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Posttransplant management in solid organ transplantation (SOT) Prof. Ileana Constantinescu What means post transplant management of the patient • • • • • • • • • • • • • • • Management of skin cancer in solid organ transplant recipients Renal function and nonrenal solid organ transplantation Treatment and prevention of post-transplant lymphoproliferative disorders Long-term management of adult liver transplant recipients Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients Prevention of cytomegalovirus infection in lung transplant recipients Development of malignancy following solid organ transplantation Infection in the solid organ transplant recipient Osteoporosis after solid organ or stem cell transplantation Systemic treatment of advanced cutaneous squamous and basal cell carcinomas Overview of care of the adult kidney transplant recipient Solid organ transplantation in HIV-infected individuals Management of the hematopoietic cell transplant recipient in the immediate posttransplant period Treatment and prognosis of cutaneous squamous cell carcinoma ESOT - http://www.esot.org Management of skin cancer in solid organ transplant recipients INTRODUCTION • Solid organ transplant recipients are at increased risk for cutaneous malignancies, a finding related to the long-term use of immunosuppression. Because some skin cancers demonstrate aggressive biologic behavior in the setting of immunosuppression, care must be taken to identify and treat early lesions appropriately. In addition to treatments that directly target cutaneous malignancies, modulation of immunosuppression and preventive measures often play an important role in the management of these patients. Organ transplant recipients with a history of skin cancer should be followed closely for the development of new lesions, locally recurrent lesions, and metastatic disease. • The management of skin cancers in organ transplant recipients will be reviewed here. The epidemiology and risk factors for skin cancers in organ transplant recipients, as well as a summary of other malignancies that develop with increased frequency after solid organ transplantation, are discussed separately. SQUAMOUS CELL CARCINOMA • Squamous cell is carcinoma (SCC) is the most common cutaneous malignancy in solid organ transplant recipients . As in the immunocompetent population, cutaneous SCC is most likely to occur in patients with fair skin. • In comparison to SCC in immunocompetent patients, SCC in organ transplant recipients is more likely to manifest as aggressive disease . The prognosis is poor for the 5 to 8 percent of patients who develop metastases; in a retrospective study that included 58 organ transplant recipients with distant or systemic metastases of cutaneous SCC, the three-year disease-specific survival rate was 29 percent . Thus, once detected, prompt, appropriate management of early SCC is essential. Patient evaluation — All lesions that are suspicious for SCC should be pathologically examined to confirm the diagnosis and to evaluate for features associated with aggressive disease. Biopsies of papular or nodular lesions should extend at least into the deep reticular dermis. Renal function and nonrenal solid organ transplantation INTRODUCTION • As outcomes following nonrenal solid organ transplantation have improved, chronic kidney disease (CKD) has become an increasingly prevalent complication in this population . CKD occurs despite advancements in immunosuppression and perioperative management, as well as attention to cardiovascular risk factors and infectious complications . • The development of CKD is associated with enhanced morbidity and mortality . • Issues relating to kidney function following nonrenal solid organ transplantation, including the evaluation of kidney function prior to nonrenal organ transplantation, are presented in this topic review. A review of calcineurin inhibitor nephrotoxicity is presented separately. PREOPERATIVE EVALUATION OF KIDNEY FUNCTION • As a general rule, the preoperative evaluation of kidney function in nonrenal solid organ transplantation candidates should focus upon establishing the likelihood of being left with adequate kidney function posttransplant and the chance of progression to end-stage renal disease (ESRD). Patients who are likely to have stage 4 or stage 5 chronic kidney disease (CKD) after the early posttransplant period and/or those with established primary renal disease that is likely to progress at a rapid pace (thereby requiring chronic kidney replacement therapy shortly after transplant) should be listed for combined organ transplant. It should be noted that, in an era of ever-increasing organ shortage, in which waiting times for kidneys are lengthening, combined nonrenal and renal organ transplantation should be considered very judiciously. • The vast majority of patients with normal or mild impairment in kidney function should receive a nonrenal solid organ transplant alone. However, normal or near-normal serum creatinine levels do not necessarily reflect normal kidney function, especially in states