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PubMed1990

Influence of early function on long-term pediatric cadaveric renal allograft survival.

The significance of early renal graft function on long-term transplant survival is controversial. From our pediatric renal transplant population we studied 151 children who had an initial cadaveric renal transplant, were dependent on dialysis before transplantation and were 5 to 19 years old at transplantation. We used dependence upon dialysis as the parameter for early graft function. There was a statistically significant difference in long-term graft survival between patients who were independent of and dependent on dialysis at 1 week and 1 month postoperatively. Our results show that early renal graft function is important for long-term graft survival. All efforts should be directed to obtaining early renal graft function by proper organ procurement, storage, operative technique and aggressive postoperative management.

Actuarial Analysis↗

PubMed1982

Changes in human natural killer activity early and late ater renal transplantation using conventional immunosuppression.

The natural killer (NK) cell activity of human peripheral blood lymphocytes falls following major surgical procedures including renal transplantation but in non-immunosuppressed individuals returns to normal levels within the first 72 hr after operation. In renal allograft recipients, if this early postoperative fall is excluded from the analysis, NK cell function appears to follow changes in allograft function, suggesting that in vivo, as has been reported in vitro, NK activity is generated during activation of the alloreactive process. In an additional group of patients whose grafts were functioning for between 3 and 102 months after cadaveric renal transplantation using conventional immunosuppression, NK function was depressed in comparison with that of control subjects. However, some patients who were more than 48 months post-transplant had normal NK cell activity. Collectively, these results suggest that NK cell function may recover despite the continued administration of conventional immunosuppressive agents.

Adolescent↗

PubMed1992

Recurrence of disease in patients retransplanted for focal segmental glomerulosclerosis.

The natural history of focal segmental glomerulosclerosis in patients retransplanted after loss of a primary allograft is not well established. We studied 14 patients with FSGS who were retransplanted between April 1964 and September 1990 to determine if recurrence in a second or subsequent allograft could be predicted. In this group, 8 of the primary allografts were lost to recurrent disease and 6 to rejection. None of the 6 patients who lost their primary allograft to rejection without evidence of recurrent FSGS suffered recurrent disease after retransplantation. In contrast, 3 of the 8 patients who lost their primary allograft rapidly to FSGS suffered recurrent disease and loss of function in all subsequent allografts. The remaining 5 patients had prolonged function of the primary allograft ranging between 4 and 10.5 years, despite recurrence of FSGS. Of these 5 patients, 2 have excellent renal function after retransplantation without recurrence of FSGS in the secondary allograft at 9 and 10.5 years posttransplant; 2 have lost their secondary allograft to recurrent FSGS, but are free of recurrence in the third allograft at 0.5 and 5.8 years postoperatively; 1 maintains a serum creatinine level of 1.9 mg% despite recurrence of FSGS in the secondary allograft at 1 year postoperatively. Our data show that, without recurrence of FSGS in the primary allograft, further renal transplants will be free of recurrent disease. Based on this finding, we advocate use of living-related donors for second transplants in these patients. With rapid recurrence of FSGS and subsequent accelerated loss of the primary allograft, further renal transplants carry a high likelihood of recurrent FSGS and graft loss. A substantial proportion of patients with recurrent FSGS in the primary allograft will have prolonged renal function, and are likely to have excellent results with subsequent allografts.

Adolescent↗

PubMed1999

Histopathological findings in renal allografts at time of transplantation and correlation with onset of graft function.

Histopathological changes quantified using the chronic allograft damage index (CADI) have been shown to predict subsequent graft outcome and developing chronic rejection. The aim of the study reported here was to investigate the extent to which cadaveric renal allografts exhibit histopathological changes at time of transplantation, focusing on changes covered by the CADI. We also analysed whether any histopathological change predicts delayed graft function. One hundred and twenty-eight cadaveric kidney allografts with adequate protocol biopsy were studied. Tubular epithelial anisometric vacuolization was the commonest change, found in 62% of grafts and scored moderate or severe in 28% of these cases. Other prevalent changes were interstitial fibrosis, vascular hyalinosis, glomerular sclerosis and tubular basement-membrane thickening in 40%, 37%, 28% and 22% of biopsies, respectively. Intensities were, however, scored as mild in over 95% of specimens. The mean CADI for all grafts was 0.74. A significant difference in CADIs was seen between grafts from donors under and over 40 years of age. Grafts with early, delayed and no function had a similar incidence of histopathological changes. Histopathological changes in renal allografts were mostly uncommon and mild at time of transplantation, but some grafts exhibited changes which were quantified using the CADI. Though histopathological changes quantified with the CADI are predictive of subsequent graft function, they did not affect onset of graft function.

