Efficacy and safety of low molecular weight heparin in renal transplantation

BACKGROUND: Deep venous thrombosis (DVT) is a common problem with potentially devastating results in patients undergoing major surgical procedures. Certain renal transplant recipients are particularly at risk for allograft loss as a consequence of renal vein and artery thrombosis. Over the past few years, low molecular weight heparin has been well established as an accepted modality of treatment and prophylaxis of DVT. The efficacy and safety of low molecular weight heparin in the prophylaxis of DVT following renal transplantation in adults has not previously been reported. METHODS: Dalteparin was administered to 120 adult renal transplant recipients postoperatively at the Oregon Health Sciences University. RESULTS: No patient developed allograft arterial or venous thrombosis. One patient developed subclavian vein thrombosis. No bleeding complications were encountered, and side effects were very minimal. CONCLUSION: Prophylaxis with dalteparin is an effective and safe modality for the prevention of thrombosis in adult patients undergoing renal transplantation.     

Pathogenesis of abnormal keratinization in ichthyosiform cetrimide dermatitis: an ultrastructural study

OBJECTIVE AND BACKGROUND: Orthotopic liver transplantation is both a difficult and a demanding surgical procedure. It is not unexpected that cardiovascular dysfunction is present in some individuals being evaluated for liver transplantation. Thus, all potential liver transplant recipients seen at this center undergo a full cardiac evaluation prior to being accepted for transplantation. The goal of this report was to review the components of the cardiovascular evaluation utilized at the Oklahoma Transplantation Institute and to determine their overall usefulness as well as the ability of the process to identify individuals at high risk for a cardiac misadventure during liver transplantation. MATERIALS AND METHODS: Between June 25, 1993 and June 30, 1995, a total of 154 consecutive patients with chronic liver disease were evaluated. The primary liver disease of each was established utilizing specific serologic and biochemical tests, ultrasonographic and abdominal tomographic findings, as well as hepatic histology results and hepatic iron and copper level determinations. Each liver transplant candidate underwent a full cardiac evaluation consisting of the following: nuclear ventriculography to estimate the left ventricular ejection fraction (at rest and during exercise), right ventricular ejection fraction, cardiac output, stroke volume and cardiac index; uptake images using thallium and adenosine to identify foci of cardiac ischemic or fixed defects; echocardiography to define the dimensions of the various cardiac chambers, wall thicknesses, cardiac contractility and morphology of the cardiac valves. Finally, coronary arteriography was performed in 26 patients (16.9%) who were suspected of having clinically important coronary artery disease. It should be noted that all of the cardiac evaluations were performed by a single cardiologist. RESULTS: Eight of the 154 potential liver transplant candidates (5.2%) were determined as not being eligible for liver transplantation because of an inadequate cardiac status based upon an initial history and physical examination. Forty-one of the remaining 146 patients (28.1%) underwent liver transplantation. The remaining 105 subjects have not been transplanted for reasons not related to the cardiac status. Eight of the 41 (19.5%) transplanted patients had a clinically advanced cardiac problem recognized prior to liver transplantation. Four of these eight required a specific cardiac intervention prior to liver transplantation consisting of coronary bypass surgery (n = 1), coronary artery balloon dilation (n = 2) or pericardiectomy (n = 1). The remaining four patients required no pretransplant cardiac intervention and were transplanted. None of these experienced any cardiac complications during, or in the 3 months following, the liver transplant procedure. Only one patient experienced a specific postoperative cardiac complication, consisting of an episode of high grave A-V block requiring transplant placement of a cardiac pacing device. This patient had hemochromatosis. CONCLUSIONS: Based upon this experience, it can be concluded that coronary artery disease per se is not an absolute contraindication for liver transplantation. With appropriate treatment, liver transplantation can be performed safely in individuals with confounding cardiac disease. Nuclear ventriculography and echocardiography are essential procedures in evaluating potential liver transplant recipients in an effort to exclude those with occult cardiomyopathy. Coronary arteriography is indicated only in selected cases with evidence of cardiac ischemia or infarction.     

