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.

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.

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.

[The role of apoptosis in hepatic graft rejection]. / Il ruolo dell'apoptosi nel rigetto del trapianto epatico.

In 1965, Kerr described a type of death, apoptosis, with different characteristics from necrosis. Apoptosis has an important role in the development and cell homeostasis. Excessive or insufficient apoptosis contributes to the pathogenesis of pathology like ischemia, neurodegeneration, autoimmunity, viral infection, and tumor growth or regression. Apoptosis is subdivided into four sequential phases: order of death; death of cell; phagocytosis of apoptotic bodies and degradation of apoptotic bodies. Death programs converge on sequential activation of a proteases family, caspases. Some aspects of graft rejection can be interpreted as failure of apoptosis in host immunity cells; sometimes rejection involves induction of apoptosis. Apoptotic-type lesions were found in early vascular occlusions, one of the cause of graft failure. Then, an augmented apoptosis in hepatic graft biopsy can be used like a signal of early vascular occlusion. In hepatic transplantation, apoptosis is followed by a proteolytic cascade, which causes sequential activation of caspases. Synthetic inhibitor of caspases can be used, then, in the prevention and/or treatment of pathologies with implication of apoptosis due to ischemia-reperfusion. These inhibitors are not enough for prevention of hepatic lesions, even if caspases inhibitor can be a strategy for treatment of hepatic graft rejection.

[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.

Role of microcirculation in transplantation.

Microcirculatory derangements in organ transplantation, characterized by capillary perfusion failure and inflammation-associated leukocyte recruitment, are major determinants for the manifestation of graft dysfunction and destruction. Although preservation/cold storage, posttransplant reperfusion, and rejection have to be considered as individual factors that contribute to injury, recent studies have indicated that ischemia-reperfusion-associated events may trigger immune-response-mediated late rejection. There is major evidence that the microcirculatory derangements induced by cold preservation and reperfusion involve oxygen radicals, complement, phospholipase A2, leukotrienes, thromboxane, platelet-activating factor, and endothelin-1 as well as the activation and function of leukocytic and endothelial selectins, beta 2-integrins, and ICAM-1. This view is based on the fact that blockade or neutralization of these inflammatory mediators and adhesion molecules results in significant amelioration of microvascular graft dysfunction. In parallel, rejection-mediated microcirculatory derangements may not only be ameliorated by immunosuppressive agents, such as cyclosporin, deoxyspergualin, or RS61443, but may, in addition, effectively be inhibited by counteracting oxygen radicals, complement, platelet-activating factor, and adhesion molecules. The introduction of novel techniques for the study of the microcirculation in men, such as thermodiffusion and orthogonal polarization spectral imaging, may in the future assist in improving both early diagnosis of microcirculatory derangements and monitoring of appropriateness of therapy in clinical transplantation surgery.

Infecciones cutáneas en pacientes sometidos a transplante y en pacientes con infección por HIV: estudio comparativo y revisión bibliográfica / Cutaneous infections in transplants patients recipients and HIV positive patients: comparative study and biblyographic review

Estudio compativo entre grupos de pacientes. El primero estaba constituido por pacientes sometidosa transplantes de diferentes órganos y el segundo, por portadores de HIV; ambos con alteracións immunitarias. Efectuamos también un estudio sobre la frecuencia de las infecciones cutáneas, así como de los gérmenes más comunes. Se revisó pormenorizadamente la bibliografia existente sobre estas patologias

Epithelial cell atypia in bronchoalveolar lavage specimens from lung transplant recipients.

In lung transplant recipients, bronchoalveolar lavage (BAL) is mainly performed to detect infectious agents. However, in addition to microorganisms, epithelial cell atypia may be identified, and determination of its significance is necessary. Specimens obtained at BAL in lung and heart-lung transplant recipients (LTRs) between 1991 and 1998 were examined for the presence of significant cytologic atypia in epithelial cells. Ten cases in 9 patients were identified, and these composed the core of our study. These transplant BAL specimens were compared with 4 BAL specimens with carcinoma from non-transplant patients (NTPs). Fourteen cytologic parameters were evaluated, and clinical and biopsy correlation was made in each case. Significant overlap in cytologic features, including background cellularity, number of atypical cell clusters, number of cells in each cluster, size of cell clusters, contour of clusters, 3-dimensionality, tenacious intercytoplasmic connections, multinucleation, nuclear size, nuclear/cytoplasmic ratio, nuclear membrane irregularity, chromatin pattern, intranuclear inclusions, and nucleolar characteristics, was observed between atypical LTR cases and NTP carcinoma cases. Clinically, all LTR cases derived from nonneoplastic conditions including harvest injury (diffuse alveolar damage), acute cellular rejection, and infections. Our study results show that evaluation of cytologic features alone does not permit differentiation of atypical cells found in nonneoplastic conditions from those in malignant conditions. Clinical and histologic correlation and awareness of the range of atypia seen in posttransplant syndromes is important in correct interpretation of these cases.

