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Biomedical subjects

A J Matas

Publications and source records attributed to A J Matas.

At least 109 records · Page 6Linked to original sources
PubMed1996

Does re-exposure to mismatched HLA antigens decrease renal re-transplant allograft survival?

UNLABELLED: We analyzed 420 kidney retransplants at the University of Minnesota, 87 of which did and 333 which did not share HLA mismatches with the previous transplant. There was no difference in outcome. We conclude that exceptions to routine HLA matching policies do not have to be made for kidney retransplants. OBJECTIVE: To determine if the kidney graft functional survival rate for retransplants is influenced by presence of HLA mismatches in common with the previous (failed) transplant. SUMMARY BACKGROUND DATA: Kidney retransplants have a lower function rate than primary grafts. An anamnestic response to HLA antigens shared with the previous donor could be one factor responsible, but reports in the literature are conflicting. METHODS: Of 420 kidney retransplants with HLA information done at the University of Minnesota, 87 shared > or = 1 HLA antigens specifically mismatched with the previous donor (63 cadaver and 24 living donor retransplants), while 333 did not (247 cadaver, 86 living donor). Patient and graft survival rates were calculated by life-table analysis for recipients with vs. without repeat mismatches, with the significance of differences determined by the Lee-Desu statistic. RESULTS: Patient and kidney graft retransplant survival rate curves were not significantly different (p > or = 0.41) for those exposed or not exposed to the same HLA mismatches as before. At 2 years, 70% vs. 61%, respectively, of cadaver grafts and 71% vs. 78%, respectively, of living donor grafts were functioning. CONCLUSIONS: The probability of a successful outcome with a kidney retransplant is no different for patients who do than for those who do not receive an organ sharing HLA mismatches with the previous donor. Exceptions to routine HLA matching policies do not need to be made for kidney retransplants.

Cadaver↗
PubMed1996

[Technical options of renal transplant in the absence of a viable ilio-caval venous circuit. Presentation of a case and review of the literature].

Congenital absence of useful ilio-caval venous segment is a very infrequent congenital anomaly and makes unfit grafting of a kidney transplant in iliac fossa. We report the case of a 18 years old male affected by this abnormality who was transplanted in intraabdominal situation. We review technical alternatives offered by the literature.

Adolescent↗
PubMed1996

The importance of early cyclosporine levels in pediatric kidney transplantation.

We studied the impact of early cyclosporine (CSA) levels on the incidence of rejection in pediatric transplant recipients. Between 1 January 1984 and 31 December 1994, a total of 234 pediatric patients underwent kidney transplants and received CSA immunosuppression. We analyzed the impact of CSA levels (at 1 wk, 2 wk, 1 month, 2 months, and 3 months) on the incidence of rejection in the first 3 and the first 6 months post-transplant. We found that CSA levels at all timepoints correlated, i.e. recipients with low levels in the early post-transplant period tended to have low levels throughout the first 12 months. Multivariate analysis for risk factors by biopsy-proven rejection in the first 3 months revealed that the CSA trough level was the critical factor (p < 0.05). Recipients with CSA trough levels < 100 ng/ml had 2.24 times the risk of rejections vs. those with blood levels > 100 ng/ml. Similarly, the CSA trough level at 1 month was the critical risk factor for biopsy-proven rejection within the first 6 months (p < 0.05). The major risk factor for graft loss within the first 12 months was a biopsy-proven rejection episode. We conclude that in pediatric kidney transplant recipients, early CSA trough levels < 100 ng/ml are associated with a significantly increased incidence of rejection in the first 6 months post-transplant.

Adolescent↗
PubMed1996

A third kidney transplant: cost-effective treatment for end-stage renal disease?