of heart failure or liver disease, where affected patients frequently have poor nutritional status, low muscle mass, weight loss, and edema. Treatment and prevention of post-transplant lymphoproliferative disorders (PTLD) INTRODUCTION • Post-transplant lymphoproliferative disorders (PTLD) are lymphoid and/or plasmacytic proliferations that occur in the setting of solid organ or allogeneic hematopoietic cell transplantation as a result of immunosuppression. They are among the most serious and potentially fatal complications of transplantation. While the majority appears to be related to the presence of Epstein-Barr virus (EBV), EBVnegative disease does occur. Three general types of PTLD have been described in transplant recipients: • ●Early lesion (plasmacytic hyperplasia and infectious mononucleosis-like PTLD) – This presents as an infectious mononucleosis-type acute illness characterized by polyclonal B cell proliferation with no evidence to suggest malignant transformation. • ●Polymorphic PTLD – Polymorphic PTLD are polyclonal or monoclonal lymphoid infiltrates that demonstrate evidence of malignant transformation but do not meet all of the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients. • ●Monomorphic PTLD – Monomorphic PTLD are monoclonal lymphoid proliferations that meet the criteria for one of the B cell or T/NK cell lymphomas recognized in immunocompetent patients. • These conditions lie along a continuum of disease and are categorized by the 2008 WHO classification system as PTLD . Of importance, small B cell lymphoid neoplasms (eg, follicular lymphomas, small lymphocytic lymphoma) and marginal zone (MALT) lymphomas arising in the post-transplant setting are not considered PTLD. Long-term management of adult liver transplant recipients INTRODUCTION • Liver transplantation is the treatment of choice for appropriately selected patients with end-stage liver disease. With improved long-term survival, more patients are being cared for outside of a transplant center, requiring more widespread familiarity with the complications seen in this patient population. Several medical problems are routinely encountered by clinicians caring for patients after liver transplantation. These include: • ●Acute or chronic rejection • ●Complications of immunosuppression including hypertension, renal insufficiency, infection, malignancy, a variety of dermatologic conditions, and metabolic diseases such as diabetes mellitus, obesity, hyperlipidemia, and bone disease • ●Biliary complications • ●Recurrence of the primary liver disease Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients INTRODUCTION • Cytomegalovirus (CMV), a member of the betaherpesvirus group, remains an important cause of morbidity and mortality in lung transplant recipients. It is the second most common infection among lung transplant recipients, after bacterial pneumonia. • While the development and availability of potent antiviral agents has decreased CMV-related mortality, there is a growing body of evidence that the indirect effects of CMV may be equally important or even more important than its direct effects of tissue injury and infection . CMV-induced immunosuppression may lead to infection with other opportunistic organisms. In addition, CMV infection and disease have been associated with acute and chronic rejection (bronchiolitis obliterans syndrome) in some, but not all studies. • The approach to the diagnosis and treatment of CMV infections in lung transplant recipients continues to evolve as transplant specialists gain experience using molecular diagnostic techniques and the potent oral antiviral agent, valganciclovir. The epidemiology, clinical features, diagnosis, and treatment of CMV infection in lung transplant recipients will be discussed here. Prevention of CMV infection in lung transplant recipients, as well as infectious complications due to pathogens other than CMV, are discussed elsewhere. EPIDEMIOLOGY • Primary cytomegalovirus (CMV) infection is acquired through close physical contact involving direct inoculation with infected cells or body fluids. Following primary infection, CMV infection persists for life. Population studies document a gradual increase in CMV seropositivity through young adulthood. Although there is considerable variability, more than one-half of adults in the United States have serologic evidence of previous infection. • CMV infection following transplantation can be acquired in one of several ways Prevention of cytomegalovirus infection in lung transplant recipients INTRODUCTION • Cytomegalovirus (CMV), a member of the betaherpesvirus group, remains an important cause of infection, resulting in substantial morbidity and increased mortality in lung transplant recipients. It is the second most common infection among lung transplant recipients after bacterial pneumonia. • While the development and availability of potent antiviral agents has decreased CMV-related mortality, there is a growing body of evidence that the indirect effects of CMV may be equally important or even more important than its direct effects of tissue injury and infection . CMV-induced