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The influence of presensitization on graft survival rate.

Graft survival rate was evaluated in 61 recipients with greater than 50 percent frequency of performed antibodies to selected panel cells. This includes recipients of primary cadaver grafts, secondary cadaver grafts, and living related grafts. Graft survival rate also was evaluated in 199 recipients with pretransplant antibodies reacting with 10 to 50 percent of panel cells and in nonsensitized patients. The results show that good graft survival can be obtained in many hyperimmunized patients, particularly in recipients of primary renal allografts (66 percent cadaver graft survival rate at 2 years). However, sensitization following rejection of an allograft appears to confer a less favorable prognosis. The nature of recipient presensitization and the precise specificity of each reactivity cannot always be explained. This is exemplified in three patients in whom broadly reactive lymphocytotoxic antibodies were not directed against HL-A antigens. Since the number of sensitized patients who await renal transplantation is increasing, there should be no hesitation in proceeding with transplantation, particularly with primary grafts. Emphasis, however, must be placed on frequent prospective recipient serum sampling so that transient high levels of cytotoxins do not escape detection and therefore can be easily selected out for cross-matching against potential donors.

Antibodies

Cytomegalovirus infection and graft survival in renal graft recipients.

We have studied 85 patients who received a renal transplant for CMV infection as well as for herpes simplex (HSV), herpes zoster (HZ), measles, mumps, rubella and hepatitis B. We found no evidence of primary or secondary infections for the non herpetic viruses except for hepatitis B infection that occurred in 17 per cent of the patients. CMV infection occurred in 87 per cent of the patients while antibody rises to HZ and HSV occurred in 30 and 13 per cent of the patients, respectively. The CMV infections occurred 2 to 4 months after the transplantation (mean time 11.1 weeks) and seemed to trigger the first episode of renal rejection that occurred earlier in the CMV infected group (mean time 12.1 weeks) than in the uninfected group (mean time 18.6 weeks). This difference in time is highly significant, p less than 0.001). However these CMV injections did not decrease the longterm survival of the grafted kidneys.

Adult

The use of linear models to investigate the "centre effect" on graft survival.

First cadaver graft survival at 90 days in six UK centres was analysed, and found to differ widely between the centres (p less than 0.0005). Linear models were used to test whether these differences could be explained by other factors known to influence graft survival, such as age of recipients, tissue typing, blood group matching or year of graft. Adjusting for these factors singly and in various combinations did not reduce the significance of the "centre effect". These results held good both when deaths with a functioning graft within 90 days were treated as exclusions and also when they were treated as graft failures.

Aging

Influence of previous immunization on skin graft survival.

The results of skin grafts transplanted in immunized and nonimmunized recipients was analysed. Specific sensitization for HLA-A or B determinants shortens graft survival if the recipients were immunized by s.c. injections of leukocytes. When the recipients had been pregnant, no such influence of specific HLA-A or B sensitization could be demonstrated. The variance in mean survival times of grafts exchanged between mixed lymphocyte culture (MLC)-positive donor-recipient combinations was significantly smaller than the variance in mean survival time (MST) of grafts exchanged between MLC-negative combinations. This difference could be the result of the influence of allograft immune-activating determinants of different strength in the MLC-negative donor-recipient combinations. Also the variance in MST of grafts in immunized recipients was significantly larger than the variance in MST of grafts in nonimmunized recipients. Apart from the obvious effect of HLA-A and B sensitization, other less well documented factors must have influenced graft survival. We did not find evidence for a graft enhancing effect of B cell-specific antibodies.

Antibodies

Blood transfusions, cytotoxic antibodies, and kidney graft survival. Preliminary results of a systematic transfusion protocol.

