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PubMed1994

Pentoxifylline reduces lung allograft reperfusion injury.

Early graft dysfunction remains a significant problem in clinical lung transplantation. Pentoxifylline, a methylxanthine derivative, has been shown to have various beneficial effects on neutrophil-induced lung injury. We investigated effects of pentoxifylline on early posttransplantation lung function in a canine allograft model. Ten dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution (50 mL/kg) and stored in an inflated state for 18 hours at 1 degrees C. In five experiments (group I), pentoxifylline was added to the flush and storage solutions (200 mg/L) at the time of harvest. The recipient animals received pentoxifylline (20 mg/kg intravenously) before reperfusion followed by pentoxifylline (0.1 mg.kg-1.min-1 intravenously) during the 6-hour posttransplantation assessment period. In group II, donors and recipients received no pentoxifylline. To evaluate only allograft function, the right main pulmonary artery and bronchus were ligated immediately after implantation. For 6 hours thereafter hemodynamics and gas exchange were assessed at 15-minute intervals while the animal was ventilated at an inspired oxygen fraction of 1.0. After 1 hour of assessment there was a significant difference in gas exchange between the groups, which persisted until the end of the study. By the end of the 6-hour assessment, the mean arterial oxygen tension was 236.7 mm Hg for group I versus 101.1 mm Hg for group II (p < 0.01), and the alveolar-arterial oxygen difference was 443.1 mm Hg versus 562.2 mm Hg (p < 0.015). Hemodynamics were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1980

In situ cold perfusion of kidneys for transplantation. An experimental and clinical evaluation.

Cadaver kidneys from donors who have sustained cardiac standstill are often unsuitable for transplantation due to prolonged warm ischemic time. In an attempt to increase the salvage rate of these kidneys, the efficacy of in situ intra-aortic cold perfusion in producing immediate function of allografted kidneys was assessed in the nonheart beating canine model. In the first experiment, kidneys harvested after cardiac standstill and immediate intra-aortic cold perfusion were demonstrated to function equally as well as kidneys harvested "optimally." In the second experiment, evaluation of intra-aortic cold perfusion on renal core temperature demonstrated rapid cooling of these kidneys to a protective range. Early clinical results in donors whose kidneys were removed after cardiac arrest demonstrate that most of the kidneys allotransplanted after in situ intra-aortic cold perfusion functioned immediately. These preliminary experimental and clinical results demonstrate the effectiveness of in situ intra-aortic cold perfusion. Wider application of this technique to donors with cardiac standstill should increase the available organs for transplantation.

Animals↗

PubMed1977

Clinical aspects of polycystic disease of the kidneys.

Seventy-eight patients were treated for polycystic disease of the kidneys. An analysis of the interval between the onset of symptoms and end-stage renal failure made it possible to give and accurate prognosis in individual cases. Pregnancy and urinary infection did not appear to accelerate deterioration of renal function, but Rovsing' operation precipitated renal failure in some cases. Forty-two patients needed replacement treatment for end-stage renal failure, and 24 patients received 29 renal allografts. Transplant function at all times was better than a matched group of 70 patients indications for removal of polycystic kidneys in graft recipients were persistnet or recurrent infection, erythraemia that failed to respond to conservative treatment, and to make room for the transplant.

Adolescent↗

PubMed1997

Comparative rest and exercise hemodynamics of allograft and prosthetic valves in the aortic position.

