Cold storage induces time-dependent F2-isoprostane formation in renal tubular cells and rat kidneys.
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BACKGROUND: Previous findings suggest a possible role for free radicals in cold-storage-associated tissue injury. Because free radical-induced lipid peroxidation catalyzes the cyclooxygenase-independent formation of vasoconstrictive F2-isoprostanes, the hypothesis that isoprostanes are produced during cold storage was tested in this study. METHODS: Total isoprostanes (free and esterified) in renal tubular epithelial (LLC-PK1) cells or whole kidneys, subjected to cold storage, were quantitated employing the gas chromatographic-mass spectroscopic method. LLC-PK1 cells were stored at 4 degrees C in a University of Wisconsin (UW) solution for 0, 24, 48, and 72 hours or 48 hours with desferrioxamine (DFO) or the lazaroid compound 2-methyl aminochroman (2-MAC). In the rat model, kidneys were perfused and stored for 48 hours in the UW solution with or without added DFO or 2-MAC. RESULTS: Isoprostanes in LLC-PK1 cells increased by fivefold following 24 hours of cold storage (36 +/- 2 pg/well to 185 +/- 6, mean +/- SE, following 24 hours of cold storage, P < 0.0001), and the levels continued to increase significantly at 48 and 72 hours. DFO and 2-MAC caused significant suppression of isoprostane formation. Cold storage of the kidneys in UW solution for 48 hours was accompanied by an eightfold increase in isoprostanes compared with control kidneys not subjected to cold storage (25.0 +/- 3.0 vs. 2.9 +/- 0.1 ng/g, P < 0.0001). The addition of 2-MAC or DFO to the UW solution was associated with a near complete suppression of 48-hour cold-induced isoprostane formation. CONCLUSION: Our findings provide evidence for the formation of large quantities of antioxidant-suppressible isoprostanes in kidney cells and whole kidney during cold-preservation. Based on this, it is hypothesized that (a) isoprostanes, which are potent renal vasoconstrictors, may contribute to immediate post-transplant vasoconstriction and dysfunction in kidneys subjected to extended cold storage, and that (b) the addition of 2-MAC or DFO to a UW solution in such circumstances may attenuate these alterations partly by suppressing isoprostane formation. (+info)
Chronic rejection of mouse kidney allografts.
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BACKGROUND: Chronic renal allograft rejection is the leading cause of late graft failure. However, its pathogenesis has not been defined. METHODS: To explore the pathogenesis of chronic rejection, we studied a mouse model of kidney transplantation and examined the effects of altering the expression of donor major histocompatibility complex (MHC) antigens on the development of chronic rejection. RESULTS: We found that long-surviving mouse kidney allografts develop pathological abnormalities that resemble chronic rejection in humans. Furthermore, the absence of MHC class I or class II antigens did not prevent the loss of graft function nor alter the pathological characteristics of chronic rejection. Expression of transforming growth factor-beta (TGF-beta), a pleiotropic cytokine suggested to play a role in chronic rejection, was markedly enhanced in control allografts compared with isografts. However, TGF-beta up-regulation was significantly blunted in MHC-deficient grafts. Nonetheless, these differences in TGF-beta expression did not affect the character of chronic rejection, including intrarenal accumulation of collagens. CONCLUSIONS: Reduced expression of either class I or II direct allorecognition pathways is insufficient to prevent the development of chronic rejection, despite a reduction in the levels of TGF-beta expressed in the allograft. This suggests that the severity of chronic rejection is independent of the level of MHC disparity between donor and recipient and the level of TGF-beta expression within the allograft. (+info)
Dialysis modality and the risk of allograft thrombosis in adult renal transplant recipients.
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BACKGROUND: Renal vascular thrombosis (RVT) is a rare but catastrophic complication of renal transplantation. Although a plethora of risk factors has been identified, a large proportion of cases of RVT is unexplained. Uremic coagulopathy and dialysis modality may predispose to RVT. We investigated the impact of the pretransplant dialysis modality on the risk of RVT in adult renal transplant recipients. METHODS: Renal transplant recipients (age 18 years or more) who were enrolled in the national registry between 1990 and 1996 (N = 84,513) were evaluated for RVT occurring within 30 days of transplantation. Each case was matched with two controls from the same transplant center and with the year of transplantation. The association between RVT and 18 factors was studied with multivariate conditional logistic regression. RESULTS: Forty-nine percent of all cases of RVT (365 out of 743) occurred in repeat transplant recipients with an adjusted odds ratio (OR) of 5.72 compared with first transplants (P < 0.001). There were a significantly higher odds of RVT in peritoneal dialysis (PD)-compared with hemodialysis (HD)-treated patients (OR = 1.87, P = 0.001). Change in dialysis modality was an independent predictor of RVT: switching from HD to PD (OR = 3.59, P < 0.001) and from PD to HD (OR = 1.62, P = 0.047). Compared with primary transplant recipients on HD (OR = 1.00), the highest odds of RVT were in repeat transplant recipients treated with PD (OR = 12.95, P < 0.001) and HD (OR = 4.50, P < 0.001). Other independent predictors of RVT were preemptive transplantation, relatively young and old donor age, diabetes mellitus and systemic lupus erythematosus as causes of end-stage renal disease, recipient gender, and lower panel reactive antibody levels (PRAs). CONCLUSIONS: The strongest risk factors for RVT were retransplantation and prior PD treatment. Prevention of RVT with perioperative anticoagulation should be studied in patients who have a constellation of the identified risk factors. (+info)
Adhesion molecule polymorphisms in chronic renal allograft failure.