Adult↗

PubMed1992

Effects of storage temperature on viable bioprosthetic heart valves.

Long-term in vivo success of bioprosthetic allografts is dependent upon retention of cellular functions, such as protein synthesis. The purpose of the experiments presented in this report was to determine the storage conditions necessary for retention of protein synthetic functions in human allograft heart valve leaflets. Tissue viability was assessed by measurement of tritiated-glycine incorporation into proteins. Comparison of short-term (less than 3 month)- and long-term (1 and 2 years)-cryopreserved heart valve leaflet storage in a liquid nitrogen freezer below -135 degrees C demonstrated preservation of fibroblast protein synthesis. In contrast, storage in a mechanical freezer at -80 degrees C resulted in a time-dependent loss of fibroblast protein synthesis. There was no statistically significant effect on protein synthesis in leaflets stored for 1 week at 4 degrees C compared to control cryopreserved liquid nitrogen-stored leaflets. After 2 weeks of 4 degrees C storage leaflet protein synthesis declined significantly to 15% that of cryopreserved controls. These results demonstrate that liquid nitrogen storage of valve bioprostheses is required for long-term preservation of cellular functions.

Bioprosthesis↗

PubMed2003

Allograft meniscal transplantation: background, techniques, and results.

In the early arthritic knee, meniscal allograft transplantation alleviates pain and provides for a measurable improvement in functional level in appropriately selected postmeniscectomy patients. The allograft heals readily to the host, develops a normal appearance, and repopulates with the host cells. The allograft functions similarly to autograft tissue in its load-sharing properties. Theoretically, restoration of normal meniscal anatomy should decelerate or prevent further degenerative changes; however, this particular indication remains investigational. Basic science and clinical results support the intermediate-term efficacy of allograft meniscus transplantation in symptomatic meniscectomized patients as long as relevant comorbidities are corrected and significant coexisting arthritis is absent. Excellent pain relief and improved function can be achieved when rigid indications are adhered to.

Anterior Cruciate Ligament↗

PubMed2006

Functional changes in articular cartilage after meniscal allograft transplantation: a quantitative histochemical evaluation in rabbits.

PURPOSE: To evaluate quantitatively functional changes in articular cartilage after immediate and delayed meniscus transplantation in rabbits. TYPE OF STUDY: Experimental study. METHODS: Thirty rabbits were divided into 5 groups: groups A and C were subjected to meniscectomy only, groups B and D underwent meniscal transplantation immediately after meniscectomy, and group E had delayed transplantation 6 weeks after meniscectomy. Six nonoperated knees served as controls. Functional changes in articular cartilage were examined at 6 weeks (groups A, B) and 1 year (groups C, D, E, controls) after surgery by measuring proteoglycan content of the extracellular matrix as a measure of its quality and lactate dehydrogenase (LDH) activity in chondrocytes as a measure of their vitality. RESULTS: At 6-week and 1-year follow-up, no significant differences were found between the immediate transplant group and postmeniscectomy group. The delayed transplant group showed a significantly decreased proteoglycan content compared with the postmeniscectomy group. No significant differences in cellular LDH activity were found between the immediate transplant group and postmeniscectomy group at 6 weeks and 1 year. However, the delayed transplant group showed a significant decrease in LDH activity compared with the postmeniscectomy group. CONCLUSIONS: Immediate meniscal transplantation in rabbits did not significantly reduce degenerative changes of articular cartilage in comparison with meniscectomy on a short-term and long-term basis, whereas delayed transplantation led to more degenerative changes than meniscectomy. CLINICAL RELEVANCE: Before meniscus transplantation can be considered as an alternative to meniscectomy in clinical practice, it has to be determined whether this procedure has any protective effect on articular cartilage on the long term.

