摘要:

&NA;Recently, Clayberger et al. demonstrated that ALLO‐TRAP, small synthetic peptides derived from a conserved region of the&agr;1 helix of certain HLA class I molecules, inhibited human CTL responses in vitro. In rats, ALLOTRAP 07 therapy combined with a subtherapeutic dose of cyclosporine led to the permanent acceptance of heart allografts. In the present study, the effect of ALLOTRAP on the survival of skin allografts in mice was studied. The tail skin of male C57B1/6 (H‐2b) mice was grafted on the back of male CBA (H‐2k) recipients. In untreated animals, the skin graft was rejected after 11.6±1.13 days (MST±SD). Cyclosporine administered orally for 5 days after transplantation prolonged graft survival to 13.1±2.13 days. ALLOTRAP 2702 prolonged graft survival to 16.57±2.15 days when administered orally for five days posttransplantation and to 18.86±0.38 when administered intraperitoneally until rejection. Thus, ALLOTRAP peptides derived from human MHC class I sequences, in addition to inhibiting human T cell responses in vitro, also prolong allograft survival in rats and mice.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;No immunosuppression agent is as yet available that prevents the process of chronic allograft rejection, the most critical cause of late organ allograft loss. RS61443 (mycophenolate mofetil) inhibits de novo DNA synthesis as well as diminishes expression of cell surface molecules and antibody production. As these factors seem important in the pathophysiology of the chronic phenomenon, we investigated the effects of the agent in an established model of chronic rejection of kidney allografts in a F344‐to‐Lewis rat strain combination. All recipients were treated for the first 10 days after engraftment with low‐dose cyclosporine (1.5 mg/kg/day) to reverse an initial acute rejection episode. Since functional and morphological changes do not become manifest in this model until after 12 wk, treatment with RS61443 (15 mg/kg/day, p.o.) was either initiated at the day of grafting (Gp 1) or 8 wks thereafter (Gp 2), and continued throughout the follow‐up period. Non‐RS61443‐treated allografted rats receiving vehicle only (Gp 3) developed progressive proteinuria after 12 wk. Peak cellular infiltration (particularly macrophages in glomeruli and perivascular areas) at 16 wk was associated with densely expressed adhesion molecules (ICAM‐1 on endothelium), cytokines and growth factors (TNF‐&agr;and TGF‐&bgr;in glomeruli and PDGF on arterial smooth muscle cells). Interstitial fibrosis, with tubular atrophy, glomerulosclerosis, and varying degrees of intimal proliferation and luminal obliteration of vessels, progressed thereafter. In vitro binding of MNC from naive animals to chronically rejecting allografted kidneys generally confirmed the immunohistological observations, peaking at 12 wk; this binding was significantly inhibited by mAbs against specific adhesion molecules (CD11a, CD18, and ICAM‐1). Serum‐allospecific IgG and IgM peaked at 1‐2 wk after engraftment in the control recipients, decreasing thereafter. Although IgM declined to baseline after 12 wk, low levels of allospecific IgG persisted throughout the follow‐up period. In contrast, recipient treatment with RS61443 (both Gp 1 and Gp 2) allowed the allografts to function normally throughout follow‐up period. Proteinuria was virtually absent, and morphological and immunohis‐tological manifestations of the chronic process were markedly diminished. In addition, treated recipients developed no significant side effects, including leukopenia, anemia, thrombopenia, nephrotoxicity, and hepatotoxicity. It appears that this agent can safely prevent the changes of chronic rejection of kidney allografts in this rat model.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;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.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;To determine whether pregnancy had a long‐term influence on the survival or function of renal allografts, a case‐control study was conducted. Patients were selected from a pool of 915 patients transplanted at the University of Cincinnati from 1967 to 1990. The pregnancy group consisted of 18 women who became pregnant 3 months to 17 years after transplantation and who elected to continue pregnancy. There were 26 nonpregnant female controls, and 23 male control renal transplant recipients. Matching criteria were cause of end‐stage renal disease (ESRD), donor source, age at transplantation, calendar year of transplantation, time from transplantation to pregnancy, and serum creatinine concentration at the time corresponding to conception. Matching was performed by one investigator, who had no knowledge of long‐term outcome in any of the patients. The three groups were well‐matched with regard to these criteria. Male controls had higher baseline creatinine clearances than pregnancy cases or female controls. During pregnancy, serum creatinine levels fell by 20%, and creatinine clearance rose by 53%. Immediately after pregnancy, these values returned to baseline. Graft survival, with a mean posttransplant follow‐up of 11‐12 years, was 77.8% in the pregnancy cases, 69.2% in the female controls, and 69.6% in the male controls. By life‐table analysis, none of these differences was significant. Among surviving grafts, serum creatinine levels and creatinine clearances remained stable throughout the follow‐up period. In this study, using well‐matched male and nonpregnant female cohorts for comparison, pregnancy did not have an adverse long‐term effect on renal allograft function or survival.