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Allograft Failure (allograft + failure)

Distribution by Scientific Domains

Medical Sciences	92%

Kinds of Allograft Failure

renal allograft failure

Selected Abstracts

Inflammation in Areas of Tubular Atrophy in Kidney Allograft Biopsies: A Potent Predictor of Allograft Failure

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010
R. B. Mannon
The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new-onset late graft dysfunction (N = 337). We found inflammation (,iatr') and tubulitis (,tatr') in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death-censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10,4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16,5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure. [source]

Impact of Immunosuppressive Medication on the Risk of Renal Allograft Failure due to Recurrent Glomerulonephritis

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009
A. V. Mulay
Recurrent glomerulonephritis is a major problem in kidney transplantation but the role of immunosuppression in preventing this complication is not known. We used data from the United States Renal Data System to examine the effect of immunosuppressive medication on allograft failure due to recurrent glomerulonephritis for 41 272 patients undergoing kidney transplantation from 1990 to 2003. Ten-year incidence of graft loss due to recurrent glomerulonephritis was 2.6% (95% confidence interval [CI]: 2.3,2.8%). After adjusting for important covariates, the use of cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus or prednisone was not associated with graft failure due to recurrent glomerulonephritis. There was no difference between cyclosporine and tacrolimus or between azathioprine and mycophenolate mofetil in the risk of graft failure due to recurrent glomerulonephritis. However, any change in immunosuppression during follow-up was independently associated with graft loss due to recurrence (adjusted hazard ratio 1.30, 95% CI: 1.06,1.58, p = 0.01). In patients with a pretransplant diagnosis of glomerulonephritis, the risk of graft loss due to recurrence was not associated with any specific immunosuppressive medication. The selection of immunosuppression for kidney transplant recipients should not be made with the goal of reducing graft failure due to recurrent glomerulonephritis. [source]

Factors in older cadaveric organ donors impacting on renal allograft outcome

CLINICAL TRANSPLANTATION, Issue 1 2001
Deborah J Verran
Transplantation of renal allografts (RA) from older donors has become more common, despite conflicting data on outcome between reports from large series versus individual centres. Factors other than donor age per se may contribute to RA outcome. The outcome of RA procured from 114 older donors over 55 yr of age in NSW, between 1990 and 1997, was analysed. Corresponding donor factors, including demographics, medical history, inotrope use, major hypotension and findings at procurement, were also analysed. Of the potential RA, 8% were discarded and the remainder transplanted. Factors significantly associated with renal discard were pre-transplantation donation biopsy abnormality (p<0.001) and a history of cardiovascular (CV) disease in the donor (p<0.02). Donor aortorenal atherosclerosis (AS; p<0.09) and a donor age of 65 yr or older (p<0.08) were common in the discard group. The never function rate was 7.6% and was associated with a history of a discarded partner kidney (p<0.05). The delayed graft function rate was 33% and was associated with a history of donor CV disease. At a median follow up of 5 yr, the death censored allograft failure rate was 24%. Allograft failure was associated with a history of donor hypertension (p<0.05). Donor AS (p<0.7) tended to have been more common in the allograft failure group. A number of cadaveric organ donor factors documented at procurement may be associated with inferior outcome of RA. These include biopsy abnormality, history of donor CV disease and history of donor hypertension. A donor age of 65 yr or older or significant visible aortorenal AS may also be factors. This retrospective review of kidneys procured from 114 older cadaveric organ donors identifies factors apart from donor age, which may have a negative impact on both allograft utilisation and outcome. Theses factors include renal biopsy abnormality, history of donor CV disease, discard of a partner kidney and donor hypertension. Visible AS in the donor aorta documented at renal procurement may also be a factor. [source]