How to assess a patient's support system and personal abilities prior to liver transplantation

Most liver transplant programs have come to accept the importance of evaluating the psychosocial status of potential liver transplant recipients prior to liver transplantation. The goal is to utilize a thorough assessment of the candidate's support system and personal abilities in order to predict post-transplantation compliance and overall medical-surgical outcome. To achieve this goal, it has been necessary to include a large number of multidisciplinary specialists including social workers, nurses, and psychologists as well as physicians in the evaluation process. Each disclipline contributes to the overall assessment and management of these candidates prior to and following liver transplantation. The purpose of this report is to describe how one spectrum of issues relating to a potential candidate's strengths and vulnerabilities are assessed in the liver transplant program at the University of Kentucky.     

Nicardipine as antihypertensive therapy in liver transplant recipients: results of long-term use

Arterial hypertension is frequent in liver transplant recipients on cyclosporine A (CsA). Nicardipine is a calcium channel blocker (CCB) that has been shown to be efficient in controlling postoperative hypertension. However, its use has been limited in organ recipients because of its reported interaction with CsA metabolism. In this report, we studied the results of the long-term use of nicardipine after liver transplantation. Forty-nine consecutive liver transplant recipients with a follow-up longer than 2 years were studied. Immunosuppressive regimen was based on CsA and prednisone. Patients with immediate postoperative hypertension received intravenous nicardipine, secondarily switched to oral nicardipine (group 1, n = 27). Patients with delayed hypertension (i.e., >2 weeks posttransplant) received other antihypertensive drugs which did not interact with CsA metabolism. These patients and those without hypertension formed group 2 (n = 22). The two groups were similar for age, sex, body weight, and transplantation indications. Interaction of nicardipine with CsA metabolism was confirmed. Whereas cyclosporine blood levels were similar in both groups at any time during the study, the mean cyclosporine daily dose required to achieve such levels was 30% lower in group 1 compared with group 2 (P < .01). This resulted in a significant cost-containment. The use of nicardipine was not associated with an increased incidence of graft rejection or CsA toxicity episodes. The results in liver transplant recipients showed that nicardipine interacts with CsA metabolism, leading to a 30% reduction in CsA dose and does not increase the risk of CsA toxicity or graft rejection. Nicardipine can be used safely for the treatment of arterial hypertension after liver transplantation with a potential cost-containment.     

First case of missense mutation (LDH-H:R171P) in exon 4 of the lactate dehydrogenase gene detected in a Japanese patient

BACKGROUND: The quality of life, psychologic sequelae, and functional status of liver transplant recipients with recurrent hepatitis C virus (HCV) hepatitis have not been well defined. METHODS: Perceived quality of life, psychologic distress, depression, adaptive coping, and functional status were prospectively assessed in 59 liver transplant recipients at baseline (before transplantation) and 6 and 12 months after transplantation; comparisons were made between patients with recurrent HCV hepatitis and all other patients. RESULTS: Recurrent HCV hepatitis developed in 41% (14/34) of the patients with HCV. At 6 months, the patients with recurrent HCV hepatitis had significantly lower functional status (P=0.013) and experienced less gain in physical functioning from baseline than other patients (P=0.02). Quality of life, depression, and psychologic distress were not different at 6 months for patients with recurrent HCV hepatitis compared with all other patients. At 12 months, the patients with recurrent HCV hepatitis had significantly lower quality of life (P=0.003), greater depression (P=0.045), higher psychologic distress (P=0.05), and lower physical functioning (P=0.008) than all other patients. CONCLUSION: Recurrent HCV hepatitis in liver transplant recipients is associated with impairment in quality of life, functional status, and greater depression compared with patients who did not have HCV and those without HCV recurrence.     

