No evidence for recipient-derived hepatocytes in serial biopsies of sex-mismatched liver transplants.

BACKGROUND: Bone marrow-derived hematopoietic stem cells (BM-HSCs) have been shown to act as source for hepatic regeneration in rodent models; however, their ability to participate in human liver regeneration remains controversial. The aim of this study was to investigate the origin of hepatocytes in sex-mismatched cases of orthotopic liver transplantation in longitudinally performed liver biopsies. METHODS: Paraffin-embedded liver biopsy samples of 14 patients after sex-mismatched (female-to-male) liver transplantation were investigated. Biopsies were taken at multiple time points and subjected to histologic examination. Immunohistochemical staining with a hepatocyte-specific antibody and fluorescent in situ hybridization for visualization of Y chromosomes were performed to analyze the presence of recipient-derived hepatocytes. RESULTS: We analyzed 30 liver biopsy samples ranging from 1 week to more than 3 years after transplantation. There was no evidence for recipient-derived hepatocytes in liver transplants at any time point. We were able to detect recipient-specific chromosomal status in inflammatory cells within the liver but not within hepatocytes. Results were independent of liver injury at the time of biopsy, caused by hepatitis C recurrence or rejection episodes. CONCLUSIONS: Our results show no evidence for involvement of BM-HSCs in liver regeneration after orthotopic liver transplantation. We think that recipient BM-HSC-derived hepatocyte repopulation is a very rare event at best and is not of clinical relevance.

Evaluation of the malnutrition-inflammation score in kidney transplant recipients.

BACKGROUND: Chronic protein-energy wasting, termed malnutrition-inflammation complex syndrome, is frequent in patients with chronic kidney disease and is associated with anemia, morbidity, and mortality in patients on maintenance dialysis therapy. The Malnutrition-Inflammation Score (MIS) recently has been developed and validated in dialysis patients. STUDY DESIGN: Observational cross-sectional study. SETTING & PARTICIPANTS: 993 prevalent kidney transplant recipients. PREDICTOR: MIS computed from change in body weight, dietary intake, gastrointestinal symptoms, functional capacity, comorbid conditions, decreased fat store/Systemic Global Assessment, signs of muscle wasting/Systemic Global Assessment, body mass index, serum albumin level, and serum transferrin level. OUTCOMES: Markers of inflammation and malnutrition, including serum C-reactive protein, interleukin 6, tumor necrosis factor alpha, serum leptin, prealbumin, body mass index, and abdominal circumference. The relationship was modeled by using structural equation models. RESULTS: Mean age was 51 +/- 13 years, 57% were men, and 21% had diabetes. Median time from transplant was 72 months. MIS significantly correlated with abdominal circumference (r = -0.144), serum C-reactive protein level (r = 0.094), serum interleukin 6 level (r = 0.231), and serum tumor necrosis factor alpha level (r = 0.102; P < 0.01 for all). A structural equation model with 2 latent variables (malnutrition and inflammation factor) showed good fit to the observed data. LIMITATIONS: Single-center study, lack of information about vascular access, presence of nonfunctioning kidney transplant, relatively high refusal rate. CONCLUSIONS: Our results confirm that MIS reflects both energy-protein wasting and inflammation in kidney transplant recipients. This simple instrument appears to be a useful tool to assess the presence of protein-energy wasting in this patient population.

Plasma nitrite and nitrate levels as a noninvasive marker of pathology after human small bowel transplantation.

INTRODUCTION: Small bowel transplantation provides a potentially life-saving treatment of severe intestinal failure. Lack of a noninvasive marker of disease makes diagnosis of rejection dependent on frequent endoscopy and biopsy. We hypothesized that increased plasma nitrite and nitrate (NOx) levels measured after small bowel transplant would be associated with abnormal final pathology. METHODS: We measured total plasma NOx levels (the stable end products of the L-arginine/nitric oxide biosynthetic pathway) in 120 prospectively collected samples taken from 27 patients after small bowel transplantation. We used immunohistochemistry to detect inducible nitric oxide synthetase expression in 19 tissue biopsies from 9 patients. RESULTS: We found NOx concentrations to be statistically different between pathologic categories (e.g., normal, mild, moderate, and severe rejections, nonspecific enteritis), although there was sufficient overlap to prompt caution clinically. After establishing from the dataset a "normal" plasma NOx level of 50 microM, we found that combined assessment of plasma NOx levels and clinical suspicion of pathology could accurately predict which patients were histologically normal and those requiring further evaluation with endoscopy and biopsy. CONCLUSIONS: We conclude that serum NOx levels are significantly associated with small bowel pathology after transplant, although not specifically enough with rejection to be relied on for clinical discrimination.

