No Improvement in Long-Term Liver Transplant Graft Survival in the Last Decade: An Analysis of the UNOS Data

We analyzed change in outcomes during two successive 5-year periods (period I = 1992–1996 vs period II = 1997–2002) among 35 186 deceased adult liver transplant recipients reported to the United Network for Organ Sharing (UNOS) Registry. The 5-year graft survival was 67.4% in the first period and 67.5% in the second, though the 1-year survival had improved from 81.0 to 83.5%. Comparison of blended survival rates during the two study periods showed decreased long-term graft survival in period II, explicable by an increased number of hepatitis C virus cirrhosis (HCV) patients and an increase in patients with HCV antibodies (HCVab) during this later period. Analysis wherein these patients with HCV were excluded revealed the same long-term graft survival during both periods. Non-HCV patients who had HCVab also had worse 5-year graft survival. We conclude that hepatitis C prevented improved outcomes during period II and that improved, more effective, treatment for hepatitis C virus would have great positive impact on overall survival of liver transplant recipients.     

The Quality of Health Insurance Service Delivery for Kidney Transplant Recipients: A Patient Perspective

Increased attention has been devoted to improving quality care in kidney transplantation. The discourse on quality care has focused on transplant center metrics and other clinical parameters. However, there has been little discussion on the quality of health insurance service delivery, which may be critical to kidney recipients’ access to transplantation and immunosuppression. This paper describes and provides a framework for characterizing kidney transplant recipients’ positive and negative interactions with their insurers. A consecutive cohort of kidney recipients (n = 87) participated in semistructured interviews on their interactions with insurance agencies. Patients reported negative (37%) and/or neutral or positive (79%) interactions with their insurer (a subset [16%] reported both). Perceived negative experiences included: poor service, logistical difficulties with confusing and time‐consuming paperwork, poor communication, rude behavior and concerns about adequate coverage. Positive experiences related to: having good coverage, a simple application process, straightforward transactions and helpful communication. Findings suggest that even when patients have insurance coverage, difficult interactions with insurers and limited skills in navigating insurance options may limit their access to needed medications and health services. Future research is needed to test this hypothesis in a larger population.     

Influenza Virus Infection in Adult Solid Organ Transplant Recipients

BACKGROUND: Solid organ transplant (SOT) recipients have been reported to be more susceptible to influenza virus. However, little is known about the clinical epidemiology and the implications of influenza viral infection among SOT recipients. METHODS: Cohort study of influenza viral infection in SOT recipients at the University of Pittsburgh Medical Center. RESULTS: Between November 1990 and April 2000, 30 cases of influenza were diagnosed in SOT recipients at our center, including influenza A (n = 22) and influenza B (n = 8). These included recipients of lung (n = 19), liver (n = 5) and kidney (n = 6) transplants. The incidence of influenza viral infection was 41.8 cases/1,000 person years (PYs), 2.8 cases/1000 PYs and 4.3 cases/ 1,000 PYs among lung, liver and renal transplant patients, respectively (p <0.0001). Symptoms were reported in all patients and included malaise, myalgia/ arthralgia, fever, cough, and shortness of breath. Secondary bacterial pneumonia occurred in five patients (17%). Other complications were seen in three SOT recipients (2 liver and 1 kidney) and included: myocarditis, myositis, and bronchiolitis obliterans. Biopsy of the transplanted organ was performed in 21 SOT recipients (18 lung, 1 liver and 2 kidney) at the time of influenza viral infection. Overall, 62% (13/21) showed variable degrees of acute allograft rejection, and included 61% (11/18) of lung, and 100% (2/2) of kidney transplant recipients. CONCLUSIONS: Influenza infection is associated with significant morbidity in different groups of SOT recipients. Studies are needed to determine if yearly chemoprophylaxis with antiviral drugs might benefit this patient population.     

