摘要:

FK506 can show efficacy in transplant rejection even after other immunosuppressive drugs have been ineffective. However, the lack of a suitable animal model has hindered the study of FK nephrotoxicity, which has been noted as a common adverse effect in human trials. In this paper, we report a model of chronic FK nephrotoxicity in which renal structure and function are worsened by sodium depletion. Pairfed male Sprague-Dawley rats were given FK (6 mg/kg p.o.) or vehicle for 21 days on a low-salt or normal diet. There was no significant difference in body weight between FK and vehicle groups. The FK whole-blood trough levels (3–10 ng/ml) in rats are similar to those in FK treated transplant patients. In sodium-depleted rats, FK clearly decreased GFR (0.09±0.03 ml/min/100 g vs. 0.94±0.06 ml/min/100 g in the vehicle group,P<0.01), urinary osmolarity (UOsm,P<0.01) and plasma magnesium (P<0.01) and increased plasma creatinine (Pcr,P<0.01), fractional excretion of magnesium (P<0.01), urine volume (P<0.01), plasma renin activity (PRA,P<0.05), and alanine aminopeptidase (AAP,P<0.05) as compared with those in the vehicle group. Salt depletion significantly potentiated these functional changes as compared with those in the normal salt group (GFR, UOsm, Pcr, PRA, and AAP of the low salt group vs. those of the normal salt group,P<0.05 by ANOVA). In the sodium-depleted rats, the main lesion in the rat kidneys was focal collapse and vacuolization in proximal tubules, but there was also significant interstitial fibrosis. In contrast, no injury was observed in the sodium-replete rat kidneys. In conclusion, an experimental model of FK nephrotoxicity in sodium-depleted rats has been developed that is characterized by reduced GFR and structural damage to the proximal tubule accompanied by interstitial fibrosis. Sodium depletion appears to potentiate these changes at blood levels similar to those achieved in patients receiving FK.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The criteria for acceptance of candidates for renal transplantation varies throughout the United States. The Patient Care and Education Committee of the American Society of Transplant Physicians conducted a survey of all U.S. centers that participate in the United Network for Organ Sharing (UNOS) concerning their evaluation of adult candidates for kidney transplantation. The response to each question was examined according to the specialty of the individual who filled out the questionnaire, as well as the type of transplant center (university or private) and the size of the center.The response rate to the survey was 81% (147/182). We found the following: (1) university-based and larger centers accepted more medically complicated patients; (2) 83% noted that attendance to dialysis was an important indicator of compliance after transplantation; (3) 79% did not require preoperative blood transfusions for cadaver kidney recipients; (4) 66% set no specific upper age limit for transplantation; (5) 56% excluded patients with chronic active hepatitis in the setting of hepatitis B antigenemia; (6) 50% had no specific policy for evaluating hepatitis C antibody-positive patients, while 54% excluded the use of hepatitis C antibody-positive donors, and (7) 15% obtained coronary angiography on all diabetic patients.U.S. transplant centers have a heterogeneous approach to the evaluation of patients for renal transplantation, particularly in the areas of viral hepatitis, cardiovascular disease, and noncompliance. University-based centers and centers that perform a larger number of transplants accept more medically complicated patients.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Cytokines appear to play a major role in acute transplant rejection (AR); however, the specific cytokines initiating AR are not known. To investigate gamma-interferon messenger RNA (mRNA) as a key factor in AR induction, we performed reverse transcription-polymerase chain reaction (RT-PCR) on renal allograft fine-needle aspirates (FNA). Fifteen FNA from 15 patients were processed and interpreted in the standard fashion, the percent of tubular cells with MHC class II expression (DR) quantitated, and aliquots of FNA obtained for RT-PCR. RT-PCR was performed with primers to y-IFN with cyclophylin and insulin primers as controls. Retrospective clinical diagnoses were made for each FNA sample. Following RT-PCR, all FNA and FNAs from control normal and AR nephrectomy specimens had cyclophylin present, and in the 9 samples tested insulin was absent. Five patients had AR clinically and by FNA criteria; all 5 had elevated DR and γ-IFN mRNA present in FNA. Five patients had tubular necrosis or cyclosporine toxicity clinically, and FNA without immune activation or elevated DR and negative γ-IFN mRNA. Two patients had immune activation by FNA with elevated DR; both FNA expressed γ-IFN mRNA by Southern blot, one only weakly, and both patients subsequently developed clinical AR. Two patients had recently treated AR, one with persistent DR elevation without immune activation and negative γ-IFN mRNA in FNAs. This study demonstrates that RT-PCR can be performed with renal allograft FNA samples. The findings suggest intragraft γ-IFN mRNA expression occurs in active AR preceding clinical AR, thus defining incipient AR. Detection of γ-IFN mRNA may offer an early diagnostic tool for detection of AR.