BACKGROUND: Allograft aortic valve replacement has gained widespread acceptance. However, there is little information about in vivo allograft valve function at rest and during exercise. METHODS: Cardiac catheterization was performed to measure hemodynamic variables at rest and during supine bicycle exercise in 44 patients who had had aortic valve replacement using allograft valves or Bicer or St. Jude Medical prosthetic valves 19 to 27 mm in diameter. Sixteen patients received an allograft valve; 17, a Bicer valve; and 11, a St. Jude Medical valve. There were no significant differences between the three groups in age, body surface area, left ventricular end-systolic and end-diastolic volume indices, exercise cardiac index, exercise heart rate, or work load achieved. Left ventricular and ascending aortic pressures were measured simultaneously according to the transseptal method. RESULTS: The mean pressure gradient was generally higher for the Bicer and St. Jude Medical valves than for the allograft valves, both at rest and during exercise. Significant differences were obtained in patients with small-sized valves (21 and 23 mm); pressure gradients were higher in the prosthetic valve groups. In patients with large-sized prosthetic valves (25 mm), there were no significant differences between the three groups at rest and during exercise. However, there was no pressure gradient at all for allograft valves. CONCLUSIONS: Exercise cardiac catheterization confirms that the allograft aortic valve is an ideal substitute from the hemodynamic aspect, particularly in patients with a small aortic root and in those who perform strenuous exercise.

Aortic Valve↗

PubMed1988

Changes in energy metabolism of allografts after liver transplantation.

To evaluate the function of energy metabolism in allografts after liver transplantation, changes in hepatic energy charge levels, oxidative and phosphorylative activities of mitochondria and arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate; KBR) were studied in piglets. Hepatic energy charge levels decreased to 0.831 +/- 0.010 at 3 days and 0.836 +/- 0.009 at 3 weeks after operation compared to the preoperative value of 0.868 +/- 0.006 (p less than 0.01), and returned to 0.856 +/- 0.007 at 6 weeks. Mitochondrial oxidative and phosphorylative activities were moderately enhanced to 19.14 +/- 2.07 (10(-10) mol ATP/mg of mitochondrial protein/s) at 3 days and 20.89 +/- 1.72 at 3 weeks compared to the preoperative value of 16.74 +/- 2.36, and returned to 16.65 +/- 1.54 at 6 weeks. There was no significant difference in the concentrations of mitochondrial respiratory components, except in cytochrome c + c1. KBR decreased immediately at the beginning of the anhepatic phase and rapidly recovered to the preoperative level within 60 min after revascularization of allografts. There was no change in KBR during the postoperative course except in cases with clinical deterioration. From these results, it is suggested that the mitochondrial capacity for ATP synthesis was enhanced to compensate for the decreased energy charge level and that a decreased KBR is a sign of a critically deranged metabolic function in allografts.

Adenosine Triphosphate↗

PubMed1997

Prostaglandins in liver transplantation.

This review summarizes experimental studies and clinical experiences with prostaglandins in liver transplantation emphasizing two randomized, double blinded placebo controlled clinical trials of prostaglandin E1 (PGE1) involving nearly 300 liver transplant recipients. Resource utilization and pharmacoeconomic aspects are also discussed. In the randomized trials, PGE1 did not affect patient and graft survival. Acute cellular rejection and primary allograft non-function were not reduced by PGE1. Postoperative renal failure was significantly less frequent among PGE1 patients in both trials and in one study perioperative blood product utilization was significantly lower. PGE1 treated patients had reduced intensive care unit length of stay, shorter hospitalization, and significantly lower total health care charges. Despite its failure to show improvements in patient and graft survival, rejection, or primary non-function, PGE1 use in hepatic allograft recipients reduces morbidity and results in notable reduction in the cost of liver transplantation.

Alprostadil↗

PubMed2006

Janus tyrosine kinases and signal transducers and activators of transcription regulate critical functions of T cells in allograft rejection and transplantation tolerance.

Full activation of T cells requires three sequential signals. Engagement by antigen presenting cells (APC) delivers signals 1/2, whereas signal 3 is delivered by multiple cytokines to regulate the immune homeostasis by influencing proliferation, differentiation, and survival/death. Signaling by cytokines acting through their receptors is delivered by two major molecular families, namely Janus tyrosine kinases (Jaks) and signal transducers and activators of transcription (Stats). Findings obtained from mice genetically deficient in Jaks and Stats suggest that these molecules may serve as therapeutic targets to prevent allograft rejection, induce transplantation tolerance, and inhibit autoimmune disease and lymphoid-derived tumors. This review describes the role of Jak tyrosine kinases and Stat transcription factors and their putative function in regulating T and B cell activity.

Animals↗

PubMed2002

Determinants of hypofiltration during acute renal allograft rejection.

