Reduction Of Immunosuppressive Therapy Research Articles

Extramedullary plasmocytoma: A rare malignancy in renal transplant recipient

Extramedullary plasmacytoma in a post renal transplant recipient is an extremely rare type of post transplant lymphoproliferative disorder (PTLD) which warrants significant reduction in immunosuppressive therapy leading to increased risk of rejections and even graft loss. We describe a 49 year old male patient who after 14 years of renal transplant presented with extramedullary plasmacytomas in pancreas, gums, subcutaneous tissue and transplant kidney. He was treated with high dose melphalan followed by rescue autologous hematopoetic stem cell transplant and concurrent reduction in immunosuppression following which he achieved complete remission maintained on 5 years of follow up with astable allograft function. This case, to best of our knowledge is first case to be successfully managed with a rescue autologous hematopoetic stem cell transplant in a renal transplant patient with multifocal extramedullary plasmacytomas.

Case-based session: cardiac masses: Wednesday 3 December 2014, 11:00-12:30 * Location: Agora

Case-based session: cardiac masses: Wednesday 3 December 2014, 11:00-12:30 * Location: Agora

Disseminated adenoviral infection masquerading as lower urinary tract voiding dysfunction in a kidney transplant recipient

Viral infections continue to cause significant morbidity in immunosuppressed kidney transplant patients. Although cytomegalovirus, Epstein-Barr virus and polyoma "BK" virus are more frequently encountered, the Adenovirus can cause multi-organ system infections, and may be difficult to diagnose because it is not often considered in the initial work up in kidney transplant recipients. We present an unusual case of a kidney recipient 1 year post-transplant with disseminated adenoviral infection, who had an initial presentation of lower urinary tract voiding dysfunction with hematuria and sterile pyuria. This progressed to a severe tubulointerstitial nephritis and acute kidney injury that improved with reduction of immunosuppression. Serial blood viral loads are useful for monitoring the course of infection. Urinary adenoviral infection should be considered in the differential diagnosis whenever a kidney transplant recipient presents with unexplained lower tract voiding dysfunction, hematuria, and sterile pyuria. The allograft kidney and bladder can be targets of viral proliferation. Early diagnosis with reduction of immunosuppressive therapy is essential to clear the virus and maintain allograft function.

Towards gene therapy for EBV-associated posttransplant lymphoma with genetically modified EBV-specific cytotoxic T cells

AbstractEpstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2rγnull mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy.

Desensitization With Plasmapheresis and Anti-Cd20 for ABO Incompatible Kidney Transplantation From Living Donor: Experience of a Single Center in Italy

ObjectiveBlood group incompatibility in kidney transplants from a living donor can be successfully overcome by using various desensitization protocols: intravenous immunoglobulin, plasmapheresis (PP), immunoadsorption, and double filtration PP. Patients and MethodsFrom July 2010 to October 2013, we performed 10 ABO incompatible kidney transplantation (KT) procedures from a living donor. The desensitization protocol was based on rituximab and PP + cytomegalovirus immune globulin. All patients received induction with basiliximab, except 1 case treated with Thymoglobuline® (ATG) for the simultaneous presence of donor-specific antibody. Tacrolimus and mycophenolate mofetil were initiated at the time of desensitization and continued after the transplant. ResultsAfter a mean follow-up of 11.6 ± 10.4 months, all patients are alive with a functioning graft. The mean serum creatinine concentration at 1 month, 3 months, 6 months, and 1 year was 1.48 ± 0.29, 1.47 ± 0.18, 1.47 ± 0.27, and 1.5 ± 0.27 mg/dl. Three episodes of acute cellular rejection occurred in 2 patients. There was only 1 case of BK virus infection, treated with reduction of immunosuppressive therapy. The protocol biopsy specimens at 1, 3, and 6 months were C4d positive in the absence of acute rejection. ConclusionsDesensitization with rituximab, PP, and anti–cytomegalovirus immune globulin allowed us to perform transplants from living donors to ABO incompatible recipients with excellent results and reduced costs.

