Başkent Üniversitesi Yayınları
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Item Influence of Endothelial Nitric Oxide Synthase Gene Polymorphisms (-786T/C, 4a4b, 894G/T) on Iranian Kidney Transplant Recipients(Başkent Üniversitesi, 2013-02) Azarpira, Negar; Ayatolahi, Maryam; Darai, Masumeh; Bahador, Ali; Geramizadeh, Bita; Aghdai, Mahdokht H.Objectives: Nitric oxide is a major mediator in vascular biology and regulator of regional blood flow. Its production is catalyzed by the enzyme endothelial nitric oxide synthase. Protective actions of nitric oxide in ischemia and reperfusion are due to its potential as an antioxidant and anti-inflammatory agent, along with its inhibitory effects on cell signaling pathways of nuclear proteins, such as NF-κB. The endothelial nitric oxide synthase gene polymorphisms affect endothelial nitric oxide synthase activity and are associated with endothelial dysfunction. This study sought to examine the association between single nucleotide polymorphisms in endothelial nitric oxide synthase gene (rs 2070744, 27VNTR, and rs1799983) and the development of acute rejection in renal transplant patients. Materials and Methods: Sixty-six renal transplant recipients (33 patients with an episode of acute rejection and 33 recipients an episode of acute rejection), between June 2010 and March 2011, were included. The polymorphism was determined by simple polymerase chain reaction and polymerase chain reaction-restriction fragment-length polymorphism analysis. Results: There was only a significant association of endothelial nitric oxide synthase -786T allele and acute rejection (P = .03). Recessive model of T-786C alleles (TT vs TC+CC) and acute rejection confirmed a significant association (odds ratio: 3.12; 95% CI: 0.01-9.83; P = .025). Haplotype CbG was higher in recipients without rejection as compared to rejection group (OR: 0.42, 95% CI: 0.16-1.13; P < .05). Respecting the endothelial nitric oxide synthase gene 894G/T single nucleotide polymorphisms and 27VNTR, no significant association between the allele/genotype and acute rejection was seen. Conclusion: Recipient endothelial nitric oxide synthase gene polymorphisms do not alter the risk of acute rejection after a renal transplant. Rejection is a complex immunologic event. Therefore, finding associated genetic variants demands a multicentric larger sample size.Item Rhinomaxillary Mucormycosis in a Renal Transplant Recipient: Case Report(Başkent Üniversitesi, 2012-12) Azarpira, Negar; Khademi, Bighan; Kazemi, Kourosh; Ashraf, Mohamd JavadObjectives: Rhinomaxillary mucormycosis is a clinical manifestation of zygomycosis in solid-organ transplant recipients. Without proper diagnosis and treatment, rhino-orbital-cerebral zygomycosis, particularly a central nervous system disease, will develop with substantial complications. Case report: A 42-year-old man who had undergone renal transplant was admitted to our otolaryngology department with unilateral bloody nasal discharge. Mucormycosis was detected in the necrotic tissue of the maxillary sinus. Surgical ablation of the infected parts, along with antifungal treatment, restricted extension of the infection. Conclusions: Early detection of opportunistic infections in transplant recipients plays an important role in preventing dissemination. Fungal infections, including zygomycosis, should be considered in all solid-organ recipients, especially in persons with local unusual manifestations. Early diagnosis and successful treatment reduce mortality.Item Vitamin D Receptor Genotype in Pancreas Allograft: A Pilot Study(Başkent Üniversitesi, 2012-10) Rahsaz, Marjan; Esfandiari, Elaheh; Aghdaie, Mahdokht Hossein; Daraie, Masumeh; Karimi, Mohammad Hossein; Yaghubi, Ramin; Ayatollahi, Maryam; Geramizadeh, Bita; Nikeghbalian, Saman; Azarpira, NegarObjectives: Transplanting of pancreatic grafts is an established treatment for diabetes mellitus. Polymorphisms in genes, coding for proteins involved in an immune response, may influence immunologic and nonimmunologic mechanisms that lead to allograft loss. Vitamin D receptor agonists have been shown to increase long-term allograft survival in humans. Materials and Methods: Twenty-one pancreatic recipients transplanted in the Transplantation center of Shiraz University of Medical Sciences were selected and genotyped for the polymorphism of the vitamin D receptor genes (FokI), and the association of each genotype with acute