This study sought to determine the extent to which GFR is decreased during acute renal allograft rejection in human subjects and to determine the mechanism of the decrease in GFR. Eight patients with biopsy-proven acute rejection were compared with 18 recipients of optimally functioning renal allografts. GFR and renal plasma flow (RPF) were measured as the clearance of inulin and para-aminohippuric acid, respectively. Arterial BP was determined, blood was sampled, and plasma oncotic pressure (pi(A)) was measured. Glomeruli obtained by biopsy during rejection were subjected to morphometric analysis, for determination of K(f). Control morphometric values for healthy glomeruli were provided by 10 living donors from whom biopsies were obtained at the time of organ donation. The subjects in the acute rejection group exhibited a significantly reduced GFR of 17 +/- 4 ml/min per 1.73 m(2), compared with 72 +/- 4 ml/min per 1.73 m(2) for control subjects (P < 0.001). With the use of a sensitivity analysis to take into account the unknown para-aminohippuric acid extraction ratio, the RPF rate was calculated to have likely been significantly decreased, by 45 to 70%, in the acute rejection group. Neither the plasma oncotic pressure nor the mean arterial pressure differed between the two groups. Morphometric analysis revealed no difference in the single-nephron K(f) values for the acute rejection group, compared with the control group. These results indicate that acute renal allograft rejection causes a profound decrease in GFR, which is attributable to a decrease in RPF alone or in combination with a decrease in the glomerular transcapillary hydraulic pressure gradient (DeltaP).

Acute Disease↗

PubMedDate not supplied

Heterotopic and orthotopic liver transplants in inbred rat strains.

The functioning and survival of orthotopic liver allotransplants in toto were compared with heterotopic partial and whole allotransplants in inbred rats. In contrast to the rapid and aggressive rejection of the heterotopic allografts, the orthotopic whole-liver allografts survived for prolonged periods. These latter grafts were subjected to mild cellular attack 11 to 12 days following transplantation, but they survived without the massive cellular infiltration and hepatocytolysis seen in the heterotopic partial grafts. Biliary secretion by the orthotopic whole-liver allografts was functional throughout the survival period and was markedly increased during the final stages of survival, whereas the heterotopic liver grafts ceased to excrete normal bile by day 9, after which they were completely depigmented.

Anastomosis, Surgical↗

PubMed1994

Prolonged cardiac xenograft survival is induced by intrathymic splenocyte injection.

The shortage of suitable human organs currently limits widespread utilization of clinical transplantation. Successful xenotransplantation could potentially eliminate the shortage of suitable organs for transplantation. The present study determines the effect of intrathymic donor spleen cell injection on the survival of cardiac xenografts performed without post-transplant immunosuppression. Wistar-Furth rats served as recipients of Lewis rat cardiac allografts or Golden Syrian hamster cardiac xenografts either with or without intrathymic donor spleen cell injection. Some xenograft cohorts were pretreated with four doses of cyclophosphamide prior to cardiac transplantation. Graft function was assessed by daily graft palpation and rejection was defined as cessation of graft function. Cardiac allograft median survival time (MST) was 8 days in untreated recipients. Pretreatment with intrathymic donor spleen cell injection led to essentially indefinite allograft survival (MST > 100 days). Control xenograft survival was 3 days with no significant prolongation seen when intrathymic donor spleen cell injection was performed (MST = 2.5 days). The addition of pulse-dose cyclophosphamide resulted in markedly prolonged xenograft survival (MST = 30 days) compared to control (P < 0.01) and to cyclophosphamide alone (MST = 9.5 days, P < 0.01). Cardiac xenografts undergo a vigorous rapid rejection. The time course of rejection was not altered by the intrathymic presence of donor cells under conditions which lead to indefinite survival of cardiac allografts. A brief period of pretransplant cyclophosphamide treatment markedly improved the success of the thymic tolerance protocol in xenografts. This finding suggests that temporary inhibition of humoral immunity may be permissive for the development of thymic tolerance to cell-mediated immunity in xenotransplants.