immunosuppression may lead to infection with other opportunistic organisms. In addition, CMV infection and disease have been associated with acute and chronic rejection (bronchiolitis obliterans syndrome) in some but not all studies. • The approach to prevention of CMV infections in lung transplant recipients continues to evolve as transplant specialists gain experience using molecular diagnostic techniques and the potent oral antiviral agent valganciclovir. The prevention of CMV infection in lung transplant recipients will be discussed here. The clinical manifestations, diagnosis, and treatment of CMV infection in lung transplant recipients and infectious complications due to agents other than CMV are discussed elsewhere. EPIDEMIOLOGY • Primary CMV infection is acquired through close physical contact involving direct inoculation with infected cells or body fluids. Following primary infection, CMV infection persists for life. Population studies document a gradual increase in CMV seropositivity through young adulthood. Although there is considerable variability, more than one-half of adults in the United States have serologic evidence of previous infection. • CMV infection following transplantation can be acquired in one of several ways Development of malignancy following solid organ transplantation INTRODUCTION AND OVERVIEW • The chronic use of immunosuppressive agents to prevent allograft rejection increases the long-term risk of malignancy, compared with that of the general population. This topic will review the general issue of malignancy following solid organ transplantation. The problems of second malignancies following bone marrow transplantation and the development of lymphoproliferative disorders following solid organ transplantation are discussed separately. GENERAL EPIDEMIOLOGY • There is an increased risk of a wide range of cancers associated with solid organ transplantation. The most extensive data come from a cohort study that analyzed the frequency of malignancy in over 175,000 solid organ transplant recipients during the period 1987 to 2008 . The most common organs transplanted included kidney, liver, heart, and lung (in 58, 22, 10, and 4 percent of cases, respectively). • Overall, malignancy was identified in over 10,656 cases, which correlated with a standardized incidence ratio (SIR) of 2.10 (95% CI 2.06-2.14), compared with the general population, and an excess absolute risk (EAR) of 719 cases per 100,000 person-years. • A significantly increased risk of malignancy was associated with more than 30 different primary sites. The tumor sites with a fivefold or greater increase, compared with the general population, included the following: • Kaposi sarcoma (KS; SIR 61 and EAR 15) Infection in the solid organ transplant recipient INTRODUCTION • Solid organ transplantation has increased worldwide since the first successful human kidney transplant was performed in 1954. As immunosuppressive agents and graft survival have improved, infection and malignancy have become the main barriers to disease-free survival after organ transplantation. As a result of the growing population of immunosuppressed patients with prolonged survival, an increased incidence and spectrum of opportunistic infections is observed . Guidelines for the diagnosis and treatment of infection in transplant recipients have been developed . • The risks of infection and an overview of specific infections in the solid organ transplant recipient will be reviewed here. The pretransplant evaluation for solid organ and hematopoietic cell transplant (HCT) recipients, prophylaxis of infections in solid organ transplant and HCT recipients, and an overview of infections following HCT are discussed separately. GENERAL PRINCIPLES • When infection occurs, early and specific diagnosis and rapid and aggressive treatment are essential to good clinical outcomes. • ●Potential etiologies of infection in these patients are diverse, including common, community-acquired bacterial and viral diseases and uncommon opportunistic infections of clinical significance only in immunocompromised hosts . Pulmonary processes can progress rapidly and may constitute medical emergencies . These include infections due to Pneumocystis jirovecii (formerly P. carinii), Nocardia asteroides, Aspergillusspp, Cryptococcus neoformans, cytomegalovirus (CMV), varicella-zoster virus (VZV), influenza, respiratory syncytial virus (RSV), Rhodococcus equi, and Legionella spp. • ●Inflammatory responses associated with microbial invasion are impaired by immunosuppressive therapy, which results in diminished symptoms and muted clinical and radiologic findings. As a result, infections are often advanced (disseminated) at the time of clinical presentation. Osteoporosis after solid organ or stem cell transplantation INTRODUCTION • Transplantation has become an established therapy for end-stage kidney, heart, lung, and liver diseases, as well as for several hematologic disorders. Improved survival of transplant recipients has raised awareness of post-transplant complications, such as osteoporosis. Post-transplant osteoporosis and fracture