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Outcomes of pregnancies from 115 female kidney transplant recipients maintained on cyclosporine before and during pregnancy were obtained from questionnaires, hospital records, and telephone interviews. The mean age of conception was 29 years with a mean transplant interval of 2.2 years. There were 156 outcomes (2 sets of twins): ectopic 1%, therapeutic abortion 12%, miscarriage 16%, stillborn 2.6%, live birth 68.6%. The incidence of prematurity (<37 weeks) was 56%, and that of low birthweight (<2500 g) 49.5%. Complications occurred in 21.7% of newborns, but with only 1 neonatal death. Liveborn infants had a mean gestational age of 35.6 weeks (term 37–42 weeks) and a mean birthweight of 2407 g. The incidence of drug-treated hypertension prior to pregnancy was 51.7%; of diabetes prior to pregnancy, 11.7%; of pre-eclampsia, 24.8%; and of rejection during pregnancy or within 3 months postdelivery 14.5%. When infants born to women with or without a given risk factor were compared, mothers with prepregnancy drug-treated hypertension had significantly lower-birth-weight infants (2250 vs. 2603 g,P=0.028 by Wilcoxon). Similarly, mothers with prepregnancy creatinine ≥1.5 mg/dl had smaller infants (2090 vs. 2505 g,P=0.031 by Wilcoxon). There was a trend toward lower birthweight in infants of diabetic recipients. Of 107 recipients interviewed, 12(11%) experienced graft loss, 8 associated with graft dysfunction or rejection during pregnancy. There was 1 graft loss during pregnancy due to rejection and 8 grafts were lost within 2 years of the pregnancy. There was one maternal death 4.3 years postpregnancy. For the 8 recipients who lost their graft within 2 years of pregnancy, outcomes included 1 miscarriage and 7 live births. The 7 live births had a mean gestational age of 35.7 weeks and a mean birthweight of 2194 g. Five of 8 recipients who had graft loss within 2 years of pregnancy were in the drug-treated hypertensive group. Prepregnancy factors that appear to increase the risk to the newborn of a female kidney transplant recipient include maternal drug-treated hypertension, diabetes, and serum creatinine ≥1.5 mg/dl. More data are needed before specific prepregnancy predictors for maternal graft loss can be determined in this population.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The purpose of this study was to analyze different regimens of viral prophylaxis after combined pancreas-kidney transplantation (PKT). Over a 4-year period, we performed 82 PKTs with quadruple immuno-suppression with OKT3 induction. Four regimens of prophylaxis were studied. The first 30 patients received standard intravenous immunoglobulin (FVTG; 0.5 g/kg) for 6 doses and oral acyclovir for 3 months. The next 34 recipients received intravenous ganciclo-vir (2.5 mg/kg) twice daily for 2 weeks followed by oral acyclovir for 3 months. In the third group, patients were randomized to 5 doses over 2 months of either standard FVIG (n = 9) or CMV hyperimmune globulin (Cytogam; n = 9; 100–150 mg/kg) plus 2 weeks of IV ganciclovir followed by 3 months of oral acyclovir. The 4 groups were similar with respect to clinical, demographic, and immunologic variables, including donor and recipient CMV serologic status and blood transfusions. All patients were monitored for viral infections in the first 6 months after PKT. The regimens of prophylaxis resulted in (1) no major non-CMV (including no EBV) viral infections; (2) 3 cases of minor non-CMV viral infections (shingles); and (3) no differences in the incidence, timing, or severity of symptomatic CMV infections in the 4 groups. No death or graft loss was due to viral infection. Prophylaxis is effective in reducing the incidence of non-CMV viral infections and may reduce the severity of symptomatic CMV infection. However, we could not show any added benefit of either Cytogam or standard IVIG when used in combination with other antiviral agents. For economic as well as efficacy reasons, we recommend that IVIG preparations not be used routinely with antilymphocyte therapy but only in high-risk situations such as primary CMV exposure.