Medium-term outcome of fundoplication after lung transplantation

DISEASES OF THE ESOPHAGUS, Issue 8 2009
P. R. Burton
SUMMARY Gastroesophageal reflux disease (GERD) in lung transplant recipients has gained increasing attention as a factor in allograft failure. There are few data on the impact of fundoplication on survival or lung function, and less on its effect on symptoms or quality of life. Patients undergoing fundoplication following lung transplantation from 1999 to 2005 were included in the study. Patient satisfaction, changes in GERD symptoms, and the presence of known side effects were assessed. The effect on lung function, body mass index, and rate of progression to the bronchiolitis obliterans syndrome (BOS) were recorded. Twenty-one patients (13 males), in whom reflux was confirmed on objective criteria, were included, with a mean age of 43 years (range 20,68). Time between transplantation and fundoplication was 768 days (range 145,1524). The indication for fundoplication was suspected microaspiration in 13 and symptoms of GERD in 8. There was one perioperative death, at day 17. There were three other late deaths. Fundoplication did not appear to affect progression to BOS stage 1, although it may have slowed progression to stage 2 and 3. Forced expiratory volume-1% predicted was 72.9 (20.9), 6 months prior to fundoplication and 70.4 (26.8), six months post-fundoplication, P= 0.33. Body mass index decreased significantly in the 6 months following fundoplication (23 kg/m2 vs. 21 kg/m2, P= 0.05). Patients were satisfied with the outcome of the fundoplication (mean satisfaction score 8.8 out of 10). Prevalence of GERD symptoms decreased significantly following surgery (11 of 14 vs. 4 of 17, P= 0.002). Fundoplication does not reverse any decline in lung function when performed at a late stage post-lung transplantation in patients with objectively confirmed GERD. It may, however, slow progression to the more advanced stages of BOS. Reflux symptoms are well controlled and patients are highly satisfied. Whether performing fundoplication early post-lung transplant in selected patients can prevent BOS and improve long-term outcomes requires formal evaluation. [source]

Mechanical characteristics of the bone,graft,cement interface after impaction allografting

JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 1 2005
Hanspeter Frei
Impaction allografting is an attractive procedure for the treatment of failed total hip replacements. The graft,cement,host bone interface after impaction allografting has not been characterized, although it is a potential site of subsidence for this type of revision total hip reconstruction. In six human cadaveric femurs, the cancellous bone was removed proximally and local diaphyseal lytic defects were simulated. After the impaction grafting procedure, the specimens were sectioned in 6 mm transverse sections and pushout tests were performed. From the adjacent sections the percentage cement contact of the PMMA cement with the endosteal bone surface was determined. The host bone interface mechanical properties varied significantly along the femur largely due to different interface morphologies. The apparent host bone interface shear strength was highest around the lesser trochanter and lowest around the tip of the stem. A significant positive correlation was found between the percentage cement contact and the apparent host bone interface shear strength (r2 = 0.52). The sections failed in 69% of the cases through a pure host bone interface failure without cement or allograft failure, 19% failed with local cement failure, and 12% with a local allograft failure. The apparent host bone interface strength was on average 89% lower than values reported for primary total hip replacements and were similar to cemented revisions proximally and lower distally. This study showed that cement penetration to the endosteal surface enhanced the host bone,graft interface. © 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source]

Molecular adsorbent recirculating system treatment for patients with liver failure: the Hong Kong experience

LIVER INTERNATIONAL, Issue 6 2006
Alexander Chiu
Abstract: Background: The molecular adsorbent recirculating system (MARS) is an extracorporeal liver dialysis system that allows selective removal of bilirubin and other albumin-bound toxins. We reported here our experience with the use of this technique for management of liver failure at Queen Mary Hospital, Hong Kong. Methods: From December 2002 to 2004, a total of 74 MARS sessions were performed on 22 patients. The cause of liver failure included acute liver failure (n=2), acute on chronic liver failure (n=12), posthepatectomy liver failure (n=4), and posttransplantation allograft failure (n=4). Results: MARS treatment showed significant reduction in total bilirubin level, serum ammonia level and blood urea, and nitrogen (P<0.001 for all three parameters). Five patients (22.7%) were able to bridge to transplantation and one patient (4.5%) made a spontaneous recovery. The 30-day mortality rate was 72.7%. Conclusions: Our results indicated that MARS can effectively improve serum biochemistry and is suitable for temporarily supporting patients with liver failure where transplantation is not immediately available. There is, however, no clear evidence showing that MARS can increase survival, improve the chance of transplantation or assist liver regeneration. Future studies in the form of randomized-controlled trials are crucial to characterize the true potential of this treatment. [source]

Factors that identify survival after liver retransplantation for allograft failure caused by recurrent hepatitis C infection