Animals↗

PubMed2004

Cryopreservation alters antigenicity of allografts in a porcine model of transplant vasculopathy.

UNLABELLED: The need for arterial grafts in coronary surgery to complement autologous vessels has generated interest in cryopreservation of small diameter allografts. We evaluated functional and histologic changes occurring in cryopreserved allografts 3 months after porcine femoral artery transplants. METHODS: Twenty recipient and 15 donor pigs included a control group of 16 fresh and 12 cryopreserved nonimplant arteries were used. Fresh (n=5) and cryopreserved (n=5) autografts were implanted to assess cryopreservation effects in the absence of rejection. Fresh allografts with or without treatment with cyclosporine (CsA) (n=6 of 8) and cryopreserved allografts with or without treatment with CsA (n=6 of 10) were performed to study the antigenicity of cryopreserved allografts. Arteries were stained with hematoxylin and eosin, Masson's trichrome, and orcein for morphometric analyses and immunostained to identify endothelial cells, smooth muscle cells, T lymphocytes, and macrophages. RESULTS: Among nonimplant arteries, cryopreservation reduced alpha-actin expression and increased the luminal area. All implanted autografts were patent. Cryopreserved autografts showed reduced alpha-actin expression and developed intimal hyperplasia compared to fresh autografts. Treatment with CsA improved the patency of fresh allografts from 0% to 83% (P <.01) and of cryopreserved allografts from 40% to 100% (P <.05). Cryopreserved allografts showed substantial intimal hyperplasia, and fresh allografts had more T lymphocyte infiltration in the intimal layer with aneurysmal dilatation. CONCLUSIONS: Cryopreservation reduces the deposition of inflammatory cells and prevents the thrombosis or aneurysmal lesions observed in fresh allografts. Therefore, cryopreservation modifies the antigenicity of vascular allografts.

Animals↗

PubMed1981

Cyclosporin A hepatotoxicity in 66 renal allograft recipients.

Liver functional abnormalities were seen in 13 (19.7%) of 66 recipients of cadaveric renal homografts treated with cyclosporin A and prednisone. However, such presumed hepatotoxicity was a minor problem in the use of cyclosporin A. The complication was less frequent than that of nephrotoxicity, was as easily manageable with reductions in the cyclosporin A dosage, and generally did not cause clinical illness. In an occasional case, late hepatotoxicity can force a therapeutic change from cyclosporin A to azathioprine, but careful consideration should be given to the dangers of subsequent rejection.

Azathioprine↗

PubMed2000

Time dependency of factors affecting renal allograft survival.

The function of renal transplants can deteriorate at any time posttransplant, but the risks and mechanisms may differ at different times posttransplant. Survival of 522 consecutive cadaveric renal transplant recipients followed for at least 6 mo were analyzed, with patient death censored. The overall risk factors in univariate analysis were acute rejection requiring antibody therapy (AR), delayed graft function, elevated serum creatinine at 6 mo, high panel-reactive antibodies, and donor age > or =55 yr, with borderline effects of recipient age and female gender. These risks were studied in each of three intervals posttransplantation: < or =6 mo, 6 mo to 5 yr, and >5 yr. Of the 135 graft failures, 53 occurred < or =6 mo, 61 between 6 mo and 5 yr, and 21 beyond 5 yr. By multivariate analysis. the risks for graft failure in interval < or =6 mo were AR (hazard ratio (HR) = 4.86, P < 0.001); delayed graft function (HR = 1.47, P = 0.06): and high panel-reactive antibodies (HR = 2.04, P = 0.0(3). Between 6 mo and 5 yr, the risks for graft loss were AR (HR = 2.87, P < 0.001) and serum creatinine at 6 mo > or =150 micromol/L (HR = 3.69, P < 0.001). Beyond 5 yr the risk factors were donor age > or =55 yr (HR = 5.87, P = 0.002), with a borderline effect of kidneys from female donors (HR = 2.28, P = 0.07). HLA-A, -B, and -DR matching and presensitization had most of their effect through early AR and impaired function. The results indicate that risks for graft loss are time-dependent: early losses correlate with injury and rejection, but late events correlate with donor age and possibly workload.