Given the organ donor shortage, some question whether a third kidney transplant can be justified. We studied the outcome of 51 third transplants (mean age 28 +/- 2 yr) done between 1 January 1985 and 31 December 1994. We compared hospital stay (mean +/- S.E.), cost, readmissions, readmission days, and outcome of third (vs. first and second) transplants. We found that patient survival for third transplants was equivalent to first and second transplants; graft survival was not as good. However, when third transplant recipients with recurrent disease (specifically, hemolytic uremic syndrome and focal sclerosis) were excluded from our analysis, we found no difference in 5-yr graft survival (vs. first or second transplant recipients). Of the 51 third transplant recipients, 41 had a cadaver donor transplant. Third cadaver transplant recipients tended to have a longer hospital stay (p = NS) than first cadaver transplant recipients but had no more readmissions or readmission days than first and second cadaver transplant recipients. Employment data are available for 28 third transplant recipients; 16 (57%) are currently working or going to school. Of the 21 recipients who responded to quality of life questionnaires, 17 (81%) reported being healthy and all 21 (100%) said transplantation was not a drawback to their health. We conclude that third transplants should be considered for selected patients with renal failure whose first and second transplants have failed. Such patients can often be successfully transplanted.

Actuarial Analysis↗
PubMed1995

Chronic renal allograft rejection in the first 6 months posttransplant.

Between May 1, 1986 and May 31, 1992 at the University of Minnesota, we interpreted 129 renal allograft biopsy specimens (done in 48 grafts during the first 6 months posttransplant) as showing changes consistent with chronic rejection. For this retrospective analysis, we reexamined these biopsies together with clinical information to determine: (a) whether a diagnosis other than chronic rejection would have been more appropriate, (b) how early posttransplant any chronic rejection changes occurred, and (c) if the diagnosis correlated with outcome. We found that (1) chronic rejection is uncommon in the first 6 months posttransplant; it was documented in only 27 (2.4%) of 1117 renal allografts and was preceded by acute rejection in all but 3 recipients (for these 3, the first biopsy specimen showed both acute and chronic rejection). (2) Chronic vascular rejection was seen in 1 recipient as early as 1 month posttransplant; the incidence increased over time and was associated with an actual graft survival rate of only 35%. (3) The most frequent cause of arterial intimal fibrosis in the first 6 months posttransplant was arteriosclerotic nephrosclerosis (ASNS) of donor origin. Long-term graft function for recipients with ASNS was 67%. (4) Early-onset ischemia or thrombosis was seen in 14 recipients and predicted poor outcome: only 35.7% of these recipients had long-term graft function. (5) Cyclosporine (CsA) toxicity was implicated in only 3 recipients, who had mild diffuse interstitial fibrosis in association with elevated CsA levels. Other variables (including systemic hypertension, urinary tract infection, obstructive uropathy, neurogenic bladder, cobalt therapy, and recurrent disease) were not significantly associated with chronic renal lesions in the first 6 months posttransplant. A significant number of biopsies were originally interpreted as showing chronic rejection, but the diagnosis was changed upon reevaluation in conjunction with clinical data. We conclude that many factors coexist to produce chronic lesions in biopsies during the first 6 months posttransplant, so clinical correlation is needed before establishing a diagnosis of chronic rejection.

Adolescent↗
PubMed1995

Organ-specific patterns of donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in lung, kidney, and liver transplant recipients.