[Placentation in the human: a transplantation or tumor model?]. / Die Plazentation beim Menschen: Ein Transplantations-oder Tumormodell?

In human placentation, anchoring villi develop to attach the placenta to the wall of the uterus. This attachment is brought about by extensive infiltration of the maternal tissue by cytotrophoblast cells of fetal origin. As trophoblast cells do not express classical histocompatibility antigens (HLA antigens), increasing doubt has been cast upon the "transplantation" model of pregnancy. However, more recently discovered, previously unknown HLA antigens on the invasive cytotrophoblast cells could lead to maternal immune responses similar to those observed following organ transplantation. Nevertheless, the biological behaviour of the invasive cytotrophoblast cells suggests more parallels with the processes of invasion and metastasis seen in malignant tumours, although there is regulation of the timing and extent of cytotrophoblast invasion of the uterus in normal pregnancy. In this survey, findings relating to the control of infiltration by the cytotrophoblast are reviewed, with particular reference to immunology and tumour biology. Possible effects on pregnancy and parturition due to failure of the regulatory processes involved in placentation are discussed.

Allograft vascular disease: comparison of heart and other grafted organs.

A striking resemblance exists between the vasculopathy in several different allografts. The arteriopathy of epicardial coronary arteries is diffuse, involving proximal, distal, and small branch segments in a generally concentric pattern of intimal thickening. Smooth muscle cells in a lipid- and glycosaminoglycan-rich matrix are the predominant components of this expanded intima. Varying amounts of collagen are present, more being present late posttransplant. A superficial and, to a lesser degree, deep, bandlike infiltrate of T cells and macrophages is uniformly present, although it is somewhat more prominent in early lesions as compared to more severely narrowed arteries from longer-term, susceptible grafts. The media is likewise altered by areas of lipid and glycosaminoglycan deposition associated with smooth muscle cell loss and phenotypic modulation. The media is altered in an outside-to-inside direction, with percolation of adventitial leukocytes into the outer media. Virtually all of the coronary features are seen in the medium to large arteries of liver, pancreas, and kidney allografts. Chronic rejection in lung allografts is manifest by obliterative bronchiolitis; vascular changes, although architecturally similar, are somewhat less common and result in less-severe luminal narrowing. The role of allograft vasculopathy in chronic lung rejection is thus less certain. A finding perhaps unique to epicardial coronary arteries of heart allografts is the presence of eccentric lesions more typical of native atherosclerosis. Many of the latter grafts probably have preexistent, undetected donor disease. Sequential evaluation of vascular changes is limited in human biopsy material by their general absence in endomyocardial or core liver needle specimens. Fortunately, vascular changes can be detected in some renal and pancreas core needle biopsies, and these findings may provide an avenue for monitoring the effectiveness of immunosuppressive therapy, antiviral or lipid-altering therapies, or modifications of smooth muscle cell proliferation and glycosaminoglycan deposition yet to be developed.

[Pathological anatomy of organ transplantation]. / Anatomía patológica del trasplante de órganos.

We review some morphological aspects shared by all allografts. The main points are: 1) The expression of antigens of histocompatibility, essentially DR, allows the diagnosis of acute rejection with a significant specificity; 2) A lesion similar to "Quilty" effect may be seen in other allografts, and it is the first manifestation of an acute rejection; 3) Fine-needle aspiration biopsy may help in the follow-up of kidney transplant but has been demonstrated ineffective in other transplants; 4) The morphology of rejection is different according to the type of immunosuppressive therapy; 5) The basic lesions of chronic rejection are vascular, but chronic rejection may be diagnosed without vessels in the biopsy specimen, by the degree of atrophy of the parenchyma; 6) For the characterization of lymphomas in transplanted patients is necessary study the clonality of tumor cells, the gene rearrangement and the lymphoid subset; 7) Molecular Pathology may help in the early diagnosis of viral infections after transplantation.

Infección en el paciente trasplantado / Infection in the transplanted patient

Se revisa en forma breve la evolucion de la infeccion en el paciente trasplantado y se analizan 611 pacientes que recibieron trasplante de organos por el grupo de trasplantes de la Universidad de Antioquia, Hospital Universitario San Vicente de Paul, en los cuales se observó que, en cualquier momenta de su evolucion, el 38.8 por ciento presento algun tipo de infeccion viral, siendo las más frecuentes por citomegalovirus y herpes. Las infecciones del sistema nervioso central, tuvieron una incidencia del 3.3 por ciento. La mortalidad por meningitis por criptococo y por pneumocystis carinii, fue del 100 por ciento y 71 por ciento, respectivamente.