rejection was evaluated. A control group of 100 unrelated otherwise healthy individuals, from the Iranian Blood Transfusion Organization were enrolled. The individuals were selected from Shiraz (a city located in Southern Iran), and the genotype frequency was compared with control group. Results: The overall prevalence acute rejection was 28% (6/21). In the genotype study, homozygous FF presented in 15 patients (71%), heterozygous Ff presented in 6 patients (29%), and no homozygous ff was identified. In the control group, there were 50% with FF, 48% with Ff, and 2% with the ff genotype identified. The only genotype that was detected in rejection group was FF, while the frequency of FF in the nonrejection group was 60%. Conclusions: This study examined several patients to determine whether the vitamin D receptor (FokI) genotype is involved in acute allograft rejection and requires deeper investigation.Item Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population(Başkent Üniversitesi, 2012-02) Rahsaz, Marjan; Aghdaie, Mahdokht H.; Banihashemi, Mehrzad; Malekhoseini, Seid Ali; Malekpour, Zahra; Darai, Masumeh; Moini, Maryam; Geramizadeh, Bita; Nikeghbalian, Saman; Azarpira, NegarObjectives: Tacrolimus is widely used as an immunosuppressive drug in liver transplant recipients with a narrow therapeutic range and variable individualized pharmacokinetics. Tacrolimus is a substrate of cytochrome P-450 3A enzyme and the drug transporter, P-glycoprotein. Materials and Methods: We determined the genotypic frequencies of cytochrome P-4503A5 (rs776746), and ABCB1 (rs1045642), single nucleotide polymorphisms in a population of 100 Iranian liver transplant patients, and investigated the influence of the above-mentioned single nucleotide polymorphisms on tacrolimus concentrations. At 7 and 30 days after transplant, tacrolimus dosages (mg/kg/d), trough blood levels (T0), and dose-adjusted concentrations (concentration/dosage ratio) were determined. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis, was used for genotyping cytochrome P-4503A5*3 [6986A>G] as well as ABCB1 [3435C>T]. Results: Ninety-five percent of the population showed a cytochrome P-4503A5*3/*3 genotype. ABCB13435TT genotype was observed in 33 cases (33%); whereas 51 cases (51%) carried 3435CT, and 16 cases (16%) carried 3435CC. With regard to the ABCB1 and cytochrome P-4503A5, they showed no influence on tacrolimus dosing requirements at 1 week or 1 month after transplant. No association of any genetic variant with the acute rejection rate was found. Conclusions: Finally, as the liver donor genotype influences tacrolimus pharmacokinetics with regard to expression of cytochrome P-4503A5, far more than the genotype of the recipient; therefore, it should be considered before recommending any personal immunosuppressive treatment based on pharmacogenetics.Item Thiopurine S-Methyltransferase Polymorphism in Iranian Kidney Transplant Recipients(Başkent Üniversitesi, 2011-08) Aghdaie, Mahdokht Hossein; Malekhoseini, Seid Ali; Rahsaz, Marjan; Darai, Masumeh; Sagheb, Mehdi; Geramizadeh, Bita; Azarpira, NegarObjectives: Thiopurine S-methyltransferase is an enzyme that catalyzes S-methylation of azathioprine as an immunosuppressive drug. Genetic polymorphisms influence thiopurine S-methyltransferase activity. There are 3 variant alleles: thiopurine S-methyltransferase*2, *3A, and *3C are responsible for more than 95% cases of low-enzyme activity. Materials and Methods: We studied these polymorphisms and the occurrence of azathioprine adverse effects in 50 renal transplant recipients undergoing triple immunosuppressive therapy including azathioprine, cyclosporine, and prednisone. Thiopurine S-methyltransferase genetic polymorphism was determined by polymerase chain reaction restriction fragment length polymorphism assay and allele-specific polymerase chain reaction methods. Azathioprine dosage; leukocyte, erythrocyte, and platelet counts; and graft rejection episodes were analyzed during hospitalization. Results: Two patients (2%) were heterozygous for thiopurine S-methyltransferase*3C, the remaining patients were thiopurine S-methyltransferase wild-type *1/*1 (98%). Thiopurine S-methyltransferase wild-type homozygous and heterozygous patients were administered similar azathioprine dosages at the beginning of treatment (2.42 ± 0.50 and 2.52 ± 0.40 mg/kg/24 h). During subsequent days, mean azathioprine dosage administered to thiopurine