Cigdem Kekik

FGF-23 associated with the progression of coronary artery calcification in hemodialysis patients

BackgroundDisordered mineral metabolism is implicated in the pathogenesis of vascular calcification in hemodialysis (HD) patients. Fibroblast growth factor 23 (FGF-23) is the main regulator of phosphate metabolism. In this prospective study, we aimed to investigate the association of serum FGF-23 with progression of coronary artery calcification in HD patients.MethodsSeventy-four HD patients (36 male/38 female, mean age: 52 ± 14 years) were included. Serum FGF-23 levels were measured by ELISA. Coronary artery calcification score (CACS) was measured twice with one year interval. Patients were grouped as progressive (PG) (36 patients-48%) and non-progressive (NPG).ResultsAge, serum phosphorus, baseline and first year CACS were found to be significantly higher in the PG compared to NPG group. Serum FGF-23 levels were significantly higher in PG [155 (80–468) vs 147 (82–234), p = 0.04]. Patients were divided into two groups according to baseline CACS (low group, CACS ≤ 30; high group, CACS > 30). Serum FGF-23 levels were significantly correlated with the progression of CACS (ΔCACS) in the low baseline CACS group (r = 0.51, p = 0.006), but this association was not found in high baseline CACS group (r = 0.11, p = 0.44). In logistic regression analysis for predicting the PG patients; serum FGF-23, phosphorus levels and baseline CACS were retained as significant factors in the model.ConclusionsSerum FGF-23 was found to be related to progression of CACS independent of serum phosphorus levels. FGF-23 may play a major role in the progression of vascular calcification especially at the early stages of calcification process in HD patients.

Influence of cytokine gene polymorphisms on graft rejection in Turkish patients with renal transplants from living related donors.

BACKGROUND Certain cytokine gene polymorphisms (CGPs) have been shown to be associated with renal transplant rejection episodes or graft outcomes. We sought to evaluate the relationships between gene polymorphisms and acute rejection episodes (RG, n = 19) versus stable graft function (NRG, n = 71) in transplant recipients compared with healthy control subjects (HCG, n = 150). The follow-up time period was 18 months. Using polymerase chain reaction sequence-specific primers with the Heidelberg kit we genotyped 22 single nucleotide polymorphisms distributed across 13 cytokine and cytokine receptor genes. RESULTS Interleukin (IL)-2 TT/GT haplotype was found in 36.8% of RG patients and 6.7% of HCG but not among the NRG (P < .0001; .0007). The IL-2 GG/TT haplotype was observed among 13 NRG and nine HCG patients (P = .007); the IL-2 GG/GG haplotype, 18.7% HCG and 4.2% NRG patients (P = .0033); and the IL-2 TT/TT haplotype, five NRG and eight HCG patients, but none of the RG cohort (P > .05). The transforming-growth factor-beta 1 CG/CC haplotype was noted in 15 NRG (21.1%) and four HCG but no RG patients (P < .0001). The IL-2 +166 GT genotype was detected in 36.8% of RG, 8.5% of NRG, and 14.7% of HCG patients (P = .005, .0244). The IL-2 -330 GG genotype was demonstrated in 32 healthy controls and three nonrejection transplant patients (P = .0007). Significant differences were concluded between NRG and HCG for IL-6 565 AG, IL-1beta -511 TT and +3962 CC/CT/TT genotypes. DISCUSSION We observed significant differences among the frequencies of IL-2 gene polymorphisms among RG and NRG subjects, which agreed with previous clinical, but not in vitro studies.

The frequency of HLA class I and II alleles in Turkish childhood acute leukaemia patients.

In this study, blood samples were taken from 200 patients with childhood acute leukaemias, including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), and from 100 healthy volunteers (controls). The frequency of the human leucocyte antigen (HLA)-DRB1*04 allele was significantly higher, and the frequencies of the HLA-A23 and HLA-B7 antigens were significantly lower, in patients with ALL compared with controls. Among patients with AML, the frequency of the HLA-B49 antigen and the HLA-DRB1*15 allele were significantly higher, whereas the frequencies of the HLA-A11 and HLA-B38 antigens were significantly lower compared with controls. The frequency of the HLA-DRB1*04 allele was also significantly higher in male patients with ALL and AML, whereas the HLA-DRB1*13 allele was found significantly less frequently in male AML and female ALL patients than in controls. To date, this is the only study to evaluate the associations between HLA molecules and leukaemia in a Turkish population with acute childhood leukaemia.