Cellular Immunity to Epstein-Barr Virus in Liver Transplant Recipients Treated with Rituximab for Post-Transplant Lymphoproliferative Disease

The evaluation of long-term cellular immunity to EBV in pediatric orthotopic liver transplant (OLT) recipients after treatment with the humanized anti-CD20 monoclonal antibody (Rituximab) has not yet been explored. At our institution, one child with EBV-related mononucleosis-like syndrome and five children with polymorphic-EBV-PTLD occurring 6-88 months after OLT were treated with Rituximab. Treatment was well tolerated. All children achieved complete remission. After Rituximab, B-lymphocytes were undetectable in the peripheral blood and EBV-load, monitored with real-time PCR, decreased to undetectable levels in all children from >4000 copies/microg DNA at diagnosis. Four to eight months after Rituximab, EBV-load increased (>4000 copies/microg DNA) in four children, and PTLD recurred in three. Their frequency of EBV-specific T-cell precursors, measured by Elispot analysis, remained lower than in healthy controls. Rituximab effectively induced regression of PTLD in OLT recipients. However, EBV-specific T-cell immunocompetence, which may be crucial for the long-term control of EBV-mediated proliferation, did not improve.     

Long-Term Prospective Study of Steroid Withdrawal in Kidney and Heart Transplant Recipients

A large prospective study of steroid withdrawal was performed within the framework of the Collaborative Transplant Study to analyze long-term graft and patient outcome in renal and heart transplant recipients. Steroids were withdrawn no earlier than 6 months posttransplantation. A comparison of 7-year outcomes in renal transplant recipients (94% receiving cyclosporine; 97% Caucasian) showed a benefit of steroid withdrawal versus steroid continuation in retrospectively matched controls, for graft survival (81.9%± 1.8% vs. 75.3%± 1.2%, p = 0.0001), patient survival (88.8%± 1.5% vs. 84.3 ± 1.0%; p = 0.0016) and death-censored graft survival (91.8%± 1.3% vs. 87.9%± 1.0%: p = 0.0091). Steroid withdrawal was associated with improved graft survival in heart recipients also (76.2%± 2.4% vs. 66.9%± 1.7%, p = 0.0008). A total of 58.6% of renal recipients and 44.3% of heart recipients never required steroids during follow up. Rates of acute rejection and renal dysfunction did not differ between steroid-free and steroid-continuation groups. Steroid withdrawal was associated with significantly improved cardiovascular risk factors compared with steroid continuation. Rates of the development of osteoporosis and cataracts did not differ in the entire patient cohort, but were strikingly lower in patients taken off steroids during the first posttransplant year.     

Invasive Fungal Infections in Low-Risk Liver Transplant Recipients: A Multi-Center Prospective Observational Study

Prevention of invasive fungal infections (IFIs) in orthotopic liver transplant (OLT) recipients utilizing postoperative systemic antifungal prophylaxis, typically with fluconazole, is justified among those at high risk for IFI. Use of postoperative antifungal prophylaxis for low-risk OLT recipients is widely practiced but not universally accepted nor supported by data. We conducted a prospective observational study among 200 OLT recipients who were at low risk for IFI and did not receive postoperative antifungal prophylaxis. Patients were considered low risk if they had /=units of 40 blood products or return to the operating room for intra-abdominal bleeding; return to the operating room for anastomotic leak or vascular insufficiency; preoperative serum creatinine of >/=2 mg/dL; and perioperative Candida colonization. Patients were followed 100 d post-transplantation for evidence of IFI. Of 193 eligible patients, 7 (4%) developed an IFI. Three (2%) IFIs were due to Candida spp. and potentially preventable by standard fluconazole prophylaxis. Three patients developed invasive aspergillosis; one developed late onset disseminated cryptococcosis. Liver transplant recipients at low risk for IFI can be identified utilizing pre-determined criteria, and post-transplantation antifungal prophylaxis can be routinely withheld in these patients.     

Post Transplant Erythrocytosis in Hypercalcemic Renal Transplant Recipients

In vitro data suggest that calcium plays an important role in normal and disordered erythropoiesis. The purpose of this study is to determine whether there is an association between serum calcium, various hormone levels, and the development of post transplant erythrocytosis (PTE). Data were collected on 283 patients who underwent renal transplantation between 1994 and 1998. The relationship between serum calcium and PTE development was tested using the chi-square test. Univariate and multivariable adjusted models were employed to determine predictors of maximum hematocrit. Selected patients underwent measurement of intact parathyroid hormone (PTH), 1,25-dihydroxy vitamin D, and erythropoietin (EPO). Seventy-three patients (26%) developed PTE. Post transplant erythrocytosis was more common in patients with hypercalcemia compared with patients with normal serum calcium (34% vs. 18%, p = 0.002). In multivariable analyses, serum calcium was a strong independent predictor of maximum hematocrit post transplant, even after adjustment for renal function. A serum calcium of >or=10.2 mg/dL was associated with greater than two-fold increased odds of PTE. There were no differences in hormone levels between subjects with hypercalcemia and PTE, subjects with PTE alone, and subjects with hypercalcemia alone. Hypercalcemia is associated with the development of PTE in renal transplant recipients.     