Since pretransplant blood transfusions have been shown to prolong the survival of kidney grafts, a new transfusion policy has been started in the frame of Swisstransplant. Before surgery all patients receive at least two and, if possible, five transfusions (whole blood or packed red blood cells). The present study includes 101 recipients of primary cadaver grafts. Of these, 41 were transfused regularly according to the new protocol, 46 had irregular transfusions because of therapeutic necessity, and 14 had no transfusion before grafting. The 1-year survival rate in pretransfused patients was over 70% as compared to 45% in the nontransfused group. There was no significant association with the number of transfusions, but a slight improvement in graft survival was seen in patients deliberately transfused when compared with those transfused because of severe anaemia. A delay of more than 3 months between the last transfusion and transplantation significantly decreased graft survival at 6 months (84 versus 58%; P less than 0.02). The occurrence of cytotoxic antibodies, both antiperipheral blood lymphocytes (PBL) and anti-B cell antibodies, was investigated in relation to the number of transfusions received. Broad-spectrum anti-PBL antibodies (greater than 50% of random panel) were found in 5 of 74 patients transfused according to the protocol (7%) and in 15 of 93 patients transfused for severe anaemia (16% P, not significant). Of 71 recipients followed up for 6 months, 15 (21%) produced anti-PBL antibodies with limited specificity (less than 50%), and 4 (6%) produced broad-spectrum antibodies. Anti-B cell antibodies (less than 50%) were produced in 21 of 64 patients (33%). Six patients (9%) had broad-spectrum activity. The occurrence of these antibodies was not associated with the number of transfusions received and did not significantly influence the graft survival at 6 months. The change in transfusion policy seems to have improved graft survival without producing strong presensitization in a prohibitive proportion of the patients on hemodialysis.

Antilymphocyte Serum

Long-term haemodialysis-an enhancing factor for cadaveric graft survival.

In 220 consecutive cadaveric kidney transplants, graft survival in patients dialysed for a period of two years or longer was significantly greater than in those dialysed for less than two years. More blood transfusions were received and the formation of HLA antibodies was greater in the group dialysed for more than two years. A positive cross match was the basis for excluding 21% of the HLA positive patients from transplantation during a one year period of observation. When these same HLA positive patients had more than two subsequent opportunities for donor-recipient selection the exclusion rate dropped to 2%. The longer period of dialysis with more blood transfusions had a favourable influence on cadaveric graft survival whereas the formation of HLA antibodies had a negative influence. Even in HLA positive patients graft survival was better in the long-term dialysis group when compared with the group dialysed for a shorter period. These results suggest that longer dialysis with more blood transfusions represents an enhancing factor for cadaveric kidney grafts.

Blood Transfusion

Immunologic factors determining survival of cadaver-kidney transplants. The effect of HLA serotyping, cytotoxic antibodies and blood transfusions on graft survival.

We assessed immunologic factors determining graft survival in 510 recipients of primary cadaver allografts at one center. The degree of HLA match grade did not directly affect graft survival (54 per cent in no-antigen match, and 42 per cent in three-antigen match, at two years). There was no correlation between the HLA match grade and the degree of stimulation of the mixed lymphocyte culture. Patients receiving more than five blood transfusions had a significantly better graft survival than nontransfused recipients (52 versus 23 per cent, respectively, at two years, P less than 0.001). The beneficial effect of transfusions was noted whether or not lymphocytotoxic antibodies were produced, provided adequate screening was performed before transplantation. Transfusions did not alter the degree of stimulation in the mixed lymphocyte culture. More liberal use of transfusions and frequent screening for cytotoxic antibodies would probably result in more effective cadaver-kidney transplantation.

Blood Transfusion

Differential kidney graft survival associated with interaction between recipient ABO group and pretransplant blood transfusion.

In 1973 we reported significantly superior survival of kidneys transplanted to blood group O recipients compared with recipients of those from blood groups A, B, and AB taken together. In this extended series, the difference between these categories was less prominent and no longer significant. In the present study, blood transfusion significantly improved the survival of kidney grafts in patients of blood group O, but not of combined A, B. and AB groups. The difference between the graft protecting effect of transfusion in group O and combined groups A, B, and AB recipients was also significant. This suggests that the improvement in subsequent graft survival after transfusion is either confined to blood group O recipients, or is much stronger in them than in recipients of other groups. Our previous policy of restriction of blood transfusion is seen as one of the causes of the reduced superiority of group O over other groups in this extended series in comparison with our 1973 series. It seems that transfusion of group O recipients can markedly improve the prognosis of a subsequent first kidney graft.

