Sirolimus Impairs Gonadal Function in Heart Transplant Recipients

The impact of sirolimus on hormone levels involved in the hypothalamus-pituitary-gonad axis in male heart transplant recipients was investigated. A pair-matched analysis with 132 male heart transplant recipients on either sirolimus based- or calcineurin inhibitor-based immunosuppression was performed. Matching criteria were age, years after transplantation and creatinine levels. Measured parameters were testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sexual hormone-binding globulin (SHBG) and free androgen index (FAI). Mean testosterone was 3.86 +/- 1.41 ng/mL in the sirolimus group and 4.55 +/- 1.94 ng/mL in the controls (p = 0.025). Serum LH was 12.82 +/- 11.19 mlU/mL in the sirolimus patients and 6.2 +/- 5.25 mlU/mL in the controls (p = 0.015). Follicle stimulating hormone levels were 13.31 +/- 18.4 mlU/mL vs. 7.32 +/- 5.53 mlU/mL, respectively (p = 0.015). The analysis revealed a significant decrease in testosterone and a significant increase in FSH and LH in the sirolimus group. The duration of sirolimus treatment correlated positively with SHBG (p < 0.01), LH (p < 0.05) and FSH (p < 0.05) and negative with the FAI (p < 0.05). Sirolimus trough levels correlated with LH and FSH levels (p < 0.01). Heart transplant recipients treated with sirolimus revealed significantly lower testosterone levels and a significant increase in gonadotropic hormones. These effects were trough-level dependent. All candidates awaiting organ transplantation should be informed about these adverse effects.     

Emerging Issues in Hepatitis C Virus-Positive Liver and Kidney Transplant Recipients

Hepatitis C virus (HCV) infection is a major health care issue in liver and kidney transplantation. Besides negatively affecting both patient and graft survival, HCV is associated with a heightened risk for new onset diabetes mellitus (NODM). The mechanisms underlying the diabetogenicity of HCV are complex but are likely to involve insulin resistance caused by inhibitory actions of the virus on insulin regulatory pathways in the liver. The resultant glucose dysregulation is an important determinant of increased morbidity and mortality in liver and kidney recipients. This review highlights the concerns for outcomes in HCV-positive liver and kidney transplant patients with particular focus on the interrelationship between hepatitis C and diabetes. Data about the potential role of calcineurin inhibitors, corticosteroids and mycophenolate mofetil in HCV infection and HCV-associated NODM will also be discussed.     

Hepatitis E Virus-Related Cirrhosis in Kidney-and Kidney–Pancreas-Transplant Recipients

Hepatitis E virus (HEV) infection was thought to be responsible for acute hepatitis that did not become chronic. However, we have recently reported that HEV infection can evolve to chronic hepatitis, at least in solid-organ transplant patients. We report on two cases of rapidly progressive of HEV-related cirrhosis that occurred in two organ-transplant patients. Case 1: A kidney–pancreas-transplant patient developed acute HEV hepatitis 60 months after transplantation, which evolved to chronicity as defined by persisting elevated liver-enzyme levels and positive serum HEV RNA. At 22 months after the acute phase, she presented with cirrhosis and portal hypertension, that is ascites and esophagus varices. Case 2: A kidney-transplant patient developed acute hepatitis 36 months after transplantation, which persisted and remained unexplained for 38 months. Then, HEV RNA was searched for in their serum and stools, and was found to be positive in both. Retrospective analysis of available stored serum, mainly the serum obtained at the acute phase, confirmed the diagnosis of chronic hepatitis E. In both cases, a liver biopsy showed cirrhosis. We conclude that HEV infection cannot only evolve to chronic hepatitis, but can also be responsible for rapidly progressing cirrhosis in organ-transplant patients.     