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;Outcomes fr3om 197 pregnancies in 141 female kidney transplant recipients were analyzed from data collected via questionnaires, hospital records, and phone interviews. All recipients were maintained on cyclosporine (CsA) before and during pregnancy. Of the livebirths, 54% were premature (<37 wk) and 50% were low‐birthweight (LBW) (<2500 g). The incidence of recipient drug‐treated hypertension (HTN) was 56%; preeclampsia, 29%; infections and complications 22%; and rejection during pregnancy and up to 3 mo. post delivery (rej.), 11%. Graft loss within 2 years of delivery occurred in 9% of recipients (GrL <2). No recipients reported a pregnancy after a postpregnancy graft loss. Mean serum creatinine was reported before, during, and after pregnancy. Mean cyclosporine doses were similar in recipients during and after pregnancy. Data were analyzed by logistic regression using SAS. Outcomes included prematurity, LBW, rej., and GrL <2. In a case‐controlled study comparing a recipient group with graft dysfunction during pregnancy vs. a group with good graft function, there was a trend toward lower mean prepregnancy CsA doses (in mg/kg) in the graft dysfunction group. A decline in recipient graft function during pregnancy is associated with lower newborn birthweights and lower maternal graft survival in cyclosporine treated female kidney recipients. Pregnancy‐related infections and complications are associated with rejection and graft loss in this population. Close monitoring of CsA dosing and serum creatinine levels during pregnancy and immediately postpartum is recommended as CsA dosage adjustment may be required.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;Three groups of patients were reviewed. Primary carcinomas were found in donors kidneys of 47 recipients. In 30 instances a tumor was present at harvesting. When a neoplasm was removed immediately pretransplantation or early posttransplantation there were no recurrences in 14 recipients. In another two instances, a tumor was not removed or was incompletely excised pretransplantation and both recipients died of metastases. Fourteen other patients received kidneys from donors in whom the opposite kidney had a malignancy. Thirteen remained tumor‐free and one had allograft nephrectomy for rejection 3 months posttransplantation when a carcinoma was found. In 17 recipients an allograft neoplasm was not recognized at harvesting. In 9 it was discovered at graft nephrectomy an average of 3 months posttransplantation. In a tenth patient a hypoechogenic area, found on routine posttransplant ultrasonography, progressively increased in size and proved to be malignant. Another 7 patients developed metastases from renal carcinomas an average of 12 months posttransplantation. Preexisting carcinomas were found in 350 recipients. Seventy‐one patients with incidentally discovered tumors had no recurrences no matter when nephrectomy was performed in relationship to transplantation. Of 279 patients with symptomatic renal tumors, 70 (25%) had recurrences, 63% of which occurred in patients treated ≤2 years pretransplantation. De novo cancers were found posttransplantation in 256 recipients. Renal carcinomas were 4.6% of posttransplant cancers compared with 3% of tumors in the general population. In 222 patients their own diseased kidneys were involved, in 24 tumors occurred in the allograft, and in 10 cases the site was not stated. Development of neoplasia seemed to be related not to the immunosuppressive therapy but to the underlying cause of renal failure, especially analgesic nephropathy. A disproportionate number of carcinomas (15%) involved the renal pelvis, most likely because of prior analgesic abuse.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;A group of 204 adult patients was entered into a prospective, randomized trial comparing FK506/prednisone with FK506/azathioprine/prednisone after renal transplantation between August 1, 1991 and October 11, 1992. The purpose of the study was to see if the addition of azathioprine would reduce the incidence of rejection and improve graft survival. The recipient population was unselected, with 61 (30%) patients undergoing retransplantation, 37 (18%) having a panel‐reactive antibody greater than 40%, and 33 (16%) over 60 years of age. The mean recipient age was 43.8±13.7 years (range 17.6‐78). The mean donor age was 34.0±20.1 years (range 0.3‐75); 13% of the cadaveric kidneys were from pediatric donors less than 3 years of age and were transplanted en bloc. The mean cold ischemia time was 31.4±8.4 hr. Living donors were the source of 13% of the kidneys. The mean follow‐up was 22±4 months (range 12‐29). Overall one‐year actual patient survival was 94%. Overall one‐year actual graft survival was 87%. Patients starting on double therapy had a one‐year actual patient survival of 96% and a one‐year actual graft survival of 92%. Patients starting on triple therapy had a one‐year actual patient survival of 91% (P=ns compared with double therapy), and a one‐year actual graft survival of 82% (P<0.02, compared with double therapy). Overall results with first cadaver transplants included a one‐year actual patient survival of 94% and one‐year actual graft survival of 88%, with no differences between double and triple therapy. The overall incidence of rejection was 48%, with 54% in the double therapy group and 41% in the triple therapy group (P<.07). The incidence of steroid‐resistant rejection requiring antilymphocyte therapy (OKT3 or ATGAM) was 13%, and was not different between the double and triple therapy groups. The mean serum creatinine was 1.8±0.8 