Post-transplant lymphoproliferative disorder in childhood

Introduction: Among possible complications of transplantation the post-transplant lymphoproliferative disease due to immunosuppressive therapy is of paramount importance. In most cases the direct modulating effect of Epstein–Barr virus on immune cells can be documented. Aim: The aim of the authors was to evaluate the incidence os post-transplant lymphoproliferative diseases in pediatric transplant patients in Hungary. Method: The study group included kidney, liver and lung transplant children followed up at the 1st Department of Pediatrics, Semmelweis University, Budapest and stem cell transplant children at Szent László Hospital, Budapest. Data were collected from 78 kidney, 109 liver and 17 lung transplant children as well as from 243 children who underwent allogenic stem cell transplantation. Results: Between 1998 and 2012, 13 children developed post-transplant lymphoproliferative disorder (8 solid organ transplanted and 5 stem cell transplanted children). The diagnosis was based on histological findings in all cases. Mortality was 3 out of the 8 solid organ transplant children and 4 out of the 5 stem cell transplant children. The highest incidence was observed among lung transplant children (17.6%). Conclusions: These data indicate that post-transplant lymphoproliferative disease is a rare but devastating complication of transplantation in children. The most important therapeutic approaches are reduction of immunosuppressive therapy, chemotherapy and rituximab. Early diagnosis may improve clinical outcome and, therefore, routine polymerase chain reaction screening for Epstein–Barr virus of high risk patients is recommended. Orv. Hetil., 2014, 155(8), 313–318.

Digestive Cryptosporidiosis in an Allogeneic Hematopoietic Stem Cell Transplant Recipient: A Case Report

Cryptosporidium has emerged as a major cause of diarrheal illness worldwide, especially among young children and patients with infectious or iatrogenic immune deficiencies. The authors report a case of mild cryptosporidiosis with delayed diagnosis in a stem cell transplant recipient probably due to confusion between digestive cryptosporidiosis and acute gastrointestinal graft-versus-host-disease. Clinical and parasitologic improvement was observed after a 3-day course of nitazoxanide and especially a reduction of immunosuppressive therapy.

Management of Non-Melanoma Skin Cancer in Solid Organ Transplant Recipients

Non-melanoma skin cancer (NMSC) is the most frequent cancer observed in solid organ transplant recipients (SOTR). Early diagnosis, patient education, and modification of immunosuppression are effective measures for reduction of NMSC incidence. Many risk factors have been identified, including age at transplantation, fair skin, type of immunosuppressive drugs, cumulative sun exposure, viral infections, and various genetic markers. Skin self-examination and photoprotection should be encouraged in all transplanted patients. Long-term skin surveillance, early diagnosis and aggressive treatment of any suspicious lesion, reduction of immunosuppressive therapy, and conversion to mammalian target-of-rapamycin (m-TOR) inhibitors can be also effective measures for reduction of NMSC incidence.

Post-transplant lymphoproliferative disorder: Case reports of three children with kidney transplant

Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases, characterized by abnormal lymphoid proliferation following transplantation. It is a disease of the immunosuppressed state, and its occurrence is mostly associated with the use of T-cell depleting agents, and also intensification of immunosuppressive regimens. In the majority of cases, PTLD is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The 2008 World Health Organization classification for lymphoid malignancies divides PTLD into four major categories: early lesions, polymorphic PTLD, monomorphic PTLD and Hodgkin PTLD. The treatment and prognosis depend on histology. The cornerstone of PTLD therapy includes reduction/withdrawal of immunosuppression, monoclonal anti CD-20 antibody (rituximab) and chemotherapy. We reported here our experiences with three patients, two girls aged 7.5 and 15 and a 16-year old boy. They had different organ involvement: brain, combined spleen-liver and intestines, respectively. Even though EBV was a trigger of lymphoid proliferation as it was confirmed by histopathology or in cerebrospinal fluid, qualitative EBV-PCR was positive only in one patient at disease presentation. Reduction of immunosuppression therapy was applied in treatment of all three patients, while two of them received rituximab and ganciclovir. They had an excellent outcome besides many difficulties in diagnosis and management of disease. Qualitative EBV-PCR is not useful marker in pediatric transplant recipients. Our suggestion is that patients with the risk factors like T-cell depleting agents, immunosuppressant protocol or increasing immunosuppressive therapy and EBV miss-match with donor must be more accurately monitored with quantitative EBV PCR.

