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ABSTRACT: Preservation injury is a major contributing factor to primary allograft failure or poor initial graft function after an orthotopic liver transplant (OLT). We examined the histopathological findings from postreperfusion wedge biopsy specimens in relation to early graft function during the first postoperative week among OLT patients at our center. We reanalyzed subcapsular postreperfusion biopsy specimens from 88 patients to histologically grade the lesions. Grafts were grouped as good function, initial poor function (an alanine aminotransferase or aspartate aminotransferase level >1500 IU/L during week 1), or primary nonfunction (death or retransplantation). Only 1 patient experienced primary nonfunction; the remaining patients fell into the other 2 groups: ie, good function or initial poor function. When patients were compared using numerous morphologic and clinical features, no statistical relation was observed regarding clinical data on bile duct complications, donor type, graft volume, patient age, or type of stent. Histological features of neutrophilic infiltration of the subcapsular region, hepatocellular ballooning, and macro/microvesicular steatosis were not related to initial poor graft function; in contrast, there were prominent sinusoidal neutrophilic infiltrations and hepatocellular necrosis. Preservation-reperfusion injury (grade 2 or grade 3 neutrophilic infiltration) occurred in 78.6% of initial poor function patients and in 39.7% of good function patients. Subcapsular neutrophilic infiltration, a sign of surgical hepatitis, did not provide prognostic information about graft survival. Similar to other studies, we observed neutrophilic infiltration and necrosis away from the capsule to predict subsequent graft function.
Transplantation Proceedings 09/2009; 41(7):2747-8. · 1.00 Impact Factor
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ABSTRACT: Chronic allograft nephropathy and calcineurin inhibitor toxicity may cause graft loss. After kidney transplantation, especially among those patients with chronic allograft nephropathy, sirolimus may be a good alternative to calcineurin inhibitors. Unlike calcineurin inhibitors, sirolimus is devoid of significant nephrotoxicity, but approximately 30% to 50% of patients on sirolimus therapy display mild or severe adverse effects. We sought to report our experience with sirolimus conversion among patients with chronic allograft nephropathy as well as the mild versus severe adverse effects that limit the drug's use.
We analyzed the outcomes of 88 patients (64 men and 24 women) of overall mean age of 35.9 +/- 9.9 years (range, 21-59 years) who had undergone kidney transplantation. Immunosuppressive therapy had been converted from a calcineurin inhibitor to sirolimus because of biopsy-proven chronic allograft nephropathy, calcineurin inhibitor toxicity, or presence of malignancy. We excluded patients with prior acute rejection episodes. Subjects were divided into two groups with respect to their creatinine levels: Group A < 2 mg/dL and Group B >or= 2 mg/dL. After conversion to sirolimus, possible adverse effects of sirolimus were evaluated at the follow-up inset. Each patient underwent a physical examination, and estimation of serum lipid and electrolyte levels as well as hemoglobin concentration.
At the time of conversion of the 88 renal transplant patients, their mean duration after grafting was 48 +/- 15 months (range, 4-296). The prior treatment consisted of a calcineurin inhibitor, prednisolone, and mycophenolate mofetil. After conversion, the calcineurin inhibitor was stopped and sirolimus was begun. The 48 Group 2 patients (34 men, 14 women) of overall mean posttransplant time of 22.7 +/- 14.6 months who underwent conversion displayed a mean serum creatinine increase to 3.2 +/- 1.4 mg/dL, including 17 subjects who underwent rejection. The 40 Group 1 patients (30 men, 10 women) with a mean overall posttransplant period of 67.6 +/- 49.9 months showed an fall in serum creatinine level to 1.4 +/- 0.5 mg/dL among only 3 patients. While 5/88 patients showed no increase in proteinuria (5.6%); 83 (94.4%) did experience it. Proteinuria increased from a mean of 192 +/- 316 to 449 +/- 422 mg/d. Only three patients displayed heavy proteinuria (>3 g/d); sirolimus was discontinued for this reason. Proteinuria was well controlled in the other patients with angiotensin-converting enzyme and/or angiotensin II receptor inhibitor agents. After sirolimus conversion, serum cholesterol levels increased from 187 +/- 42 to 214 +/- 52 mg/dL, and serum triglyceride levels increased from 161 +/- 61 to 194 +/- 102 mg/dL. All but four patients responded to statin therapy, with serum lipid levels falling to acceptable levels. Another four patients developed unilateral lower extremity edema with sirolimus discontinued for this reason. One patient displayed generalized arthralgia.