Although their relative importance and interaction are unclear, donor antigen(Ag)*-specific hyporeactivity and allogeneic microchimerism have been associated with improved long-term graft outcome and a lower incidence of chronic rejection in solid organ transplant recipients. We have postulated that a critical level of donor antigen, for a critical time period, is necessary to develop and maintain donor antigen-specific hyporeactivity; both the level and the time may differ by organ transplanted. In our current study, we tested donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in liver and kidney recipients and compared these values with our previous findings in lung recipients. We tested 25 liver recipients at 12 to 29 months posttransplant: 10 (40%) had developed donor antigen-specific hyporeactivity; 5 (20%), peripheral blood allogeneic microchimerism. For all but 1 of the chimeric and hyporeactive recipients, the level of donor cells was very low (< 1:20,000). Five hyporeactive recipients and all 15 donor antigen-responsive recipients did not have detectable levels of peripheral blood microchimerism. No chronic rejection has developed in any of these recipients to date--however, a lower incidence of acute rejection was observed for those recipients with donor antigen-specific hyporeactivity (30% versus 60% without) or with peripheral blood allogeneic microchimerism (20% versus 55% without) (P = ns). These results differ from our previous findings in 19 lung recipients: at 12 to 18 months posttransplant, 35% of them had developed donor antigen-specific hyporeactivity; 47%, peripheral blood allogeneic microchimerism. All donor antigen-specific hyporeactivity recipients as well as some donor antigen-responsive recipients had peripheral blood allogeneic microchimerism. We expanded our current study to include 26 recipients and a quantitative estimate of the level of allogeneic microchimerism. We observed that the hyporesponsive recipients tended to have higher levels of donor cells in their peripheral blood (> 1:6,000) than did the responsive recipients. We previously reported that 22% of kidney recipients had developed donor antigen-specific hyporeactivity at 12 to 18 months posttransplant. In our current study of 33 kidney recipients, we observed peripheral blood allogeneic microchimerism in 7 (21%) at 12 to 18 months posttransplant. The level of donor cells was very low (approximately 1:75,000), with no correlation between donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism at the time point tested. These studies emphasize the organ-specific nature of the development of donor antigen-specific hyporeactivity and the persistence of peripheral blood allogeneic microchimerism. Donor antigen-specific hyporeactivity correlates with very low levels of donor cells in liver recipients, while a higher critical level of donor cells is important in lung recipients. Additional sequential early posttransplant studies are necessary to further define the possible interrelationship between donor antigen and the development and maintenance of donor antigen-specific hyporeactivity.

Antigen Presentation↗
PubMed1995

Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The multivariate analysis.

The impact of delayed graft function on outcome after cadaver renal transplantation has been controversial, but most authors fail to control their analyses for the presence or absence of rejection. We studied 457 adult recipients of primary cadaver allografts at a single institution during the cyclosporine era. All patients received sequential immunosuppression. The incidence of delayed graft function (defined as dialysis being required during the first week after transplant) was 23%. There was a significant association between delayed graft function and cold ischemia time > 24 hr (P = 0.0001) and between delayed graft function and the occurrence of at least one biopsy-proven rejection episode (P = 0.004). Actuarial graft survival was not significantly different when comparing delayed graft function versus no delayed graft function for patients without rejection (P = 0.02). However, it was significantly worse for patients with both delayed graft function and rejection versus those with delayed graft function but no rejection (P = 0.005), as well as for grafts preserved > 24 hr versus < or = 24 hr (P = 0.007). By multivariate analysis, delayed graft function per se was not a significant risk factor for decreased graft survival for patients without rejection (P = 0.42). In contrast, rejection significantly decreased graft survival for grafts with immediate function (relative risk = 2.3, P = 0.0002), particularly in combination with delayed graft function (relative risk = 4.2, P < 0.0001). While cold ischemia time > 24 hr was also a significant risk factor (relative risk = 1.9, P = 0.02), other variables (preservation mode, 0 HLA Ag mismatch, age at transplantation, gender, diabetic status, and panel-reactive antibody at transplantation) had no impact on graft survival. Patient survival was significantly affected by the combination of delayed graft function and rejection (relative risk = 3.1, P < 0.0001), age at transplantation > 50 years (relative risk = 2.6, P < 0.0001), and diabetes (relative risk = 1.8, P = 0.006). Further studies are necessary to elucidate the mechanisms linking delayed graft function and rejection, which, in combination, lead to poor allograft outcome.

Adult↗
PubMed1995

Retransplantation after renal allograft loss due to noncompliance. Indications, outcome, and ethical concerns.

Noncompliance is increasingly recognized as a major cause of renal allograft loss, but the results of retransplantation of such patients have never been described. At our center, 52 of 3525 kidney recipients between June 1, 1963 and December 31, 1993 lost their graft due to overt noncompliance. Of these, 14 (27%) underwent retransplantation after thorough interdisciplinary evaluation. All but 1 patient had returned to dialysis before retransplantation. Of the retransplanted grafts, 2 were lost (1 technical failure, 1 chronic rejection in a compliant patient); both recipients were retransplanted once again. Currently, all retransplanted patients are alive and have a functioning graft. We conclude that for selected patients with graft loss due to noncompliance excellent results can be achieved with retransplantation. However, the issue of retransplanting previously noncompliant patients in the face of a significant donor organ shortage requires public debate.