Gadolinium-enhanced MRI for tumor surveillance before liver transplantation: center-based experience.

OBJECTIVE: The purpose of this study was to evaluate prospectively acquired institutional results to determine the accuracy of gadolinium-enhanced MRI in liver tumor surveillance before transplantation. SUBJECTS AND METHODS: One hundred fifteen patients underwent MRI of the abdomen within 90 days before liver transplantation. Images were acquired with gadolinium-enhanced 3D gradient-echo sequences in the arterial, venous, and delayed phases. Detection of hepatocellular carcinoma (HCC) was based on the imaging criteria arterial phase enhancement, delayed phase hypointensity, and development of an enhancing outer margin capsule. Imaging findings were compared with findings at histopathologic evaluation of the explanted liver. RESULTS: Thirty-six HCCs in 27 patients were detected at histopathologic evaluation. Patient-based analysis showed the sensitivity of MRI was 88.9% (24/27); specificity, 97.7% (false-positive findings in two patients); and accuracy, 95.7%. MRI depicted 28 of 36 HCCs, resulting in a lesion-based sensitivity of 77.8%. Although all 18 HCCs 2 cm or larger were depicted with MRI, only 10 of 18 HCCs smaller than 2 cm were correctly diagnosed. However, two HCCs measuring smaller than 2 cm at pathologic examination were rated as dysplastic nodules on MRI. CONCLUSION: Contrast-enhanced MRI can be used as a primary diagnostic method for accurate detection and characterization of HCC 2 cm or larger as required by the criteria of the Model for End-Stage Liver Disease used by the United Network for Organ Sharing. MRI can be considered a standard tool for surveillance before liver transplantation. Reduction in cost and risk may be derived from the diminished need for other diagnostic imaging studies and biopsy and the avoidance of use of iodinated contrast agents in imaging of patients with cirrhosis, many of whom have impaired renal function.

Regeneração cardíaca. Coração: um órgão pós-mitótico? / Cardiac regeneration: the heart: a postmitotic organ?

A apresentação de evidências de divisão celular e da existência de atividade reparativa intrínseca ao tecido miocárdico gerou uma mudança de paradigma na aceitação do coração como um órgão de população celular dinâmica, a qual atinge um estado de homeostasia a partir de um equilíbrio entre morte e replicação celular. Neste contexto, a terapia celular tenta dar respostas a questões básicas como: contexto clínico ideal para tratamento, tipo celular de escolha, dose e frequencia de tratamento e via de escolha para administração de células...

Evidence of myocardial tissue cell division and repair activities has generated a change of paradigm in accepting the heart as a dynamic cell organ reaching a state of homeostasis as of a point of equilibrium between cell death and replication. Against such scenario, cell therapy tries to find answers to basic issues such as: ideal clinical setting for treatment, cell type choice, dose and frequency for treatment, and choice cell administration.

Hip pain in renal transplant recipients: symptomatic gluteus minimus and gluteus medius tendon abnormality as an alternative MRI diagnosis to avascular necrosis.

OBJECTIVE: The purpose of this study was to review the diagnosis on MRI and radiography of 24 renal transplant recipients with hip pain suspicious for avascular necrosis and to investigate whether there is an association between kidney transplant patients with end-stage renal disease and symptomatic gluteus minimus and medius tendon abnormality. CONCLUSION: Symptomatic gluteus minimus and medius tendon lesions and abnormalities can occur in renal allograft recipients. The MRI findings of this entity allow an alternative diagnosis in this patient population.

Impact of repetitive episodes of antibody-mediated or cellular rejection on cardiovascular mortality in cardiac transplant recipients: defining rejection patterns.

BACKGROUND: In our previously published work dealing with antibody-mediated (vascular) rejection (AMR), we defined patterns of rejection (AMR and cellular rejection [CR]) based on a review of biopsy diagnoses taken in the first 6 to 12 weeks post-transplant. We have shown the significance of these pattern designations in relation to patient and allograft outcome in five outcome analyses. The current retrospective analysis was done to determine whether our previous criteria for pattern designations provided the greatest degree of discrimination between AMR and CR. METHODS: Six hundred sixty-five patients from the U.T.A.H. Cardiac Transplant Program were included in our study. Patients induced with OKT3 immunosuppression were excluded. We analyzed the relationship of a number of either AMR or CR episodes to cardiovascular mortality. We constructed Kaplan-Meier survival curves to assess the impact of incremental numbers of AMR or CR episodes on cardiovascular mortality. RESULTS: Three or more episodes of AMR resulted in a statistically significant increase in cardiovascular mortality. By contrast, CR episodes did not increase the risk of cardiovascular mortality. CONCLUSIONS: Based on our findings, we believe that clinical trials should be designed to test treatments based on predominant rejection patterns and that end-points for trials should be defined by number of biopsies positive for either CR or AMR. This approach may lead to improved patient and allograft survival.