男性心脏移植受者性功能恢复情况调查

目的 :了解男性心脏移植受者术后的性功能恢复状态。　方法 :对 11例男性心脏移植受者移植前后的性功能状态 (包括性欲、夜间及清晨勃起、自感勃起强度、性生活满意度和性生活频率等 )进行调查。　结果 :移植前受者性功能均普遍下降 ,而心脏移植后 10例受者性功能得到明显改善。　结论 :男性心脏移植受者术后的性功能状况得到明显改善 ,性功能的恢复受到心理社会因素影响。     

Perceptions of Transitional Care Needs and Experiences in Pediatric Heart Transplant Recipients

Survival following pediatric heart transplantation (HTx) continues to improve. The transition from pediatric to adult care is becoming a pivotal stage in the ongoing medical management of this population. Published data support enhanced outcomes for adolescent patients with increased attention to transitional care. The purpose of this study was to explore the 'transition experience' of adolescent HTx recipients and families.
All teens (12–18 years) and parents at a single-center HTx program were invited to participate in semistructured interviews. Qualitative, phenomenological methodology was used to build theoretical knowledge and guided the data collection and analysis. The study population included 14 patients (7 males) with a mean age of 15.7 ± 1.8 years (11.7–17.8 years) and at a mean of 4.1 ± 3.3 years post-HTx (0.3–9.2 years) at the time of study participation. Major themes identified included: (i) adolescent disinterest and apathy regarding transition to adult care versus parental anxiety about their child's eventual departure from the pediatric transplant center, (ii) perceived differences in pediatric versus adult care and (iii) identification of strategies described as helpful in facilitating the transition. Understanding the experiences and perceptions of adolescent HTx recipients and their parents is crucial to planning effective transitional care and necessary for evidenced-based practice.     

Hepatitis E Virus‐Induced Neurological Symptoms in a Kidney‐Transplant Patient with Chronic Hepatitis

It has been shown that hepatitis E virus (HEV) may be responsible for chronic hepatitis in solid‐organ transplant patients. It has also been suggested that HEV may be responsible for atypical neurological symptoms during the acute phase. However, the relationship between the neurological symptoms and HEV infection was based on the detection of anti‐HEV IgM in the sera. Herein, we report a case where neurological symptoms, that is peripheral nerve involvement with proximal muscular weakness that affected the four limbs joints with central nervous‐system involvement and bilateral pyramidal syndrome, occurred in a kidney‐transplant patient who was chronically infected by HEV. For the first time, HEV RNA was detected in the serum and cerebrospinal fluid. In addition, clonal HEV sequences were analyzed in both compartments, that is serum and cerebrospinal fluid. The discovery of quasispecies compartmentalization and its temporal association suggests that neurological symptoms could be linked to the emergence of neurotropic variants.     

Hepatitis E virus in sheep in Italy

Hepatitis E virus (HEV) is the leading cause of human enterically transmitted viral hepatitis occurring around the world both as outbreaks and as sporadic cases. The accumulating literature indicates that domestic pigs and wild boars are the main reservoirs of genotype 3 and genotype 4 for human infections in industrialized countries. However, the recent identification of HEV from various animal species poses additional potential concerns for HEV zoonotic infection. In this study, the role of sheep as potential host of hepatitis E virus (HEV) was investigated. By screening 192 sheep from seven farms located in Abruzzo Region (Southern Italy), HEV‐specific antibodies were detected in the sera of 41 animals (21.3%) whilst the RNA of HEV, genotype 3, was detected in 20 faecal (10.4%) and three serum samples (1.6%). Upon sequence analyses of a partial ORF2 gene region of eight HEV positive samples, the sheep sequences all grouped together within HEV genotype 3 subtype c, being most closely related to HEV strains identified in goat and wild boar from Abruzzo. This is the first study that demonstrates, serologically and molecularly, the presence of HEV in sheep population in a European country.     