Association of HLA phenotypes of end-stage renal disease patients preparing for first transplantation with anti-HLA antibody status

Patients with pre-transplantation high levels of panel reactive antibody (PRA) have an increased risk of graft failure, and renal transplantation in sensitized patients remains a highly significant challenge worldwide. The influence of anti-human leukocyte antigen (HLA) antibodies on the development of rejection episodes depends on patient-specific clinical factors and differs from patient to patient. The HLA typing of the recipient might influence the development of anti-HLA antibodies. Some HLA antigens appear to be more immunogenic than others. The aim of this study is to demonstrate the distribution of HLA phenotypes in PRA-positive and PRA-negative end-stage renal disease (ESRD) patients on the basis of having sensitizing events or not. Our study included 642 (mean age: 41.54; female/male: 310/332) ESRD patients preparing for the first transplantation and who are on the cadaveric kidney transplantation waiting list of Istanbul Medical Faculty in 2008–2009. Class I HLA-A,B typing was performed by complement-dependent cytotoxicity (CDC) method, whereas class II HLA-DRB1 typing was performed by low-resolution polymerase chain reaction (PCR)-sequence-specific primer (SSP). All serum samples were screened for the presence of IgG type of anti-HLA class I- and II-specific antibodies by enzyme-linked-immunosorbent assay (ELISA). PRA-negative group consisted of 558 (86.9%) and PRA-positive group included 84 (13.1%) patients. We have found statistically significant frequency of HLA-A3 (p = 0.018), HLA-A66 (p = 0.04), and HLA-B18 (p = 0.006) antigens in PRA-positive patients and DRB1*07 (p = 0.02) having the highest frequency in patients with sensitizing event history but no anti-HLA development suggesting that DRB1*07 might be associated with low risk of anti-HLA antibody formation.

Impact of HLA on the Underlying Primary Diseases in Turkish Patients with End-Stage Renal Disease

The number of patients with end stage renal disease (ESRD) is increasing faster than the number of renal transplantations performed per year worldwide. Of the primary diseases leading to ESRD, diabetic nephropathy is the leading cause. The purpose of the present study is to investigate the association of HLA with the primary diseases leading to ESRD in Turkish patients. A total of 3230 individuals comprising 587 ESRD patients and 2643 healthy controls were enrolled into the study. Class I HLA-A, -B typing was performed by CDC method, while class II HLA-DRB1 typing was performed by low resolution PCR-SSP. We found a significant negative association between almost all A locus antigens and primary disease groups classified as chronic glomerulonephritis and hypertensive nephrosclerosis (p < 0.05). HLA-B58 and HLA-DRB1*03 significantly correlated with amyloidosis and diabetic nephropathy, respectively. Determination of HLAs as risk factors for primary diseases leading to ESRD might be beneficial in preventing progression to ESRD and recurrence of the primary disease post-transplantation.

Relationship Between HLA Tissue Type, CMV Infection, and Acute Graft-vs-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: Single-Center Experience

After allogeneic hematopoietic stem cell transplantation, risk factors for cytomegalovirus (CMV) reactivation include pretransplantation donor and recipient CMV serologic status and posttransplantation development of acute graft-vs-host disease (aGvHD). Human leukocyte antigen (HLA) allele type is an additional factor in CMV infection. The present study included 108 patients who received an allogeneic stem cell graft from an HLA-identical sibling between 1993 and 2004. All recipients and donors were typed for HLA-A, HLA-B, and HLA-DR alleles using serologic or molecular methods. All recipients received grafts because of a hematologic disease from HLA full-matched donors. In pretransplantation seropositive patients with aGvHD, no significant difference was observed in patients who developed CMV infection compared with those without CMV infection. Seropositive patients without aGvHD but with posttransplantation CMV infection demonstrated a higher incidence of HLA-A30, HLA-B40, and HLA-DRB1*15 compared with those without CMV infection. In conclusion, it seems that certain HLA alleles may have either a protective or predisposing role in CMV reactivation, which might be helpful in estimating the risk of aGvHD and designing individualized therapy.

Anti-HLA antibody profile of Turkish patients with end-stage renal disease.

Exposure to human leukocyte antigens (HLA) via blood transfusions, pregnancies, and previous transplantations can result in anti-HLA antibody production. The presence of anti-HLA antibodies in recipient sera before transplantation is an important risk factor. To demonstrate the anti-HLA antibody status of Turkish end-stage renal disease (ESRD) patients, 674 patients (mean age, 40.35 +/- 13.15 years; female/male, 328/346) were enrolled into the study. Anti-HLA antibody screening and identification tests were performed using an enzyme-linked immunosorbent assay (ELISA) method. The panel-reactive antibody (PRA)-negative group consisted of 564 (83.6%) and the PRA-positive group consisted of 110 (17.3%) patients. Of the 110 (17.3%) PRA-positive patients, 43 (6.4%) were class I (+) and class II (-); 19 (2.8%) were class I (-) and class II (+); 48 (7.1%) were both class I and II (+). The most frequent antibodies were directed against the A2 crossreactive group (CREG) and the A10 CREG with less frequent reactions against the B7 CREG, indicating antibodies to both frequent (members of A2 CREG) and relatively rare (members of A10 CREG and B7 CREG antigens). These data also suggested that some antibodies occur at greater than expected frequency because of shared epitopes. Our findings confirmed the significant correlation between female gender, pregnancy, failed graft history, long dialysis duration, and blood transfusions with PRA positivity (P < .05).

Genetic association of interleukin-2, interleukin-4, interleukin-6, transforming growth factor-β, tumour necrosis factor-α and blood concentrations of calcineurin inhibitors in Turkish renal transplant patients.