Clinicopathological Study Of 12 Cases Of EBV-Associated Post-Transplant Lymphoproliferative Disorder (PTLD) After Allogeneic SCT: A Single Institution Analysis Of 825 Transplants Including 572 Cord Blood Transplants In Toranomon Hospital

BackgroundEBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is uncommon but one of serious complications after allogeneic stem cell transplantation (SCT). However, there has been little literature published on clinicopathological feature of it. MethodWe retrospectively investigated 825 cases of allogeneic SCT (unrelated bone marrow (uBM) 159, related peripheral blood (rPB) 94, cord blood (CB) 572) at Toranomon Hospital between January 2006 to November 2012. EBV-PTLD was defined as histologically confirmed Epstein-Barr virus (EBV) positive lymphoproliferative disorder developed after allogeneic SCT. ResultsWe identified 12 cases of EBV-PTLD in our cohort. Cumulative incidence of EBV-PTLD at 2 years was 1.5%. Median time from allogeneic SCT to the diagnosis of EBV-PTLD was 6.4 (2.5-26) months. Eight patients were male and median age at the diagnosis of EBV-PTLD was 58.5 years (28-66). Underlying diseases were acute myeloid leukemia (n=5), myelodysplastic syndrome (1), acute lymphoblastic leukemia (2), adult T cell leukemia-lymphoma (1), aplastic anemia (2) and chronic myeloid leukemia in blastic phase (1). Conditioning regimens were fludarabine-based (n=10) and TBI/CY (n=2). None had an antithymocyte globulin-containing regimen. Donor sources were uBM (n=1) and CB (11). EBV serology before allogeneic SCT was tested in 11 and all were positive. Patients who received CB showed higher incidence of EBV-PTLD compared to those in non-CB cohort (2.2% vs 0.6%, p < 0.01), although patients characteristics was different between them. One patient developed PTLD after third allogeneic SCT. All but one patients had a history of acute graft-versus-host disease (aGVHD) of grade I (n=2), grade II (6) and grade III (3), respectively. Chronic GVHD was observed in 6 patients. Eight patients were on immunosuppressive therapy (IST) with calcineurin inhibitors and/or steroids when EBV-PTLD was suspected for the first time. Although lymphadenopathy was detected by CT scan in 7 patients, surface lymph nodes were swollen in only 3 patients. Initial manifestations were fever in 8, and diarrhea in 5 patients. EBV-PTLD was diagnosed from lymph nodes (n=3), skin (3), bone marrow (2), stomach/duodenum (1), colon (2), and lung (1), respectively. Histological feature was monomorphic (n=4), polymorphic (2), early lesion (4), and unknown (2), respectively. LMP1 and EBNA2 was positive in 40% (4/10) and 30% (3/10), suggesting latency status of I in 50% (6/12), II in 8.3% (1/12), III in 25% (3/12), and unknown in 16.7% (2/12). EBV DNA of 100 copies/microL or above was detected in peripheral blood in all of the EBV-PTLD cases. The treatment for EBV-PTLD were rituximab alone (n=3), rituximab plus reduction of IST (6), rituximab plus cytotoxic chemotherapy (1), and observation alone(2). Although 8 patients achieved response, 2 patients suffered a relapse of EBV-PTLD. With a median follow up of 27.5 (4.1-47.7) months, 2-year overall survival was 46.9% after diagnosis of EBV-PTLD. Eight patients died and 4 are alive without relapse of EBV-PTLD. Causes of death were EBV-PTLD (n=2), relapse of underlying disease(3), infectious disease(2), and aGVHD(1). ConclusionTwelve cases of EBV-PTLD were identified in 825 transplants. Cumulative incidence of EBV-PTLD at 2 years was 1.5%. The incidence of EBV-PTLD after CB transplant was higher than that after non CB transplant, although we have to take into consideration that patients feature was different between them. Response to rituximab and/or reduction of IST was observed in 8 patients with a 2-year overall survival rate of 46.9%. Patients with prior aGVHD and with longer duration of immunosuppressive therapy may have an increased risk of developing EBV-PTLD. Since the initial manifestations were often equivocal, and survival rate after diagnosis is not high, having EBV-PTLD in mind as one of the possibilities is critical for prompt diagnosis. Disclosures:No relevant conflicts of interest to declare.