Adult↗

PubMed2001

[Effects of Fas ligand expression on pancreatic islet allografts].

OBJECTIVE: To investigate the immune privilege of islet allgrafts induced by the Fas ligand (FasL) expressed by co-transplanted testicular Sertoli cells and the effects of FasL gene transfected into islet cells on pancreatic islet allografts. METHODS: The allogeneic islets and testicular cells from rats were co-transplanted into diabetic recipients. Pancreatic islet cells were firstly infected with the recombinant adenovirus AdV-FasL and then transplanted into the diabetic recipients. Allograft survival, islet function and apoptosis of infiltrative lymphocytes in allografts and gene-transfected islet allografts were observed. RESULTS: All the animals receiving islet allografts alone returned to a diabetic status in several days (mean survival time = 6.3 +/- 0.56 days). When the number of testicular cells co-transplanted with islets increased to 1 x 10(7), all the animals remained normoglycemic throughout the follow-up period (P < 0.05). Sertoli cells expressing FasL induced apoptosis of infiltrative lymphocytes in the allografts. In the group of FasL gene transfection, the rejection of allografts was accelerated and the allograft survival time shortened to 3.4 +/- 0.24 days (P < 0.05). Pancreatic islets infected with AdV-FasL demonstrated positive staining for FasL at the 24th hour and increased intensity at the 48th hour after transplantation. After the transplantation, apoptosis of FasL-transfected islet cells occurred. CONCLUSIONS: Co-transplantation of testicular Sertoli cells expressing FasL and islets can induce apoptosis of activated lymphocytes and allows long-term survival of allogeneic islets because of immune privilege. However, direct expression of FasL by islet allografts infected with AdV-FasL accelerates the islet rejection by islet cell apoptosis and granulocytic infiltration.

Animals↗

PubMed1991

Conversion from cyclosporin to azathioprine in renal allograft recipients.

Renal function in five patients who were on a combination of Cyclosporin A (CyA) and Prednisone for 2-6 years following renal transplantation, were evaluated, in order to consider change from CyA-prednisone combination to conventional therapy. (Azathioprine-prednisone combination). This was necessitated by CyA nephrotoxicity, its high cost and unreliable monitoring. The maintenance dose of CyA ranged between 200 and 400 mg per day. The BUN levels during CyA treatment ranged from 6 to 15 mmol/l (normal 3.7-6.7 mmol/l), and plasma creatinine from 200 to 300 Umol/l (normal 67-107 Umol/l). The serum electrolytes were normal. The urine outputs were normal. Rejections were treated by pulses of one gram of methyl-prednisolone daily for 3 days. Maintenance prednisolone ranged from 10-15 mg per day. After tapering off the CyA and eventually stopping it, Azathioprine 100-150 mg daily with prednisolone 10-15 mg per day were instituted. There were significant drops in creatinine and BUN levels after the change over, with general well being and good urinary outputs. The patients refused consent for renal biopsy to prove CyA histologic toxicity.

Adult↗

PubMed2003

Objective, real-time, intraoperative assessment of renal perfusion using infrared imaging.

Allograft ischemia induces delayed graft function and is correlated with increasing rates of rejection. There is not currently a way to objectively measure the effects of ischemia in real-time, nor to relate therapies combating reperfusion injury with their intended effects. An infrared (IR) method utilizing a focal plane array detector camera was developed for real-time intraoperative IR imaging of renal allografts, and evaluated in a pilot trial to quantify perfusion in recipients of live (n = 8) and cadaveric donor (n = 5) allografts. Digital images were taken for 3-8 min postreperfusion. Image data were compared to ischemic time and allograft function to assess potential clinical relevance. Cold ischemic time ranged from 0.5 to 29 h and was bimodally distributed between living and cadaveric donors. Renal rewarming time (RT) as determined by IR imaging correlated with cold ischemic time (p < 0.001, R 2 = 0.81), and predicted the subsequent return of renal function with RT negatively correlated to the regression slopes of creatinine (p = 0.02, R 2 = 0.38) and BUN (p = 0.07, R 2 = 0.26). Intraoperative IR imaging noninvasively provides clinically relevant real-time whole kidney assessment of reperfusion. This technology may aide in the objective assessment of therapies designed to limit reperfusion injury, and allow for quantitative assessment of allograft ischemic damage.

