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Biomedical subjects

A J Matas

Publications and source records attributed to A J Matas.

At least 163 records · Page 9Linked to original sources
PubMed1994

Pilot evaluation of 15-deoxyspergualin for refractory acute renal transplant rejection.

15-deoxyspergualin (DSG) is a novel immunosuppressant which has been shown to be effective in preventing and treating rejection in animal allo- and xenotransplant models. Preliminary clinical studies suggest that DSG is an effective antirejection agent. In our study, 4 patients with biopsy-proven rejection episodes that were resistant to steroid and antibody therapy were then treated with DSG. All 4 rejection episodes responded to DSG therapy and all 4 kidneys continue to function (follow-up 7-15 months). However, 2 patients had additional rejection episodes after DSG therapy. Side effects during DSG treatment were minimal; 1 patient, who had also had multiple courses of antibody, developed a lymphoproliferative tumor 2 months after DSG administration. We conclude that DSG is effective in treating refractory renal transplant rejection episodes. Additional studies are necessary to determine the ideal place for DSG in treating renal transplants recipients with rejection.

Adolescent↗
PubMed1994

Chronic rejection--definition and correlates.

With current immunosuppressive protocols, the incidence of graft loss to acute rejection has been markedly reduced; however, there has been no change in graft loss to chronic rejection. Recently, attention has been focused on the prevention and management of chronic rejection. Because neither the clinical course nor the biopsy is definitive for the diagnosis of chronic rejection, we believe both should be included in the definition. For kidney transplant recipients, the major risk factor for development of chronic rejection appears to be a previous acute rejection episode. Other risk factors include low-dose maintenance immunosuppression and previous infection. For extrarenal transplant recipients, CMV and HLA mismatch have been implicated. Noncompliance probably plays a role for all patients. Laboratory studies have suggested that the development of chronic rejection (or lack thereof) may be due to an interplay of immunoregulatory factors. Patients with anti-HLA antibodies have an increased incidence of late graft loss whereas those with antiidiotypic antibodies or with donor-specific hyporesponsiveness (in MLC) have improved outcome and less chronic rejection. These findings have led to five testable hypotheses as to the pathogenesis of chronic rejection: 1) chronic rejection is inadequately treated acute rejection; 2) chronic rejection can be prevented by maintaining adequate long-term immunosuppression; 3) preventing or adequately treating infection will prevent chronic rejection; 4) the balance of immunoregulatory factors determines chronic rejection; 5) chronic rejection is the result of noncompliance. Each may play a role in some patients. Clinical and laboratory studies of risk factors and of the influence of intervention are necessary.

Graft Rejection↗
PubMed1994

Prolonged survival without posttransplant immunosuppression in a large animal model.

BACKGROUND: T cells that receive T-cell antigen receptor signals but do not undergo mitosis become unresponsive to subsequent antigenic stimulation. This can be achieved by antigen presentation to T cells in the absence of critical costimulatory signals from antigen-presenting cells (APC) or in the presence of the antiproliferative drug rapamycin. In mice, peritransplant infusion of adherent APC-depleted splenocytes, which do not provide costimulatory signals to T cells in vitro, leads to T-cell unresponsiveness in vivo and specifically prolongs the survival of skin grafts that express the major histocompatibility complex (MHC) molecules expressed by the transfused cells. Our goal was to determine whether in vivo infusion of adherent APC-depleted donor peripheral blood mononuclear cells (PBMC), with or without rapamycin, induces prolonged kidney allograft survival in a large animal model. METHODS: MHC homozygous inbred miniature swine (SLAcc) were transfused with dendritic cell-monocyte-depleted (G10-passed) PBMC (2.5 x 10(8) cells) from MHC disparate SLAdd donors, with and without three peritransfusion infections of rapamycin (0.25 mg/kg/day intramuscularly) the day before, the day of, and the day after the transfusion. SLAcc recipients received an SLAdd kidney transplant 6 days later. No posttransplant immunosuppression was given. RESULTS: In contrast to donor-specific whole blood transfusions, which uniformly resulted in sensitization and hyperacute rejection (less than 1 day), renal allograft survival in animals that received a transfusion of G10-passed PBMC from their eventual kidney donor was similar (mean, 8.1 +/- 4.5 days) to untreated controls (mean, 7.8 +/- 5.0 days). Pretransplant rapamycin alone also had no effect on survival (mean, 7.7 +/- 8.1 days) versus controls. The combination of G10-passed blood and peritransfusion rapamycin, however, increased survival significantly (mean, 27.3 +/- 10.4 days) (p = 0.01 versus untreated recipients or recipients of only G10-passed PBMC; p = 0.03 versus recipients of rapamycin alone). CONCLUSIONS: Pretransplant transfusion with costimulator-deficient donor PBMC plus peritransfusion rapamycin treatment, but neither alone, prolongs renal allograft survival in pigs without posttransplant immunosuppression. This strategy, once optimized, may be applicable to human transplant tolerance.

