https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-6143.2004.00450.x

Cancer after kidney transplantation in the United States.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673699061541.pdf

Cancer in patients on dialysis for end-stage renal disease: an international collaborative study.

Many complications after renal transplantation can be prevented if they are detected early. Guidelines have been developed for the prevention of diseases in the general popu- lation, but there are no comprehensive guidelines for the pre- vention of diseases and complications after renal transplanta- tion. Therefore, the Clinical Practice Guidelines Committee of the American Society of Transplantation developed these guidelines to help physicians and other health care workers provide optimal care for renal transplant recipients. The guide- lines are also intended to indirectly help patients receive the access to care that they need to ensure long-term allograft survival, by attempting to systematically define what that care encompasses. The guidelines are applicable to all adult and pediatric renal transplant recipients, and they cover the outpa- tient screening for and prevention of diseases and complica- tions that commonly occur after renal transplantation. They do not cover the diagnosis and treatment of diseases and compli- cations after they become manifest, and they do not cover the pretransplant evaluation of renal transplant candidates. The guidelines are comprehensive, but they do not pretend to cover every aspect of care. As much as possible, the guidelines are evidence-based, and each recommendation has been given a subjective grade to indicate the strength of evidence that sup- ports the recommendation. It is hoped that these guidelines will provide a framework for additional discussion and research that will improve the care of renal transplant recipients.

Recommendations for the Outpatient Surveillance of Renal Transplant Recipients

Anemia occurs commonly in patients with chronic heart failure (CHF) and has been proposed as a novel therapeutic target in this patient population. The present review will summarize the current knowledge of the prevalence, causative factors, and pathophysiological correlates of anemia in CHF. Potential risks and benefits of therapy with erythropoietic agents for the treatment of anemia in CHF will also be discussed. Prevalence of Anemia in CHF Estimates of the prevalence of anemia in patients with CHF and low ejection fraction range widely from 4% to 61% (median 18%).1–15 Variability in estimated prevalence is partly attributable to use of inconsistent definitions of anemia in individual reports. The World Health Organization definition of anemia (hemoglobin concentration 13.0 g/dL in men and 12.0 g/dL in women) takes into account known gender differences in distribution of hemoglobin values, 16 whereas the National Kidney Foundation defines anemia as hemoglobin 12 g/dL in men and postmenopausal women. 17 These standard definitions of anemia are not based on wellestablished physiological or population norms. Published reports in CHF populations have used these and other study-specific definitions of anemia (including other arbitrary or statistically defined hemoglobin and hematocrit categories and administrative diagnostic codes from hospital records). Despite these inconsistencies in the definition of anemia cases, most studies indicate that the prevalence of anemia is increased in CHF populations with comorbid kidney disease, advanced age, and more severe symptoms (range, 30% to 61%) when compared with less symptomatic ambulatory populations (range, 4% to 23%). In patients with CHF and preserved ejection fraction, the few published reports indicate that anemia is also highly prevalent in this group.18–20 Underlying Cause of Anemia in CHF Anemia occurs when there is a deficiency in new erythrocyte production relative to the rate of removal of aged erythrocytes. Erythropoietin, a 30.4-kDa glycoprotein growth factor produced primarily by kidney, is the key component of the homeostatic system for regulation of red blood cell mass and tissue oxygen delivery.21–24 Erythropoietin prevents the programmed cell death of erythrocyte progenitor cells and thereby stimulates their proliferation, maturation, and terminal differentiation. 23 Any abnormality that reduces renal secretion of or bone marrow response to erythropoietin may result in anemia. Iron deficiency is present in 30% of anemic patients with CHF, so the majority of observed anemia is normocytic, often classified as anemia of chronic disease. Clinical characteristics commonly associated with increased risk of anemia in CHF populations are listed in the Table. Although risk factors for anemia identified in cross-sectional studies do not provide evidence of a causal link, these observations suggest that several distinct mechanisms may commonly contribute to anemia in patients with CHF. Several of the most important potential causal pathways will be discussed briefly below and are summarized in Figure 1. Chronic kidney disease is a common comorbidity in patients with CHF and is a strong independent predictor of increased risk of anemia in several studies. In chronic kidney disease populations without heart failure, moderate to severe kidney disease (defined as glomerular filtration rate [GFR] 60 mL/min) is associated with diminished erythropoietin production and a progressive decrease in hemoglobin values that is linearly related to reduction in GFR.25 The estimated prevalence of at least moderate chronic kidney disease (defined as GFR 60 mL/min) in CHF populations is 20% to 40%. 4,9,26,27 Anemia is frequently associated with decreased body mass index in published reports, a finding that suggests that patients with cachexia are at greater risk for anemia. Serum levels of proinflammatory cytokines are increased in cachectic patients with CHF and may contribute to development of anemia by several mechanisms. Proinflammatory cytokines including tumor necrosis factor- (TNF-), interleukin-1, and interleukin-6 have been shown to disrupt multiple aspects of erythropoiesis, including reduction of renal erythropoietin secretion, suppression of erythropoietin activity in red blood cell precursors in the bone marrow level, and reduction of bioavailability of iron stores for hemoglobin synthesis.28–31 Proinflammatory cytokines also increase levels of the liverderived peptide hormone, hepcidin.32,33 Hepcidin interacts with ferroportin and other iron transport proteins in the enterocyte to inhibit gut iron absorption and thereby reduces iron bioavailability for hemoglobin synthesis. 32,33 In a mouse