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BACKGROUND: Chronic allograft failure (CAF) is a major cause of late graft loss in renal transplantation. Up-regulation of adhesion molecules has been demonstrated in renal allograft biopsies during both acute and chronic rejection, and these molecules are known to regulate leukocyte migration into the graft. METHODS: A single-center retrospective study was performed between 1985 and 1996 on renal transplant recipients who developed CAF. Genotyping was performed for five polymorphisms in intercellular adhesion molecule-1 (ICAM-1), E-selectin, and L-selectin. Frequency data for the polymorphisms in the CAF group (N = 62) and their matched donors, where available (N = 33), were compared with a group of recipients with graft survival of more than 10 years (N = 110) and a group of United Kingdom (UK) controls (N = 101). RESULTS: A variant allele in exon 4 of ICAM-1 (R241) was more common in the CAF recipients compared with both long-term survivors and UK controls (19.4 vs. 10.0 and 9.4%, P = 0.015 and 0.025). In addition, stratification by time to graft failure caused by CAF revealed more rapid failure in the presence of another ICAM-1 variant in the recipient (E469) in exon 6 (P = 0.033). CONCLUSIONS: ICAM-1 polymorphisms may represent a predetermined genetic risk factor for CAF. The polymorphism in exon 4 is in the Mac-1 binding site, and that in exon 6 is in the fifth immunoglobulin-like domain. Potential mechanisms of action of ICAM-1 variants in CAF include an alteration of activity as an adhesion molecule, altered costimulation, or a minor histocompatibility antigen. (+info)
Sex hormones and gender-related differences: their influence on chronic renal allograft rejection.
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BACKGROUND: Renal hemodynamics and immune responses differ between males and females. Thus, sex hormones and genetically determined gender differences may determine the process of chronic rejection to some extent. METHODS: Female (F) or male (M) F344 kidneys were orthotopically transplanted into ovariectomized female Lewis recipients and were treated for 16 weeks with either estradiol, testosterone, or vehicle. RESULTS: Testosterone treatment resulted in increased urinary protein excretion independently of the donor gender, as well as extended glomerular sclerosis, interstitial fibrosis, and severe vascular lesions. Additionally, mononuclear cell infiltration was most pronounced in these animals, in parallel to an increased expression of intercellular adhesion molecule-1 (ICAM-1), fibronectin, laminin, and transforming growth factor-beta (TGF-beta) in the grafts. Estradiol treatment resulted in an improved graft function, reduced glomerular sclerosis, and a diminished cellular infiltration, in parallel to a reduced ICAM-1, fibronectin, laminin, and TGF-beta expression. In animals treated with vehicle, the gender of the donor influenced the outcome. Grafts of male origin had good graft function and histology, whereas grafts from female donors developed severe proteinuria and glomerular, interstitial, and vascular damage. CONCLUSIONS: These results suggest that a protective effect of estradiol on the progression of chronic rejection exists that is independent of donor gender. Additionally, a male kidney may benefit from the absence of testosterone, whereas the function of a female kidney deteriorates in the absence of estradiol. (+info)
Bone loss in long-term renal transplantation: histopathology and densitometry analysis.