Chronic allograft nephropathy or calcineurin inhibitor toxicity can lead to loss of graft kidney function. Calcineurin inhibitor toxicity can lead to chronic allograft nephropathy. Patients with a low baseline serum creatinine level who undergo sirolimus conversion showed stabilized kidney function. Late conversion of patients with a serum creatinine above 2 mg/dL face a risk of graft failure. Sirolimus displayed a limited incidence of serious adverse effects; mild or moderate adverse effects, such as hyperlipidemia and proteinuria, were easily controlled with countermeasure therapy.
Transplantation Proceedings 09/2009; 41(7):2789-93. · 1.00 Impact Factor
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ABSTRACT: It is uncertain whether tumors arising in transplant patients resemble ones that develop de novo in pathogenesis, morphology, and behavior. This study sought to investigate some clinical, morphological, and immunohistochemical features of several posttransplantation malignancies compared with similar de novo tumors. The study group consisted of 40 malignant tumors encountered in 1350 transplant patients (1229 kidneys, 113 livers, 8 hearts) between 1986 and 2006. Tumors with 3 or more examples were compared with randomly selected controls. These included Kaposi's sarcoma (n=14); extranodal lymphoma (n=9); squamous cell carcinoma (n=6); and nodal lymphoma (n=3). The variables that were analyzed were the localization, predisposing lesions, degree of differentiation, and host response. For lymphomas, we also determined histological subtype, origin, and Ki-67 proliferation index. Most tumors (36/40, 90%) occurred in patients with renal transplants. However, the relative frequency was higher among liver transplant cases (3.53% vs 2.92% for kidney transplants). No malignancy was seen in heart transplant cases. Squamous cell carcinomas were better differentiated (P<.05) compared with controls and they were more frequently associated with precursor lesions (P<.05). Kaposi's sarcomas involved internal organs more frequently in posttransplant patients, and the Ki-67 proliferation index was higher in posttransplantation nodal lymphomas. However, these factors were not significantly different (P>.05). Our findings suggested that certain posttransplantation malignancies display unique characteristics compared with their de novo counterparts.
Transplantation Proceedings 06/2007; 39(4):1057-62. · 1.00 Impact Factor
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ABSTRACT: Orthotopic liver transplantation (OLT) remains a major medical and surgical challenge in small pediatric patients. From April 2003 through October 2005, 17 infants (each of whom weighed less than 10 kg) underwent the procedure. Four were girls and 13 were boys (mean age, 15.7 +/- 9.3 months [range, 2-36 months]; mean weight at the time of transplantation, 7.4 +/- 2.6 kg [range, 6-10 kg]). All transplants were obtained from living-related donors. Sixteen left lateral segments and 1 left lobe were transplanted. The median graft-to-recipient weight ratio was 3.5% +/- 1.2% (range, 1.5%-6.1%). During the early postoperative period, hepatic arterial thrombosis was identified in 2 infants, and a biliary leak in 1. Hepatic arterial thrombosis was treated by reanastomosis with polytetrafluoroethylene grafting in the first patient and by surgical embolectomy in the second. The biliary leak was treated with percutaneous drainage. In 1 infant, portal vein stenosis, which was identified during the late postoperative period, was treated by percutaneous balloon dilatation. At this time, 14 (82.3%) infants were alive, exhibiting good graft function at a median follow-up of 11 months (range, 2-36 months). Three infants died: 1 on postoperative day 47 from adult respiratory distress syndrome, 1 on postoperative day 12 from sepsis, and 1 on postoperative day 65 from sepsis associated with EBV infection. Episodes of acute rejection, which occurred in 5 patients, were treated with pulse steroid therapy. On follow-up, histologic examination revealed hepatocellular carcinoma in 2 infants and Burkitt's lymphoma in 1 infant. Our data confirm that extensive use of living-related donors in liver transplantation can result in an excellent outcome for small pediatric patients.