LIVER TRANSPLANTATION, Issue 12 2004
Guy W. Neff
Hepatitis C virus (HCV) is becoming the most common indication for liver retransplantation (ReLTx). This study was a retrospective review of the medical records of liver transplant patients at our institution to determine factors that would identify the best candidates for ReLTx resulting from allograft failure because of HCV recurrence. The patients were divided into 2 groups on the basis of indication for initial liver transplant. Group 1 included ReLTx patients whose initial indication for LTx was HCV. Group 2 included patients who received ReLTx who did not have a history of HCV. We defined chronic allograft dysfunction (AD) as patients with persistent jaundice (> 30 days) beginning 6 months after primary liver transplant in the absence of other reasons. HCV was the primary indication for initial orthotopic liver transplantation (OLT) in 491/1114 patients (44%) from July 1996 to February 2004. The number of patients with AD undergoing ReLTx in Groups 1 and 2 was 22 and 12, respectively. The overall patient and allograft survival at 1 year was 50% and 75% in Groups 1 and 2, respectively (P = .04). The rates of primary nonfunction and technical problems after ReLTx were not different between the groups. However, the incidence of recurrent AD was higher in Group 1 at 32% versus 17% in Group 2 (P = .04). Important factors that predicted a successful ReLTx included physical condition at the time of ReLTx (P = .002) and Child-Turcotte-Pugh score (P = .008). In conclusion, HCV is associated with an increased incidence of chronic graft destruction with a negative effect on long-term results after ReLTx. The optimum candidate for ReLTx is a patient who can maintain normal physical activity. As the allograft shortage continues, the optimal use of cadaveric livers continues to be of primary importance. The use of deceased donor livers in patients with allograft failure caused by HCV remains a highly controversial issue. (Liver Transpl 2004;10:1497,1503.) [source]

Retransplantation for hepatic allograft failure: Prognostic modeling and ethical considerations

LIVER TRANSPLANTATION, Issue 4 2002
Scott W. Biggins
Retransplantation already accounts for 10% of all liver transplants performed, and this percentage is likely to increase as patients live long enough to develop graft failure from recurrent disease. Overall, retransplantation is associated with significantly diminished survival and increased costs. This review summarizes the current causes of graft failure after primary liver transplant, prognostic models that can identify the subset of patients for retransplantation with outcomes comparable to primary transplantation, and ethical considerations in this setting, i.e., outcomes-based versus urgency-based approaches. [source]

BK virus nephropathy after allogeneic stem cell transplantation: A case report and literature review,

AMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2009
Lazaros J. Lekakis
Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus-associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non-renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment-related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy-proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis-dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post-HCT PVAN are provided. Am. J. Hematol. 2009. © 2008 Wiley-Liss, Inc. [source]

Inflammation in Areas of Tubular Atrophy in Kidney Allograft Biopsies: A Potent Predictor of Allograft Failure

Systematic Evaluation of Pancreas Allograft Quality, Outcomes and Geographic Variation in Utilization

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010
D. A. Axelrod
Pancreas allograft acceptance is markedly more selective than other solid organs. The number of pancreata recovered is insufficient to meet the demand for pancreas transplants (PTx), particularly for patients awaiting simultaneous kidney-pancreas (SPK) transplant. Development of a pancreas donor risk index (PDRI) to identify factors associated with an increased risk of allograft failure in the context of SPK, pancreas after kidney (PAK) or pancreas transplant alone (PTA), and to assess variation in allograft utilization by geography and center volume was undertaken. Retrospective analysis of all PTx performed from 2000 to 2006 (n = 9401) was performed using Cox regression controlling for donor and recipient characteristics. Ten donor variables and one transplant factor (ischemia time) were subsequently combined into the PDRI. Increased PDRI was associated with a significant, graded reduction in 1-year pancreas graft survival. Recipients of PTAs or PAKs whose organs came from donors with an elevated PDRI (1.57,2.11) experienced a lower rate of 1-year graft survival (77%) compared with SPK transplant recipients (88%). Pancreas allograft acceptance varied significantly by region particularly for PAK/PTA transplants (p < 0.0001). This analysis demonstrates the potential value of the PDRI to inform organ acceptance and potentially improve the utilization of higher risk organs in appropriate clinical settings. [source]

Influence of Cyclooxygenase-2 (COX-2) Gene Promoter Polymorphism ,765 on Graft Loss After Renal Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009
C. Courivaud
A G,C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position ,765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19,4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99,3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position ,765 (G,C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management. [source]