mg/dl. The mean BUN was 33±21 mg/dl, with no significant difference between the therapy groups. The mean serum cholesterol was 192±49 mg/dl. A total of 56% of the patients are off prednisone, and 35% of the patients are not taking any antihypertensive medications. Other complications included cytomegalovirus—14%; new‐onset diabetes—16% (half of which was reversible); and posttransplant lymphoproliferative disorder—1%. There was a high incidence of crossover between the two groups, 27% of the patients in the double therapy group requiring the addition of azathioprine, and 45% of the patients in the triple therapy group requiring its discontinuation (usually temporary). These results show that FK506 is an excellent immunosuppressive agent after renal transplantation and that azathioprine is not routinely effective as a third agent. A high quality of life resulted from the ability to use no (56%) or low‐dose maintenance steroids.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;Thromboxane synthase (TS) catalyzes the formation of thromboxane (TxA2) in monocytes/macrophages, platelets, and various tissues. TxA2is likely to play a role in graft dysfunction due to its vasoconstrictive and platelet aggregatory properties.We studied the expression of TS in 7 normal native kidneys, 29 consecutive renal allograft biopsies (performed for rising serum creatinine, n=23, and delayed graft function, n=6), and one transplant nephrectomy specimen with severe acute rejection. TS expression was determined by immunocytochemistry using a monoclonal antibody against human TS, Kon‐7. Histologic grading of the transplant biopsy specimens was based on the Banff classification. The degree of TS staining was graded in the glomeruli, interstitium, tubules and vessels from 0 to 3+.Of 29 biopsies, 13 had chronic nephropathy (CN), 6 had acute rejection (AR) with chronic nephropathy (AR/CN), 4 had acute rejection (AR), and 6 had acute tubular necrosis (ATN). TS staining of native kidneys showed sporadic interstitial cells. The biopsy and transplant nephrectomy specimens showed significant staining, predominantly in the glomeruli and interstitium. Positively staining cells appeared to be of macrophage/monocyte lineage by morphology. The mean glomerular staining grade was significantly increased in specimens with AR (2.3±0.9) and the mean interstitial staining was increased in specimens with AR/CN (2.2±0.9). Follow‐up renal function 6 months post‐biopsy showed that patients with higher TS staining grades had a faster decline in graft function. In conclusion, TS expression is increased in patients with acute rejection with or without chronic nephropathy and is associated with more rapid deterioration in function.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;Urine cytology (UC) has proved to correlate well with core and fine‐needle aspiration kindey biopsies of renal allograft recipients undergoing acute rejection (AR). This study was undertaken to compare the relative usefulness of urine flow immunocytometry (UFC) (using fluorescinated antibodies anti‐HLA‐DR, anti‐CD3 and antirenal epithelial cells) with UC in its ability to diagnose AR by analyzing 200 urine specimens during a prospective double‐blind study of 40 renal transplant recipients. Clinical diagnosis was retrospectively assigned to one of the following categories: group I—AR, 15; group II—ischemic injury period (first 5 days postop.), 12; group III, 173 (including 168 stable grafts, 1 pyelonephritis and 4 cyclosporine toxicity), by investigators blinded to the urine results. Both tests were highly sensitive for the diagnosis of AR (UC=86.6% vs. UFC=100%;P=NS) with a specificity after the ischemic injury period of 78% by UC and 87.9% by UFC. Samples obtained during AR revealed higher levels of expression of HLA‐DR as well as higher numbers of CD3‐positive cells. These tests had specificity values of 95.3% and 97.6%, respectively, for the diagnosis of AR. The degree of immune activation (established by numbers of lymphocytes/lymphoblasts seen by UC) correlated with the severity of biopsyproven ARs and with response to antirejection therapy. In conclusion, both test are highly accurate in diagnosing AR. The highest specificity value was obtained when both UC and UFC were utilized together (93%). We suggest that the routine use of these tests can provide an important adjunct to the evaluation of renal transplant recipients.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

&NA;For this study, we analyzed the role of rejection in graft failure in children. Rejection results were examined after 3004 pediatric renal transplants (1367 living donor, 1637 cadaver source). A total of 3453 (1298 living donor, 2155 cadaver source) rejection episodes have occurred, for rejection ratios of .95 for living donor and 1.32 for cadaver source transplants, with a constant difference of 18% points after four months, in the percentage of patients ever experiencing a rejection. Rejection results were examined by patient age (0‐1 vs. 2‐5 vs. 6‐12 vs. ≥13). Rejection ratios, annualized rejection frequency, time to first rejection, and mean number of rejections for patients with rejection were not elevated in the younger patients. However, for the initial rejection episode, recipients less than six years of age had significantly (P< .001) poorer outcome from the rejection episode with an increased risk of graft failure in both donor source groups. This age effect on rejection outcome is only seen with the first rejection episode and is not observed with subsequent rejection episodes.

ISSN:0041-1337    

出版商:OVID    

年代:1995

数据来源: OVID