Animals↗
PubMed1994

Steroid-related complications in the cyclosporine era.

Steroid withdrawal has potential risks (rejection) and benefits (fewer complications). Most data on steroid-related complications predates cyclosporine (CsA). We tabulated the incidence of posttransplant complications considered to be steroid-related in 748 adult kidney transplant recipients (with at least 1 year of follow-up) on CsA and prednisone. Using logistic regression analysis, we considered the effects of pre- and postoperative variables for these complications: cataracts; new-onset post-transplant diabetes; bone/joint complications; avascular necrosis; and posttransplant hypertension. Variables included pretransplant steroid therapy; initial steroid dose; prednisone dose at 1 month and 1 year; steroid-treated rejection episodes; cumulative time on steroids; sex; age; race; pretransplant hypertension; pretransplant diabetes; donor source; nonsteroid treated rejection episodes; other immunosuppressive therapy; cumulative time on dialysis; and previous renal or extrarenal transplants. Cataracts occurred in 21.1%, new-onset posttransplant diabetes in 7.6%, bone/joint complications in 49.9%, avascular necrosis in 5.5%, and post-transplant hypertension in 74.9% of recipients. Significant variables for cataract development were prednisone dose at 1 year (odds ratio [OR] = 1.32; p < 0.05), cumulative time on steroids (OR = 1.65; p < 0.001), age > 50 years (OR = 1.85; p < 0.0001), and pretransplant diabetes (OR = 1.63; p < 0.0001). For new-onset posttransplant diabetes, age > 50 years (OR = 1.63; p < 0.05) and nonwhite race (OR = 2.12; p < 0.001) were significant. For bone/joint complications, cumulative time on steroids was significant (OR = 1.45; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Hyperlipidemia in long-term survivors of pediatric renal transplantation.

The prevalence of hyperlipidemia in adolescents and young adults who are long-term survivors of pediatric renal transplantation with stable graft function has not previously been examined. We studied 33 renal transplant recipients aged 5 to 23 years, who were an average of 7.4 years (range 3 to 11 years) post-transplant. We found hypercholesterolemia in 17 (total cholesterol (TC) > 5.18 mmol/l). Both low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels were increased, such that the mean TC/HDL-C and apolipoprotein B/apolipoprotein A1 (Apo B/Apo A1) ratios were below levels associated with increased coronary artery disease risk. Subjects with hypercholesterolemia did not differ from those with normal cholesterol values in current age or age at transplant, serum creatinine, serum albumin, serum triglycerides, HDL-C, TC/HDL-C ratio, Apo B/Apo A1 ratio, prednisone dose, body mass index, gender, use of thiazides or beta blockers, or family history of premature atherosclerosis. Coronary risk factors appear to cluster in these patients, with hypertension in 53% of those with hypercholesterolemia. Lipid profiles were not different in patients treated with prednisone-azathioprine vs. prednisone-azathioprine-cyclosporine A immunosuppression. A significant correlation was found between prednisone dose (mg/m2) and TC, LDL-C and TC/HDL-C. According to National Cholesterol Education Program guidelines, 32% of these long-term survivors of pediatric renal transplantation warrant at least dietary intervention and 10% are candidates for treatment with lipid-lowering drugs. This proportion is likely to increase as the safety of lipid-lowering agents is established in younger children.

Adolescent↗
PubMed1994

Nutrition and growth in pediatric renal transplant recipients.

Pediatric renal failure patients undergo similar rates of growth retardation on all forms of dialysis, but appears to be worst in the patients not dialyzed before transplant and on TF. These patients had an average age of 27 months before transplant. Table 1 shows that all groups undergo progressive decline in growth as the interval from diagnosis to transplant increases. This is not affected by the number of calories supplied. Pretransplant TF seems to improve catch up growth after transplant, but we saw no definite effect on growth in the pretransplant period. Renal transplantation uniformly improves growth in this population.

Child, Preschool↗
PubMed1993

Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota.