Wnt Pathway Regulation in Chronic Renal Allograft Damage

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009
C. Von Toerne
The Wnt signaling pathway, linked to development, has been proposed to be recapitulated during the progressive damage associated with chronic organ failure. Chronic allograft damage following kidney transplantation is characterized by progressive fibrosis and a smoldering inflammatory infiltrate. A modified, Fischer 344 (RT1lvl) to Lewis (RT1l) rat renal allograft model that reiterates many of the major pathophysiologic processes seen in patients with chronic allograft failure was used to study the progressive disease phenotype and specific gene product expression by immunohistochemistry and transcriptomic profiling. Central components of the Tgfb, canonical Wnt and Wnt-Ca2+ signaling pathways were significantly altered with the development of chronic damage. In the canonical Wnt pathway, Wnt3, Lef1 and Tcf1 showed differential regulation. Target genes Fn1, Cd44, Mmp7 and Nos2 were upregulated and associated with the progression of renal damage. Changes in the Wnt-Ca2+ pathway were evidenced by increased expression of Wnt6, Wnt7a, protein kinase C, Cam Kinase II and Nfat transcription factors and the target gene vimentin. No evidence for alterations in the Wnt planar cell polarity (PCP) pathway was detected. Overall results suggest cross talk between the Wnt and Tgfb signaling pathways during allograft inflammatory damage and present potential targets for therapeutic intervention. [source]

Transplantation of Kidneys from Donors at Increased Risk for Blood-Borne Viral Infection: Recipient Outcomes and Patterns of Organ Use

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009
P. P. Reese
Kidney transplantation from deceased donors classified as increased risk for viral infection by the Centers for Disease Control (CDC) is controversial. Analyses of Organ Procurement and Transplantation Network (OPTN) data from 7/1/2004 to 7/1/2006 were performed. The primary cohort included 48 054 adults added to the kidney transplant wait list. Compared to receiving a standard criteria donor (SCD) kidney or remaining wait-listed, CDC recipients (HR 0.80, p = 0.18) had no significant difference in mortality. In a secondary cohort of 19 872 kidney recipients at 180 centers, SCD (reference) and CDC (HR 0.91, p = 0.16) recipients had no difference in the combined endpoint of allograft failure or death. Among centers performing >10 kidney transplants during the study period, the median proportion of CDC transplants/total transplants was 7.2% (range 1.1,35.6%). Higher volume transplant centers were more likely to use CDC kidneys compared to low and intermediate volume centers (p < 0.01). An analysis of procured kidneys revealed that 6.8% of SCD versus 7.8% of CDC (p = 0.13) kidneys were discarded. In summary, center use of CDC kidneys varied widely, and recipients had good short-term outcomes. OPTN should collect detailed data about long-term outcomes and recipient viral testing so the potential risks of CDC kidneys can be fully evaluated. [source]

Cancer Mortality in Kidney Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009
B. A. Kiberd
Immunosuppression is associated with an increased risk of cancer in kidney transplant recipients compared to the general population. It is less clear whether standardized cancer mortality ratios (SMRs) are also increased. This study's hypothesis is that SMRs are not increased because of competing risks of death. During the median follow-up of 5.05 years (Q1,Q3: 2.36,8.62), there were 1937 cancer deaths and 36 619 noncancer deaths among 164 078 first kidney-only transplant recipients captured in the United States Renal Data System between January 1990 and December 2004. The observed cancer death rate was 206 per 100 000 patient-years compared to an expected rate of 215 per 100 000 patient-years in the general population. The overall age- and sex-adjusted SMR was only 0.96 (95% CI 0.92,1.00). However, patients <50 years had SMRs significantly greater than unity while patients >60 had SMRs lower than unity. Up to 25% of cancer-related deaths occurred after allograft failure. These findings challenge the notion that cancer is a major cause of premature death in all kidney transplant recipients and has implications for design of cancer prevention strategies in kidney transplant recipients. [source]