ABO Blood-Group System

Transfusion and kidney graft survival in Finland.

The influence of blood transfusions prior to kidney transplantation on graft survival was analyzed in a series of 406 first transplantations, including 321 necro-kidneys. Among the 131 females with necrokidneys, 14 had not been pregnant or received transfusions, neither had 70 of the 190 male necrokidney recipients been transfused. In comparison with these controls, a slightly better graft survival was observed in the "immune-triggered" patients, especially in those with no detectable lymphocytotoxic antibodies before transplantation, and more markedly in female than in male patients. The effect of pregnancies seemed the same as that of transfusions. The age and pretransplantation dialysis treatment of the recipient appeared irrelevant to graft survival. "Immune-triggering" slightly improved graft survival also in the living donor category.

Blood Transfusion

Association of graft survival with host response to hepatitis B infection in patients with kidney transplants.

We studied the relation of host response to hepatitis B infection before transplantation with survival of kidney grafts in 79 patients receiving 87 transplants. Antibody to hepatitis B surface antigen (anti-HBs) signaled early graft rejection (median survival congruent to two months), whereas hepatitis B surface antigen (HBsAg) signaled delayed rejection (greater than 22 months). Patients with neither HBsAg nor anti-HBs had graft survival times (median congruent to 16 months) similar to the HBsAg carriers but significantly longer than the anti-HBs-positive patients (p less than 0.01). Similar results were observed when patients who received HLA-identical kidneys or had anti-HLA antibodies before transplantation were excluded. The highest probability of graft rejection was in patients with anti-HBs who received kidneys from male donors. The probability that such grafts would survive for four months was less than 20 per cent. HLA-nonidentical kidneys transplanted into patients with anti-HBs have a poor prognosis, whereas such grafts in HBsAg carriers have as good a prognosis as grafts in uninfected recipients.

Antibodies, Viral

Influence of HLA-A, B, C, and D matching and pretransplant blood transfusions on kidney graft survival.

A significant influence of matching both for the HLA-A and B and the D/DR antigens on graft survival in patients transplanted with kidneys from living related or cadaveric donors is demonstrated. A generally reduced survival of cadaveric grafts during the last few years may at least in part be explained by the use of more three and four antigen-mismatched donors. The beneficial effect of pretransplant blood transfusions on graft survival in our material is almost nulled when uremic patients, dying while waiting for a transplant, are also considered. In addition, significantly more high-risk patients are included in the nontransfused patient group.

Blood Transfusion

The influence of donor age on graft survival.

Recent papers report differing conclusions concerning use of kidneys from different donor age groups. We analyzed graft survival of 652 consecutive cadaver kidney donor-recipient pairs. Overall cumulative graft survival was 45 per cent at two years post transplantation. Kidneys from donors aged less that fifteen, sixteen to thirty. thirty-one to forty-five, and forty-six to sixty years had a cumulative graft survival of 51, 44, 39, and 40 percent, respectively. The difference is not statistically significant. When both donor and recipient ages are controlled, the pediatric aged kidney may be superior in the pediatric recipient or the older normotensive adult recipient. Use of properly selected cadaver kidneys in patients of all age ranges is encouraged.

Adolescent

HLA typing and primary cadaver graft survival.

Analysis of 463 consecutive primary cadaver renal transplants showed no influence of HLA match grade on renal allograft survival. Additional categorization according to HLA match grade and degree of presensitization again showed no correlation between match grade and graft survival. Mismatches and matches of specific antigens, cross-reacting groups of antigens, and effect of matching at both locus A and B were also evaluated. There was no significant effect on graft survival except when mismatches against donor A2 and cross-reacting group A2, A28 occurred. A trend toward better graft survival was suggested in recipients matched for A9 and cross-reacting group A9, Aw 23, Aw 24. Although HLA match grade did not influence ultimate graft survival, HLA typing remains important, especially to avoid mismatch against donor A2 antigen. In addition, subsequent detection of new specificities, particularly in other than the A and B loci, may provide significance in the future.