The Transplant Evaluation Rating Scale. A revision of the psychosocial levels system for evaluating organ transplant candidates

Psychosocial criteria play an important role in evaluating organ transplant candidates. The Transplant Evaluation Rating Scale (TERS) classifies patients' level of adjustment in 10 aspects of psychosocial functioning that are thought to be important in adjusting to transplantation. On the basis of pretransplant psychiatric consultations, 35 liver transplant recipients received retrospective TERS ratings. Results showed significant correlations between TERS scores and visual analogue scale ratings of five outcome variables at 1-3 years posttransplant. Significant interrater reliability was also found. The TERS represents a promising instrument for transplant candidate selection as well as a valuable tool for further research.     

Amplification of simian retroviral sequences from human recipients of baboon liver transplants

Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy virus (SFV) and baboon endogenous virus (BaEV), in multiple tissue compartments. The presence of baboon mitochondrial DNA was also detected in these same tissues, suggesting that xenogeneic "passenger leukocytes" harboring latent or active viral infections had migrated from the xenografts to distant sites within the human recipients. The persistence of SFV and BaEV in human recipients throughout the posttransplant period underscores the potential infectious risks associated with xenotransplantation.     

Liver transplant and pregnancy

Advances in transplantation medicine present the perinatal health care provider with a unique challenge: care of the woman during pregnancy after organ transplantation. Pregnancy in liver transplant recipients is complicated by hypertension, preeclampsia, anemia, and preterm birth. Neonates born to women after liver transplant are not at increased risk for congenital anomalies. Evidence to date supports that pregnancy does not have a deleterious effect on hepatic graft function or survival if the woman has stable hepatic function before pregnancy. The article focuses on the issues involved with perinatal management of the woman who is a liver transplant recipient.     

Response distribution as an explanation of the mirror effect

STUDY OBJECTIVE: Few studies have examined predictors of quality of life and adjustment after lung transplantation. This study determined whether pretransplant psychological measures predicted physical health, quality of life, and overall adjustment posttransplant. Cross-sectional analyses also examined differences in adjustment and quality of life for lung transplant candidates and recipients. DESIGN AND PARTICIPANTS: Seventeen transplant candidates and 60 transplant recipients completed questionnaires measuring adjustment and quality of life. In addition, we examined archival data on 107 transplant candidates who had received pretransplant psychological assessments, and posttransplant physical health status data were collected on these patients. Of the 107 patients who provided a pretransplant psychological assessment, 32 completed the questionnaires measuring posttransplant adjustment and quality of life. SETTING: University medical center transplant service. RESULTS: Cross-sectional analyses indicated significantly better adjustment and quality of life posttransplant. Pretransplant psychological variables were not associated with measures of posttransplant physical health. Hierarchical multiple regression analyses found that pretransplant anxiety and psychopathology predicted posttransplant adjustment (beta's ranging from 0.32 to 0.68) and greater pretransplant anxiety also predicted worse posttransplant quality of life (beta's ranging from 0.29 to 0.62). Subjective sleep disturbances were associated with poorer adjustment and quality of life (beta's ranging from 0.36 to 0.75), and were found to mediate the relationship between presurgical anxiety and posttransplant adjustment and quality of life. CONCLUSIONS: This study found that psychological status pretransplant predicted adjustment and quality of life posttransplant. Moreover, increased anxiety levels pretransplant predicted subsequent subjective sleep disturbances, which were, in turn, associated with poorer adjustment and quality of life. The benefits of pretransplant stress management interventions are discussed.     

