient was transferred to the intensive care unit with risk of , particularly virally mediated , com- hypotension, hyperkalemia, worsening anion gap metabolic pared with the general population (4). PTLD represents acidosis, and rising serum creatinine of 5.9 mg/dl. He was 21% of all cancers in solid organ transplants recipients started on and ultimately intubated. He received compared with 4%–5% in the immunocompetent popula- chemotherapy with rituximab, etoposide, prednisone, vin- tion (1). Among the solid organs transplanted, kidney cristine, cyclophosphamide, and doxorubicin hydrochloride. recipients have the lowest risk of PTLD (1), with a bimodal He became severely pancytopenic, with LDH.7000 IU/ml incidence in the early post-transplant period and a second and ferritin of 10,000 ng/ml. Over the ensuing week, he peak later 10–14 years post-transplant. Early-onset PTLD is required platelet and red blood cell transfusions and de- more common in children (2.4%–15% incidence), and it is veloped pulmonary infiltrates. Bronchoscopy demonstrated characterized by EBV tissue positivity, extranodal disease, fungal hyphal elements, and antifungal therapy was added and a monomorphic subtype (5). EBV seronegative recip- to a regimen of broad spectrum antibiotics. EBV fell ients receiving an EBV-positive organ have a 10- to 75-fold dramatically postchemotherapy to 0.13106 copies per 1 ml, higher risk compared with seropositive recipients (5). Clin J Am Soc Nephrol 14: 751–753, May, 2019 PTLD after Kidney Transplantation, Agarwal et al. 753

Interestingly, the vast majority of tumors in solid organ allograft dysfunction and multiorgan involvement, and even transplantation originate from the recipient cells (6). with early detection and aggressive therapy, the disease Clinical presentation of PTLD is variable. It may be was fatal. asymptomatic, or it may present with pleiotropic symp- toms affecting any or multiple sites, including skin, solid organs, brain, and bone, and B symptoms of fatigue, night Acknowledgments sweats, weight loss, and low-grade fever. In contrast We appreciate the clinical support and management by Drs. Alan to other non-Hodgkin , PTLD carries a high Kirk, S. John Swanson, and Douglas Hale and the entire National incidence of extranodal involvement, including the gastro- Institutes of Health/National Institute of and Digestive intestinal tract (20%–30% of patients), the solid allograft and Kidney Diseases intramural kidney transplant program. JASN (10%–15% of patients), and the central nervous system Dr. Mannon serves on the editorial board of . (5%–20% of patients) (5). This case was presented at the American Society of Nephrology The diagnosis of PTLD is made by histopathologic tissue Kidney Week 2018 Nephrology Quiz and Questionnaire, San Diego, examination and characterized by the World Health Or- CA, October 26, 2018. ganization 2017 classification (reviewed in ref. 5). PTLD is Disclosures classified into nondestructive, polymorphic, monomorphic Dr. Mannon reports grants from Quark Pharmaceuticals, CSL PTLD and Hodgkin lymphoma–like PTLD. The EBV- in situ Behring, Mallinckrodt, and Transplant Genomics and personal encoded RNA hybridization assay is recommended fees from Sanofi outside the submitted work. Dr. Agarwal has in all patients, although the frequency of patients who are nothing to disclose. EBV negative has increased and now represents 48% of all PTLD (7). Compared with EBV-positive PTLD, EBV-negative PTLD occurs later post-transplant, has monomorphic histol- References ogy, is diagnosed often at an advanced stage, and is di- 1. Opelz G, Do¨hler B: Lymphomas after solid : A agnosed often with central nervous system involvement, but collaborativetransplantstudyreport.AmJTransplant4:222–230,2004 it does not carry a worse prognosis. It responds equally to 2. HillP,CrossNB,BarnettAN,PalmerSC,WebsterAC:Polyclonaland monoclonal antibodies for induction therapy in kidney transplant therapy, achieving similar rates of complete remission (7). recipients. Cochrane Database Syst Rev 1: CD004759, 2017 The treatment options for PTLD include a reduction in 3. 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Parker A, Bowles K, Bradley JA, Emery V,Featherstone C, Gupte G, tabolite ( or mycophenolate), and continuation Marcus R, Parameshwar J, Ramsay A, Newstead C; Haemato- of prednisone at 10 mg daily (8). Response to reduction oncology Task Force of the British Committee for Standards in occurs within 2–4 weeks. In the critically ill patient, all Haematology and British Transplantation Society: Management immunosuppression is discontinued. It is essential to of post-transplant lymphoproliferative disorder in adult solid or- gan transplant recipients - BCSH and BTS Guidelines. Br J Hae- monitor function during immunosuppression reduc- matol 149: 693–705, 2010 tion, because there is a 38% risk of rejection. In patients who 9. Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, do not respond to reduction of immunosuppression, the Mollee P, Zaucha JM, Dreyling MH, Du¨hrsen U, Reinke P, standard therapy is rituximab alone, with a complete Verhoef G, Subklewe M, Hu¨ttmann A, Tousseyn T, Salles G, response rate of 25% (9). In nonresponders, rituximab is Kliem V, Hauser IA, Tarella C, Van Den Neste E, Gheysens O, Anagnostopoulos I, Leblond V,Riess H, Choquet S: Response to followed by four cycles of cyclophosphamide, doxorubicin, rituximab induction is a predictive marker in B-cell post- vincristine, and prednisone chemotherapy, with a complete transplant lymphoproliferative disorder and allows successful response rate of 70%. The PTLD-1 prospective trial stratification into rituximab or R-CHOP consolidation in an established a risk-stratified sequential treatment approach international, prospective, multicenter phase II trial. JClin Oncol 35: 536–543, 2017 with rituximab plus cyclophosphamide, doxorubicin, vin- 10. Caillard S, Cellot E, Dantal J, Thaunat O, Provot F, Janbon B, cristine, and prednisone as the standard therapy for PTLD Buchler M, Anglicheau D, Merville P, Lang P, Frimat L, Colosio C, irrespective of EBV status (9). Alamartine E, Kamar N, Heng AE, Durrbach A, Moal V, Rivalan J, In the current era, the overall median survival is Etienne I, Peraldi MN, Moreau A, Moulin B; FrenchPTLD Registry: 6.6 years post-PTLD diagnosis (9). Retransplantation after A French cohort study of kidney retransplantation after post- transplant lymphoproliferative disorders. Clin J Am Soc Nephrol treatment is considered in select patients after 1 year of 12: 1663–1670, 2017 complete remission. The risk for PTLD recurrence is ,2% after retransplantation (10). Here, the patient had all of the Published online ahead of print. Publication date available at poor prognostic features associated with PTLD with severe www.cjasn.org.