Animals↗

PubMed2003

The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is due to both immunologic and non-immunologic factors and results in the development of nonspecific pathologic features that may even be present in long-term well-functioning renal allografts. To investigate the natural history of CAN and potential risk factors associated with progression of these histologic lesions, this study evaluated the of histologic alterations of 124 sequential protocol biopsies performed at 2, 3, and 5 yr after transplantation in 46 patients who exhibited histologic evidence of CAN in the 1-yr biopsy. The occurrence of late acute rejection (AR) greater than 4 mo posttransplant was significantly associated with the development of histologic CAN. In contrast, early clinical AR occurring within 3 mo had no impact on the subsequent development of CAN at 1 yr. Subclinical AR was evident in association with CAN in 50%, 32%, 19%, and 16% of cases with CAN at 1, 2, 3, and 5 yr, respectively. These acute lesions correlated significantly with histologic progression defined as an increased CADI score of the follow-up biopsies. Furthermore, a group of patients who exhibited repeated subclinical AR in the sequential follow-up biopsies had a lower creatinine clearance at 5 yr after transplantation and worse long-term graft survival. In contrast, the absence of evidence of acute inflammation in association with CAN at any time point was associated with minimal deterioration in renal function or progression of renal lesions during the observation period. These results suggest that the persistence of chronic active inflammation may be responsible for the histologic progression of CAN.

Acute Disease↗

PubMed2000

Pathogenetic mechanisms of cardiac allograft vasculopathy--impact of nitric oxide.

In the cytokine-enriched environment of the chronically rejecting allograft, nitric oxide (NO) is predominantly produced by the inducible isoform of NOS synthase (NOS2) expressed by recipient-derived infiltrating immune cells as well as donor-derived vascular smooth muscle cells and endothelial cells. Early and persistent upregulation of NOS2 in allografts with cardiac allograft vasculopathy and downregulation of NOS2 coinciding with immunosuppressive attenuation of cardiac allograft vasculopathy have suggested NO as a regulator of cardiac allograft vasculopathy, the hallmark of chronic rejection. Pathogenetically, the development of cardiac allograft vasculopathy can be divided into an early phase, characterized by endothelial dysfunction, and a later phase, characterized by structural changes of vessel wall morphology. Several lines of evidence have shown that NO might play an essential role in both phases. Endothelial dysfunction due to immune-mediated injury of endothelial cells has been suggested as an early response-to-injury event in the pathogenesis of cardiac allograft vasculopathy. Functional studies in human transplant recipients have documented endothelial dysfunction of coronary artery vessels. Administration of L-arginine, the precursor of NO, improved endothelial function of both epicardial coronary arteries and coronary microvasculature indicating a protective effect of NO. To assess the impact of NO on the development of late structural changes, the severity of cardiac allograft vasculopathy was assessed in mice with targeted deletion of NOS2. A significant increase of vascular occlusion in NOS2-knockout mice demonstrated an antiarteriosclerotic effect of NOS2. In part, this effect could be explained by reduced neointimal smooth muscle cell accumulation after alloimmune injury. Taken together, NO plays an important role in maintaining vessel integrity after transplantation. Disruptions in NO pathways seem to play a key role in the progression from endothelial dysfunction to structural changes.

Animals↗

PubMed2005

Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation.

