Başkent Üniversitesi Makaleler
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Item Severe Tacrolimus Toxicity in Rabbits(Başkent Üniversitesi, 2007-06) Giessler, Goetz A.; Gades, Naomi M.; Friedrich, Patricia F.; Bishop, Allen T.Objectives: Tacrolimus is an effective immunosuppressant, safely administered in clinical practice by monitoring blood levels. In experimental transplants, many dosage regimens have been reported, often without such determinations. Anorexia and organ toxicity commonly occur. We report the toxic effects of tacrolimus in rabbits receiving intramuscular injections (1 mg/kg/d) and the subsequent dosage modifications that resulted in improved animal survival without toxic effects. Materials and Methods: To obtain nontoxic drug concentrations in the blood, 3 dosage regimens were required. Drug concentrations were targeted using therapeutic human values as a guide (range, 5-20 ng/mL). First, a group of 12 Dutch Belted rabbits received vascularized femoral allografts and were treated with intramuscular dosages of tacrolimus (1 mg/kg/d) for 14 days. Subsequently, dosage reductions in 10 more rabbits, to 0.2 mg/kg/d for 14 days, were necessary. Finally, another group of 20 rabbits was treated with 0.08 mg/kg for 3 days, and then every other day thereafter. Weight loss > 30%, cardiopulmonary failure, and/or creatinine levels > 221 µmol/L were the criteria approved by our local Institutional Animal Care and Use Committee for euthanizing the animals. Treated animals were compared with 20 nonimmunosuppressed controls that underwent the same operation. Results: At an intramuscular dosage of 1 mg/kg/d, the mean tacrolimus blood level was 90.7 ng/mL. Ten of the 12 animals in the original group died or required euthanasia. At necropsy, renal failure, cardiac abnormalities, and pulmonary edema were found. The tacrolimus dosage of 0.2 mg/kg/d produced a mean tacrolimus blood level of 17.6 ng/mL; however, 8 of the subsequent 10 rabbits died when given this dosage. Ultimately, the 0.08 mg/kg regimen in 20 rabbits permitted survival of 18 animals with a mean tacrolimus blood level of 6.8 ng/mL. None of 20 nonimmunosuppressed controls died after surgery. Conclusions: For successful immunosuppression, Dutch-Belted rabbits require intramuscular tacrolimus dosages lower those required in other rabbit breeds. This has not been reported previously. The 0.08 mg/kg/d dosage combined with intermittent drug level monitoring permits survival without significant complications.Item Cytomegalovirus Disease with Atypical Presentation in a Renal Transplant Patient: Case Report(Başkent Üniversitesi, 2006-06) Khosravi, Masoud; Nobakht, Ali; Nikokar, Abdolah R.Infection is a major problem after kidney transplantation. Cytomegalovirus (CMV) is the most common viral infection affecting transplant patients. This report presents a rare clinical manifestation of CMV in the form of a hemorrhoid in a 58-year-old woman. One week after undergoing an external hemorrhoidectomy, the patient presented with fever, leukopenia, and thrombocytopenia. Pathological analysis showed CMV in the hemorrhoidal tissue, which was confirmed via a positive PP65 antigenemia assay. Therapy with ganciclovir (250 mg IV b.i.d. for 2 weeks) was started. The patient’s response to treatment was good, and she has been doing well since that time. Her plasma creatinine level 2 years later was 79.2 µmol/L (normal range, 53-106 µmol/L). Physicians must always be aware of the hazards of CMV in immunocompromised patients with typical, and even with atypical, presentations. Taking into consideration the statement, “prophylaxis precedes treatment,” nephrologists must try to detect CMV in their patients (especially during the first 6 months after transplantation) prior to the appearance of any clinical manifestations. If CMV is detected, pre-emptive therapy with ganciclovir should be started.Item Ischemic Training and Immunosuppressive Agents Reduce the Intensity of Ischemic Reperfusion Injury after Kidney Transplantation(Başkent Üniversitesi, 2006-06) Treska, Vladislav; Molacek, Jiri; Kobr, Jiri; Racek, Jaroslav; Trefil, Ladislav; Hes, OndrejObjectives: Ischemia-reperfusion injury affects posttransplant renal function, directly increases the probability of acute rejection, and is associated with chronic rejection and impaired long-term function. Animal studies suggest that ischemic preconditioning enhances resistance to ischemia and may be augmented by treating donors using immunosuppressant agents. This study sought to confirm the hypothesis that a