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The waiting list for cadaver kidney transplantation continues to grow. Yet there has been little increase in the number of living-donor transplants. At many centers, willing relatives are turned down as potential donors because of poor HLAABDR matching with the recipient. It has been our policy to accept the 0-haplo-type-match (O-HTM) living-related donor. We studied long-term (6-year) outcome of 0-HTM transplants compared with the outcome of transplants from 1− and 2-HTM recipients and from cadaver donors.Since 1984, 352 adults have received primary living-related renal transplants, and had a minimum of 1 year of follow-up: 92 2-HTM, 216 1-HTM, and 44 O-HTM. In the same period and with the same follow-up, 362 adults have received primary cadaver (CAD) renal transplants. Immunosuppression consisted of cyclosporine, azathioprine, and prednisone (triple therapy) for living-donor and sequential therapy for CAD recipients. ABDR match (mean±SD) for 0 HTM was 1.3±8; CAD, 2.0±1.6; % peak panel-reactive antibodies (PRA) for 0 HTM was 1.2±5.3; 1 HTM, 6.7±20; 2 HTM, 7.5±21; CAD, 15.5±30. The percentage of PRA at the time of transplant for 0 HTM was .7 ± 4.4; 1 HTM, 4.1 ± 1.6; 2 HTM, 6±18; CAD, 7.2±20. While the number of ABDR matches was significantly fewer for 0 HTM than for the other groups, the % PRA at transplant and the peak % PRA were less in the O-HTM group. Other demographics were not significantly different. Patient survival was significantly lower in the CAD group vs. 2-HTM recipients (P<.05). The living-related grafts had significantly greater survival than the CAD grafts (P<.05), but there was no significant difference between 0-, 1-, and 2-HTM graft survival. The most common causes of graft loss in all groups were death and chronic rejection.In our experience, the long-term graft survivals of 0-HTM and 1-HTM transplants are the same, and both are superior to CAD results, using 0-HTM living-related donor transplants should be continued and encouraged.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Should HLA antigens that were mismatched in a renal transplant that failed be avoided in subsequent transplants? There were 890 retransplantations reported to the UCLA International Kidney Transplant Registry between 1985 and 1993 that had been performed in the face of a repeat HLA incompatibility. The 1− and 3-year regraft survival rates were 67% and 55%, respectively, for these retransplants, compared with 73% and 60% for 3220 regrafts with no HLA-A, -B, or -DR antigens mismatched twice (P=0.030). When the repeat HLA-mismatched antigens were examined by locus, there was no difference in regraft survival comparing patients with no repeat HLA incompatibilities with those mismatched twice for HLA-A or -B antigens only, but there was a significant long-term decrease in survival of patients mismatched twice for HLA-DR antigens. The 377 patients mismatched twice only for HLA-A or -B antigens had 1− and 3-year regraft survival rates of 67% and 59%, respectively, compared with 65% (P=0.289) and 50% (P=0.025) for 281 patients with HLA-DR repeat mismatches only. Repeat mismatches for a combination of HLA-A or -B and -DR antigens resulted in 65% and 44% 1− and 3-year regraft survival in 129 patients. The half-lives for retransplants with repeat HLA class I, II, and I and II incompatibilities were 8, 6, and 4 years, respectively (P=0.005). The data do not support preemptive avoidance of repeat HLA-A or -B incompatibilities. The crossmatch test excludes relevant mismatches. Repeated HLA-DR incompatibilities are not excluded by crossmatch tests and have a deleterious effect on long-term regraft survival. HLA-DR antigens mismatched in a previous failed transplant should be avoided.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

FK506 trough levels were measured by ELISA in paired whole-blood and plasma samples in 59 liver transplant recipients. Patients with nephrotoxicity had higher FK506 whole-blood and plasma levels (27.5±3.2 ng/ml and 1.44±0.14 ng/ml) than patients with stable liver function (15.2±2.1 ng/ml and 0.98± 0.15 ng/ml,P<0.05 andP<0.01, respectively). Patients with acute rejection had FK506 whole-blood and plasma levels within the same range as patients with stable liver function. Patients with severe neurotoxic-ity had significantly higher FK506 whole-blood and plasma levels (31.3±6.8 ng/ml and 3.9±1.4 ng/ml) in comparison with patients with mild-to-moderate neurotoxicity (18.1±2.4 ng/ml and l.l±0.13 ng/ml) (P=0.048 andP<0.001, respectively). Long-term use of FK506 was associated with a significant reduction in glomerular filtration rate at 1-year posttransplant in patients on primary FK506 treatment (33%,P<0.001).