Humans↗

PubMed2000

Transforming growth factor-beta1 gene transfer ameliorates acute lung allograft rejection.

BACKGROUND: The aim of the current work was to study the feasibility of functional gene transfer using the gene encoding for transforming growth factor-beta1, a known immunosuppressive cytokine, on rat lung allograft function in the setting of acute rejection. METHODS: The rat left lung transplant technique was used in all experiments, with Brown Norway donor rats and Fischer recipient rats. After harvest, left lungs were transfected ex vivo with either sense or antisense transforming growth factor-beta1 constructs complexed to cationic lipids, then implanted into recipients. On postoperative days 2, 5, and 7, animals were put to death, arterial oxygenation measured, and acute rejection graded histologically. RESULTS: On postoperative day 2, there were no differences in acute rejection or lung function between animals treated with transforming growth factor-beta1 and control animals. On postoperative day 5, oxygenation was significantly improved in grafts transfected with the transforming growth factor-beta1 sense construct compared with antisense controls (arterial oxygen tension = 411 +/- 198 vs 103 +/- 85 mm Hg, respectively; P =.002). Acute rejection scores from lung allografts were also significantly improved, corresponding to decreases in both vascular and airway rejection (vascular rejection scores: 2.0 +/- 0. 5 vs 2.8 +/- 0.6; P =.04; airway rejection scores: 1.3 +/- 0.7 vs 2. 3 +/- 0.8, respectively; P =.02). The amelioration of acute rejection was temporary and decreased by postoperative day 7. CONCLUSIONS: The feasibility of using gene transfer techniques to introduce novel functional genes in the setting of lung transplantation is demonstrated. In this model of rat lung allograft rejection, gene transfer of transforming growth factor-beta1 resulted in temporary but significant improvements in lung allograft function and acute rejection pathology.

Acute Disease↗

PubMed1975

[Late results of replacement of the antrio-ventricular valve].

From 1966 to 1969 mitral-valve-allografts have been implanted for mitral valve replacement in 11 and for tricuspid valve replacement in two patients. Three patients died immediately after the operation. Eigth allografts in mitral position and one in tricuspid position functioned well. One case was complicated by candida albicans. There were no thromboembolic complications. Long-term follow up revealed late deterioration of allograft function in every case. Four allografts have been replaced four are still functioning four to six years postoperatively. Because of the poor durability of the results this method of mitral valve replacement is not used any more.

Adult↗

PubMed2005

Perturbation of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 results in differential outcomes in cardiac vs islet allograft survival.

BACKGROUND: Various studies indicate the requirements for tolerance induction may vary between different transplanted tissues and organs. Consequently, we compared the efficacy of anti-leukocyte function-associated antigen-1 (LFA-1)/anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody therapy for facilitating cardiac vs islet long-term allograft acceptance in mice. METHODS: BALB/c (H-2d) mouse cardiac or islet allografts were transplanted into recipient CBA/J (H-2k) mice. Monoclonal anti-body therapy with anti-LFA-1, anti-ICAM-1, the combination, or control rat immunoglobulin (Ig) was administered intraperitoneally on Days 0 to 5. Cardiac allograft function was assessed by palpation and islet graft function by blood glucose monitoring. Mixed lymphocyte assays were performed to assess proliferation of CD4 and CD8 T-cells under conditions of stimulator-cell ICAM-1 and/or LFA-1 deficiency. RESULTS: Anti-ICAM-1 therapy resulted in a modest prolongation of cardiac allografts but in pronounced survival of islet allografts. Anti-LFA-1 therapy promoted significant long-term survival of both cardiac and islet allografts. Surprisingly, combined anti-LFA-1/anti-ICAM-1 therapy abrogated long-term islet, but not cardiac, allograft acceptance relative to either monotherapy. Mixed lymphocyte reactions demonstrated complete blockade of CD4 and CD8 T-cell proliferation under conditions of ICAM-1 deficiency alone or in combination with anti-LFA-1 therapy. CONCLUSION: These results indicate that optimal therapies for some allografts (vascularized-heart) may not translate to other types of allografts (cellular-islet). Thus, the type of transplant represents an independent variable for optimizing strategies to promote indefinite allograft acceptance. Complete inhibition of CD4 and CD8 T-cell proliferation during ICAM-1/LFA-1 blockade suggests a threshold signal may be dependent upon ICAM-1/LFA-1 for regulatory tolerance to occur and that this signal may be lost under conditions of minimal graft cellular mass.