Comparison of De Novo Cancer Incidence in Australian Liver,Heart and Lung Transplant Recipients

Population‐based evidence on the relative risk of de novo cancer in liver and cardiothoracic transplant recipients is limited. A cohort study was conducted in Australia using population‐based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984–2006). Standardized incidence ratios (SIRs) were computed by cancer type, transplanted organ and recipient age. Cox regression models were used to compare cancer incidence by transplanted organ. During a median 5‐year follow‐up, the risk of any cancer in liver and cardiothoracic recipients was significantly elevated compared to the general population (n = 499; SIR = 2.62, 95%CI 2.40–2.86). An excess risk was observed for 16 cancer types, predominantly cancers with a viral etiology. The pattern of risk by cancer type was broadly similar for heart, lung and liver recipients, except for Merkel cell carcinoma (cardiothoracic only). Seventeen cancers (10 non‐Hodgkin lymphomas), were observed in 415 pediatric recipients (SIR = 23.8, 95%CI 13.8–38.0). The adjusted hazard ratio for any cancer in all recipients was higher in heart compared to liver (1.29, 95%CI 1.03–1.63) and lung compared to liver (1.65, 95%CI 1.26–2.16). Understanding the factors responsible for the higher cancer incidence in cardiothoracic compared to liver recipients has the potential to lead to targeted cancer prevention strategies in this high‐risk population.     

Management of Hepatitis C in Liver Transplant Recipients

Recurrent hepatitis C virus (HCV) disease is the leading cause of graft loss in liver transplant recipients with pre-transplant HCV infection. While natural history is variable, median time to recurrent cirrhosis is less than a decade. Factors contributing to risk of recurrence and rate of fibrosis progression are only partially known. Older donor age, treatment of acute rejection, cytomegalovirus infection and high pre-transplant viral load are most consistently linked with worse outcomes. Whether these factors can be modified to positively impact on HCV disease progression is unknown. The main therapeutic approach for patients with recurrent HCV disease has been the treatment with interferon and ribavirin (RBV) once recurrent disease is documented or progressive. Efficacy is lower than in nontransplant patients and tolerability, especially of RBV, is a major limitation. Stable or improved fibrosis scores are seen in the majority of sustained responders. Optimal dose, duration and timing of treatment have not been determined. Alternative strategies under study include pre-transplant treatment of decompensated cirrhotics, preemptive antiviral therapy started within weeks of transplantation and prophylactic therapy using HCV antibodies. Ongoing studies may establish a future role for alternative treatment approaches. Additionally, limited overall efficacy of interferon-based therapy in the transplant setting highlights the urgent need for new drug therapies.     

Association of Race and Socioeconomic Position with Outcomes in Pediatric Heart Transplant Recipients

We assessed the association of socioeconomic (SE) position with graft loss in a multicenter cohort of pediatric heart transplant (HT) recipients. We extracted six SE variables from the US Census 2000 database for the neighborhood of residence of 490 children who underwent their primary HT at participating transplant centers. A composite SE score was derived for each child and four groups (quartiles) compared for graft loss (death or retransplant). Graft loss occurred in 152 children (122 deaths, 30 retransplant). In adjusted analysis, graft loss during the first posttransplant year had a borderline association with the highest SE quartile (HR 1.94, p = 0.05) but not with race. Among 1‐year survivors, both black race (HR 1.81, p = 0.02) and the lowest SE quartile (HR 1.77, p = 0.01) predicted subsequent graft loss in adjusted analysis. Among subgroups, the lowest SE quartile was associated with graft loss in white but not in black children. Thus, we found a complex relationship between SE position and graft loss in pediatric HT recipients. The finding of increased risk in the highest SE quartile children during the first year requires further confirmation. Black children and low SE position white children are at increased risk of graft loss after the first year.     