Adolescent↗
PubMed1995

Beyond hyperacute rejection. Accelerated rejection in a discordant xenograft model by adoptive transfer of specific cell subsets.

If hyperacute rejection is prevented in the guineapig (GP)-to-Lewis rat (Lew) cardiac xenograft (CXg) model, an accelerated rejection involving cellular infiltration occurs in 3 to 4 days. In previous work using an adoptive transfer model, we found that this accelerated rejection was facilitated by either sensitized splenocytes or sensitized serum. In the current study, in an attempt to determine which splenocyte subset(s) facilitated this process, sensitized splenocytes, with or without subset depletion were injected, into complement- and natural antibody-depleted Lew recipients of GP CXgs. Graft survival was 4.18 +/- 0.75 days with no injection (n = 11), 4.13 +/- 0.99 days with naive splenocytes (n = 8), 1.80 +/- 0.45 days with sensitized splenocytes (n = 5), 2.67 +/- 1.03 days with CD4(W3/25+) depletion of the sensitized splenocytes (n = 6), 3.13 +/- 0.84 days with CD8(OX8+) cell depletion (n = 8), 4.70 +/- 0.68 days with macrophage depletion (n = 10), and 4.22 +/- 0.41 days with B cell depletion (n = 9). Cellular infiltrates, hemorrhage, myocyte necrosis, and endothelial deposition of IgG, IgM, and fibrin were seen in rejected grafts. In most groups, infiltrating cells consisted of CD4 (W3/25+), CD8 (OX8+), IL2R+ cells, macrophages, and natural killer (NK) cells. However, in the macrophages-depleted group, activated (ED2+) macrophages and NK cells were significantly reduced. Total IgM, anti-GP IgM, and anti-GP IgG rebounded in all groups over several days but were not consistent at the time of rejection. Lewis rats rejecting GP CXgs early had lower final titers than those rejecting later. Total IgG titers rebounded to baseline by posttransplant day 1 and were therefore similar in all groups at the time of rejection. These findings suggest that this accelerated rejection requires interaction between macrophages and B cells, since depletion of either significantly alters the rejection tempo. A possible explanation is that xenoreactive IgG antibodies, synthesized by sensitized B cells, bind their target antigens--but also bind sensitized macrophages through their Fc region, thus causing rejection by antibody-dependent cell-mediated cytotoxicity.

Acute Disease↗
PubMed1995

Prolongation of renal allograft survival in a large animal model by oral rapamycin monotherapy.

We assessed the efficacy of 5 dose levels of oral rapamycin for prolonging renal allograft survival in pigs. Untreated and triple therapy groups (cyclosporine, azathioprine, and prednisone) served as controls. Immunosuppression was administered for 28 days posttransplant and then stopped. Rapamycin whole-blood concentrations were followed weekly. Chemistry, hematology, and lipid values were monitored post-transplant. For rapamycin-treated pigs, median survival time (MST) correlated with both dose and trough levels (ng/ml). All kidneys had some degree of rejection seen on necropsy. After rejection, pneumonia was the most common cause of death. No specific end-organ toxicity was noted on histopathologic examination. Triglyceride and cholesterol levels increased in all treated pigs (both rapamycin and triple therapy) vs. untreated controls--however, all values were within normal limits. Mean ALT levels increased in weeks 2 to 4 in the higher-dose rapamycin groups but returned to baseline in pigs surviving after the drug was stopped. ALT levels did not increase above twice normal in any group. Creatinine levels correlated with the degree of rejection seen on biopsy. We noted no other toxicities. We conclude that rapamycin, given as oral monotherapy, is an effective and safe immunosuppressant in our large animal renal allograft model. Outcome correlated with dose and whole-blood levels.

Administration, Oral↗
PubMed1995

Removal of baboon and human antiporcine IgG and IgM natural antibodies by immunoadsorption. Results of in vitro and in vivo studies.