PURPOSE: To evaluate the efficacy of a low-dose chemotherapy regimen in children with Epstein-Barr virus (EBV) -positive, post-transplantation lymphoproliferative disease (PTLD) after organ transplantation who have experienced failure with front-line therapy for PTLD. PATIENTS AND METHODS: Eligible patients received cyclophosphamide (600 mg/m2 intravenous for 1 day) and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles. RESULTS: Thirty-six patients treated on study were assessable for analyses. Front-line therapies for PTLD before study entry included immune suppression reduction or withdrawal (n = 36), antiviral therapy (n = 33), surgical resection (n = 8), rituximab (n = 2), and interferon alfa (n = 1). Reasons for failure of front-line therapy included progressive disease (PD; n = 33) and persistent disease with concurrent allograft rejection (n = 3). Thirty patients (83%) had stage III to IV disease, 92% had extranodal disease, and 75% had > or = three sites of disease. The overall response rate was 83% (75% complete response + 8% partial response). The relapse rate was 19%, with only one of five relapsed patients alive and disease-free. Four patients presented with fulminant, disseminated PTLD; only one of these four patients achieved a response, and all four died of PD. Two patients died of treatment-related toxicity. Three patients (8%) experienced allograft loss, but two of the three patients are alive and disease-free after a second transplantation. The 2-year overall, relapse-free, and failure-free (without PTLD and with functioning original allograft) survival rates were 73%, 69%, and 67%, respectively. CONCLUSION: This low-dose chemotherapy regimen is effective for children with EBV-positive, nonfulminant PTLD who have experienced treatment failure with front-line therapy, and this study represents the largest series of PTLD patients treated prospectively with a uniform chemotherapy regimen.

Adolescent↗

PubMed1990

[Personal experience with segmental corporo-caudal allotransplantation of the pancreas in an experiment on dogs].

In the Institute for Surgery, its Experimental Centre, has already several years an experimental transplantations of pancreas been carried out with the aim of learning surgery technique and performing a clinical transplantation of that organ. In our work we have used a technique of corporacaudal allotransplatation of pancreas with vascular anastomosis. As the blood vessels of the graft we have used the arteria and vena lienalis with parts of aorta and portal vein, which have been anastomosed with a. and v. iliaca communis of the pancretotomized recipient. We have used techniques of the open pancreatic duct, ligated pancreatic duct, our own technique of permanent bleeding of the pancreatic graft during the transplantation pancreaticojejunostomy and pancreatico-vesicular anastomosis. As the parameters of function of allograft we are using: glycaemia, i.v. GT test, K constant, insulinaemia, amylasaemia, length of survival of animals and pathohistological finding. The average term of survival of experimental animals was 28 days. During the function of alograft the experimental animals shown some signs of laboratory subclinical diabetes. Refusal of transplant was followed by sudden increase of glycaemia, without any clinical or laboratory sign of anticipation of the refusal.

Animals↗

PubMed1996

Antihypertensive drug treatment in chronic renal allograft rejection in the rat. Effect on structure and function.

To gain insight into the contribution of immunologic and hemodynamic factors in the progressive demise of structure and function in chronic renal allograft dysfunction, we studied the histological changes, the immunostainable glomerular anionic sites, and glomerular capillary hydrostatic pressures of rat renal allografts with chronic rejection. Recipient animals were left untreated, received 8 weeks of treatment with the immunosuppressive drug cyclosporine, or received antihypertensive drugs consisting of the combination of reserpine, hydralazine and hydrochlorothiazide, the angiotensin-converting enzyme inhibitor cilazapril, or the angiotensin II receptor blocker L-158,809. Grafts in untreated recipients developed chronic interstitial inflammation, as well as vascular and glomerular lesions consistent with chronic rejection. These lesions were associated with immunohistochemical loss of the negatively charged heparan sulfate proteoglycan side chain. All treatment regimens decreased the systemic and glomerular capillary pressures and were associated with no loss of function, decreased proteinuria, and a tendency to improved graft function. Cyclosporine prevented all histological manifestations of rejection, and antihypertensive drugs decreased the extent of glomerular mesangiolysis and glomerulosclerosis; L-158,809 and cilazapril also inhibited graft atherosclerosis and tubular atrophy. We conclude that chronic rejection is primarily an immune-mediated process, but hemodynamic and angiotensin II-mediated effects may play a pivotal role in the expression of immune-mediated lesions.

Animals↗

PubMed2002

Cyclosporin withdrawal with concomitant conversion from azathioprine to mycophenolate mofetil in renal transplant recipients with chronic allograft nephropathy: a 2-year follow-up.