Cytokines are essential for the control of the immune response as most of the immunosuppressive drugs target cytokine production or their action. The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are immunosuppressive drugs widely used after renal transplantation to prevent allograft rejection. They are characterized by large interindividual variability in their pharmacokinetics; therefore, monitoring their blood concentrations is important to predict their optimal dosage following transplantation. Calcineurin inhibitors inhibit the phosphatase activity of calcineurin, thereby suppressing the production of other cytokines such as transforming growth factor (TGF‐β), tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐2, and IL‐4. The aim of this study was to investigate the relationship between polymorphisms of cytokines and blood concentrations of CNIs in renal transplant patients. The study included 53 CsA‐treated renal transplant patients and 37 tacrolimus‐treated renal transplant patients. Cytokine polymorphisms were analysed using polymerase chain reaction (PCR) sequence‐specific primers with the cytokine CTS‐PCR‐sequence‐specific primers Tray Kit; University of Heidelberg. Blood concentrations of CNIs were determined with Cloned Enzyme Donor Immunoassay (CEDIA) method. Patients with TC genotype of TGF‐β at codon 10 had lower CsA blood concentrations than the TT and CC genotypes (P = 0.005) at 1 month in CsA treatment group. The ratio of blood concentration/dose of CsA for patients with TGF‐β1‐codon 10 TC genotype was lower than for patients with TT, CC genotypes, and the dose given to these patients was higher in the first month (P = 0.046). The ratio of blood concentration/dose of CsA for patients with IL‐2‐330 GG genotype was higher than for patients with GT, TT genotypes, and the dose given to these patients was lower at first month and sixth months (P = 0.043, P = 0.035 respectively). The tacrolimus blood concentrations were significantly higher in patients with the genotype GG of IL‐2‐330 (P = 0.012) at the third month. Patients who had the TC genotype TGF‐β codon 10 had lower CsA blood concentrations and this group had higher acute rejection (P = 0.033). These results suggest that the genotyping for TGF‐β‐codon 10, IL‐2‐330 and IL‐6‐174 polymorphisms may help individualized immunosuppressive dosage regiments.

The Effect of TGFB1 and CD14 Gene Polymorphisms on the Clinical Findings of Cystic Fibrosis in Turkish Patients

Abstract Significant effects of several modifying genes on the clinical features of cystic fibrosis (CF) have been reported. In the present study, the researchers investigated the effects of transforming growth factor beta 1 (TGFB1) and cluster of differentiation 14 (CD14) polymorphisms on the clinical status of patients with CF. The present study included sixty-five patients with CF and eighty five healthy controls with no pulmonary disease. Single-nucleotide polymorphisms in the TGFB1 gene (rs1800469, rs1800470, rs8179181) were studied using DNA sequence analyses; the CD14 gene polymorphism rs2569190 was evaluated using restriction fragment length polymorphism analysis. The frequency of rs1800469 (TT genotype) was significantly higher in the healthy controls than in the patients with CF. Thus, the TT genotype may be protective against CF. Although rs8179181 (CT genotype) may have an overall negative effect, this genotype may have a favourable effect on growth parameters. However, these results should be confirmed in larger studies.

High soluble CD30 levels and associated anti-HLA antibodies in patients with failed renal allografts

Introduction Serum soluble CD30 (sCD30), a 120-kD glycoprotein that belongs to the tumor necrosis factor receptor family, has been suggested as a marker of rejection in kidney transplant patients. The aim of this study was to evaluate the relationship between sCD30 levels and anti-HLA antibodies, and to compare sCD30 levels in patients undergoing hemodialysis (HD) with and without failed renal allografts and transplant recipients with functioning grafts. Methods 100 patients undergoing HD with failed grafts (group 1), 100 patients undergoing HD who had never undergone transplantation (group 2), and 100 kidney transplant recipients (group 3) were included in this study. Associations of serum sCD30 levels and anti-HLA antibody status were analyzed in these groups. Results The sCD30 levels of group 1 and group 2 (154 ± 71 U/mL and 103 ± 55 U/mL, respectively) were significantly higher than those of the transplant recipients (group 3) (39 ± 21 U/mL) (p<0.001 and p<0.001). The serum sCD30 levels in group 1 (154 ± 71 U/mL) were also significantly higher than group 2 (103 ± 55 U/mL) (p<0.001). Anti-HLA antibodies were detected in 81 (81%) and 5 (5%) of patients in groups 1 and 2, respectively (p<0.001). When multiple regression analysis was performed to predict sCD30 levels, the independent variables in group 1 were the presence of class I anti-HLA antibodies (β = 0.295; p = 0.003) and age (β = -0.272; p = 0.005), and serum creatinine (β = 0.218; p = 0.027) and presence of class II anti-HLA antibodies (standardized β = 0.194; p = 0.046) in group 3. Conclusions Higher sCD30 levels and anti-HLA antibodies in patients undergoing HD with failed renal allografts may be related to higher inflammatory status in these patients.