S-methyltransferase wild-type homozygous patients was similar to heterozygous patients, but with no statistical difference (P = .28). Three patients had an acute rejection episode during this time. Five patients (10%) had reduced azathioprine dosage owing to adverse effects. Adverse reactions consisted of hematotoxicity (n=2), hepatotoxicity (n=1), and gastrointestinal toxicity (n=2). All recipients were wild-type homozygotes. Conclusions: The frequency of thiopurine S-methyltransferase gene mutations is low among our patients. The incidence of adverse reactions to azathioprine was also low, even in patients carrying a variant of thiopurine S-methyltransferase. We conclude that determining thiopurine S-methyltransferase genotype is not useful in our population to predict adverse reactions to azathioprine.Item Vitamin D Receptor Polymorphisms in Liver Transplant Recipients(Başkent Üniversitesi, 2010-12) Azarpira, Negar; Daraie, Masumeh; Geramizadeh, Bita; Salahi, HeshmatolahObjectives: Liver transplant is an established treatment for end-stage liver failure. Vitamin D has been shown to exert multiple immunomodulatory effects, which act through its own receptor (vitamin D receptor). In the present study, the association between Iranian patients with liver transplant and the polymorphism of vitamin D receptor FokI T>C (rs10735810) was investigated. Materials and Methods: The candidate gene locus was genotyped in 51 liver transplant recipients, and the association of each genotype with allograft acute rejection was evaluated. Results: In this study, we found no evidence to suggest that vitamin D receptor FokI polymorphism determines the incidence of acute rejection after liver transplant. The distribution of alleles was not different according to the underlying liver disease. Conclusions: Larger epidemiologic studies are needed to elucidate the importance of vitamin D receptor gene polymorphism in transplant recipients.Item CTLA4 CT60 A/G Gene Polymorphism in Liver Transplant Recipients(Başkent Üniversitesi, 2010-09) Azarpira, Negar; Daraie, Masumeh; Aghdaie, Mahdokht Hosein; Malekhosseini, Seyed AliObjectives: Cytotoxic T-lymphocyte antigen 4 (CTLA4) has a critical role in the down-regulation of the immune response. We retrospectively examined the association between acute rejection and the single nucleotide polymorphism A/G in the CTLA-4 CT60 gene in liver transplant recipients. Materials and Methods: Fifty-one liver transplant recipients with at least 3 months’ follow-up were selected and genotyped for CTLA-4 CT60 polymorphism (HpyCH4 IV). The association of each genotype with allograft acute rejection was evaluated. Results: The mean age of patients was 27.9 ± 15.17 years (minimum, 1 year, maximum, 55 years), with 39% male and 61% female. Overall, 17 recipients (33.3%) experienced acute rejection within the first 3 months after a liver transplant. In our study, 50% of the patients (n=26) have G/A , 31% (n=16) have A/A, and 17% have G/G genotypes (n=9). Distribution of alleles was not different according to underlying liver disease. There also was no difference in sex, age, and distributions of CTLA-4 CT60 alleles with acute rejection episodes. Conclusions: CT60 A/G dimorphism within the 3'-UTR of CTLA4 gene does not influence acute rejection development in liver transplant. However, organ rejection is determined by a combination of several genetic traits rather than a single gene. Therefore, more studies with larger patient numbers are necessary to investigate the effect of combinations of genetic phenotypes involved in this process.Item Procalcitonin and C-reactive Protein Serum Levels After Hematopoietic Stem-Cell Transplant(Başkent Üniversitesi, 2009-06) Azarpira, Negar; Daraie, Masumeh; Aghdaie, Mahdokht; Ramzi, ManiObjectives: Hematopoietic stem-cell transplant is a curative therapy for several malignant and nonmalignant disorders. The purpose of this study was to investigate the association of serum levels of high-sensitivity C-reactive protein and procalcitonin with complications such as acute graft-versus-host disease, veno-occlusive disease, and infection after hematopoietic stem-cell transplant. Materials and Methods: Serum high-sensitivity C-reactive protein and procalcitonin levels were sequentially measured with an enzyme-linked immunosorbent assay and a semiquantitative immunochromatographic assay in 35 patients who had undergone hematopoietic stem-cell transplant. Results: The high-sensitivity C-reactive protein serum level was increased in patients with acute graft-versus-host disease and in those with sepsis. Increased procalcitonin levels were associated only with bacterial infection. Only procalcitonin levels differentiated patients with infection from those with another transplant-related complication. Veno-occlusive disease did not alter C-reactive protein or procalcitonin levels. Conclusions: Our results support theories that serum levels of high-sensitivity C-reactive protein and procalcitonin are biomarkers for transplant-related complications such as graft-versus-host disease or infection and that the procalcitonin level can differentiate patients with infection from those with graft-versus-host disease.Item Brain Tumor as an Unusual Presentation of Posttransplant Lymphoproliferative Disorder(Başkent Üniversitesi, 2009-03) Azarpira, Negar; Rakei, Mohamad; Torabineghad, SiminObjectives: Posttransplant lymphoproliferative disorder following solid organ transplant is a life-threatening form of posttransplant malignancy. Its occurrence is typically associated with Epstein-Barr virus and profound immunosuppressive therapy. We describe a case of posttransplant lymphoproliferative disorder in the brain parenchyma, 4 years after renal transplant. Case Report: A 23-year-old man was evaluated for generalized headache 4 years after receiving a deceased donor renal transplant. After initial immunosuppression with tacrolimus and prednisolone, mycophenolate mofetil was added for maintenance immunosuppression. A tumor in the right occipitoparietal lobe was detected by magnetic resonance imaging and excised. Immunohistochemical testing of the tumor revealed B-cell marker and Epstein-Barr virus. After surgery, the dosage of immunosuppressive drugs was reduced, and the patient was treated with chemotherapy and radiotherapy. Our patient is well after treatment. Conclusions: Reduction in immunosuppressive therapy is an important component of treatment for Epstein-Barr virus-positive posttransplant lymphoproliferative disorder and may lead to remission in early disease. If reduced immunosuppression fails to control early disease, cytotoxic chemotherapy, surgery and radiotherapy, antiviral therapies, and cell-based therapies are other options for treatment.Item Interleukin-10 Gene Polymorphism in Bone Marrow Transplant Recipients(Başkent Üniversitesi, 2008-03) Azarpira, Negar; Geramizadeh, Bita; Darai, Masumeh; Aghdaie, Mahdokht Hossein; Ramzi, ManiObjectives: Graft-versus-host disease is the main complication after hematopoietic stem cell transplant, occurring even after donor and recipient human leukocyte antigen matching, apparently because of donor/recipient minor histocompatibility antigen mismatches and cytokine polymorphisms. Interleukin-10 suppresses several activities of the immune response by inhibiting T helper 1 and T helper 2 cells. These properties suggest that interleukin-10 could act as a suppressive mediator and prevent graft-versus-host disease. This study evaluates the association between the interleukin-10 promoter gene polymorphism and transplant outcomes among 18 recipients of cytokine-mobilized peripheral blood stem cells from human leukocyte antigen-matched sibling donors. Materials and Methods: We analyzed 3 single-nucleotide polymorphisms in the proximal region of the interleukin-10 promoter gene (-1082/-819/-592) by the amplification refractory mutation system and polymerase chain reaction-restriction fragment length polymorphism methods. Eighteen donors and their recipients who had undergone an allogeneic peripheral blood stem cell transplant at the Bone Marrow Transplant Center in Nemazi Hospital (Shiraz, Southern Iran) between September 2005 and September 2006 were enrolled. Results: The GCC haplotype (1082*G/819*C/592*C) was predominant in both the donor and the recipient, but no significant correlations were present between the GCC haplotype in either the donor or the recipient and the risk of acute graft-versus-host disease (P = .56). Conclusions: The interleukin-10 promoter gene polymorphism was found not to be associated with acute graft-versus-host disease in patients after an allogeneic peripheral blood stem cell transplant from human leukocyte antigen-matched sibling donors. Additional studies with larger samples are necessary to further define the influence of interleukin-10 on the immune response after bone marrow transplant.