Transplantation began at the University of Minnesota in 1963. Treatment of diabetes and its complications has been emphasized since 1966, when the first pancreas-kidney transplant was done. Of 3,640 kidneys transplanted by 1992, 1,373 were for diabetic recipients, including 658 from living donors and 715 from cadaver donors. The results progressively improved; since 1984, survival rates of kidney grafts have been similar for diabetic and nondiabetic recipients, with three fourths of the grafts functioning at 4 years. As of 1992, 501 pancreas transplants had been done, including 170 simultaneous with a kidney, 142 after a kidney, and 188 alone for nonuremic diabetic patients; again, the results have improved: by the 1990s, graft survival rates were similar in the 3 recipient categories. Successful pancreas transplants have been shown by our coworkers to stabilize or improve neuropathy and prevent recurrence of diabetic nephropathy in kidney grafts. In an attempt to simplify endocrine replacement therapy, we have done 63 human islet transplants, 34 as allografts for patients with type I diabetes and 29 as autografts after total pancreatectomy to treat chronic pancreatitis. Insulin independence occurs for about 50% of islet autograft recipients. Two recent islet allograft recipients treated with 15-deoxyspergualin have had sustained insulin independence. We anticipate that endocrine replacement therapy by transplantation will become routine for diabetic patients as methods to prevent rejection are refined.

Diabetes Mellitus, Type 1↗
PubMed1993

Renal transplantation for infantile cystinosis: long-term follow-up.

Renal transplantation for infantile cystinosis corrects renal failure and prolongs survival. However, after transplantation, the disease may develop in the allograft and continue to progress in nonrenal organs. We studied seven children (6 boys, 1 girl) with infantile cystinosis who received 11 renal transplants (3 cadaver, 8 living-related) between May 1969 and December 1986. The age at transplant ranged from 6 to 12 years (mean, 9.1 years). Four children received second renal transplants at a mean age of 17 years (range, 16 to 22 years). The mean period of follow-up was 138 +/- 47 months. Three children received cysteamine therapy prior to transplantation. Nonrenal complications of infantile cystinosis present before transplantation were photophobia (n = 3), corneal crystals (n = 5), hypothyroidism (n = 1), rickets (n = 6), and short stature (n = 7). Graft and patient survival did not differ from controls matched for the time of transplantation. Two patients died (1 pneumococcal sepsis, 1 respiratory failure due to pulmonary fibrosis) with functioning grafts 5 and 14 years posttransplant. Complications that developed posttransplant included photophobia (n = 1), corneal crystals (n = 2), hypothyroidism (n = 4), polyneuropathy (n = 1), pulmonary fibrosis (n = 1), abnormal electroencephalogram without clinical seizures (n = 1), bladder stones (n = 1), and diabetes mellitus (n = 2). One patient received a corneal transplant. All seven children failed to show improvement in growth following transplantation. Cystine crystals are present in graft-infiltrating cells, but do not seem to affect kidney allograft function.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1993

Half-life and risk factors for kidney transplant outcome--importance of death with function.

Transplant center outcome is being increasingly scrutinized, so it is critical to have a consistent approach to data analysis. Standard practice has been to include death with function as a graft loss. But doing so may obscure other important risk factors and make it difficult to compare centers. To document this data analysis problem, we studied half-life and risk factors for long-term graft survival in 2230 kidney transplant recipients who had > or = 1 year of function. Four separate Cox regression analyses were done, differing in how death with function is considered: death with function considered a graft loss (analysis 1); all deaths censored (analysis 2); definitively non-transplant-related deaths censored, i.e., deaths from infection, malignancy, or cardiac problems analyzed as a graft loss (analysis 3); and definitively non-transplant-related as well as cardiac deaths censored (analysis 4). For each analysis, variables included immunosuppressive protocol, age at transplant, donor source, diabetes, gender, transplant number (primary vs. retransplant), and HLA ABDR mismatches (0 vs. > or = 1 mismatch). There were important differences in risk factors, depending on how death with function is considered. For example, when all deaths are considered a graft loss, age > 50, cadaver donor source, diabetes, retransplantation, and > 0 antigen mismatch were found to be risk factors for long-term graft survival. However, when all deaths are censored, age > 50, cadaver donor source, retransplantation, and diabetes were no longer risk factors. In fact, age > 50 was associated with significantly better graft survival when all deaths are censored (analysis 2), suggesting that the increased graft loss seen in these patients is nonimmunologic. Similarly, t1/2 is markedly different for different patient subgroups depending on how death with function is considered. For example, nondiabetic living donor (non-HLA-identical) recipients > 50 have a t1/2 of 9 +/- 1 years when death with function is considered a graft loss; for the same group, t1/2 is 62 +/- 28 years when death with function is considered. For diabetic patients < or = 50, when death with function is considered a graft loss, t1/2 is 9 +/- 0.9 years for living donor recipients and 7 +/- 0.7 years for cadaver donor recipients. For the same patients, when death with function is censored, t1/2 is 27 +/- 4 years for living donor recipients and 24 +/- 4 years for cadaver donor recipients. Our analysis suggests that death with function needs to be considered in analyzing kidney transplant outcomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