Transplantation Proceedings 01/2007; 38(10):3585-7. · 1.00 Impact Factor
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ABSTRACT: Angiogenesis plays an important role in tumor growth, metastasis, and prognosis. Vascular endothelial growth factor (VEGF) is a potent endothelial mitogen and acts on the angiogenic stimulation of human neoplasias. In infiltrative ductal carcinoma (IDC), VEGF expression is correlated with high vascularity. Tumor-associated macrophages (TAMs) contribute to tumor proliferation, progression and angiogenesis and have a complex role in tumor biology. In this study, the correlations between microvessel density (MVD), VEGF expression, and TAMs and their relations to clinicopathological parameters such as tumor size, metastatic lymph node, mitotic activity index (MAI) and tumor grade were investigated in 48 cases of IDC and 30 infiltrative lobular carcinoma (ILC) cases. MVD showed a significant positive correlation with TAMs, VEGF, metastatic lymph nodes, tumor size and grade in IDC (P < 0.001). In ILC, MVD and tumor size were positively correlated (P = 0.003), while MVD was not correlated with VEGF, TAMs, MAI, metastatic lymph nodes, and grade. These findings are suggestive of angiogenesis stimulation in IDCs by VEGF, driving the macrophages into the tumor area. MVD and TAMs were found to be important prognostic factors in IDCs. On the other hand, however, VEGF did not contribute to angiogenesis in ILCs, and MVD and TAMs did not have any prognostic significance. These results suggest the involvement of factors not related to VEGF in the angiogenesis of lobular carcinoma.
Journal of experimental & clinical cancer research: CR 10/2006; 25(3):365-72. · 1.50 Impact Factor
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ABSTRACT: Cholesterol crystal embolization is a potential complication of atherosclerosis. Approximately one-third of the patients who develop this problem have a history of vascular surgery, angiography or angioplasty hours to weeks before onset. The skin and the kidneys are most frequently involved, but any organ can be affected. Livedo reticularis of the lower extremities and acrocyanosis (known as "blue toe syndrome") are the most common cutaneous manifestations. Histological examination is the only way to definitively diagnose cholesterol crystal embolization. Recently, it has been proposed that cholesterol embolization is associated with vasculitis, and some authors have labeled this condition a "vasculitis look-alike." There is still no specific treatment for this problem, even in cases that progress to renal failure. However, a few case reports in the literature have noted successful treatment with corticosteroids and cyclophosphamide in patients with deteriorating renal function. In this article, we describe two cases of severe cholesterol crystal embolization accompanied by renal dysfunction) and blue toe syndrome. Both patients benefited from corticosteroid and cyclophosphamide therapy.
Rheumatology International 04/2006; 26(5):454-60. · 1.88 Impact Factor
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ABSTRACT: As a cause of graft dysfunction, tubulointerstitial nephritis (TIN) seems to be the third most common pathology after rejection and cyclosporine nephrotoxicity. Among 540 needle biopsies obtained from 280 renal transplant patients between 1996 and 1999, acute TIN was detected in 23 patients (8%). The cause of acute TIN was secondary to bacterial infection in 17 patients and secondary to cytomegalovirus (CMV) infection in three patients. The remaining three cases showed granulomatous pyelonephritis due to Mycobacterium tuberculosis (n = 2) and Candida albicans (n = 1). During follow-up, 13 of 23 patients (56.5%) showed at least one acute rejection episode. The average number of urinary tract infection (UTI) episodes in the 23 patients was 1.4 +/- 07. We observed that the number of UTI episodes showed a significant association with the development of chronic allograft nephropathy (P = .03) and graft loss (P < .01). Twelve patients (52.2%) lost their grafts during 5 years posttransplantation. Only 6 of 17 patients with bacterial TIN lost their graft at a mean time of 52.5 +/- 14 months. But all patients with CMV TIN or granulomatous TIN lost their grafts at a mean time of 31 +/- 3.1 months and 39 +/- 3 months, respectively (P < .05). In conclusion, these results support the pathological role of tubulointerstitial nephritis as a pathway of graft rejection or renal allograft deterioration among recipients after transplantation.
Transplantation Proceedings 03/2006; 38(2):466-9. · 1.00 Impact Factor
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ABSTRACT: [corrected] Hepatic stellate cells (HSCs) are nonparenchymal elements that play a major role in fibrogenesis due to various pathologies. HSCs are easily activated by certain injuries, which produce contraction and relaxation of HSCs, resulting in hepatic microcirculatory disturbances. The present study sought to analyze the expression of alpha-smooth muscle actin (alpha-SMA) positive HSCs in liver allografts during acute rejection episodes (ARE), determining whether it was related to the pathogenesis of this immune response.