Coccidioidomycosis in Liver Transplant Recipients in an Endemic Area

Coccidioidomycosis is an infection caused by Coccidioides species, which are endemic for the Southwestern United States and parts of Central America and South America. Most infected individuals are asymptomatic or have mild‐to‐moderate respiratory illness. Coccidioidomycosis is more severe in patients with depressed cellular immunity, such as organ transplant recipients. We retrospectively reviewed charts of 391 liver transplant recipients (mean follow‐up, 38.7 months; range, 2–105 months). Before transplantation, 12 patients had a history of coccidioidomycosis and 13 patients had asymptomatic seropositivity. Of these 25 patients, 23 had no active coccidioidomycosis posttransplantation and 2 had reactivated infection. One of 5 patients with indeterminate serology before transplantation died of disseminated coccidioidomycosis shortly after transplantation. De novo coccidioidomycosis developed in 12 patients (3%) who had no evidence of coccidioidomycosis pretransplantation. Of 15 total episodes of posttransplantation coccidioidomycosis, 10 (66%) occurred during the first year. Dissemination was noted in 33% of active coccidioidomycosis after transplantation; two patients (13%) died of coccidioidomycosis. Because most coccidioidal infections occurred in the first posttransplantation year despite targeted antifungal prophylaxis, we recommend a new strategy of universal antifungal prophylaxis for 6–12 months for liver transplant recipients who reside in the endemic area.     

Rejection Under Alpha Interferon Therapy in Liver Transplant Recipients

Interferon alpha (IFN) is the corner stone drug for the treatment of recurrent hepatitis C (HCV) in liver transplant (LT) recipients. One of its serious potential adverse effects is acute and chronic rejection. The aim of this study was to review our experience using IFN-based therapy, in order to examine the incidence and the risk factors for rejection, and the outcome of patients who developed rejection. Between September 1990 and December 2004, 70 LT recipients were treated. Patients started antiviral treatment 16 (1-137) months after LT. Histological follow-up was available in all patients according to protocol biopsies. Rejection was diagnosed and graded according to Banff classification. Twenty-one percent of patients developed acute rejection (5 mild, 9 moderate and 1 severe) during IFN-based therapy. Patients were treated for 8 (1-15) months prior to rejection. Previous history of acute rejection before IFN therapy and treatment with pegylated-IFN was significantly associated with rejection (p = 0.04 and p = 0.02, respectively). The rejection was successfully treated in 87% of patients. No chronic rejection or graft losses were observed. Acute rejection under IFN-based therapy often occurs in LT recipients, but early diagnosis with protocol biopsies and early treatment can lead to a favorable outcome.     

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.     

Assessment of Psychoeducational Outcomes After Pediatric Liver Transplant

Outcomes research in pediatric liver transplant (LT) has focused on mortality and morbidity but there is a need to also evaluate functional outcomes. Standardized cognitive testing was administered to a cohort of children with infantile chronic liver disease who were transplanted at the University of Alberta during their preschool years. Thirty children had comprehensive assessments with the Bayley Scales of Infant Development or Wechsler testing. Patient variables potentially associated with cognitive delay were analyzed with multiple regression analysis. The mean DQ/IQ score (developmental quotient/intelligence quotient) was 81 ± 17. Delay (DQ/IQ score < 70), and borderline delay (DQ/IQ 70–84) were each present in 27% of the cohort, with only 46% demonstrating normal cognition. Regression analysis demonstrated that the decreased IQ was associated with pretransplant growth retardation and elevated calcineurin inhibitor levels. Performance IQ had strong correlation with pretransplant growth retardation and elevated serum ammonia, R²= 45%, compared to verbal IQ that was associated was elevated calcineurin inhibitor levels, R²= 23%. Children post-LT are at high risk for cognitive delay or borderline delay. This is the first study to demonstrate the association calcineurin inhibitors with impaired IQ and also the unique finding of different variables predictive of impaired verbal intelligence quotient (VIQ) versus performance intelligence quotient (PIQ).     