Genetically Modified EBV-Specific Cytotoxic T Lymphocytes Induce Regression Of EBV Lymphoproliferation Despite Immunosuppression In Xenografted Mice: A Novel Strategy For EBV-Associated Post-Transplant Lymphoproliferative Disease

BackgroundEBV associated lymphoproliferative disease (PTLD) remains a major cause of morbidity and mortality after stem cell (SCT) or solid organ (SOT) transplant. Adoptive transfer of ex vivo-derived EBV-specific cytotoxic T lymphocytes (EBV-CTL) to reconstitute immunity to the oncogenic virus EBV has been highly effective for both the prophylaxis and treatment of PTLD after SCT, where immunosuppression could be withdrawn before transfer of EBV-CTLs. In contrast, the application of this approach for the treatment of PTLD in SOT patients, although feasible, has been challenging with restricted expansion, persistence and efficacy of the adoptive transferred T cells. This difference is likely to reflect the need for the on-going immunosuppression to prevent graft-rejection post SOT which inhibits the virus-specific T cell responses. Our group has previously genetically engineered EBV-CTL to enable them to function in vitro in the presence of the calcineurin inhibitor Tacrolimus (FK506) through retroviral transfer of a calcineurin mutant (CNA12). AimTo examine the ability of genetically engineered EBV-CTLs resistant to FK506 to control EBV+ B cell lymphoma progression in vivoin a xenogeneic mouse model in the presence of FK506. MethodsNOD/SCID/IL2rgnull (NSG) mice were inoculated subcutaneously with 5×106 EBV-transformed lymphoblastoid B cell lines (LCL) labelled with F-Luc to develop human EBV+ lymphoma. To evaluate in vivo antitumor activity, 5×106 CTLs retrovirally transduced with CNA12 or eGFP control CTLs were injected intravenously after 7 days in the presence or absence of FK506 (10mg/kg/day). Tumour growth was analysed using the Xenogen-IVIS system. ResultsAdoptive transfer of autologous CNA12 transduced CTLs induced EBV+ lymphoma regression in the presence of FK506, as assessed both by IVIS and tumour size, whereas FK506 treated mice receiving eGFP control CTLs had tumour progression (P<0.05). This resulted in significantly improved survival of mice treated with CNA12-CTL in the presence of FK506 than eGFP-CTLs treated animals (P<0.0001). CNA12 transduced EBV CTLs persisted longer and expanded more (P<0.0001) than eGFP-CTLs in peripheral blood of mice treated with FK506 demonstrating a selective growth advantage and enrichment of CTLs resistant to immunosuppression. Immunohistochemical staining showed that adoptively transferred CTLs home to the tumour and an increase of tumour infiltrating T cells in CNA12-CTL compared with eGFP-CTLs treated mice in the presence of FK506 was observed. ConclusionsOur results demonstrate that CNA12 modified EBV-CTL can induce regression of EBV-associated tumours in vivo in the face of on-going immunosuppression with FK506. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy. Disclosures:No relevant conflicts of interest to declare.

Fast Achievement Of a First Metabolic Complete Remission In a Lung Transtplanted Patient With Multiple Comorbidities and a CD30 Positive Anaplastic Large Cell Post-Transplant Lymphoproliferative Disorder (T-PTLD/ALCL) By Treatment With Brentuximab Vedotin Monotherapy