Using immunohistochemistry and a semiquantitative scoring system, the expression of alpha-SMA in HSCs was analyzed in liver allografts with ARE (group 1, n = 64) or without ARE (group 2, n = 20). Normal liver tissue from transplant donors (group 3, n = 53) served as the control materials.
Significantly more alpha-SMA positive HSCs were found in group 2 than in the other two groups (P < .05). The minimal difference observed between groups 1 and 3 was not statistically significant. As well, no statistical association was found between expression of alpha-SMA and the clinical parameters of age, gender, etiology of liver failure, donor type (partial or whole), posttransplantation period, and liver function tests.
While these results represent preliminary findings, it may be possible that HSC expression is a protective mechanism during ARE in hepatic allograft patients. If this is true, enhanced expression of this protein may mitigate ARE in liver allograft patients.
Transplantation Proceedings 03/2006; 38(2):589-93. · 1.00 Impact Factor
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ABSTRACT: We sought to determine the extent and time course of recipient-derived chimerism after transplantation and the relationship with acute rejection episodes (ARE) and HLA typing in hepatic allograft patients.
We studied 18 needle liver biopsy specimens from patients who had undergone orthotopic liver transplantation. Fluorescent in situ hybridization (FISH) analysis for X and Y chromosomes was performed in all cases with a sex mismatch. To evaluate the HLA matching, we used serological and polymerase chain reaction (PCR) methodology.
There was a sex mismatch between the recipients and donors in all cases. X and Y chromosome chimerism was detected in 14 of 18 (83%; 31.14 +/- 27.4) patients. Also, no statistical association was found between the presence and the extent of chimerism and clinicopathological parameters (P < .05).
Our results suggest that chimerism was frequently seen in liver allografts, but it did not influence the occurrence of ARE, tissue compatibility, or histopathological changes in the posttransplantation period. The clinical, immunological, and histopathological relevance of chimerism remain unclear. These results may relate to the small number of patients and disproportion of chimerism-positive versus-negative cases. Further prospective studies will be required to clarify these findings in a larger population of liver transplant patients.
Transplantation Proceedings 03/2006; 38(2):598-601. · 1.00 Impact Factor
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ABSTRACT: Chronic allograft nephropathy (CAN) is usually progressive; its natural course can only be modified in the initial stages. In this study, we graded Tc-99m diethylenetriaminepentaacetic acid (DTPA) renogram curves with respect to the perfusion/uptake pattern and correlated these findings with biopsy results in patients with CAN.
This study included 63 renal allograft recipients with biopsy-proven CAN. The agent used for renal scintigraphy was Tc-99m DTPA. Quantitative evaluation of perfusion included calculation of the ratio of peak perfusion counts divided by plateau counts (P:PL). Deterioration of renal function was accompanied with a gradual loss of a peak and plateau pattern. For the evaluation of uptake in relation to perfusion pattern, we graded the renogram curves into four based on the presence of a peak and plateau pattern and the presence of an uptake peak.
In patients with CAN, the mean P:PL was significantly lower than that of the control group. The serial changes in successive grades of CAN in respect to uptake-perfusion pattern was a gradual loss of peak and plateau pattern followed by a decline in uptake. In recipients with high-grade CAN, an uptake peak was absent.
Evaluation of Tc-99m DTPA time-activity curves revealed a progressive change in perfusion-uptake pattern in patients with CAN. According to our results, deterioration of perfusion preceded the decline in uptake. Serial renogram changes are thought to reflect initial hypoperfusion followed by increased intraglomerular pressure and finally glomerulosclerosis. These findings have implications for the pathophysiology and management of CAN.