Low level of interleukin 10 synthesis during liver allograft rejection

Interleukin 10 (IL-10) is a macrophage and T-cell-derived cytokine with potent immunosuppressive properties. To assess its role in liver allograft rejection, we evaluated the plasma level and in situ production of IL-10 after liver transplantation and designed in vitro studies to asses the effects of IL-10 on the allogeneic response. Normal controls and liver transplant recipients with acute rejection, chronic rejection, other complications (recurrent hepatitis C, biliary complications), or no complications were evaluated. The plasma IL-10 level was measured by an immunoenzymatic technique. IL-10 expression in the liver was detected on frozen liver biopsies by in situ hybridization and immunohistochemistry. Plasma IL-10 levels were not elevated during acute or chronic rejection, when compared with liver recipients with uncomplicated transplants. IL-10 mRNA and protein expressions in the liver graft were restricted to rare scattered sinusoidal cells of transplant recipients with acute or chronic rejection, as well as in those with no complications. In mixed lymphocyte cultures performed with peripheral blood mononuclear cells (PBMC) from normal subjects, IL-10 decreased the cell proliferation in a dose-dependent manner, and this immunosuppression was synergistic with that of cyclosporine or FK506. These findings indicate that IL-10 production is low during allograft rejection. Thus, IL-10 therapy in association with cyclosporine or FK506 might be proposed after liver transplantation.     

Cardiac evaluation of liver transplant recipients: QT dispersion in electrocardiogram

Increased QT dispersion, the interlead variability of the QT interval length in the 12-lead electrocardiogram, reflects uneven ventricular repolarization as a sign of cardiomyopathy. We analyzed QT dispersion in the preoperative electrocardiogram of 100 adult liver transplant recipients and 20 healthy control subjects. In 12% of the liver recipients, QT dispersion was increased above 65 ms (mean + 3SD). Six of these patients had a liver storage disease (haemochromatosis, Wilson's disease or amyloidosis). Five had a history of cardiac disease. Severe intraoperative cardiac complications occurred in three patients with markedly increased QT dispersion (> or = 99 ms). In conclusion, in liver storage diseases the heart may be affected, leading to increased risk of cardiac complications, which might be predicted from increased QT dispersion. Analysis of QT dispersion, a noninvasive inexpensive technique, can be recommended to be included in the cardiac screening of liver transplant candidates.     

Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management

BACKGROUND: Precise diagnosis of central nervous system (CNS) lesions in liver transplant recipients remains problematic. Brain biopsies are often not feasible as a result of coagulopathy. We sought to determine whether selected clinical or radiologic characteristics can predict the likely etiology of CNS lesions in liver transplant recipients and thus obviate the need for diagnostic brain biopsies. METHODS: A 4-year prospective, observational, cohort study was conducted at liver transplant centers at four geographically diverse medical institutions. A total of 1730 consecutive liver transplant recipients were evaluated for CNS lesions; 60 patients with radiologically documented CNS lesions comprised the study sample. RESULTS: Vascular events (52%, 31/60), infections (181%, 11/60), immunosuppressive associated leukoencephalopathy (12%, 7/60), central pontine myelinolysis (8%, 5/60), and malignancy (3%, 2/60) were the predominant etiologies of CNS lesions. CNS lesions were most likely to occur within 30 days of transplantation (43%, 26/60); central pontine myelinolysis, subdural hematoma, acute infarcts, and Aspergillus brain abscesses were the predominant etiologies during this time. All brain abscesses were fungal; 73% (8/11) of these patients concurrently had documented extraneural (pulmonary) infection as a result of the same fungal pathogen. Thus, a diagnostic brain biopsy is not warranted in these patients. Patients on dialysis were more likely to have ischemic or infectious CNS lesions (P=0.03). Vascular events were more likely to occur in repeat transplant recipients (P=0.03). Twenty-five percent (15/60) of the CNS lesions occurred more than 1 year after transplantation; small vessel ischemic lesions, malignancy, or non-Aspergillus fungal brain abscesses accounted for all such lesions. CONCLUSIONS: A presumptive etiologic diagnosis can be established in a vast majority of CNS lesions in liver transplant recipients based on identifiable presentation that includes time of onset, unique risk factors, and neuroimaging characteristics. Empiric therapy of brain abscesses in liver transplant recipients should include antifungal and not antibacterial agents.     

