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  • 1
    Keywords: measurement ; Germany ; PERFUSION ; QUANTIFICATION ; LONG-TERM ; PIGS ; validation ; TIME ; PATIENT ; kidney ; SERA ; ACUTE REJECTION ; ALLOGRAFT SURVIVAL ; BLOOD-FLOW ; DONOR ; GRAFT ; HEPATIC MICROCIRCULATION ; IMPACT ; INDEX ; intraoperative ; LIVER-TRANSPLANTATION ; MICROCIRCULATION ; pig ; primary ; prognosis ; QUALITY ; REDUCTION ; renal ; renal function ; RENAL-FUNCTION ; REPERFUSION ; RISK-FACTORS ; TRANSPLANTATION
    Abstract: Background. We evaluated the significance of perioperative cortical microperfusion for graft function and long-term prognosis after renal allotransplantation. Thermodiffusion technology was clinically applied for the first time, after previous validation for perfusion monitoring of the renal cortex in pigs. Methods. A thermodiffusion probe was inserted into the renal cortex in 30 transplant recipients after graft reperfusion. Real-time measurements were recorded until the end of the operation. In 14 patients perfusion was measured daily until postoperative day 7. Microcirculation was correlated to serum creatinine level, scintigraphic findings, and long-term outcome. Results. In primary graft function, intraoperative perfusion was 85 7 mL/100 g per min compared with significantly lower values in cases with subsequent graft dysfunction. The best discrimination was defined for a level of 70 mL/100 g per min with a positive predictive value of 88% for detection of good graft function and 86% for nonfunction. Intraoperative perfusion was significantly different in patients with normal grafts, delayed function, and graft loss. Postoperatively, lower perfusion was found in acute tubular necrosis; a significant correlation could be noted between microcirculation and perfusion index measured by nuclear scanning (r=0.78, P〈0.01). Living-related grafts were characterized by higher intraoperative perfusion and superior graft quality. Conclusion. Thermodiffusion could be clinically applicable for the perioperative monitoring of renal graft perfusion. Intraoperative reduction of cortical microcirculation has a high predictive value with respect to detection of delayed renal function. Postoperatively, impaired renal microperfusion is associated with acute tubular necrosis. Living-related donor grafts show less microcirculatory alteration than cadaveric kidneys
    Type of Publication: Journal article published
    PubMed ID: 12717202
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  • 2
    Keywords: CELLS ; INHIBITOR ; CELL ; Germany ; INHIBITION ; GENERATION ; ENZYMES ; PROTEIN ; SURGERY ; INJURIES ; kidney ; GRAFT ; REDUCTION ; renal ; TRANSPLANTATION ; RAT ; treatment ; DECREASE ; Jun ; REJECTION ; OXYGEN ; RENAL-ALLOGRAFT ; reactive oxygen species ; INJURY ; INFILTRATION ; RE ; OXYGEN RADICALS ; ALLOGRAFT-REJECTION ; OXIDOREDUCTASE ; ENZYME-ACTIVITIES ; OXIDANT INJURY ; REACTIVE OXYGEN
    Abstract: Background. Increased oxygen radical production may not only contribute to posttransplant ischemia-reperfusion injury but also to acute rejection of renal allografts. Xanthine oxidoreductase (XOR) may constitute a relevant reactive oxygen species (ROS) source. The study was conducted (1) to determine ROS production as well as oxidant and antioxidant enzyme activities in renal grafts and (2) to modulate acute rejection by tungsten administration, a specific inhibitor of XOR. Methods. Syngraft (Lewis to Lewis, Fisher344 to Fisher344) and allograft (Fisher344 to Lewis) kidney transplantations were performed with or without tungsten administration. Analysis was performed at day 1, 3, or 9 posttransplantation. Results. Generation of ROS was enhanced, being 10-fold higher in renal allografts versus control kidneys at day 9 (P 〈 0.01); this was associated with histologic signs of acute rejection. Oxygen radicals were generated to a significant degree by enhanced XOR activity, which increased more than 10-fold in renal allografts at day 9 posttransplantation; XOR protein in glomeruli and tubulointerstitium was also elevated in allografts. In addition, NADPH oxidase activity increased significantly in allografts. The activity of antioxidant enzymes tended to decrease. Tungsten treatment resulted in a pronounced reduction of XOR activity and ROS production, without any effect on NADPH-oxidase activity; mononuclear cell infiltration and rejection signs were significantly ameliorated at day 9 posttransplantation by selective inhibition of XOR. Conclusions. A major part of ROS generation in acute rejection was contributed by XOR. ROS are not only associated with but also contribute to acute allograft rejection because inhibition of XOR alleviated rejection phenomena
    Type of Publication: Journal article published
    PubMed ID: 15201667
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  • 3