combination of ischemic training and immunosuppression prior to renal harvest would maximize a transplanted kidney’s resistance to ischemia-reperfusion injury. Materials and Methods: Landrace pigs underwent either preharvest immunosuppression plus left kidney ischemic training (group 1, n = 6) or ischemic training alone (group 2, n = 6). Immunosuppression was composed of mycophenolate mofetil (20 mg/kg) and tacrolimus (0.1 mg/kg) administered intravenously 30 minutes before training. Training comprised 2 cycles of left renal pedicle occlusion for 5 minutes followed by release (reperfusion) for 10 minutes. Warm renal ischemia was then induced by clamping the left renal pedicle for 30 minutes, followed by heterotopic left kidney transplantation. Blood from the transplanted kidney renal vein was sampled directly at 0, 10, 20, 40, and 60 minutes posttransplantation for malondialdehyde (a reactive oxygen species marker), tumor necrosis factor-alpha (TNFα), interleukins 6 and 8 (inflammatory cytokines), and erythrocyte-reduced glutathione (an antioxidant). Renal histology was graded on a 3-point scale. Results: Reperfusion levels of malondialdehyde, TNFα, and interleukin 6 were significantly lower in group 1 at both 40 and 60 minutes. None of the animals in group 1 (0/6) that received preharvest immunosuppression showed severe interstitial inflammation, compared with 4 of 6 animals in group 2 that did (P < .03). Conclusions: Preharvest immunosuppression with mycophenolate mofetil and tacrolimus significantly decreases immediate posttransplant reactive oxygen species and inflammatory cytokine production, enhances the protective effect of ischemic training, and should not only reduce ischemia-reperfusion injury in transplanted kidneys but also should enhance immediate and long-term graft function while preventing acute rejection.Item Immunosuppressive Strategies in Organ Transplantation in the Light of Innate Immunity(Başkent Üniversitesi, 2006-06) Land, Walter GottliebEvidence has accumulated to support the notion that injury-induced activation of the donor’s and the recipient’s innate immune system largely determines the outcome of organ transplantation. Future potential therapeutic strategies to suppress events of both innate immune systems, as well as approaches to mitigate allograft injury, are discussed with regard to inhibiting both complement activation and dendritic cell maturation, and to blocking innate effector functions. Applications of pharmacological drug therapy as well as gene-specific manipulations are theoretical tools to reach these goals. A variety of encouraging experimental data in this research field are already available and promise further discoveries that ultimately will lead to the design of appropriate clinical trials.Item Cyclosporine Lymphocyte Maximum Level Monitoring in De Novo Kidney Transplant Patients: A Prospective Study(Başkent Üniversitesi, 2006-06) Barbari, AG; Masri, MA; Stephan, AG; Ghoul, B El; Rizk, S; Mourad, N; Kamel, GS; Kilani, HE; Karam, ASObjectives: To determine prospectively the temporal variations of cyclosporine-A lymphocyte maximum level, whole blood maximum concentration, and total lymphocyte count in patients with de novo kidney transplantation. Materials and Methods: Lymphocyte maximum level, whole blood maximum concentration, and total lymphocyte count were prospectively measured in 35 patients at 1, 2, and 3 months after kidney transplantation. Two groups—a biopsy-proven acute rejection group (REJ+) and a rejection-free group (REJ-)—were compared. Results: Both groups had similar lymphocyte maximum levels, whole blood maximum concentrations, and total lymphocyte counts at the first month after transplantation. REJ+ patients had significantly lower lymphocyte maximum levels at 2 and 3 months (59 ± 34 and 33 ± 9 pg/Lc) and higher total lymphocyte counts (0.00204 ± 0.00078 x 109/L and 0.00203 ± 0.00022 x 109/L) when compared with their REJ- counterparts (87 ± 56 and 63 ± 30 pg/Lc, P < .05 and P < .007) and (0.00137 ± 0.00074 x 109/L and 0.0015 ± 0.0006 x 109/L, P < .02 and P < .003) respectively. Whole blood maximum concentrations were significantly higher in patients in the REJ+ group (2050 ± 623 vs 1414 ± 536 ng/mL, P < .02) at 2 months. At 3 months, the 2 groups were comparable (1158 ± 340 vs 1365 ± 525 ng/mL, P = NS). Conclusions: These results suggest that acute rejection is associated with a relatively low cyclosporine-A lymphocyte maximum level and high total lymphocyte count in the early posttransplant period. Cyclosporine-A whole blood maximum