occur in a substantial proportion of patients. • The pathogenesis, clinical manifestations, and management of bone loss after solid organ (with the exception of renal transplant) or stem cell transplantation will be reviewed here. Management of bone loss after renal transplantation is discussed elsewhere. PATHOGENESIS • Transplant-related osteoporosis and fracture are due to both pretransplant and post-transplant factors Pretransplant bone status — Many patients undergoing transplantation already have low bone mineral density (BMD). The mechanism appears to vary with the underlying disease: • ●In patients with severe heart failure (New York Heart Association [NYHA] classes III and IV) who are candidates for cardiac transplantation, chronic kidney disease, vitamin D deficiency, secondary hyperparathyroidism, hypogonadism, chronic use of heparin and/or loop diuretics, and reduced physical activity may contribute to low BMD. Systemic treatment of advanced cutaneous squamous and basal cell carcinomas INTRODUCTION • Basal cell carcinoma and squamous cell carcinoma of the skin, together referred to as nonmelanoma skin cancer (NMSC), are the most commonly diagnosed malignant neoplasms in the Caucasian population of the United States. Because many patients are treated as outpatients in an office setting, reliable statistics are difficult to obtain. Nonetheless, the National Cancer Institute estimates that approximately two million new cases occurred in 2012 . • The vast majority of patients can be successfully managed with a variety of simple procedures, such as cryotherapy, curettage and electrodesiccation, topical treatments (5fluorouracil, imiquimod), or simple surgical excision. When lesions are more advanced, Mohs micrographic surgery, more extensive surgical resection, or radiation therapy generally are generally sufficient to control locoregional disease. • Despite their high prevalence, these nonmelanoma skin cancers are rarely fatal. It is estimated that in 2012, approximately 1000 patients died of the disease. Squamous cell carcinomas are biologically more aggressive, and neglected lesions can be life threatening due to local extension or metastasis. In contrast, basal cell carcinoma is only very rarely life threatening. • The use of systemic therapy is limited to patients with distant metastases or locally advanced disease that cannot be adequately managed with surgical or radiotherapeutic techniques. • Systemic chemotherapy for basal cell and squamous cancers of the skin could be a solution. The treatment of localized basal cell and squamous cell carcinomas is an issue to be discussed. Overview of care of the adult kidney transplant recipient INTRODUCTION • Kidney transplantation is the treatment of choice for end-stage renal disease . A successful kidney transplant improves the quality of life and reduces the mortality risk for most patients when compared with maintenance dialysis. However, patients require close follow-up after transplantation since they are on complex immunosuppressive regimens that render them susceptible to infection, malignancy, and cardiovascular disease (CVD). In addition, patients often have multiple comorbidities due to, or as a cause of, their underlying end-stage renal disease. • Whereas patients are generally followed by a transplant specialist for the first three to six months following transplant, thereafter they may be seen primarily by a general nephrologist or internist, who is often able to address existing comorbidities. Whether a patient is followed by a transplant nephrologist, general nephrologist, or internist often depends upon the availability of services in proximity to the patient. While many believe that transplant nephrologists should be directly involved in care of transplant recipients for the life of the graft, this is often not practical. Communication between the internist or community-based nephrologist and the transplant center is important for optimal care of the patient, however. • This topic reviews the general medical care of the kidney transplant recipient including recommendations for monitoring allograft function and minimizing the risk of infections, malignancies, bone disease, CVD, and diabetes. These are common medical problems encountered after transplantation are also discussed. Solid organ transplantation in HIV-infected individuals INTRODUCTION • Liver, kidney, and heart transplantation are the current treatments of choice for advanced organ failure. However, human immunodeficiency virus (HIV) infection was traditionally considered an absolute contraindication for transplantation . One of the principal concerns was that immunosuppression would accelerate HIV/acquired immune deficiency syndrome (AIDS), resulting in increased mortality and a "waste" of organs. • Since highly active antiretroviral therapy (HAART) became widely available in 1996, the prognosis of HIV infection has dramatically improved. There have been significant decreases in morbidity and mortality, and, for many individuals with well-controlled viral replication, HIV/AIDS is now a chronic, manageable disease. • Previously, HIV-infected