Pepscan mapping and fusion-related properties of the major phosphatidylserine-binding domain of the glycoprotein of viral hemorrhagic septicemia virus, a salmonid rhabdovirus

In order to define factors which are important for the development of hepatitis C virus (HCV) infection and disease in transplant patients, we examined the role of class II MHC antigen restriction in viral antigen presentation to support a hypothesis of the association of this disease with an autoimmune pathogenesis. A greater degree of histocompatibility match between these donors and their HCV-negative recipients was associated with a greater predisposition to recipient HCV liver disease (ALT elevation) posttransplant. The HCV carrier state could be identified with significant amplification of autologous mixed lymphocyte reactivity (AMLR) in both long-term hemodialysis and long-term renal transplant patients, but the AMLR was absent in end-stage liver disease patients with HCV-associated cirrhosis and was insignificantly elevated in these patients with persistent infection in the first 2 years after a new liver was transplanted. There was also a moderate reduction in autologous reactivity as well as serum HCV titers among renal transplant patients who displayed biochemical evidence of chronic liver disease as opposed to those who did not. This appeared later in the course of the disease. HCV RNA could be detected in peripheral blood mononuclear cells (PBMC) of only a portion of HCV-infected renal transplant patients and these showed significantly higher autologous reactivity. In contrast, despite the fact that observations were earlier after de novo liver transplantation, HCV RNA (i.e., earlier in the course of a new or recurrent disease process) was found in PBMC of all liver transplant recipients tested. The AMLR of noninfected laboratory volunteers could be amplified by preincubating their stimulating cells (APCs) with enriched HCV possibly in immune complex (pHCV-IC). This amplification appeared only with specific combinations of HCV strains with HLA DR serotypes. In addition, HCV-primed T cells could be generated to the virus which displayed accelerated activation kinetics. Liver infiltrating lymphocytes extracted from HCV-positive end-stage diseased livers had significantly higher proliferative and cytotoxic reactivity to autologous (HCV-infected) hepatocytes than the extracted lymphocytes responding to autologous hepatocytes from HCV-negative livers. These findings offer evidence of dynamic autoimmune mechanisms in the spectrum of progression of HCV disease and may help to predict the effect of intervention at various intervals in this progression in organ transplant recipients.     

Immunization of pigs against Streptococcus suis serotype 2 infection using a live avirulent strain

BACKGROUND: To reduce the mortality rate associated with liver transplantation, it is important to identify the risk factors for increased mortality among liver transplant recipients. It has been suggested that cytomegalovirus (CMV) infection is one such risk factor, but no studies have examined mortality rates associated with the CMV serologic status of the donor and recipient by using multivariate techniques. OBJECTIVE: To study the effect of CMV on 1-year mortality rates in orthotopic liver transplant recipients. DESIGN: Intention-to-treat analysis of a cohort. PATIENTS: 146 liver transplant recipients who were enrolled in a multicenter, randomized, placebo-controlled intervention trial. SETTING: Four university-affiliated transplantation centers. RESULTS: 1-year mortality rates for the four strata of donor and recipient CMV serologic status before transplantation were as follows: seronegative donor and recipient, 11%; seronegative donor and seropositive recipient, 22%; seropositive donor and recipient, 30%; and seropositive donor and seronegative recipient, 44% (P = 0.0091). Multivariate analysis using a time-dependent Cox proportional hazards model showed that retransplantation (relative risk, 4.6 [95% CI, 1.9 to 10.7]; P < 0.001); total number of units of blood products administered during transplantation (relative risk, 1.006 per unit [CI, 1.003 to 1.010]; P < 0.001); and presence of CMV disease (relative risk, 3.9 [CI, 1.8 to 8.5]; P < 0.001), invasive fungal disease (relative risk, 3.3 [CI, 1.5 to 7.1]; P = 0.0020), and bacteremia (relative risk, 2.5 [CI, 1.2 to 5.2]; P = 0.0136) were independently associated with higher mortality rates. If post-transplantation variables that were highly correlated with donor and recipient CMV serologic status were restricted from the model, donor and recipient CMV serologic status was the only pretransplantation variable independently associated with higher mortality rates (P = 0.002). CONCLUSION: Donor and recipient CMV serologic status is a significant pretransplantation determinant for death in liver transplant recipients.     