The safe and effective removal of xenoreactive antibodies in the peritransplant period is likely to be critical for the clinical application of xenotransplantation involving disparate donor species, such as the pig. In an effort to develop an improved method for antibody removal in xenotransplantation, we have studied reusable antihuman antibody (Ig) columns in vitro and in vivo. Two types of columns were tested: (1) an antihuman Ig column containing polyclonal sheep antihuman IgG (heavy- and light-chain-specific) conjugated to sepharose CL-4B (Ig-Therasorb), and (2) an antihuman Ig column using polyclonal antihuman IgM (mu-chain-specific) conjugated to sepharose. Passage of human or baboon plasma through the Ig-Therasorb column resulted in 97.5% and 78.4% mean reductions in total IgG and IgM, respectively. Reductions in total IgG and IgM correlated with lowering of antipig IgG (54-486 fold) and IgM (9-54 fold) antibody titers as assessed by pig endothelial cell ELISA. The ability of the Ig-Therasorb to significantly reduce IgM may be attributed to the light chain specificity of this column. With the anti-IgM column, marked reductions in total (82.6-83.9%) and antipig (27-54 fold) IgM in human and baboon plasma occurred, while levels of total and xenoreactive IgG were slightly affected. Other than a dilutional effect, neither column resulted in significant reduction in albumin, fibrinogen, factor 5, and factor 8. Repeated in vivo use of either column in baboons achieved reductions in IgG and IgM that closely followed the results of our in vitro studies. No subject morbidity or mortality occurred. Use of the Ig-Therasorb column with immunosuppression in two baboons receiving pig renal xenografts achieved sustained reductions in antipig antibodies and prevented hyperacute rejection. Subjects were sacrificed at 11 and 13 days posttransplant with functioning xenografts and were found to have no evidence of vascular xenograft rejection. We conclude that anti-Ig columns represent a safe and effective method for antibody removal, without several of the limitations of other antibody removal techniques. Also, columns appear to be safe for repeated antibody removal in the posttransplant period.

Acute Disease↗
PubMed1995

Antibody removal by column immunoabsorption prevents tissue injury in an ex vivo model of pig-to-human xenograft hyperacute rejection.

Hyperacute rejection of a pig-to-primate organ xenograft is triggered by binding of anti-pig endothelial cell antibodies to the vascular endothelium of the xenograft and complement activation. Xenograft survival can be prolonged by pretransplant depletion of antibody with plasmapheresis or organ perfusion. However, these techniques have disadvantages for use immediately pretransplant or in the post-transplant period, including a marked reduction in coagulation proteins. To remove IgM and IgG from human plasma we employed a reusable Ig-binding column containing polyclonal anti-human IgG (heavy chain- and light chain-specific) conjugated to Sepharose beads (Therasorb, Baxter Corp.). Human blood was separated into plasma and cell fractions. Column absorption of plasma followed by recombination of plasma and cell fractions in the perfusion system resulted in 90.5 and 86.0% reduction in total IgG and IgM, respectively, and in a 47.0 and 69.4% reduction in IgG and IgM anti-pig endothelial cell antibodies, respectively. When the cellular fraction was recombined with untreated plasma and used to perfuse pig hearts in an ex vivo perfusion system, there was rapid cessation of normal cardiac rhythm (25.2 +/- 5.6 min) and intense deposition of Igs, complement proteins, and fibrin in the tissues. In contrast, perfusion with blood containing column-absorbed plasma was able to sustain cardiac function, with normal sinus rhythm maintained for 258 +/- 48.1 min, without tissue deposition of IgM or complement proteins and minimal deposition of IgG. We conclude that column absorption can be used effectively to deplete plasma of anti-pig endothelial cell antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Correlation of donor antigen-specific hyporeactivity with allogeneic microchimerism in kidney and lung recipients.