Immediate Retransplantation for Pancreas Allograft Thrombosis

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009
E. F. Hollinger
Early pancreas allograft failure most commonly results from thrombosis and requires immediate allograft pancreatectomy. Optimal timing for retransplantation remains undefined. Immediate retransplantation facilitates reuse of the same anatomic site before extensive adhesions have formed. Some studies suggest that early retransplantation is associated with a higher incidence of graft loss. This study is a retrospective review of immediate pancreas retransplants performed at a single center. All cases of pancreas allograft loss within 2 weeks were examined. Of 228 pancreas transplants, 12 grafts were lost within 2 weeks of surgery. Eleven of these underwent allograft pancreatectomy for thrombosis. One suffered anoxic brain injury and was not a retransplantation candidate, one was retransplanted at 3.5 months and nine patients underwent retransplantation 1,16 days following the original transplant. Of the nine early retransplants, one pancreas was lost to heparin-induced thrombocytopenia, one recipient died with function at 2.9 years and the other grafts continue to function at 76,1137 days (mean 572 days). One-year graft survival for early retransplantation was 89% compared to 91% for all pancreas transplants at our center. Immediate retransplantation following pancreatic graft thrombosis restores durable allograft function with outcomes comparable to first-time pancreas transplantation. [source]

Impact of Immunosuppressive Medication on the Risk of Renal Allograft Failure due to Recurrent Glomerulonephritis

Transplant Center Volume and Outcomes After Liver Retransplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2009
P. P. Reese
Liver retransplantation surgery has a high rate of allograft failure due to patient comorbidities and technical demands of the procedure. Success of liver retransplantation could depend on surgeon experience and processes of care that relate to center volume. We performed a retrospective cohort study of adult liver retransplantation procedures performed from January 1, 1996 through December 31, 2005 using registry data from the Organ Procurement Transplantation Network. The primary outcome was 1-year allograft failure. Liver transplant centers were categorized as small, intermediate or high volume by dividing overall liver transplants into three tertiles of approximately equal size. Mean annual volume of overall liver transplants was <50 for low-volume centers, 50,88 for intermediate-volume centers and >88 for high-volume centers. The primary analysis consisted of 3977 liver retransplantation patients. The unadjusted risk of 1-year allograft failure was 37.8%. In multivariable logistic regression, the risk of 1-year allograft failure was not significantly different between low- (reference), intermediate- (OR 0.86, CI 0.72,1.03, p = 0.11) and high-volume centers (OR 0.88, CI 0.74,1.04, p = 0.14). Results were similar when the analysis was limited to retransplantation performed >160 days after initial transplantation. Center volume is an imprecise surrogate measure for 1-year outcomes after liver retransplantation. [source]

Corneal Graft Rejection Is Accompanied by Apoptosis of the Endothelium and Is Prevented by Gene Therapy With Bcl-xL

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2007
R. N Barcia
Corneal transplants normally enjoy a high percentage of survival, mainly because the eye is an immune-privileged site. When allograft failure occurs, it is most commonly due to rejection, an immune-mediated reaction that targets the corneal endothelium. While the exact mechanism by which the endothelium is targeted is still unknown, we postulate that corneal endothelial cell loss during allograft failure is mediated by apoptosis. Furthermore, because corneal endothelial cells do not normally regenerate, we hypothesize that suppressing apoptosis in the graft endothelium will promote transplant survival. In a murine model of transplantation, TUNEL staining and confocal microscopy showed apoptosis of the graft endothelium occurring in rejecting corneas as early as 2 weeks posttransplantation. We found that bcl-xL protected cultured corneal endothelial cells from apoptosis and that lentiviral delivery of bcl-xL to the corneal endothelium of donor corneas significantly improved the survival of allografts. These studies suggest a novel approach to improve corneal allograft survival by preventing apoptosis of the endothelium. [source]

NOS2 (iNOS) Deficiency in Kidney Donor Accelerates Allograft Loss in a Murine Model