Detection of coronary artery disease in orthotopic heart transplant recipients with 64-detector row computed tomography angiography.

Cardiac transplant recipients develop coronary artery disease in the form of cardiac allograft vasculopathy (CAV), and still undergo annual left heart catheterizations for detection at most centers. We prospectively enrolled 20 cardiac transplant recipients scheduled for annual left heart catheterization with X-ray coronary angiography (XRA) to also undergo electrocardiographically gated coronary computed tomography angiography (CTA), which was performed on a 64-detector computed tomography scanner. CTA detected more CAV vs XRA in 4 patients and less CAV in 0 patient, resulting in good overall agreement between the two modalities (kappa = 0.69). CTA may be superior to conventional catheter-based angiography to identify non-obstructive vessel wall disease that may go unrecognized with catheter-based angiography alone.

Sequential gene expression profiling in lung transplant recipients with chronic rejection.

STUDY OBJECTIVES: Chronic allograft rejection is the leading cause of morbidity and mortality for long-term survivors of lung transplantation. Previous studies have implicated only isolated genes in the development of chronic rejection and have not examined multiple pathways in an individual concurrently. Using microarray technology, we identified and compared gene expression profiling in lung transplant recipients with and without chronic rejection, and follow sequential expression of genes differentially expressed between the two groups. DESIGN: Prospective, cohort study. SETTING: Single lung transplant center. PATIENTS OR PARTICIPANTS: Eleven transplant recipients with chronic rejection were matched with 9 control transplant recipients. INTERVENTIONS: All recipients underwent surveillance bronchoscopies at predetermined times to rule out infection and/or acute rejection. Gene expression profiling was obtained from hybridizing BAL fluid cell RNA to a 96-gene microarray. MEASUREMENTS AND RESULTS: Fifteen genes were found to be significantly differentially expressed between the two patient groups, and they are involved in inflammatory, fibrotic, and apoptotic pathways. Temporal expression of the significant genes demonstrated a change in their levels at the onset of chronic rejection, with normalization to prerejection levels as rejection continued. CONCLUSIONS: We conclude that microarray technology is valuable in studying the mechanism of chronic lung rejection, and the expression of genes in multiple pathways is elevated in patients with chronic lung rejection.

Use of non-absorbable polypropylene mesh for the treatment of spontaneous renal graft rupture.

Renal graft rupture (RGR) is a life-threatening complication of kidney transplantation (KT), frequently associated with rejection and acute tubular necrosis. RGR repair with the use of suture, and corsetage with various materials (including synthetic glue, polyglactin absorbable hemostatic mesh, and lyophilized human dura), is indicated in non-severe cases. However, the employment of non-absorbable synthetic mesh had not been previously reported. Here, a case of a KT from cadaveric donor with RGR associated with acute rejection is reported. The graft was salvaged with the employment of a non-absorbable polypropylene mesh. Six months after KT, the patient remains asymptomatic with normal renal function. To the best of our knowledge, this is the first report of the use of a non-absorbable polypropylene mesh to repair a RGR. In a setting in which economical restrictions are important, the use of non-absorbable synthetic mesh may represent a good option of treatment.

Use of non-absorbable polypropylene mesh for the treatment of spontaneous renal graft rupture / Uso de una malla no absorbible de polipropileno para el tratamiento de la ruptura espontánea de injerto renal

Renal graft rupture (RGR) is a life-threatening complication of kidney transplantation (KT), frequently associated with rejection and acute tubular necrosis. RGR repair with the use of suture, and corsetage with various materials (including synthetic glue, polyglactin absorbable hemostatic mesh, and lyophilized human dura), is indicated in non-severe cases. However, the employment of non-absorbable synthetic mesh had not been previously reported. Here, a case of a KT from cadaveric donor with RGR associated with acute rejection is reported. The graft was salvaged with the employment of a non-absorbable polypropylene mesh. Six months after KT, the patient remains asymptomatic with normal renal function. To the best of our knowledge, this is the first report of the use of a non-absorbable polypropylene mesh to repair a RGR. In a setting in which economical restrictions are important, the use of non-absorbable synthetic mesh may represent a good option of treatment.