    Abstract: BACKGROUND: Traditional, cohort-based survival analysis approaches may provide outdated graft and patient survival estimates in times when clinical progress is rapid. Period analysis, a survival analysis method that uses left truncation and was shown to provide more up-to-date survival estimates than traditional, cohort-based methods in other medical fields, may improve the timeliness of survival monitoring in transplantation. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we evaluated, through a series of comparisons, how well most up-to-date 5-year survival estimates potentially derivable by two commonly used cohort-based methods and the period method would have been able to predict the later observed survival of corresponding most recent transplants in the dataset between 1992 to 1994 and 2001 to 2003. RESULTS: In the analysis of overall survival, period analysis provided a best prediction for 93 of the 100 evaluated point estimates, whereas among 350 evaluated point estimates of age-specific survival, period analysis provided a best estimate on 254 occasions (72.6%), compared with 49 (14.0%) and 82 (23.4%) occasions for the cohort-based approaches. Mean average absolute differences between period estimates and the later observed survival were meaningfully lower than those obtained by traditional methods, indicating that period estimates may provide much better survival predictions for recently transplanted grafts and patients than estimates derivable at the same time by traditional survival analysis approaches. CONCLUSION: The timeliness of survival monitoring can be meaningfully improved by the application of period analysis. The use of period analysis for providing more up-to-date survival estimates in transplantation may be encouraged.
    Type of Publication: Journal article published
    PubMed ID: 20173683
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  • 4
    Abstract: BACKGROUND: Obliterative bronchiolitis poses a primary obstacle for long-term survival of lung transplant recipients and manifests clinically as bronchiolitis obliterans syndrome (BOS). Establishing a molecular level screening method to detect BOS-related proteome changes before its diagnosis by forced expiratory volume surrogate marker criteria was the main objective of this study. METHODS: Bronchoalveolar lavage was performed in 82 lung transplant recipients (48/34 with/without known BOS development) at different time points between 12 and 48 months after lung transplantation. A mass spectrometry-based method was devised to generate bronchoalveolar lavage fluid proteome profiles that were screened for BOS-specific alterations. Statistically significant marker peptides and proteins were identified and validated by in-gel digestion, tandem mass spectrometric sequencing, and quantitative immunoassays. RESULTS: Among the panel of statistically significant markers were Clara cell protein, calgranulin A, human neutrophil peptides, and the antimicrobial agent histatin. To assess their clinical relevance, a highly sensitive and specific classifier model was developed. Positive BOS classification by monitoring of seven polypeptides correlated strongly with a significant decrease in BOS-free time. Thus, it was possible to detect high-risk patients early on in the pathogenetic process. CONCLUSIONS: Monitoring the bronchoalveolar lavage fluid levels of seven polypeptides detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry allows a reliable prediction of early BOS using a Random Forest decision tree-based classifier model. The high accuracy of this robust model and its synergistic potential in combination with established forced expiratory volume-based diagnostics could make it an effective tool to supplement the current diagnostic regime after multicentric validation.
    Type of Publication: Journal article published
    PubMed ID: 21716170
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  • 5
  • 6
    Abstract: BACKGROUND: For desensitization of ABO-incompatible kidney transplant recipients we recently proposed nonantigen-specific immunoadsorption (IA) and rituximab. METHODS: We now compared clinical outcomes of 34 ABO-incompatible living-donor kidney recipients who were transplanted using this protocol with that of 68 matched ABO-compatible patients. In addition, we analyzed efficacy and cost of nonantigen-specific as compared to blood group antigen-specific IA. RESULTS: Before desensitization, the median isoagglutinin titer of 34 ABO-incompatible patients was 1:64 (Coombs technique). Patients received a median of 7 preoperative IA treatments. Twenty-four patients had a median of 2 additional plasmapheresis treatments to reach the preoperative target isoagglutinin titer of 1:8 or less. After a median postoperative follow-up of 22 months, overall graft survival in the ABO-incompatible group was not significantly different from that in ABO-compatible patients (log-rank P = 0.20), whereas patient survival tended to be lower (log-rank P = 0.05). The incidence of rejection episodes was 15% in both groups. The ABO-incompatible kidney recipients had a higher incidence of BK virus replication (P = 0.04) and nephropathy (P = 0.01) and showed more often colonization with multidrug resistant bacteria (P = 0.02). In comparison to blood group antigen-specific IA, nonantigen-specific IA showed equal efficacy but was associated with reduction in cost. CONCLUSIONS: Clinical outcomes of ABO-incompatible patients desensitized with a nonantigen-specific IA device and rituximab do not differ from that of matched ABO-compatible patients although a trend toward reduced patient survival was noted. Special attention must be paid to the higher incidence of BK virus infection in recipients of ABO-incompatible grafts.