Because recent large studies have demonstrated that mycophenolate mofetil (MMF) is superior to azathioprine (AZA) as a post-transplant immunosuppressant, it has been speculated that MMF could have a cyclosporin (CsA)-sparing effect in renal transplant recipients with chronic allograft dysfunction. Between April 1996 and October 1998, 31 patients with chronic allograft dysfunction were assigned to have conversion from AZA to MMF with concomitant CsA withdrawal. Patient and graft outcomes were analysed. Mean follow-up time after MMF conversion was 27+/-11 months. Serum creatinine concentration (sCt) significantly decreased after conversion and remained stable at the end of follow-up (227+/-31 micro mol/l vs. 185+/-50 micro mol/l; P<0.0005). Mean variation in sCt was -24% after conversion, whereas it was +20% in the year before conversion ( P<0.001). There was a significant inverse relationship between proteinuria at baseline and improvement in renal function (r=-0.35; P=0.01). Proteinuria increased during follow-up (0.79+/-0.6 vs. 1.79+/-1.08 g/day; P=0.04). Isolated CsA nephropathy was associated with the best outcome. Renal function significantly improved in patients with grade 1 chronic rejection and remained stable in patients with grade 2 chronic rejection. Two patients (6.5%) experienced late acute rejection, respectively 13 and 24 months after CsA withdrawal. Eight patients (29%) experienced systemic infections requiring hospitalization. Blood pressure control and lipid profile improved after conversion. CsA withdrawal with a concomitant switch from AZA to MMF allows a substantial and durable improvement in renal function. Both allograft histology and proteinuria at baseline are predictive of the evolution of renal function after conversion. Physicians should consider the risk of over-immunosuppression possibly associated with this therapeutic strategy.

Adult↗

PubMed1992

The endothelial heparan sulfate-antithrombin III natural anticoagulant pathway in normal and transplanted human kidneys.

This is the first study of the antithrombin III-heparan sulfate natural anticoagulant pathway in human kidneys. Immunocytochemical experiments were done to demonstrate the pathway on normal renal endothelial cells. Enzymatic studies were done to show that the antithrombin III was anchored to endothelium by molecules of heparan sulfate. Displacement studies were done with glycosaminoglycans to show that the antithrombin III was bound to its glycosaminoglycan anchor via a heparinlike binding site, and replacement studies showed that antithrombin III could be returned to the same endothelial cells from which it was displaced. Immunocytochemical studies of biopsies showed that normally functioning renal allografts manifested the endothelial antithrombin III-heparan sulfate anticoagulant pathway. The pathway was compromised or absent from the microcirculation of biopsies from rejecting or rejected renal allografts, and the diminishment of endothelial ATIII was associated with the presence of fibrin deposition. It is concluded that compromise of the antithrombin III-heparan sulfate natural anticoagulant pathway results in compromised renal function in transplanted kidneys.

Adolescent↗

PubMed1995

[Malignant neoplasms after kidney transplantation: value of an annual radiological screening program].

PURPOSE: To evaluate the prevalence of malignant neoplasms after renal transplantation by means of a radiological screening programme and to determine the role of some clinical and demographic parameters concerning pathogenesis of these malignancies. MATERIAL AND METHODS: Between November 1992 and June 1994 in a prospective study 504 consecutive renal allograft recipients (331 m, 173 f) aged 51 +/- 13 years underwent routine abdominal ultrasound examinations including the renal transplant and p.a. and lateral chest x-rays once a year. RESULTS: This screening programme revealed 11 malignant neoplasms in 11 patients (2.2%). We detected 6 renal cell carcinomas (RCC) in the patient's native kidneys, two RCCs in two renal allografts, two non-Hodgkin-lymphomas in the liver and the renal allograft, respectively, and one ovarial carcinoma. Patients with renal cell carcinomas in the native kidneys were significantly older than allograft recipients without tumors. The presence of acquired cystic kidney disease (ACKD) seems to be an additional risk for the development of RCC. There were no significant differences in the time on dialysis, the time with functional renal allograft, and the immunosuppressive therapy. CONCLUSION: Yearly abdominal ultrasound screening including the renal allograft is a valuable tool for the early detection of neoplasms in asymptomatic renal allograft recipients. However, routine yearly chest x-rays should not be performed in renal allograft recipients without preexisting tumours.

Adult↗