Animals↗

PubMed2001

Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is the principal cause of late renal allograft failure. This complex process is multifactorial in origin, and there is good evidence for immune-mediated effects. The immune contribution to this process is directed by CD4(+) T cells, which can be activated by either direct or indirect pathways of allorecognition. For the first time, these pathways have been simultaneously compared in a cohort of 22 longstanding renal allograft recipients (13 with good function and nine with CAN). CD4(+) T cells from all patients reveal donor-specific hyporesponsiveness by the direct pathway according to proliferation or the secretion of the cytokines IL-2, IL-5, and IFN-gamma. Donor-specific cytotoxic T cell responses were also attenuated. In contrast, the frequencies of indirectly alloreactive cells were maintained, patients with CAN having significantly higher frequencies of CD4(+) T cells indirectly activated by allogeneic peptides when compared with controls with good allograft function. An extensive search for alloantibodies has revealed significant titers in only a minority of patients, both with and without CAN. In summary, this study demonstrates widespread donor-specific hyporesponsiveness in directly activated CD4(+) T cells derived from longstanding recipients of renal allografts, whether they have CAN or not. However, patients with CAN have significantly higher frequencies of CD4(+) T cells activated by donor Ags in an indirect manner, a phenomenon resembling split tolerance. These findings provide an insight into the pathogenesis of CAN and also have implications for the development of a clinical tolerance assay.

Adult↗

PubMed2003

FK778, a powerful new immunosuppressant, effectively reduces functional and histologic changes of chronic rejection in rat renal allografts.

BACKGROUND: FK778 is a new derivative of the active leflunomide metabolite A77 1726. It effectively prevented acute allograft rejection in several experimental transplant models, and it is currently in phase II trials in human transplant recipients. In this study, we examined the effects of FK778 in a well-established model of chronic renal allograft rejection in the rat. METHODS: Kidneys of Lewis (LEW) and F344 rats were orthotopically transplanted into bilaterally nephrectomized LEW recipients as the isograft and allograft control, respectively. Allograft recipients were orally administered FK778 at doses of 3 mg/kg per day, 10 mg/kg per day, and 20 mg/kg per day for 10 days. Blood and 24-hr urine samples were collected once a week after grafting for plasma creatinine, allo-specific antibodies, and proteinuria determination. Kidney grafts were harvested on the 90th day after transplantation and subjected to histologic, immunohistologic, and reverse transcriptase-polymerase chain reaction analysis. Histologic sections were semiquantitatively scored using criteria adapted from the Banff' classification for transplant pathologic conditions. RESULTS: Recipients treated with FK778 for 10 days exhibited a dose-dependent decrease in proteinuria and plasma creatinine for the entire 90-day period after transplantation when compared with the allograft control. FK778, at doses of 10 mg/kg per day and 20 mg/kg per day, remarkably reduced chronic histologic changes, including tubular atrophy, glomerulosclerosis, fibrointimal hyperplasia, and transplant glomerulopathy. In addition, FK778 treatment was associated with decreased intragraft mononuclear cell infiltration, serum allo-specific immunoglobulin (Ig)M and IgG antibody production, and intragraft transforming growth factor beta messenger RNA expression in those recipients surviving 90 days after transplantation when compared with the allograft control. CONCLUSION: FK778 effectively reduces functional and histologic chronic kidney allograft rejection in the rat.

Alkynes↗