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2007
C. Du
Renal NOS2 is expressed and produces abundant nitric oxide (NO) in various renal cells in response to proinflammatory cytokines. However, the role of this enzyme in renal allograft survival remains unknown. Kidney allotransplantation was performed in the murine model of C57BL/6J (H-2d) to nephrectomized Balb/c (H-2b) mice. Here we show that deficiency in NOS2 expression in kidney donors significantly advanced allograft failure, indicated by decreasing mean survival of recipients receiving NOS2 null grafts (15.4 ± 6.4 days) as compared to those with wild type grafts (65.4 ± 28.1 days) (p = 0.0005). Consistent with survival results, NOS2 null grafts had more severe renal tubule injury and decreased renal function compared to wild type grafts. In vitro NOS2 expressing TEC had greater resistance to allogeneic lymphocyte-mediated apoptosis. The addition of exogenous NO inhibited Fas-mediated TEC apoptosis and reduced proliferation of allogeneic lymphocytes. These data suggest that endogenous production of NO through renal NOS2 activity can play a protective role in kidney grafts through attenuating Fas-mediated donor cell apoptosis as well as by inhibiting proliferation of inflammatory infiltrating lymphocytes. Enhanced donor NOS2 expression may be a useful strategy to improve kidney transplant survival. [source]

Effects of the combination of rapamycin with tacrolimus or cyclosporin on experimental intimal hyperplasia

BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 11 2002
Dr J. R. Waller
Background: Allograft vasculopathy remains the leading cause of late allograft failure following transplantation and can be inhibited by the antiproliferative drug rapamycin. This study assessed the efficacy of combining rapamycin therapy with calcineurin inhibition. Methods: Male Sprague,Dawley rats received rapamycin 0·05 mg/kg daily and either tacrolimus 0·1 mg/kg or cyclosporin 5 mg/kg daily, and findings were compared with those in an untreated control group. Animals underwent left common carotid artery balloon angioplasty; the artery was explanted after 2 weeks. Morphometric analysis was performed on transverse sections and the intima: media ratio was calculated. Profibrotic gene expression was measured with competitive reverse transcriptase,polymerase chain reaction at 14 and 28 days. Proliferation was determined with proliferating cell nuclear antigen at 14 and 28 days. Extracellular matrix deposition was quantified with Sirius red. Results: The combination of rapamycin and tacrolimus was associated with the greatest reduction in intimal thickening. Furthermore, treatment with rapamycin and tacrolimus significantly attenuated extracellular matrix deposition compared with rapamycin and cyclosporin (P < 0·02). Conclusion: The effects of rapamycin in combination with tacrolimus were better than those observed with rapamycin and cyclosporin. © 2002 British Journal of Surgery Society Ltd [source]

Smooth muscle cell proliferation but not neointimal formation is dependent on alloantibody in a murine model of intimal hyperplasia

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2006
B. Soleimani
Summary Transplant coronary artery disease is the pre-eminent cause of late cardiac allograft failure. It is primarily characterized by a concentric intimal hyperplasia, which we designate transplant intimal hyperplasia (TIH). Although the pathogenesis of TIH is predominately immune driven, the specific role of alloantibodies in the disease process remains undefined. In this study we investigated the contribution of alloantibodies to the development of TIH in a murine model. Orthotopic, carotid artery transplantation was performed between B10A(2R) (H-2h2) donor mice and B-cell deficient ,MT,/, knockout or wild-type C57BL/6 (H-2b) recipients in the absence of immunosuppression. Grafts were harvested at 35 days and subjected to planimetry and immunohistochemistry. Alloantibodies were detectable in wild-type recipients within 7 days of transplantation and recipients developed marked TIH at 35 days. Allografts harvested from B-cell deficient recipient mice also developed TIH, which was comparable in severity with wild-type recipients. However, whereas allografts from wild-type recipients showed marked intimal smooth muscle cell (SMC) proliferation, the neointima in B-cell deficient recipients lacked SMCs. Post-transplantation administration of anti-donor serum to ,MT,/, recipients restored neointimal SMC population but did not influence the severity of TIH. Significant neointimal formation occurs in the absence of alloantibodies but lacks a SMC component. Therefore, SMC migration and proliferation is antibody dependent. [source]

Tacrolimus as secondary intervention vs. cyclosporine continuation in patients at risk for chronic renal allograft failure