IntroductionPost-Transplant-Lymphoproliferative Disorders are well known known, but rare complications of solid organ or hematologic stem cell transplantations. Incidence after lung-transplantation [LU-TX] is estimated to be ∼ 4.8% (Kremer et al. 2012). Most cases present as B-cell lymphomas (> 90%) and are EBV-associated. The WHO classification discriminates multiple subtypes (early lesions, monomorphic PTLD, polymorphic PTLD & classical Hodgkin lymphoma type PTLD). Treatment options mirror this histologic diversity and range from reduction of immunosuppressive therapy only , to aggressive polychemotherapy, DLI and second transplants. Patient historyIn May 2001 a left sided single LU-TX was performed for high grade bullous emphysema in a then 50 years old male patient. Several episodes of organ rejection required the use of complex immunosuppressive combination therapies, but long-term pulmonary function was preserved and the patient could be tapered to Tacrolimus and low dose steroids for years. Over the years the patient developed multiple severe comorbidities (Diabetes, renal retention, multiple pulmonary embolic events and peripheral thrombosis, as well as cardiac insuffiency and relapsing episodes of pancreatitis). CIRS-G-severity index was 2.7/4 with an ECOG score of 3. In May 2013 the patient developed B-symptoms, cutaneous lesions and a predominantly inguinal and abdominal lymphadenopathy. Histology & StagingA lymph node excision biopsy showed a high grade T-Cell lymphoma (molecular and immunological features are sumarized in Table 1) which could be classified as ALK negative anaplastic large cell lymphoma (ALCL) type PTLD, stage IV BE cutis with additional high risk features (LDH elevation). TreatmentBecause the patient was jugded to be unfit for aggresive polychemotherapy due to multiple comorbidities and his lymphoma was found to be expressing the CD30 antigen strongly and uniformly the anti-CD 30 immunotoxin Brentuximab-Vedotin (BV) was started at 1.8mg/m² every 21 days. B-symptoms disappeared within hours from the first infusion, palpable lymph nodes regressed within 3 weeks, and the patient improved to ECOG 1 in the same period. Furthermore LDH normalized by cycle 2. A PET-CT scan after cycle 3 proved a first complete metabolic remission and the treatment will be continued for 6 cycles. Data on response will be updated at ASH. No clinically relevant toxicities were observed. ConclusionTo our best knowledge this is the 1st report of the successful use of BV in a case of T-PTLD/ALCL after SLU-TX. As this case illustrates Brentuximab-Vedotin is a highly attractive , low toxicity treatment option in patients unfit to undergo aggressive polychemotherapy and can deliver complete responses with undeniable clinical benefit even in very advanced diease. For the rarity of these diseases the performance of a randomized clinical trial comparing BV to standard treatments seems unlikely for the foreseeable future and clinical decisions on treatment allocation have to be made on a case by case basis. We would recommend to at least collect all cases of BV use in PTLD to improve the respective best available evidence.TABLE 1Features of PTLDSubtypeMonomorphicHistologyALCLKi67>90%PositiveCD30 (100%), CD5, CD2, MUM1, EMANegativeCD20, CD117,ALK, Granzyme B, PAX-5, Perforin, KL-1, AE-1, AE-3, Melan-A,CD79, EBV-CISH Disclosures:Off Label Use: Brentuximab Vedotin for PTLD treatment.

INTRAOCULAR METHOTREXATE CAN INDUCE EXTENDED REMISSION IN SOME PATIENTS IN NONINFECTIOUS UVEITIS

To assess the outcomes of the intravitreal administration of methotrexate in uveitis. Multicenter, retrospective interventional case series of patients with noninfectious uveitis. Thirty-eight eyes of 30 patients were enrolled, including a total of 54 intravitreal injections of methotrexate at a dose of 400 µg in 0.1 mL. The primary outcome measure was visual acuity. Secondary outcome measures included control of intraocular inflammation and cystoid macular edema, time to relapse, development of adverse events, and levels of systemic corticosteroid and immunosuppressive therapy. Methotrexate proved effective in controlling intraocular inflammation and improving vision in 30 of 38 eyes (79%). The side effect profile was good, with no reported serious ocular adverse events and only one patient having an intraocular pressure of >21 mmHg. Of the 30 eyes that responded to treatment, 8 relapsed, but 22 (73%) entered an extended period of remission, with the Kaplan-Meier estimate of median time to relapse for the whole group being 17 months. The eight eyes that relapsed were reinjected and all responded to treatment. One eye relapsed at 3 months, but 7 eyes again entered extended remission. Of the 14 patients on systemic therapy at the start of the study, 8 (57%) were able to significantly reduce this following intravitreal methotrexate injection. In patients with uveitis and uveitic cystoid macular edema, intravitreal MTX can effectively improve visual acuity and reduce cystoid macular edema and, in some patients, allows the reduction of immunosuppressive therapy. Some patients relapse at 3 to 4 months, but a large proportion (73%) enter an extended period of remission of up to 18 months. This larger study extends the results obtained from previous smaller studies suggesting the viability of intravitreal methotrexate as a treatment option in uveitis.