    Type of Publication: Journal article published
    PubMed ID: 25989497
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  • 7
    Keywords: CELLS ; IRRADIATION ; SURVIVAL ; Germany ; human ; IN-VIVO ; TOXICITY ; DISEASE ; DRUG ; TIME ; RAT ; RATS ; CONTRAST ; T cells ; T-CELLS ; treatment ; ANTITUMOR-ACTIVITY ; bone marrow ; BONE-MARROW ; RATES ; chemotherapy ; albumin ; SERUM ; WEIGHT ; RHEUMATOID-ARTHRITIS ; METHOTREXATE-ALBUMIN ; graft-versus-host disease ; LOSSES ; DRUGS ; ONSET ; bone marrow cells ; BONE ; spleen ; PROGRESS ; human serum albumin ; GvHD ; TUMOR-BEARING RATS ; TERM FOLLOW-UP ; allogeneic stem cell transplantation ; SERUM-ALBUMIN ; aminopterin-albumin ; CONTROLLED TRIAL ; IDENTICAL MARROW GRAFTS ; MTX-HSA ; MYCOPHENOLATE-MOFETIL
    Abstract: Background. During the last several years, major progress has been made in developing targeted chemotherapy using cytotoxic drugs covalently bound to human serum albumin (HSA). We explored the activity of two antifolates methotrexate (MTX) and aminopterin (AMPT) bound to HSA in prophylaxis and treatment of experimental acute graft-versus-host disease (aGVHD). Methods. In all, 113 female F1 hybrid BN/Lew-rats were irradiated with 8.2 Gy (n=103) or 9.9 Gy (n=10). One day after irradiation each rat received 4 x 10(7) bone marrow cells and 1.5 x 10(7) spleen T-cells from female Lew-rats. GVHD prophylaxis consisted of MTX-HSA 2 mg/kg (n=25), MTX-HSA 0.5 mg/kg (n=8), AMPT-HSA 0.65 mg/kg (n=8), MTX 0.5 mg/kg (n=17), or native HSA (n=39) given intraperitoneally (IP) on days 0, 4, 8, and 12. Treatment of aGVHD consisted of MTX-HSA 2 mg/kg (n=8) or AMPT-HSAO.5 mg/kg (n=8) given intraperitoneally at the time of onset of aGVHD and subsequently every fourth day (a total of four doses). Results. All animals receiving native HSA developed lethal aGVHD. Prophylactic treatment with MTX-HSA 2 mg/kg prevented aGVHD in 18 of 25 animals and in 6 of 8 receiving AMPT-HSA. In contrast, five out of nine rats receiving free MTX died due to aGVHD. The survival rates in the prophylactic MTX-HSA 2 mg/kg and AMPT-HSA groups were significantly higher compared to the MTX and control groups (P 〈 0.05), while non hematologic toxicity of MTX-HSA was not detectable. AMPT-HSA at a dose of 0.65 mg/kg as well as MTX at a dose of 0.5 mg/kg were associated with temporary weight loss and lethargy. Conclusions. The albumin conjugates MTX-HSA and AMPT-HSA effectively prevent experimental aGVHD
    Type of Publication: Journal article published
    PubMed ID: 16926597
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  • 8
    Keywords: ACID, acyl glucuronide, ANEMIA, ANTAGONISM, ANTIOXIDANT, BLOOD, BONE, BONE-MARROW, CELL, CELLS, CERE
    Abstract: Background. Diarrhea and anemia are side effects of mycophenolic acid (MPA), but underlying mechanisms are not fully understood. Gene expression of major-alpha-hemoglobin and catalase was suppressed in livers of mycophenolate mofetil (MMF)-treated rats, suggesting MPA attenuates cellular defense against reactive oxygen species (ROS). We investigated whether the antioxidant idebenone might alleviate MPA-related side effects. Methods. Rats were treated as follows: group 1: controls; group 2: idebenone; group 3: MMF; and group 4: MMF/idebenone. Blood was collected weekly to determine cell counts, hemoglobin, MPA, plasma albumin, total protein, creatinine, and urea concentrations. On day 28 RNA was extracted from liver, kidneys, and bone marrow (BM). Colon and jejunum were examined histologically. Results. High-dose MMF-treated rats developed diarrhea, dehydration, and weight loss. After a week, a significant decrease (P=0.001) in erythrocyte count and hemoglobin concentration was observed that was not influenced by idebenone. Degenerative changes in the jejunum were slightly attenuated by idebenone. Idebenone did not influence MPA-induced suppression of catalase. A significant suppression of major-alpha-hemoglobin and the erythropoietin (EPO)-receptor in BM of MMF-treated groups and almost complete absence of hemopoietic progenitor cells were observed. EPO-mRNA was markedly upregulated in the MMF-group and even more in the MMF/idebenone-group. Conclusion. Idebenone showed minimal benefit on MMF-related diarrhea and anemia. BM of MMF-treated rats revealed erythroid aplasia as a possible reason for anemia. Marked upregulation of EPO-mRNA presumably reflects a compensatory mechanism. Because ROS have the potential to suppress EPO expression, it can be hypothesized that enhanced EPO-mRNA expression in MMF/idebenone-treated rats is caused by antagonism of ROS