concentration failed to correlate with clinical outcome. Cyclosporine-A lymphocyte maximum level seems to offer a more reliable alternative than does whole blood maximum concentration for cyclosporine-A monitoring in patients with kidney transplantation.Item Intravenous Mycophenolate Mofetil with Low-Dose Oral Tacrolimus and Steroid Induction for Live Donor Liver Transplantation(Başkent Üniversitesi, 2005-12) Jain, Ashok; Mohanka, Ravi; Orloff, Mark; Abt, Peter; Kashyap, Randeep; Kelley, Mark; Burlee, Kari; Bozorgzadeh, AdelObjectives: Mycophenolate mofetil (MMF) is used in liver transplantation (LTx) to reduce rejection, nephrotoxicity, neurotoxicity, and the need for steroids. Lower trough concentrations and bioavailability have been reported with oral MMF in first week after LTx. These parameters improve after the first month postoperatively. Previously published studies have used oral formulations of MMF. In this study, we sought to examine survival, rejection, and nephrotoxicity rates using IV MMF in live donor liver transplantation (LDLT). Patients and Methods: Twenty-eight patients (mean age, 50.1 years; 15 men, 13 women) were examined between January 2000 and January 2004 with a mean follow-up of 17 months for survival, rejection, and renal function. Results: Four patients died at 2, 5, 8, and 18 months after LDLT from sepsis (n = 3) and recurrent hepatocellular carcinoma (n = 1). There were no retransplants; hence, patient and graft survival rates were the same (82.4%). Three patients (10.7%) experienced acute cellular rejection requiring treatment. The mean serum creatinine level prior to LDLT was 0.9 ± 0.4 mg/dL, which remained stable throughout the study. One patient required hemodialysis during the perioperative period for 8 days. Conclusions: In the current study, we demonstrate a new strategy of IV MMF administration with low-dose tacrolimus that provides for lower rates of acute rejection, better preservation of renal function, and one that is better tolerated compared with historical treatments after LTx.Item Induction Therapy(Başkent Üniversitesi, 2005-06) Bakr, Mohamed A.Transplantation is a suitable option for patients with end-stage organ failure. Many immunosuppressive agents are available, and this may pose difficulty in choosing an appropriate combination for maintenance therapy, treating episodes of acute rejection of varying severities, and tailoring therapies for specific patients. Induction therapy strategies are accomplished either by relatively high doses of conventional immunosuppressants or by using poly- or monoclonal antibodies. These antibodies are an integral part of transplant medicine today. The rationale for antibody therapy aims at augmenting immunosuppression, ensuring that delayed introduction of calcineurin inhibitors is safe, encouraging steroid withdrawal, and facilitating treatment of patients sensitized to human leukocytic antigens in addition to its crucial role in immunologic conditioning either by tolerance induction or alternatively minimizing the immunosuppressive drugs. Different trends in induction therapy initially consisted of anti-thymocyte globulin, then anti-CD3 Orthoclone, and finally anti-CD20, 25, and 52 agents. Induction therapy is associated with beneficial short- and long-term outcomes when increased risk of adverse effects related to immune system suppression are an issue, especially from cytomegalovirus and lymphomas.Item Cyclosporine Lymphocyte Maximum Level: A New Alternative for Cyclosporine Monitoring in Kidney Transplantation(Başkent Üniversitesi, 2005-06) Barbari, Antoine G.; Stephan, Antoine G.; Masri, Marwan A.; Mourad, Nina; El-Ghoul, Balsam; Kamel, Gaby S.; Kilani, Hala E.; Karam, Albert S.Objectives: To determine the relationship between clinical outcome, lymphocyte count (LC), and cyclosporine (CsA) lymphocyte maximum level (LTmL) in kidney transplant recipients. Materials and Methods: CsA LTmL was determined in patients with biopsy-proven graft dysfunction and in patients with normal graft function. Clinical outcome was compared according to CsA LTmL, dosage, blood trough (C0) and maximum (Cmax) levels, hematocrit level, and LC. Results: Rejecting patients had significantly lower LTmL than did those with normal graft function (27 ± 11 pg/Lc vs 71 ± 79 pg/Lc; P < 0.01) and similar LTmL to those with nephrotoxicity (27 ± 8 pg/Lc). Patients with normal graft function exhibited significantly lower LC (0.001292 ± 696 x 109/L) and serum creatinine levels (88.4 ± 35 µmol/L) when compared with rejecting patients (0.001717 ± 364 x 109/L, 132.6 ± 8.8 µmol/L) and those with nephrotoxicity (0.001884 ± 582 x 109/L, 123.7 ± 8.8 µmol/L) (P < 0.03, P < 0.001). No significant difference was observed among the 3 groups with regard to CsA dosage, C0, Cmax, mycophenolate mofetil (MMF) dosage, and mycophenolic acid (MPA) plasma levels. CsA LTmL closely correlated in an exponential (R2 = 0.98) and linear (R2 = 0.35) fashion with LC and hematocrit level, respectively. Conversely, CsA Cmax failed to correlate with C0 and these 2 latter parameters. Weak correlations were observed between CsA Cmax and its corresponding LTmL. Conclusions: CsA LTmL appears to correlate better than CsA Cmax with rejection-free outcome and LC. An increase in hematocrit appears to have an adverse effect on CsA lymphocyte binding. CsA LTmL may offer a new alternative for CsA monitoring in kidney transplantation.Item The Beginning of Clinical Tolerance in Solid Organ Allografts(Başkent Üniversitesi, 2004-06) Monaco, Anthony PDevelopment of effective multidrug immunosuppressive regimens and improvements in the management of chronically immunosuppressed patients have produced extraordinary patient and allograft survival in clinical organ transplantation. Unfortunately, significant problems of morbidity and mortality related to chronic immunosuppression remain. Thus, there is an enormous motivation and interest in inducing specific unresponsiveness (tolerance) to clinical solid organ allografts. Operational clinical tolerance may be defined as stable, normal graft function in the total absence of a requirement for maintenance immunosuppression. Alternatively, the concept of employing tolerogenic strategies to permit graft acceptance with dramatically reduced immunosuppression requirements is referred to as prope’ or minimal immunosuppression tolerance. There have been isolated examples of clinical tolerance, usually in the context of spontaneous or induced donor chimerism, excellent HLA matching, and/or drug weaning or patient noncompliance. The various attempts that are currently being employed to induce some type of clinical tolerance are reviewed in this manuscript. Strategies in which all immunosuppression was to be withdrawn from the recipient (donor-specific unresponsiveness) are first discussed. These include strategies that utilize initial immunoablation with varying doses of irradiation and/or lymphocytic antibodies with or without donor-specific bone marrow infusion and short-term standard immunosuppressive therapy. Strategies to induce prope’ or minimal immunosuppression tolerance that utilize induction lymphoablation with poly-clonal or monoclonal antilymphocyte antibodies, with or without donor bone marrow infusion, followed by limited low-dose immunosuppressive therapy are also discussed. The ethical considerations in testing clinical tolerance strategies and protocols are discussed in detail. The limited number of clinical tolerance studies already available affirms that carefully supervised weaning of immunosuppressive drugs in controlled tolerance trials is not unreasonable, especially when monitored by protocol allograft biopsies. Initial results suggest that aggressively treated low-grade steroid-responsive rejection reactions in the absence of immune-mediated tissue destruction does not necessarily require resumption of high-dose immunosuppression. Finally, the role of donor bone marrow infusions in facilitating tolerance/hyporesponsiveness induction needs to be studied and expanded.Item Induction of Immunosuppression with Polyclonal Antithymocyte Globulins: An Overview(Başkent Üniversitesi, 2003-12) Beiras-Fernandez, A.; Thein, E.; Hammer, C.The induction of immunological tolerance to solid organ allograft is currently a subject of major investigation due to the morbidity and mortality related to immunosuppressive therapy. Immunosuppression induction by recipient treatment may allow to tailoring the timing and dosage of standard therapy not only reducing adverse reactions but also improving the graft outcome. Depletion of recipient T cells with polyclonal antithymocyte globulins is one of the methods nowadays investigated both in experimental and clinical procedures, demonstrating a better outcome of organ engraftment. Our intention is to give an overview of the literature about the mechanisms of action of polyclonal ATGs, the status of induction treatment in clinical and experimental transplantation as well as of the possible pathophysiological relationships with acquired tolerance, delayed graft failure and ischemia-reperfusion injury.