Transplantation Proceedings 10/2005; 37(7):3124-9. · 1.00 Impact Factor
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ABSTRACT: Cytomegalovirus (CMV)-associated diseases remain a major problem in transplant recipients. Early diagnosis is critical. Presentation of early CMV colitis can be mild and nonspecific in transplant recipients. Although serology is helpful in the diagnosis, sometimes it is inadequate. Because the endoscopic features of CMV colitis are specific, colonoscopy facilitates the histopathologic examination. We present the clinical properties and advantages of early colonoscopy in transplant recipients with CMV colitis. The study group included seven patients (six men, one woman of mean age, 36.7 years (range, 22 to 64 years) whose mean transplant duration was 12.3 months (range, 1 to 72 months). Six of the seven patients experienced an acute graft rejection treated with high doses of steroids; one patient had a herpes simplex virus infection. All patients were on steroid treatment with a various combinations of immunosuppressive agents, including cyclosporine, mycophenolate mofetil, and tacrolimus. All patients presented with mild diarrhea without any blood or mucous discharge. Four patients had fever exceeding 38 degrees C; two had abdominal pain. Stool examinations revealed normal findings in six patients, while one patient had white blood cells and amoebic cysts. Serum CMV IgM and CMV pp65 antigenemia were negative in five of seven patients and two had positive results. All patients showed typical colonoscopic and histopathologic findings compatible with CMV colitis. Standard ganciclovir treatment was successful in all patients. Early and rapid colonoscopy is beneficial for the early diagnosis and management of CMV colitis in transplant recipients.
Transplantation Proceedings 10/2005; 37(7):3059-60. · 1.00 Impact Factor
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ABSTRACT: The main features of Niemann-Pick disease type B (NPD-B) are enlargement of the liver and spleen, and mild pulmonary involvement. Recurrent respiratory tract infection and progressive decline in pulmonary function are major contributors to morbidity and mortality in this patient group. Massive pulmonary involvement in early life is extremely rare. The most common finding on chest X-rays of NPD-B patients is reticular or nodular infiltration of the lungs. This article describes a very rare presentation of NPD-B in an infant who had suffered recurrent respiratory tract infections. Massive emphysema and marked infiltrative parenchymal changes (infiltration of the parenchyma) were initially attributed to congenital lobar emphysema and its compressive effects. However, NPD was suspected when a lung biopsy showed foamy cells and sea-blue histiocytes were detected in a bone marrow biopsy. The definitive diagnosis was established with an enzyme study for sphingomyelinase.
European Journal of Pediatric Surgery 09/2005; 15(4):283-6. · 0.81 Impact Factor
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ABSTRACT: Kaposi's sarcoma (KS) is an angioproliferative condition that accounts for 6% of all malignancies in organ transplant patients. When we review the literature, the results of the studies comparing the different stages and the proliferative activity of the tumor are challenging. However, we found no previous study on Ki-67 protein expression in KS that correlates skin and organ lesions. In the current study, we investigated whether there is a correlation on the proliferative activity between skin and internal organ lesions in KS. Proliferative activity of 13 biopsy specimens of KS was assessed immunohistochemically using the monoclonal antibody MIB-1 (Ki-67). Mann-Whitney U test is used for statistical analysis and a P value < .05 was considered significant. Seven of 13 cases were skin and six were internal organ KS. For skin lesions, the mean MIB-1 proliferation index was 14.5%, and it was 13% for organ lesions. There was no significant association between skin and internal organ KS in regard to MIB-1 PI (P > .05). The findings suggested that the proliferative activity in KS does not differ in skin and organ lesions. On the other hand, it should be considered that the number of cases in our study was limited and further studies with a larger series are needed.
Transplantation Proceedings 07/2005; 37(5):2190-4. · 1.00 Impact Factor
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ABSTRACT: Primary ovarian leiomyosarcomas are extremely rare tumors that comprise less than 0.1% of all ovarian malignancies. We present a case of 62-year-old postmenopausal woman with a slightly enlarged right ovary and a Color Doppler sonography resistance index (RI) measuring 0.54. The patient, after being managed with surgery alone, is alive after 14 months without any evidence of disease. This is an unusual case in that primary ovarian leiomyosarcoma was diagnosed in the setting of a slightly enlarged irregular postmenopausal ovary with a concomitant intermediate RI value on color flow Doppler evaluation. A high index of suspicion may help prevent delay in the diagnosis of this rare neoplasm.
European journal of gynaecological oncology 02/2005; 26(1):120-2. · 0.47 Impact Factor
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ABSTRACT: A 75-year-old hypertensive woman was referred with ultrasound findings of a 40 x 35 mm semi-solid right adnexal mass and right hydroureteronephrosis. She complained of headache and right-sided back pain. Computed tomography demonstrated a cystic adnexal mass that did not appear to originate from the right ovary and grade 2 hydroureteronephrosis. Magnetic resonance imaging indicated that the mass originated from the right ovary. Tumor markers were in the normal range. Exploratory laparotomy was performed to determine the origin of the lesion, and revealed a retroperitoneal mass obstructing the right ureter. The mass was completely removed and and the histopathologic diagnosis was paraganglioma.