Predominant Th1 and Cytotoxic Phenotype in Biopsies from Renal Transplant Recipients with Transplant Glomerulopathy

Transplant glomerulopathy (TGP) appears to be a pathogenic feature of chronic antibody-mediated rejection, but the pathogenesis of this histologic entity is still poorly understood. Previous studies suggest the involvement of lymphocytes but the phenotypes of these cells have never been analyzed. Here, we report the first study of mRNAs for specific markers of CD4+ T cells including Th1 (T-bet and INFγ), Th2 (IL4 and GATA3), Treg (Foxp3) and Th17 (IL-17 and RORγt) subsets, cytotoxic CD8 T cells (Granzyme B) and B-cell markers (CD20) in renal biopsies from renal transplant recipients suffering interstitial fibrosis and tubular atrophy (IF/TA) with or without TGP but with a similar inflammatory score and controls including transplant recipients with normal renal function. Only INFγ, T-bet (both functionally defined markers of Th1 CD4 T cells) and granzyme B (a CD8 cytotoxic marker) were significantly more strongly expressed in patients with TGP than in patients without TGP and normal controls. These results indicate a role of an active T-mediated inflammatory and cytotoxic process in the pathogenesis of TGP.     

Hyperhomocysteinemia in Renal Transplant Recipients

Renal transplantation is a commonly performed curative procedure for end-stage renal disease. With the increase in renal allograft half-lives, attention is now being focused on cardiovascular morbidity and death in the renal transplant recipient (RTR) population. Among the more novel cardiovascular disease (CVD) risk factors for which this group is at risk is hyperhomocysteinemia. Hyperhomocysteinemia has been associated with an increased risk of CVD, although prospective randomized trials designed to prove causality are still ongoing. Since plasma total homocysteine levels are inversely related to renal function, RTRs have a greatly increased prevalence of hyperhomocysteinemia. Other determinants of homocysteine include B-vitamins, albumin, age, and genetic polymorphisms. Although RTRs are resistant to the typical B-vitamin doses used to correct hyperhomocysteinemia in the general population, they do respond to supraphysiologic dose therapy. In terms of prevalence, etiology, and treatment of hyperhomocysteinemia, RTRs are very similar to the much larger chronic renal insufficiency population. For this reason, RTRs have been chosen as an ideal study population in investigating the effect of reducing hyperhomocysteinemia on CVD outcomes.     

Varicella Infection Following Varicella Vaccination in a Liver Transplant Recipient

Varicella infection may result in significant morbidity and mortality in patients who have received an orthotopic liver transplant (OLT). It is unclear if vaccinating these patients against varicella-zoster virus (VZV) infection is safe or effective. We report on a liver transplant recipient with no prior history of VZV infection who was given the varicella vaccine after an indirect VZV exposure. The patient was subsequently hospitalized twice for treatment of cutaneous varicella infection. We will discuss VZV infection, particularly in relation to liver transplantation, and review the prophylaxis and management of VZV infection after OLT.     

Human Ehrlichiosis in Transplant Recipients

To characterize the impact of immunosuppression on human ehrlichiosis, we reviewed cases of ehrlichiosis occurring in transplant recipients and immunocompetent patients at three hospitals in Nashville, Tennessee. Between 1998 and 2006, 15 transplant patients were identified as having ehrlichiosis, diagnosed either by whole blood polymerase chain reaction (PCR) (n = 14) or serology (n = 1). They were compared with 43 immunocompetent patients diagnosed by whole blood PCR. We retrospectively collected demographic and clinical information. The species of Ehrlichia (E. ewingii or E. chaffeensis) was determined for patients diagnosed by PCR. The 15 transplant recipients with ehrlichiosis included 7 kidney recipients, 6 heart recipients, 1 liver recipient and 1 lung recipient. Transplant recipients had more infections with E. ewingii than immunocompetent patients (23% vs. 5%, p = 0.08). Transplant recipients experienced less rash (0% vs. 36%, p = 0.006) and presented with significantly lower hepatic enzymes, but more leukopenia and renal dysfunction than immunocompetent patients. Doxycycline therapy was started within 48 h of presentation in 73% of transplant recipients and 78% of immunocompetent patients (p = 0.7). No patient died in either group. Ehrlichia infections can occur in transplant recipients who live in an endemic area. With prompt treatment, the infected transplant recipients in our study had similar, favorable outcomes compared to immunocompetent patients.