Ascites in Hepatitis C Liver Transplant Recipients Frequently Occurs in the Absence of Advanced Fibrosis

Ascites after liver transplantation is uncommon (3–7%) but causes morbidity and mortality. Although hepatitis C (HCV), pretransplant ascites, encephalopathy and cold ischemia time have been identified as predictors, neither posttransplant renal function nor the severity of recurrent HCV (inflammatory grade; fibrosis stage) has been systematically assessed. Among 173 HCV transplants (1 January 1998 to 31 December 2002), 18 patients (10%) developed posttransplant ascites. Cox proportional hazards models identified recipient female gender (hazard ratio [HR]= 12.18; p = 0.0001), cold ischemia time (HR = 1.17 per incremental hour; p = 0.021) and posttransplant creatinine (Cr) (HR = 1.56 per incremental 1.0 mg/dL; p = 0.0052) as independent predictors. Ludwig–Batts inflammation grade (HR = 1.32; p = 0.36) and fibrosis stage (HR = 1.63; p = 0.12) were not significant predictors. The 18 recipients had 19 ascites episodes; 12/19 had fibrosis stage 0, 1 or 2 (10/12 with stage 0 or 1). All 12 lacked diagnostic parenchymal or vascular histopathology. Renal function at ascites diagnosis were similar for transplants with fibrosis stage 0, 1 or 2 versus 3 or 4 (1.8 ± 1.6 vs. 1.6 ± 0.6 mg/dL; Cr clearance 39.6 ± 15.6 vs. 39.3 ± 13.4 mL/min/1.73 m²). In conclusion, recipient female gender, cold ischemia time and poor posttransplant renal function were independent predictors of ascites after HCV liver transplantation. Two thirds of ascites episodes, however, occurred without significant fibrosis or histopathology.     

Therapeutic Drug Monitoring for Everolimus in Heart Transplant Recipients Based on Exposure–Effect Modeling

Everolimus, a proliferation signal inhibitor, is an immunosuppressant that targets the primary causes of progressive allograft dysfunction, thus improving the long-term outcome after heart transplantation. The present study investigated whether therapeutic drug monitoring (TDM) of everolimus would benefit heart transplant patients. Data from a twelve-month phase III trial comparing everolimus (1.5 or 3 mg daily) with azathioprine were used to evaluate everolimus pharmacokinetics, exposure-efficacy/safety and TDM prognostic simulations. Everolimus trough levels were stable in the first year post-transplant and averaged 5.2 +/- 3.8 and 9.4 +/- 6.3 ng/mL in patients treated with 1.5 and 3 mg/day, respectively. Cyclosporine trough levels were similar in all treatment groups. Biopsy-proven acute rejection (BPAR) was reduced with everolimus trough levels > or =3 ng/mL. Intravascular ultrasound (IVUS) analysis showed evidence of reduced vasculopathy at 12 months with increasing everolimus exposure. Unlike cyclosporine, increasing everolimus exposure was not related to a higher rate of renal dysfunction. The TDM simulation, which was based on two everolimus dose adjustments and an initial starting dose of 1.5 mg/day, showed that the simulated BPAR rate (with TDM) was 21% versus 26% in the group with fixed dosing. Therefore, TDM in heart transplantation could optimize immunosuppressive efficacy and reduce treatment-related toxicity.     

Hepatitis E Virus: What Transplant Physicians Should Know

Hepatitis E virus (HEV) infection is an underdiagnosed disease in the developed world. In pediatric and adult organ transplant patients HEV infection can cause chronic hepatitis, which can lead to cirrhosis. Extra‐hepatic manifestations, such as neurological symptoms and kidney injury, have been also reported in transplant patients. In this comprehensive minireview, we summarize the current knowledge on HEV infection in transplant patients, that is, its prevalence, incidence, natural history and therapy.     