Cadaver

Correlation between magnitude of MLC and kidney graft survival in intrafamilial transplantation.

The role of HLA-A and-B and HLA-D compatibility was analyzed in 63 recipients of intrafamilial kidney grafts. At 1 year post-transplantation the survival of grafts from HLA-A and-B compatible donors was 89% and that of grafts from HLA-A and/or-B incompatible donors 77%. Recipents with a Relative Response (RR) in MLC of less than 20% towards their donors, indicating HLA-D compatibility, had a 4-year graft survival of 100%. After 1 year the graft survival of this group was statistically different (p less 0-01) from the 63% graft survival of recipients with an RR greater than 60%. An RR greater than 60% indicates HLA-D incompatibility between recipient and donor. For patients with RR less than 60% the 2-year graft survival was 46%. This was lower than that of patients with RR less than 20% (P less than 0.001) and that of patients with an RR of 20--60% (P less than 0.01). The recipients with an RR of 20--60%, indicating slight HLA-D incompatibility with their donors, had a 2-year graft survival of 88%. We concluded that graft survival was correlated to the magnitude of MLC response between recipients and donors in such a way that a high MLC response indicating HLA-D incompatibility was associated with a high frequency of graft rejection while a low MLC response was associated with graft survival. HLA-D compatibility correlated with an excellent outcome in five cases in spite of HLA-A and-B incompatibility.

Adult

[Prolonged renal graft survival after repeated blood transfusions (author's transl)].

In order to investigate the influence of pretransplant blood transfusions on renal graft survival, the results in 43 recipients with 10 or more transfusion (group A) were compared with those in 48 recipients with less than 10 or no transfusions (group B). In both groups cadaveric kidneys with mainly 3 or more mismatched histocompatibility antigens were transplanted. The incidence of preformed cytotoxic antibodies was similar in both groups (25.6% and 22.9%, respectively). The cumulative renal graft survival rate was significantly higher in the poly-transfused group: 85.6% +/- 6.1% and 73.4 +/- 7.9% after 1 and 2 years, respectively, in group A in comparison with 73.9 +/- 6.6% and 63.3 +/- 8.1% after 1 and 2 years respectively, in group B (Wilcoxon rank sum test: p less than 0.05). Severe renal rejection with a serum creatinine above 3 mg/100 ml was more frequently observed in group B than in group A. Enhancement due to blocking antibodies must be assumed as a possible explanation for the favourable effect of repeated pretransplant transfusions on graft survival rates.

Antibodies

Improvement of kidney-graft survival with increased numbers of blood transfusions.

In a study of 1360 cadaver-donor kidney transplants we found a striking correlation of increased numbers of pretransplant blood transfusions with improved transplant survival (P less than 0.0001). Graft survival rate in recipients with greater than 20 transfusions was 71 p5 per cent at one year as compared with 42p2 per cent for recipients with no transfusions; at four years the survival rates were 65p5 per cent and 30p3 per cent (P less than 10(-6). Frozen blood was less effective than nonfrozen blood in producing this effect. In contrast to previous reports based on fewer numbers of transplants, a single pretransplant transfusion of transfusions given during transplantation had no statistically significant influence on graft outcome. The beneficial effect of pretransplant transfusions was apparent at transplant centers with high or low overall success rates. Deliberate transfusion trials in prospective transplant recipients should consider this strong dose dependence of graft prolongation by transfusions.

Antibodies

[Prolonged renal graft survival induced by blood transfusion (author's transl)].

All renal allotransplants performed at the Cantonal Hospital, Zurich, in 1975 and 1976 were analysed with respect to pre-transplant blood transfusions, excluding secondary transplants, patients on dialysis outside of Switzerland, combined renal and pancreatic transplants, and women with previous pregnancies but without transfusions. Among 72 patients left for analysis there were 16 who had never received any pre-transplant blood transfusion. Their graft survival was much worse (one-year graft survival 36%) than that in patients with previous transfusions (one-year graft survival 70--80%). Patients without previous blood transfusion should, therefore, no longer be admitted for renal transplantation.

Blood Transfusion