European journal of gynaecological oncology 02/2005; 26(2):219-20. · 0.47 Impact Factor
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ABSTRACT: Leukemia is a well-known complication of cancer therapy, but development of acute myeloid leukemia (AML) after renal transplantation is rare. Immunosuppressive therapy for organ transplant recipients is complicated by high rates of malignant disease, one condition being Kaposi's sarcoma (KS).
A 22-year-old woman developed KS 1 year after renal transplantation, and then developed AML another 4 years later. When KS was diagnosed it was already in extensive stage, and she received ABV combination chemotherapy with doxorubicin plus bleomycin plus vincristine intravenously (i.v.) once daily every 2 weeks. She entered remission but the KS relapsed and 8 cycles of i.v. etoposide monotherapy were given and she re-entered remission. 19 months later, the patient was admitted to hospital with severe malaise, leukocytosis, thrombocytopenia, and anemia. The diagnosis was AML (FABM4). The patient received induction chemotherapy consisting of cytarabine and idarubicin. After completion of this induction therapy she developed neutropenic infection, dyspnea and confusion. Her condition deteriorated rapidly after that, and she died.
KS is one of the most common malignancies in renal allograft recipients, whereas AML is a less frequent problem. To our knowledge, this is the first published case of these two different malignancies developing after renal transplantation. The pathogenesis of the AML is discussed.
Onkologie 05/2004; 27(2):163-5. · 0.87 Impact Factor
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Rheumatology 04/2004; 43(3):394-6. · 4.06 Impact Factor
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ABSTRACT: Early re-ossification at the suturectomy site after craniosynostosis surgery remains an important problem. Many surgical methods have been used to address this, including placement of various types of absorbable and non-absorbable material between the bone edges at the site. This experimental study investigated the value of expanded polytetrafluoroethylene (ePTFE) membrane as a barrier to calvarial reclosure after craniosynostosis surgery in rats.
Thirty-five 2-week-old Sprague-Dawley rats were divided into two groups. In Group A (n = 17), ePTFE membranes were placed in the defect formed by a left coronal suturectomy. The Group B rats (n = 18) underwent left coronal suturectomy only. Animals were sacrificed at 1, 2 and 4 months postoperatively. In each case, the skull was removed and the operative site was examined for fibrosis, new bone formation, bone bridging, neovascularization and inflammatory response.
The two groups were similar with respect to neovascularization and new bone formation. By the end of the fourth postoperative month, 50% of the Group B specimens showed fibrosis and 50% showed bridging between the bone edges at the suturectomy site. In contrast, at the same stage in Group A, only 16.6% of the specimens exhibited a small amount of fibrosis, and none showed bone bridging between the edges.
Expanded PTFE is one of the most inert materials used in surgery. The study showed that inserting ePTFE membrane as a barrier between the bone edges at the suturectomy site prevents early re-ossification after craniosynostosis surgery in rats.
Acta Neurochirurgica 04/2004; 146(3):279-83; discussion 283. · 1.52 Impact Factor
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ABSTRACT: Hepatocyte growth factor (HGF) is a multipotent growth factor that is a powerful stimulator of DNA synthesis in a variety of cell types, especially hepatocytes. This factor is produced by nonparenchymal cells in the liver, presumably Kupffer cells, Ito cells, and sinusoidal endothelial cells. Research has shown that HGF is involved in tissue regeneration, wound healing, normal tissue growth, tumor progression, embryogenesis, and tumor invasion. Elevated serum levels of HGF have been documented in patients with acute renal failure and in renal transplant recipients; however, the importance of HGF in liver transplantation is unknown. The aim of this study was to determine whether induction of HGF expression is associated with acute rejection in liver transplants. We assessed the presence and density of HGF in hepatic allograft biopsy specimens compared with those from a control group of healthy patients.
Transplantation Proceedings 01/2004; 35(8):3022-3. · 1.00 Impact Factor
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Transplantation Proceedings 12/2003; 35(7):2775-6. · 1.00 Impact Factor