Our previous studies indicate donor antigen-specific hyporeactivity is a useful marker for identifying solid organ transplant recipients at low risk for immunological complications; the hyporeactive subgroup experiences a lower incidence of chronic rejection. One purpose of the current study was to determine whether hyporeactivity could be identified in pediatric kidney recipients and whether it correlated with improved graft outcome. Of 18 pediatric kidney recipients tested, 6 (33%) had developed donor antigen-specific hyporeactivity. All 18 experienced good graft outcome. Second, we determined whether donor antigen-specific hyporeactivity correlates with peripheral blood microchimerism and outcome in adult kidney recipients. Our previous studies of lung recipients demonstrated development of obliterative bronchiolitis in recipients with microchimerism who remain responsive, but not in recipients who had become hyporesponsive to donor antigen. Preliminary results in our current study of 23 adult kidney recipients indicate microchimerism for 6 (26%): 4 hyporesponsive and 2 responsive to donor antigen. Microchimerism was not detected for 17 recipients: 6 hyporesponsive and 11 responsive to donor antigen. One hyporesponsive/chimeric patient and 4 recipients negative for both parameters have been diagnosed with biopsy-proven chronic rejection. In summary, both hyporeactivity and chimerism are found at a higher frequency in lung than kidney recipients. Unlike lung recipients, not all hyporesponsive kidney recipients had peripheral blood chimerism. Additional numbers are needed to determine if microchimerism correlates with donor antigen-specific hyporeactivity or graft outcome.

Adult↗
PubMed1995

The emergence of xenotransplantation.

The field of transplantation is faced with a growing shortage of human organs as the list of potential recipients continues to increase. Those currently listed can already expect long waits; some die waiting. Xenotransplantation is a potential solution to this widening donor-recipient disparity. Consequently, in recent years, there have been several clinical attempts using organs from nonhuman primates and pigs. The results with nonhuman primates as donors have been encouraging, but it is unlikely that these species will provide a long-term solution to the organ shortage. Most recent xenotransplantation research has therefore shifted to more phylogenetically disparate species, such as pigs, as potential donors. The major barrier to transplantation between members of disparate species combinations has been hyperacute rejection (HAR). The elements of humoral immunity involved in this rejection process include (1) naturally occurring antibodies directed against carbohydrate and other antigens expressed on pig endothelium, and (2) the complement system, which is activated by binding of natural antibodies to their targets. Several elegant strategies to prevent HAR are being developed. The creation of transgenic pigs, whose cells express human regulators of complement activation, is one such strategy. Another promising approach has been to remove antidonor antibodies from the recipient by absorption with some recently characterized carbohydrate epitopes of porcine endothelial xenoantigens. Recent experimental work indicates that HAR can successfully be prevented by inhibition or depletion of complement. A delayed type of xenograft rejection, characterized by endothelial cell antibody deposition and cellular infiltration, occurs over the next three to four days. The likely mechanisms involved in delayed xenograft rejection include antibody-dependent cell-mediated cytotoxicity and the phenomenon of endothelial cell activation.

Animals↗
PubMed1995

Laparoscopic drainage of lymphoceles after kidney transplantation: indications and limitations.

BACKGROUND: Symptomatic lymphoceles are not uncommon after kidney transplantations. Surgical marsupialization with internal drainage is the treatment of choice. However, laparoscopic drainage is reportedly as effective, with only minimal trauma. METHODS: We attempted 14 laparoscopic lymphocele drainages during a 3-year period and studied the indications and limitations, using intraoperative ultrasonography in all cases. RESULTS: Laparoscopic drainage was successful in only 9 (64%) of 14 patients. A conversion to open laparotomy was necessary in five patients; their lymphoceles were lateral and either posterior or inferior to the kidney. Two patients with initially successful laparoscopic drainage required conversion to open laparotomy 21 and 83 days later; their lymphoceles were inferior to the kidney. Laparoscopic drainage shortened the median hospital stay by 4 days versus open surgical drainage and by 7 days versus conversion. Hospital costs for laparoscopic drainage averaged $7400 less versus open drainage and $10,300 less versus conversion. CONCLUSIONS: In patients with symptomatic lymphoceles medial and either superior or anterior to the kidney, laparoscopic drainage under intraoperative ultrasonographic guidance is easy, safe, and effective. It decreases hospitalization, convalescence, and costs. In patients with symptomatic lymphoceles lateral and either posterior or inferior to the kidney, laparoscopic drainage may fail because of anatomic inaccessibility and technical impracticability.

Adolescent↗