    Type of Publication: Journal article published
    PubMed ID: 18337669
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  • 9
    Keywords: SURVIVAL ; RISK-FACTORS ; CHILDREN ; nutrition ; MYELODYSPLASTIC SYNDROME ; VERSUS-HOST-DISEASE ; BODY-MASS INDEX ; OVERWEIGHT ; AML ; WEIGHT-LOSS
    Abstract: Background. The impact of nutritional status on outcome of allogeneic stem cell transplantation (alloSCT) is controversial. This study investigates the influence of pretransplant weight loss and serologic indicators of nutritional homeostasis on relapse and death of acute myeloid leukemia (AML) after alloSCT. Methods. Pretransplant weight loss along with serum levels of total serum protein (TSP), albumin, C-reactive protein, and leptin were collected retrospectively in a training cohort (n = 149) and correlated with clinical outcome. Metabolic risk groups were defined and tested in an independent validation cohort (n = 167). Results. We identified pretransplant weight loss and TSP as strong independent predictors of relapse and death. Patients in the metabolic high-risk group (low TSP and weight loss) had an increased risk for relapse (P = 0.0002) and death (P = 0.002), but a similar risk for acute graft-versus-host disease. Weight loss coincided with reduced pretransplant serum leptin levels. The adverse influence of weight loss and high metabolic risk on relapse and overall survival could be confirmed in the validation cohort and similarly in patients with less than or more than 5% blasts before alloSCT. Multivariate analysis of both cohorts revealed a hazard ratio for relapse of 7.78 (2.59-23.36, P = 0.0003) in the metabolic high risk group. Conclusion. Altered nutritional homeostasis before alloSCT correlates with recurrence of AML after transplantation. Studies addressing pretransplant nutritional interventions to reduce AML relapse rates are warranted.
    Type of Publication: Journal article published
    PubMed ID: 25340610
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  • 10
    Keywords: IMPACT ; HLA ; FAILURE ; BIOPSIES ; II TYPE-1 RECEPTOR ; ANTIBODY-MEDIATED REJECTION ; DONOR-SPECIFIC ANTIBODIES ; MICROCIRCULATION INFLAMMATION ; CELL-TYPES ; C4D
    Abstract: BACKGROUND: Renal transplant glomerulitis (G) is associated with acute antibody-mediated rejection (ABMR) in the presence of donor-specific antibodies. However, the long-term prognosis of isolated G (isG) in the absence of donor-specific antibodies or G in combination with T cell-mediated rejection (TCMR) remains unexplored. METHODS: Seventy recipients with G were included in this retrospective study and subdivided into 3 groups: isG, G with TCMR (G + TCMR), and G with acute ABMR. The control groups were: patients with TCMR Banff type I or II without G (TCMR) and patients without rejection (NR). Kaplan-Meier death-censored survival plots and Cox regression were used to analyze graft survival. The combined graft survival endpoint was defined as a return to dialysis or estimated glomerular filtration rate less than 15 mL/min/1.73 m. The median follow-up was 37 (14; 77) months from biopsy. RESULTS: Graft survival was significantly lower in patients with G than in the NR and TCMR groups. No significant differences were observed among the isG, G + TCMR, and ABMR groups. Graft survival was lower in the G + TCMR group than in the TCMR group. Glomerulitis was independently associated with the risk of adverse graft outcome in a multivariate Cox regression model adjusted for other confounders (hazard ratio, 4.52 [95% confidence interval, 2.37-8.68] vs controls; P 〈 0.001). CONCLUSIONS: Glomerulitis is strongly associated with increased risk of graft failure. Graft survival in patients with isG that do not meet the Banff criteria for acute/active ABMR and in patients with G accompanying TCMR is comparable to the ABMR group.
    Type of Publication: Journal article published
    PubMed ID: 25594551
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