Anemia in Chronic Heart Failure Prevalence, Etiology, Clinical Correlates, and Treatment Options

Post-transplant malignancy is recognised as being a major limitation to the success of solid organ transplantation and it is currently considered one of the unavoidable costs of long-term immunosuppressive therapy. However, the continual introduction of new immunosuppressive drugs and the growing knowledge about their different oncogenic profiles, requires a continuous evaluation of the available evidence on this topic. The incidence and risk of malignancy is elevated in solid organ transplant recipients compared with the general population. As proof of the relationship between immunosuppressive therapy and post-transplant malignancy, epidemiological data reveal that the length of exposure to immunosuppressive therapy and the intensity of therapy are clearly related to the post-transplant risk of malignancy, and that once cancer has developed, more intense immunosuppression can translate into more aggressive tumour progression in terms of accelerated growth and metastasis and lower patient survival. The association between malignancy and immunosuppressive therapy is mediated through several pathogenic factors. Indirectly, immunosuppressive drugs greatly increase the post-transplant risk of malignancy by impairing cancer surveillance and facilitating the action of oncogenic viruses. However, the direct pro- and anti-oncogenic actions of immunosuppressants also play an important role. The cancer-promoting effect of calcineurin inhibitors, independently of depressed immunosurveillance, has been demonstrated in recent years, and currently only mammalian target of rapamycin (mTOR) inhibitors have shown simultaneous immunosuppressive and antitumour properties. Reports of the initial results of the reduced incidence of cancer in organ transplant recipients receiving mTOR inhibitor therapy strongly indicate separate pathways for pharmacological immunosuppression and oncogenesis. The role of mTOR inhibitors has been firmly established for the treatment of post-transplant Kaposi's sarcoma and its role in the management of patients with other post-transplant malignancies should be clarified as soon as possible. Prevention of morbidity and mortality resulting from post-transplant malignancy should become a main endpoint in solid organ transplant programmes, and the choice and management of immunosuppressive therapy in each phase of transplantation plays a central role in this objective. Although comprehensive and rigorous information about the management of immunosuppressive therapy in transplant recipients at risk of or affected by cancer is still lacking, new experimental and clinical data about mTOR inhibitors offers novel approaches to this problem.

Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review.

The incidence of malignancies in recipients of renal transplants was compared to that in nongrafted patients on maintenance dialysis as reported to the EDTA-ERA Registry and in the general population as recorded by the cancer registries of England and Wales, of Sweden, of the (former) German Democratic Republic, and of Lombardy and Varese in Northern Italy. For tumours known to be associated with immunosuppression, namely Kaposi's sarcoma, non-Hodgkin lymphoma and the common malignancies of the skin (except melanoma), an increased incidence was confirmed for the transplanted population. Thyroid carcinoma and hepatoma were found to be more frequent in non-grafted patients on dialysis as well as after renal transplantation. An increased incidence of cancer of the cervix and of the body of the uterus was recorded only for young cohorts with a functioning graft but not for women after menopause. Most of the other malignancies had similar incidences in grafted and non-grafted populations which did not differ from those in the general populations of the cancer registries except cancer of the colon which was slightly more frequent, particularly at 10-20 years after the first transplant operation. Survival after diagnosis of cancer at the most frequent sites, such as bronchopulmonary, breast, oesophagogastric and colorectal cancer, did not differ between non-grafted patient groups on dialysis and those who developed the tumour while carrying a functioning renal transplant. Although certain specific malignancies such as non-Hodgkin lymphoma and skin tumours occur more frequently in recipients of renal grafts, the risk of developing cancer has been exaggerated and survival after diagnosis of the common cancers does not appear to be affected to any great extent by immunosuppressive therapy

F. P. Brunner

Papers

Malignancies after renal transplantation: the EDTA-ERA registry experience