Intestinal Microsporidiosis due to Enterocytozoon bieneusi in a Pediatric Kidney Transplant Recipient Successfully Treated with Fumagillin

Intestinal Microsporidiosis due to Enterocytozoon bieneusi in a Pediatric Kidney Transplant Recipient Successfully Treated with Fumagillin

Infection with hepatitis E virus in kidney transplant recipients in southeastern France

Hepatitis E virus (HEV) is an emerging cause of acute hepatitis in Europe, particularly in southern France, and HEV is a new causative agent of chronic hepatitis and cirrhosis in immunocompromised patients. However, the data regarding HEV infection after kidney transplantation are still scarce with respect to the clinical issues that have been raised, and no study has specifically focused on kidney transplant recipients. This study described the clinical features and outcomes of HEV infections in a cohort of kidney transplant recipients living in southeastern France. The epidemiological, clinical, and virological characteristics of HEV infections diagnosed by PCR over a 53-month period were retrospectively analyzed in a cohort of 1,350 kidney transplant recipients monitored at the Marseille University Hospital. Sixteen HEV infections were diagnosed, all of which were autochthonous and involved genotype 3 viruses (HEV-3). Chronic infections occurred in 80% of these patients and resolved in half of the cases after a median time of 39 months. The rate of HEV clearance was 54% after a decrease in the dose of immunosuppressants. One patient developed liver cirrhosis 14 months after infection and experienced acute rejection after a decrease in the dose of immunosuppressants. Autochthonous HEV-3 infections in kidney transplant recipients progress to chronicity in most cases and might be complicated by early liver cirrhosis. Chronic HEV infection can resolve following the reduction of immunosuppressive therapy, but ribavirin may be required if reduction of the immunosuppressant dose is not associated with HEV clearance or is inappropriate for the patient management.

Nonmelanoma Skin Cancer in Solid Organ Transplant Recipients: Update on Epidemiology, Risk Factors, and Management

Nonmelanoma skin cancers (NMSC) are the most frequently observed cancers in solid organ transplant recipients (SOTR) and may have a significant disease burden. To provide an update regarding the epidemiology and management of NMSC in SOTR. Ten-year incidence rates range from 10% in Italy to 20% in Northern Europe to 70% in Australia. More than 50% of NMSC are located on sun-exposed areas (head, dorsum of hands). Many risk factors have been identified, including age at transplantation, fair skin, type of immunosuppressive drugs, cumulative sun exposure, viral infections, and various genetic markers. Patients with a first NMSC have a 49 times higher risk of developing a subsequent NMSC. Skin self-examination and photoprotection should be encouraged in all transplanted patients. Long-term skin surveillance, early diagnosis and aggressive treatment of any suspicious lesion, reduction of immunosuppressive therapy, and conversion to m-TOR inhibitors can be also effective measures for reduction of NMSC incidence. NMSC is the most frequent cancer observed in SOTR. Early diagnosis, patient education, and modification of immunosuppression are effective measures for reduction of NMSC incidence.

Challenges and considerations in diagnosing the kidney disease in deteriorating graft function

SummaryDespite significant reductions in acute-rejection rates with the introduction of calcineurin inhibitor (CNI)-based immunosuppressive therapy, improvements in long-term graft survival in renal transplantation have been mixed. Improving long-term graft survival continues to present a major challenge in the management of kidney-transplant patients. CNIs are a key component of immunosuppressive therapy, and chronic CNI toxicity has been widely thought to be a major factor in late graft failure. However, recent studies examining the causes of late graft failure in detail have challenged this view, highlighting the importance of antibody-mediated rejection and other factors. In addition, the diagnosis of CNI nephrotoxicity represents a challenge to clinicians, with the potential for over-diagnosis and an inappropriate reduction in immunosuppressive therapy. When graft function is deteriorating, accurately determining the cause of the kidney disease is essential for effective long-term management of the patient. Diagnosis requires a thorough clinical investigation, and in the majority of cases a specific cause can be identified.