CLINICAL TRANSPLANTATION, Issue 5 2005
Thomas Waid
Abstract:, Background:, Chronic renal allograft failure (CRAF) is the leading cause of graft loss post-renal transplantation. This study evaluated the efficacy and safety of tacrolimus as secondary intervention in cyclosporine-treated kidney transplantation patients with impaired allograft function as indicated by elevated serum creatinine (SCr) levels. Methods:, Patients receiving cyclosporine-based immunosuppression who had an elevated SCr at least 3 months post-renal transplantation were enrolled. Treatment allocation was 2:1 to switch to tacrolimus or continue cyclosporine. This analysis was performed after 2 yr; patients will be followed for an additional 3 yr. Results:, There were 186 enrolled and evaluable patients. On baseline biopsy, 90% of patients had chronic allograft nephropathy. Baseline median SCr was 2.5 mg/dL in both treatment groups. For patients with graft function at month 24, SCr had decreased to 2.3 mg/dL in the tacrolimus-treated patients and increased to 2.6 mg/dL in the cyclosporine-treated patients (p = 0.01). Acute rejection occurred in 4.8% of tacrolimus-treated patients and 5.0% of cyclosporine-treated patients during follow-up. Two-year allograft survival was comparable between groups (tacrolimus 69%, cyclosporine 67%; p = 0.70). Tacrolimus-treated patients had significantly lower cholesterol and low-density lipoprotein levels and also had fewer new-onset infections. Cardiac conditions developed in significantly fewer tacrolimus-treated patients (5.6%) than cyclosporine-treated patients (24.3%; p = 0.004). Glucose levels and the incidences of new-onset diabetes and new-onset hyperglycemia did not differ between treatment groups. Conclusions:, Conversion from cyclosporine to tacrolimus results in improved renal function and lipid profiles, and significantly fewer cardiovascular events with no differences in the incidence of acute rejection or new-onset hyperglycemia. [source]

Angiotensinogen and plasminogen activator inhibitor-1 gene polymorphism in relation to chronic allograft dysfunction,

CLINICAL TRANSPLANTATION, Issue 1 2005
Kadriye Reis
Abstract:, Chronic allograft dysfunction (CAD) is the most common cause of allograft failure in the long-term, and current immunologic strategies have little effect on this condition. The renin-angiotensin system (RAS) plays important roles progression of chronic renal disease. It is thought that plasminogen activator inhibitor-1 (PAI-1) functions in the RAS, in addition to involvement in thrombotic risk and fibrosis. This study investigated possible links between angiotensinogen (AGT) genotypes (M235T/MM, MT, TT) and PAI-1 genotypes (4G4G, 4G5G, 5G5G) and CAD assessments of both types of polymorphism were performed in 82 renal allograft recipients. One hundred healthy subjects were also investigated for AGT polymorphism, and 80 healthy subjects for PAI-1 polymorphism. Genotypes were determined using polymerase chain reaction (PCR) sequence-specific primers, and PCR followed by restriction fragment length polymorphism analysis. Kidney recipients with CAD had significantly lower frequencies of the MM genotype and the M allele than the recipients without CAD (p < 0.05 and <0.001). The transplant recipients with CAD also had significantly lower frequencies of the 5G5G genotype and the 5G allele than those without CAD (p < 0.001 and <0.05). Determination of AGT M235T and PAI-1 genotypes prior to transplantation may help identify patients who at risk for chronic renal transplant dysfunction. [source]

Arteriopathy in chronic allograft rejection in liver transplantation

LIVER TRANSPLANTATION, Issue 4 2004
Aya Miyagawa-Hayashino
Chronic rejection is an important cause of liver allograft failures. The allograft undergoing chronic rejection shows affected large- and medium-sized muscular arteries with homing of foamy macrophages and enlargement of the intimal area. The objective of this study was to elucidate the pathogenesis of the intimal lesion that causes obliterative arteriopathy by identifying the origin of the foamy macrophages and mesenchymal cells present in the intimal area. Nine allografted livers (6 male and 3 female patients) from sex-mismatched donors undergoing chronic rejection were studied by combined staining of the macrophages or the mesenchymal cells in the intimal area with immunohistochemistry and in situ hybridization using a probe for the human Y chromosome. By using the specimens from female donor allografts transplanted to male recipients, it was found that 62 ± 11% of CD68+ foamy macrophages and 71 ± 4% of smooth muscle actin-positive mesenchymal cells in the intimal lesions and a few interstitial myofibroblasts were positive for the Y chromosome probe. This indicated that they were derived from the recipients. In conclusion, the thickening intimal lesion seen in obliterative vasculopathy in liver allografts consists of the foamy macrophages and mesenchymal cells of recipient origin. These circulating recipient cells migrated to the areas in advance of remodeling arteries. (Liver Transpl 2004;10:513,519.) [source]