The Incidence of Cancer in a Population‐Based Cohort of Canadian Heart Transplant Recipients

To assess the long‐term risk of developing cancer among heart transplant recipients compared to the Canadian general population, we carried out a retrospective cohort study of 1703 patients who received a heart transplant between 1981 and 1998, identified from the Canadian Organ Replacement Register database. Vital status and cancer incidence were determined through record linkage to the Canadian Mortality Database and Canadian Cancer Registry. Cancer incidence rates among heart transplant patients were compared to those of the general population. The observed number of incident cancers was 160 with 58.9 expected in the general population (SIR = 2.7, 95% CI = 2.3, 3.2). The highest ratios were for non‐Hodgkin's lymphoma (NHL) (SIR = 22.7, 95% CI = 17.3, 29.3), oral cancer (SIR = 4.3, 95% CI = 2.1, 8.0) and lung cancer (SIR = 2.0, 95% CI = 1.2, 3.0). Compared to the general population, SIRs for NHL were particularly elevated in the first year posttransplant during more recent calendar periods, and among younger patients. Within the heart transplant cohort, overall cancer risks increased with age, and the 15‐year cumulative incidence of all cancers was estimated to be 17%. There is an excess of incident cases of cancer among heart transplant recipients. The relative excesses are most marked for NHL, oral and lung cancer.     

Mycobacterium haemophilum Infections in Heart Transplant Recipients: Case Report and Review of the Literature

Non-tuberculous mycobacteria are becoming increasingly important pathogens among transplant recipients. We report a case of disseminated Mycobacterium haemophilum infection in a heart transplant recipient, manifesting as cellulitis, subcutaneous nodules, septic arthritis, and pneumonitis. Our case illustrates diverse challenges in the identification and treatment of this pathogen, such as its unique culture requirements and variable antimicrobial susceptibilities. Heightened clinical suspicion is necessary to establish a timely diagnosis so that optimal treatment can be administered.     

Infectious Complications After Heart Transplantation in Chinese Recipients

Several factors appear to influence the incidence and type of infectious complications among different populations of transplant recipients. This study sought to assess the incidence and type of infection after transplantation in Chinese heart allograft recipients. A total of 130 infectious episodes occurred in 192 consecutive heart transplantation patients between June 1993 and May 2004. The median length of follow-up was 46.7+/-38.4 months. The 1-, 5- and 10-year survival rates were 81.8+/-2.8%, 63.0+/-3.8% and 45.7+/-7.7%. Infection was the leading cause of early and late deaths. Of the infectious episodes, 66 (51%) were caused by bacteria, 35 (27%) by viruses, 10 (8%) by fungi, 7 (5%) by Mycobacterium tuberculosis and 12 (9%) by other pathogens. The most common bacterial infectious episodes were caused by methicillin-resistant Staphylococcus aureus (20 of 66). The most common viral infections were varicella zoster virus infection in 12 (34%), cytomegalovirus infection in 9 (26%) and hepatitis B virus infection in 8 (23%). There was only one episode of clinical syndrome compatible to Pneumocystis jiroveci pneumonia. In conclusion, there was low incidence of Pneumocystis jiroveci pneumonia and cytomegalovirus infection, and high incidence of Mycobacterium tuberculosis infection in Chinese heart allograft recipients.     

High Risk of Graft Failure in Emerging Adult Heart Transplant Recipients

Emerging adulthood (17–24 years) is a period of high risk for graft failure in kidney transplant. Whether a similar association exists in heart transplant recipients is unknown. We sought to estimate the relative hazards of graft failure at different current ages, compared with patients between 20 and 24 years old. We evaluated 11 473 patients recorded in the Scientific Registry of Transplant Recipients who received a first transplant at <40 years old (1988–2013) and had at least 6 months of graft function. Time‐dependent Cox models were used to estimate the association between current age (time‐dependent) and failure risk, adjusted for time since transplant and other potential confounders. Failure was defined as death following graft failure or retransplant; observation was censored at death with graft function. There were 2567 failures. Crude age‐specific graft failure rates were highest in 21–24 year olds (4.2 per 100 person‐years). Compared to individuals with the same time since transplant, 21–24 year olds had significantly higher failure rates than all other age periods except 17–20 years (HR 0.92 [95%CI 0.77, 1.09]) and 25–29 years (0.86 [0.73, 1.03]). Among young first heart transplant recipients, graft failure risks are highest in the period from 17 to 29 years of age.