Radioisotopic evaluation of renal function in cyclosporine-treated pediatric and adult renal transplant recipients and their living donors. A study of 152 donor-recipient pairs

Renal function was studied in 2 groups of renal transplant recipients and their donors by technetium-99m diethylenetriamine pentaacetic acid and a gamma camera. The pediatric group (group A) comprised 40 children and their adult kidney donors. The adult group (group B) consisted of 112 consecutive adult renal transplant recipients and their adult donors. All patients received kidneys from living donors and were given the same immunosuppression protocol (PRED plus CSA). Donor glomerular filtration rate (GFR) was determined before nephrectomy and at a mean period of 30 (range 10-50) months after nephrectomy. The graft GFR was measured at 1, 3, 6, and 12 months and at the most recent follow-up visit. Moreover, the functional reserve of the graft was assessed by infusion of dopamine and an amino acid. The postnephrectomy GFR of donors in groups A and B were 74 +/- 18 and 72 +/- 20 ml/min/1.73 m2, respectively. The GFR of pediatric recipients was significantly lower than that of adult recipients at corresponding time points along the course of follow-up. The mean values of graft GFR were 47.6 +/- 20 and 63.8 +/- 29.6 ml/min/1.73 m2 for pediatric and adult recipients, respectively (P < 0.001). Moreover, the graft functional reserve was significantly lower in pediatric recipients. These data demonstrate that adult kidneys transplanted into pediatric recipients have lower GFR than those transplanted into adults, despite corrections for body surface area. Although the reason for this phenomenon is unknown, the observation may have important implications for management of pediatric recipients.     

Can the liver with Gilbert's syndrome be used as graft of living-related liver transplantation?

Gilbert's syndrome is the common cause of non hemolytic unconjugated hyperbilirubinemia with a prevalance of 3-7%. Gilbert's syndrome may introduce a selection of potential liver donors from brain death patients. We present a case of living-related liver transplantation (LRLT) from a donor with Gilbert's syndrome. A 22-year-old woman had been diagnosed as having liver cirrhosis at the age of 5. She underwent liver transplantation with the donor's left lobe as the graft. The donor, who was the father of the patient, had been diagnosed with Gilbert's syndrome. Although the recipient was well until 11 months after surgery, she died of subacute fulminant hepatitis 16 months after surgery. However, it was clear that the liver with Gilbert's syndrome could be used as a graft of living-related liver transplantation for adult recipients.     

Role of nuclear medicine in liver transplantation

Orthotopic liver transplantation is now a very well-established technique for treating patients with end-stage liver disease. Since 1967, more than 26,000 liver transplants have been performed, including 15,000 in the United States. The overall 1-year survival rate is approximately 80% and 5-year survival is 70%. Nuclear imaging plays an important role in the management of liver transplant recipients before and after liver transplantation. The evaluation of candidates potentially includes liver-spleen scan for liver volume, multiple gated acquisition scan, adenosine or stress thallium study, bone scan, and quantitative ventilation perfusion scan for hepatopulmonary syndrome. In the post-transplant phase, the deconvolution analysis (which corrects for the problem of recirculation) is a promising tool for diagnosing rejection, although its role in the transplant population has to be established. A variety of nuclear medicine techniques are helpful in the postoperative diagnosis of biliary complications. By performing a semiquantitative analysis to discriminate hepatocyte dysfunction from biliary disease and measuring hepatocyte extraction fraction by deconvolution analysis and excretion, (T1/2 values measured by the nonlinear list squares technique) have been very promising.