La ruptura del injerto renal (RIR) es una complicación del trasplante renal (TR) que amenaza la vida, y frecuentemente está asociada a rechazo y necrosis tubular aguda. La reparación de la RIR con el uso de sutura y ferulización con varios materiales (incluyendo pegamento sintético, mallas hemostáticas absorbibles de poliglactina y duramadre liofilizada humana) está indicada en los casos no graves. Sin embargo, el empleo de mallas no absorbibles no había sido informado previamente. Aquí se informa el caso de un TR proveniente de donador cadavérico con RIR asociada a rechazo agudo. El injerto fue rescatado con el empleo de una malla no absorbible de polipropileno. Seis meses después del TR el paciente se encuentra asintomático con función renal normal. Hasta donde tenemos conocimiento, éste es el primer informe del uso de una malla no absorbible de polipropileno para reparar una RIR. En un medio con importantes restricciones económicas, el uso de mallas sintéticas no absorbibles puede representar una buena opción de tratamiento.

Nocardiosis in persons with human immunodeficiency virus infection, transplant recipients, and large, geographically defined populations.

To quantify the risk of nocardiosis in various populations, I systematically reviewed articles published between 1966 and 2004. The incidence of nocardiosis in 3 large, geographically defined populations ranged from 0.35 to 0.4 cases per 10(5) persons year. In contrast, the incidence of nocardiosis among people with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) in 1 study was 53 nocardiosis cases per 10(5) persons x year, approximately 140 times greater than that in the geographically defined populations. The frequency of nocardiosis cases in 4 populations of HIV-infected people averaged 608 cases per 10(5) persons. The incidence of nocardiosis in bone marrow-transplant recipients at 1 hospital was 128 cases per 10(5) persons x year, an incidence approximately 340 times greater than that in the geographically defined populations and in the same range as in HIV-infected people. The frequency of nocardiosis in 21 series of cases in recipients of a variety of transplanted organs averaged 1122 cases per 10(5) persons. These estimated incidence rates are imprecise because they were not collected through prospective surveillance systems, but the estimates for the 3 groups were internally consistent and provide useful information for clinicians.

Spontaneous renal allograft rupture without acute rejection.

Renal allograft rupture (RAR) is a rare but potentially serious complication in the transplanted recipients. The most common cause is acute rejection. We report four cases (0.5%) of RAR occurred in a series of 778 consecutive kidney transplantations due to severe acute tubular necrosis and renal vein thrombosis with no evidence of acute rejection. Transplant nephrectomy was performed in three patients, whereas graft repair was achieved in one patient. These data suggest that RAR may be associated with renal vein thrombosis or severe acute tubular necrosis in absence of acute rejection. Frequently nephrectomy is necessary, but conservative surgical treatment should be attempted to preserve the allograft in selected cases.

Clinical and experimental transplantation of isolated organ or tissue cells indications problems from the Polish perspective.

Clinical cell transplantation remains as a clinical experiment. Morphologically intact and functional cells transplanted into their tissue of origin undergo rapid disintegration by attacking granulocytes and macrophages, leading to the so-called early graft dysfunction. When transplanted to sites remote from their origin, the process of elimination is even faster. Among millions of transplanted cells, only a few survive in an autologous or syngeneic recipient, not to mention an allogeneic combination. What is the mechanism of elimination of the majority of transplanted cells? Which cells survive and what is their genotype and phenotype? There are several problems that should be investigated: (1) the mechanism of anoikis, namely, detachment-induced apoptosis, (2) the reaction of the innate immune system to transplanted cells, (3) the microchimerism created by the transplanted cells, and (4) the "niche" for transplanted cells within the local cell chemical environment and signalling. Our experience with transplantation of hepatocytes illustrates current problems in isolated cell grafting. Proposals to increase the in vivo survival rate of transplanted syngeneic hepatocytes are essential to the vision of the future of cell transplantation.

[Correlation between the onset of early proteinuria and the outcome of renal transplantation. Experience of a single centre]. / Correlazione tra insorgenza di proteinuria precoce e decorso clinico del rene trapiantato. Esperienza di un singolo centro.

BACKGROUND: Proteinuria is associated with an increased risk of renal failure. In chronic kidney transplant failure it is associated with poorer graft outcome. MATERIALS AND METHODS: In our Unit 405 renal transplants were performed between April 1992 and December 2001. We analysed 1) the main causes of post-transplant proteinuria and 2) the prognostic significance for graft outcome in patients with a minimum follow-up of 6 months. RESULTS: Early proteinuria was associated with a higher incidence of chronic allograft nephropathy (CAN) and de novo/recurrent nephropathies. Graft outcome was poorer in patients with early persistent proteinuria. CONCLUSIONS: Proteinuria after renal transplantation increases the risk of graft failure. We can, therefore, hypothesize that a graft biopsy is the best way to reveal the causes of proteinuria so that therapeutic interventions, which have been shown to reduce proteinuria, can be applied immediately.