Management of polyomavirus-associated nephropathy in renal transplant recipients

Polyomavirus-associated nephropathy (PVAN) remains an important infectious complication after renal transplantation, affecting 1-10% of recipients and causing graft loss in approximately 50% of cases. With the lack of effective antiviral therapy, intensive monitoring for BK virus (BKV) using nucleic acid testing or urine cytology--in combination with a reduction of immunosuppressive therapy--is advocated to detect and prevent BKV reactivation and PVAN, respectively. In this Review, new insights into BKV biology and the development of PVAN are discussed. Clinical diagnostic approaches for the detection, surveillance and therapeutic monitoring of BKV are described. In addition, various strategies for reduction of immunosuppressive therapy are reviewed and an evaluation provided of the mechanisms of action and clinical effects of currently used adjuvant medication such as cidofovir, leflunomide, intravenous immunoglobulins and fluoroquinolone antibiotics. Finally, novel compounds and their in vitro actions against BKV are discussed together with future prospects for specific antiviral drug development.

Clinical Manifestations of BK Virus Infection in Kidney Transplant Recipients: A Single Center Experience

Background: BK virus (BKV) has emerged as an important cause of graft dysfunction and failure in renal transplant recipients. Reduction of immunosuppressive therapy is accepted as the primary strategy for management of BKV infection in renal transplant recipients, a strategy which frequently results in graft dysfunction and failure. Herein, a single center experience of BKV infection in renal transplant recipients is presented with an emphasis on the management of BKV infection. Methods: We retrospectively reviewed the medical records of 107 renal transplant recipients who were treated at the outpatient clinic in Seoul National University Bundang Hospital from April 2003 to April 2011. The effects of the modification of immunosuppression on the replication of BKV and graft outcome were analyzed. Results: Of a total of 35 patient evaluated for BKV infection, 20 tested positive in at least one BK virus test. Decoy cells in urine were detected in 13 of the 20 patients. Of these patients, 7 developed BKV nephropathy. Four out of seven of the BKV nephropathy patients were diagnosed with biopsy, and the other three were diagnosed based on a high titer of BKV replication detected in plasma samples. Despite the reduction in immunosuppression and use of leflunomide in the seven BKV nephropathy patients, two patients suffered deterioration of renal function and one patient lost the graft with progressive renal dysfunction. Conclusions: BK virus nephropathy was not an uncommon disease and was a major cause of graft dysfunction or loss. Appropriate modification of immunosuppressive therapy, early in the course of BK nephropathy or before the occurrence of massive replication of BKV, is essential for the protection of renal allografts.

Post renal transplantation Kaposi's sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy

Kaposi's sarcoma (KS) is a vascular malignancy primarily involving the skin. This neoplasm occurs commonly in acquired immunodeficiency syndrome (AIDS) and post solid organ transplantation. Human herpesvirus type 8 (HHV-8) has been shown to play a causative role in AIDS-associated KS and in post renal transplantation KS. Based on a MEDLINE search, we present a review of the current information on the epidemiology, pathogenesis, diagnosis and treatment of post-transplantation KS (PT-KS) with an emphasis on renal transplantation. The different frequencies of PT-KS in different parts of the world seem to be related to seroprevalence of HHV-8 infection. Following renal transplantation and the administration of immunosuppressive therapy, HHV-8 may reactivate. The renal tubular epithelium is a site for HHV-8 latency. Rates of PT-KS in seropositive recipients and anti-HHV-8 mismatched recipients (donor+/recipient-) are approximately 13% and 4.6%, respectively. Additional risk factors for the development of PT-KS include skin color, country of birth, age at the time of transplantation, and different induction regimens including anti-thymocyte globulin, steroid, or anti-interleukin 2-receptor antagonists. Skin is the major site of involvement. Surprisingly, involvement of the transplanted organ has been reported to be extremely rare. Reduction in immunosuppressive therapy and switching to mammalian targets of rapamycin inhibitors, such as sirolimus, are effective treatments for PT-KS. In patients with no response to reduction in immunosuppressive therapy, systemic chemotherapy with different regimens has been reported to be successful. PT-KS in renal transplant patients is an important problem specifically in southern Europe and the Middle East. In the majority of patients, the diagnosis based on clinical suspicion is always essential. Clinicians should bear in mind that PT-KS may threaten graft function and hence result in rejection complications. Appropriate management increases patient survival.