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BACKGROUND: There is little information of the spectrum and factors implicated in the bone loss in long-term renal transplantation, and virtually no data using both histomorphometric and densitometric analysis. METHODS: Twenty-three males and 22 females (13 postmenopausal) were studied with a bone biopsy and densitometry. Sixteen patients were on cyclosporine A monotherapy, 20 on azathioprine + prednisolone, and 9 on cyclosporine A + prednisolone or triple therapy. The mean time after transplantation was 127 +/- 70 months. RESULTS: No group had a significant decrease in bone mineral density (BMD) of the axial skeleton compared with an age- and sex-matched normal population. Compared with sex-matched young controls, osteopenia was observed in all groups at the femoral neck (except premenopausal women and triple therapy) and in the triple-therapy group at the L1-L4 spine region. At the distal radius, osteopenia was found in all the groups. Histopathological diagnosis was mixed uremic osteodystrophy in 46.5%, adynamic bone in 23.2%, hyperparathyroid disease in 13.9%, and normal bone in 16.3%. The diagnosis was not different according to immunosuppressive therapy, but men tended to show more mixed uremic bone disease. There was no significant difference in BMD between histopathological subtypes. In general, patients showed slight osteoclast function increase, osteoblast function decrease, and marked retardation of dynamic parameters. The cyclosporine A monotherapy group had a significantly lower appositional rate than azathioprine + prednisolone. Men had a significantly lower bone volume than women, and premenopausal women had a significantly lower mineralizing surface than postmenopausal women and men. In the multivariate analysis, male gender, time after transplantation, old age, and time on dialysis prior to transplantation were significant predictive factors for a negative effect on bone mass. CONCLUSIONS: Long-term renal transplant-patients showed reduced BMD in both trabecular and cortical bone. This reduction in BMD was not as severe as in short-term reports and was associated with osteoclast stimulation, osteoblast suppression, and retardation of mineral apposition and bone formation rates. Bone mass loss was not different between the immunosuppression therapy groups. Male gender and age were the strongest predictive factors for low bone mass. (+info)
Immunomodulatory functions of low-molecular weight hyaluronate in an acute rat renal allograft rejection model.
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Low molecular weight hyaluronate (LMW-HA) blocks interactions between T lymphocyte CD44 and hyaluronate (HA), a heteropolysaccharide that is expressed on the surface of endothelial cells and ubiquitously in the extracellular matrix. This study was undertaken to assess the ability of LMW-HA to modify the course of experimental acute renal allograft rejection. Lewis (LEW) rats were bilaterally nephrectomized and received an orthotopic, fully MHC-mismatched, Wistar-Furth (WF) kidney transplant. Animals received either no treatment, low doses of cyclosporin A (CsA) on days 0 to 5, LMW-HA on days 0 to 5, or CsA plus LMW-HA on days 0 to 5 after transplantation. With no treatment, CsA monotherapy, or HA monotherapy, animals rejected their allografts at a median of 15, 13, and 7.5 d, respectively (P = NS). In contrast, combined CsA plus LMW-HA therapy prevented acute rejection and significantly prolonged graft survival (P = 0.008) to a median of 49.0 d. CsA/LMW-HA-treated grafts also demonstrated better preservation of renal function at day 30 (serum creatinine level, 1.38+/-0.8 mg/dl), compared with surviving animals treated with CsA alone (2.9+/-0.55 mg/dl, P<0.05). Histologic graft analysis of CsA/LMW-HA-treated animals at day 7 after transplantation showed minimal rejection and leukocyte infiltration, compared with all other groups. Intragraft gene expression analysis, using semiquantitative reverse transcription-PCR, at the same time point showed reductions of CD4, CD8, and interferon-gamma transcript levels in the combined-treatment group. This is the first study demonstrating the immunomodulatory functions of LMW-HA in vivo in the setting of organ transplantation. Defining the exact mechanisms that underlie this immunomodulation may provide the rationale to develop novel strategies for use in clinical transplantation. (+info)
Body composition in renal transplant patients: bioimpedance analysis compared to isotope dilution, dual energy X-ray absorptiometry, and anthropometry.
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Whether multifrequency bioelectrical impedance analysis (MF-BIA), a relatively new method for measuring body composition, is also applicable for accurate body composition measurements in renal transplant (RTx) patients is not known. Therefore, the use of MF-BIA is validated in 77 RTx patients with a stable renal function at least 2 yr posttransplantation. MF-BIA is compared to isotope dilution techniques for measurement of body water compartments, and to dual energy x-ray absorptiometry (DEXA) and anthropometry for measurement of fat and fat free mass. Finally, DEXA and anthropometry are compared to each other. Method agreement is assessed by intraclass correlation coefficients (ICC) and plotted by Bland and Altman analysis. MF-BIA significantly underestimates total body water (TBW, 0.7+/-2.1 L) and overestimates the extracellular water (ECW, 3.3+/-1.8 L) compared to isotope dilution; the ICC between both techniques is 0.943 for TBW and 0.846 for ECW. The percentage body fat (BF) measured by MF-BIA is significantly higher than both BF measured by DEXA (3.4+/-4.7%) or by anthropometry (5.5+/-5.2%). The ICC between MF-BIA and DEXA is 0.887 and between MF-BIA and anthropometry 0.856. BF measured by DEXA is significantly higher than BF measured by anthropometry (2.1+/-4.4%); their ICC is 0.913. In conclusion, MF-BIA seems to be suitable for measurement of TBW in RTx patients; however, method agreement between isotope dilution and MF-BIA for the measurement of ECW is not satisfactory. In the assessment of fat and fat free mass, the reliability of MF-BIA appears to be questionable. Method agreement between DEXA and anthropometry seems to be slightly better. (+info)