individuals with very advanced disease frequently died from opportunistic infections (OIs). Among such individuals, the presence of chronic diseases, such as renal insufficiency, coronary artery disease, diabetes mellitus, or liver failure (associated with hepatitis B [HBV] or C virus [HCV] coinfection), were not significant causes of mortality. The situation is currently quite different as these comorbidities, as well as others, are real medical problems for many individuals with well-controlled HIV replication. • Such improvements in the long-term prognosis of those with HIV infection have prompted many transplant programs to reevaluate their policies regarding the exclusion of patients with HIV infection. A review of the issues surrounding solid organ transplantation in HIV-infected patients is presented here. OUTCOMES BEFORE HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) • Prior to the availability of a reliable diagnostic test for HIV infection, some individuals unknowingly infected with HIV underwent solid organ transplantation . Others acquired HIV infection by receiving an organ from a HIV-positive individual. Management of the hematopoietic cell transplant recipient in the immediate posttransplant period INTRODUCTION • Among patients undergoing hematopoietic cell transplantation (HCT), advances in hematopoietic support; improvements in antibiotics, antifungal agents, and antiviral drugs; and better medications to control side effects of treatment such as nausea, vomiting, diarrhea and pain have all had a major impact on the clinical course. • In terms of decreased morbidity and mortality after autologous transplantation, probably the single most important advance has been the introduction of mobilized peripheral blood progenitor cells (PBPCs) as the source of hematopoietic stem cells. This approach results in more rapid recovery, which has significantly reduced the duration of antibiotic therapy, the degree of mucositis, the length of hospitalization, and the risk of the transplant procedure itself. These positive developments have resulted in a marked decline in the discomfort that patients experience in the transplant setting. • The term "hematopoietic cell transplantation" (HCT) will be used throughout this review as a general term to cover transplantation of progenitor cells from any source (eg, bone marrow, peripheral blood, umbilical cord blood). Otherwise, the source of such cells will be specified (eg, autologous PBPC transplantation). • General supportive care measures for patients following HCT and long term complications of HCT will be reviewed here . Hematopoietic support after HCT and the prevention and treatment of acute and chronic graft versus host disease are discussed separately. • The diagnosis and treatment of pulmonary, renal, and infectious complications following HCT are also presented separately. Treatment and prognosis of cutaneous squamous cell carcinoma INTRODUCTION • Cutaneous squamous cell carcinoma (SCC) is a common cancer arising from malignant proliferation of the keratinocytes of the epidermis. Treatment of cutaneous SCC is indicated since progression of the tumor may lead to local tissue destruction or metastasis resulting in significant morbidity or death. Early treatment provides the best opportunity to cure cutaneous SCC. • In contrast to basal cell carcinoma (BCC), which rarely metastasizes, around 2 to 5 percent of cutaneous SCCs metastasize to regional lymph nodes or more distant sites. The approach to treatment is dependent upon the presence or absence of tumor features and patient characteristics that portend an increased risk for aggressive tumor behavior. Cutaneous SCCs that do not have high-risk features have low frequencies of recurrence and metastasis. • The treatment of cutaneous SCCs without features associated with aggressive behavior (low-risk cutaneous SCC) and the prognosis of cutaneous SCC will be reviewed here. The management of high-risk and metastatic cutaneous SCCs, the treatment of keratoacanthomas, and the risk factors, clinical features, and diagnosis of cutaneous SCC are reviewed separately. APPROACH TO TREATMENT • The risk of locoregional recurrence and regional or distant metastasis is the most important factor for determining the approach to the treatment for cutaneous squamous cell carcinoma (SCC). Examples of characteristics that impact the risk for recurrence and metastasis include the site, size, and histologic features of a tumor, as well as patient comorbidities . "High-risk" SCCs are tumors that exhibit characteristics that are associated with an elevated risk for aggressive tumor behavior. • A consensus on the specific characteristics that define high-risk SCC has not been established and major entities such as the National Comprehensive Cancer Network (NCCN) and the American Joint Committee on Cancer (AJCC) have described dissimilar "high-risk" criteria . We follow the NCCN criteria when categorizing tumors as high-risk or low-risk for determining the approach to treatment . The features of high-risk cutaneous SCC are reviewed in greater detail separately.