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

It is well recognized that hepatitis recurs in virtually all patients who undergo orthotopic liver transplantation for cirrhosis secondary to chronic hepatitis C (HCV). The present report describes the biochemical and histologic findings of recurrent hepatitis in 25 such patients. One patient was found to have hepato-cellular carcinoma at the time of OLT and was excluded from further analysis. All post-OLT laboratory values were reviewed. Liver biopsies were performed on protocol 6, 12, 24, and 36 months following OLT. Additional biopsies were performed as necessary to evaluate abnormalities in serum liver chemistries. A total of 104 biopsies was obtained; hepatitis consistent with recurrent HCV was present in 68 (65%). Other biopsy findings included cytomegalovirus hepatitis; acute, chronic, or resolving rejection; cholestasis with or without an underlying hepatitis; steatosis, and cen-trilobular necrosis. Histologic hepatitis appeared in all patients within 12 months following OLT. Despite these histologic findings, serum ALT was normal for prolonged periods in over 50% of such patients. In all cases this hepatitis was mild and did not progress over a mean follow-up of 22 months (maximum 44 months), as judged by Knodell histologic activity score (mean score: 4.0 ± 0.3). Five patients developed cholestatic jaundice, far out of proportion to the degree of histologic hepatitis. In 2 patients this was secondary to chronic rejection. The other 3 patients had drug-induced cholestasis that resolved after various medications were discontinued. HCV did not contribute to graft dysfunction in any of the 24 patients. To date, our data suggest that post-OLT hepatitis in patients with preexisting HCV is a relatively benign process. Severe cholestatic jaundice in such patients is not secondary to HCV, and should stimulate a search for other possible causes of graft dysfunction. The long-term consequences of recurrent HCV following hepatic transplantation remain to be determined.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The cytokine release syndrome (CRS) accompanying OKT3 therapy is a major cause of posttransplant morbidity. The pathogenesis of this syndrome has been attributed to the synthesis of tumor necrosis factor, interleukin 2 (IL-2), interleukin 6 (IL-6), and γ-inter-feron in response to T lymphocyte stimulation by 0KT3. The hemorrheologic agent pentoxifylline (PTX) inhibits the synthesis of TNFα in vitro in response to a variety of stimuli, including OKT3. We performed a randomized, double-blinded trial of PTX during 0KT3 induction in recipients of cadaveric renal allografts. Patients received either PTX 800 mg or placebo 2 hr before the initial dose of OKT3 and every 8 hr thereafter during the first 3 posttransplant days. Serum TNFa and IL-6 concentrations were measured pre-OKT3 and at 2 and 6 hr post-OKT3 on the first 3 posttransplant days.Despite the achievement of apparently adequate plasma levels of PTX and its active metabolites, no difference was observed in the incidence or severity of clinical manifestations of CRS. Serious manifestations of CRS—including acute pulmonary edema, encepha-lopathy, and aseptic meningitis—were not seen in either group. Serum TNFa and IL-6 concentrations were similar in PTX and control patients throughout the course of the study. Plasma levels of PTX and its active metabolites did not correlate with serum TNFa levels, serum IL-6 levels, or the incidence and severity of clinical manifestations of CRS.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID