Urinary CXCL9 and CXCL10 Levels and Acute Renal Graft Rejection.

BACKGROUND: Monitoring of chemokines, CXCL9 and CXCL10, in serum may present a non-invasive detection method for rejection. OBJECTIVE: To investigate the relationship between urinary levels of CXCL9 and CXCL10 and graft function following renal transplantation. METHODS: 75 living-related donor renal transplant recipients were studied. Urinary levels of chemokines were collected pre-operatively, on post-operative 1st day, 7th day, 1st month, 3rd month, and at the time of rejection. Chemokines levels were assayed using and enzyme-linked immunosorbent assay. RESULTS: Clinical variables were monitored. 10 (15%) patients had biopsy-proven rejection during the follow-up period. The urinary CXCL9 level in those with rejection was significantly higher than that in those with non-rejection group at the 1st day (p<0.001), 7th day (p<0.001), and at the time of rejection (p=0.002). The urinary CXCL10 level was also significantly higher in those with rejection compared with non-rejection group at 1st day (p<0.001), 7th day (p<0.001), and at the time of rejection (p=0.001). Serum creatinine level was strongly correlated with the urinary CXCL9 and CXCL10 levels at the time of rejection (r=0.615, p=0.002; and r=0.519, p=0.022, respectively). Among those with T cell-mediated rejections the mean urinary CXCL10 level increased to as high as 258.12 ng/mL. CONCLUSION: Urinary CXCL9 and CXCL10 levels might have a predictive value for T cell-mediated rejection in early post-transplantation period. Measurement of urinary CXCL9 and CXCL10 levels could provide an additional tool for the diagnosis of rejection.

Predictive Value of Interleukin 2 and Interleukin 8 on Early Rejection in Living Related Kidney Transplant Recipients.

INTRODUCTION: Early diagnosis of rejection in kidney transplant (KTx) recipients is of paramount importance for long-term graft survival. Cytokines play an important role in rejection via activating T cells. Neutrophil accumulation in the graft indicates cell-mediated rejection. Cellular infiltration is mediated through chemoattractant factors. The aim of this study was to investigate the relationship between graft function and serum levels of interleukin 2 (IL-2) and interleukin 8 (IL-8) in KTx. METHOD: Sixty-five patients undergoing KTx were enrolled in the study. Serum samples of IL-2 and IL-8 were collected the day before the operation, on postoperative days 1 and 7 day, and during the first and third month after the onset of rejection. The enzyme-linked immunosorbent assay method was used to determine the IL-2 and IL-8 values. RESULTS: A total of 9 (13.8%) patients had rejection documented on biopsy samples. Fifty-six patients had stable graft function (SGF). IL-2 and IL-8 values before KTx of both the rejected and SGF patients were not statistically different. Univariate analysis revealed that IL-2 and IL-8 were correlated with rejection (P = .046, P = .015). IL-8 levels were higher in the rejection group compared to the SGF group on the seventh day and first month postoperatively (P = .023, P = .038). The rejection group maintained higher levels of IL-8 for 11 days (range: 7-30) compared to the SGF group (P = .002) and the IL-8 levels correlated with serum creatinine levels (r = 0.621, P = .001). IL-2 levels were higher in the rejection group on days 1 and 7 compared to the SGF group (P = .042, P = .031). IL-2 and IL-8 levels were correlated with low eGFR in the third month in the rejection group (r = 0.421, P = .037; r = 0.518, P = .008). CONCLUSION: Determining the cytokine levels in the early post-KTx period may be helpful in tailoring immunosuppressive regimens in patients with a risk of rejection.

Influence of uridine diphosphate-glucuronosyltransferases (1A9) polymorphisms on mycophenolic acid pharmacokinetics in patients with renal transplant.

BACKGROUND: There are differences in pharmacokinetic of mycophenolic acid among individuals. The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MPA. The aim of this study was to explain MPA pharmacokinetics in UGT1A9 1399 C > T polymorphisms in Turkish renal transplant patients. PATIENTS AND METHODS: One hundred and twenty-five living-donor transplant recipients and 100 healthy control subjects underwent UGT1A9 1399 C > T genotyping using polymerase chain reaction-restriction fragment length polymorphism. Concentrations of MPA were determined with Cloned Enzyme Donor Immunoassay (CEDIA). Besides that, all the patients were monitored for acute rejection and graft function during the study period. RESULTS: The UGT1A9 1399 C > T CC, CT, and TT genotype frequencies among patients were, respectively, 68.0%, 23.2%, and 8.8%. The CC, CT, and TT genotype frequencies among controls were, respectively, 63.0%, 23.0%, and 14.0%. There was no significant difference between patients and controls (p = .480, p = .999, p = .286, respectively). At first month, respectively, through blood concentrations of MPA were significantly higher in UGT1A9 1399 C > T TT carriers than in CT and CC carriers (p = .046). The doses for these patients were lower at first month (p = .021). Acute rejection episodes were not associated with the CC vs CT or TT genotypes (p = .064). CONCLUSIONS: Our results demonstrated a correlation between the UGT1A9 1399 C > T polymorphism and MPA pharmacokinetics among renal transplant patients. Determination of UGT1A9 polymorphism may help to achieve target of MPA blood concentrations.

Association Between HLA Antibodies and Different Sensitization Events in Renal Transplant Candidates.

BACKGROUND: Human leukocyte antigen (HLA) allo-immunization is caused by various events such as blood transfusions, pregnancies, or organ transplantations, which can lead to sensitization. In this retrospective study, we evaluated different sensitization models and their effects on panel-reactive antibody (PRA) profiles of renal transplantation candidates. METHODS: Anti-HLA class I/II antibody screening tests were performed in 906 renal transplantation candidates with the use of a microbead-based assay (Luminex). RESULTS: Two hundred ninety-seven (32.8%) of the patients were determined as positive in terms of PRA, and 609 (67.2%) were negative. Sensitized and non-sensitized patients were compared separately in terms of each sensitization type. The anti-HLA class I, II, and I+II positivity rates in patients sensitized only by blood transfusion were 13.1%, 6.3%, and 14.1%, the rates with pregnancy sensitization were 35.5%, 29%, and 45.2%, and rates with previous transplantation sensitization were 15.6%, 34.4%, and 38.9%, respectively. Prevalence of PRA positivity was significantly higher in patients with previous pregnancy than with transplantation and transfusion (odds ratio, 1.003; 95% confidence interval, 0.441-2.281; P = .031). The risk of developing HLA class I antibodies was higher in pregnancies (P < .001), and the risk of developing anti-HLA class II antibodies was higher in patients who had undergone a previous transplantation (P < .001). The rate of developing HLA-B antibodies in patients sensitized by pregnancy were significantly higher compared with sensitization after transfusion (P = .015), as was the rate of developing HLA-DQ antibodies in patients sensitized by previous transplantation compared with sensitization through pregnancy (P = .042). CONCLUSIONS: In patients who are waiting for kidney transplantation, sensitization by pregnancy and transplantation have a significant impact on development of HLA class I and class II antibodies.

Comparison of Two Different Inhalation Anesthetics on Grafted Kidney Function in Patients Undergoing Renal Transplantation Surgery: Desflurane or Sevoflurane?

BACKGROUND: Anesthetic management of patients during renal transplantation is vitally important for ensuring proper functioning of kidneys that have undergone ischemia-reperfusion damage. The goal of this prospective study was to compare the effects of 2 different inhalation agents (sevoflurane and desflurane) on grafted kidney function in renal transplantation surgery. METHODS: Sixty-five patients who were scheduled for living donor renal transplantation were enrolled in the study. General anesthesia was performed on all patients. Thirty-five pairs of recipients and donors were anesthetized with sevoflurane (group S) and 30 pairs of recipients and donors were anesthetized with desflurane (group D). Each patient's demographic characteristics, immunologic and clinical data, and hemodynamic parameters were recorded. The estimated glomerular filtration rate was calculated in the preoperative period and on postoperative days 1 and 7. The blood samples were collected before the operation and on postoperative days 1 and 7 for measurement of serum creatinine, neutrophil gelatinase-associated lipocalin, and interleukin 18. RESULTS: There were no significant differences in demographic characteristics or immunologic data between group D and group S. Intraoperative heart rate and mean arterial blood pressure were the same between groups. Creatinine, estimated glomerular filtration rate, neutrophil gelatinase-associated lipocalin, and interleukin 18 values did not differ between groups (P > .05) in the preoperative period and postoperative days 1 and 7. CONCLUSIONS: Sevoflurane and desflurane had no adverse effects on grafted kidney functions according to short-term graft outcomes in patients undergoing living donor renal transplantation.

Influence of Proton Pump Inhibitors on Mycophenolic Acid Pharmacokinetics in Patients With Renal Transplantation and the Relationship With Cytochrome 2C19 Gene Polymorphism.

BACKGROUND: Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation. MATERIALS AND METHODS: A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively. RESULTS: The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups (P < .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI (P < .05). Gastrointestinal side effects were significantly higher in MMF with lansoprazole group than in MYF with lansoprazole group (P < .05). However, no differences were found according to genotype distribution in all groups (P > .05). CONCLUSION: Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. Both genetic and clinical factors in pharmacokinetics may help to make further progress toward individualized therapy to yield maximum efficacy with minimal side effects.

Effect of Donor Nephrectomy Technique on Recipient Lymphatic Drainage.

AIM: We sought to evaluate the postoperative recipient lymphatic drainage depending on open donor nephrectomy (ODN) or laparoscopic (LDN) techniques. METHOD: Between March 2012 and August 2014, 58 patients underwent renal transplantation from living-related donors. Thirty donors underwent ODN (group 1), and 28 LDN (group 2). Operations were performed by the same surgeons. Both cranial and caudal drainage catheters for lymphatic leakage were placed preoperatively and all the recipients received tacrolimus, mycophenolate mofetil, and steroid as immunosuppressive regimen. None of the patients had coagulation abnormalities. RESULTS: All grafts were functioning during the early postoperative period and diuresis was ensured. No difference was observed on early postoperative period regarding to acute rejection (P = .329) or infection (P = .546). No difference was seen concerning mycophenolate mofetil and mycophenolate sodium regimens among the 2 groups (P = .227). In groups 1 and 2, the cranial drainage catheters were not taken out until postoperative days 5.5 ± 2.5 (range, 0-11) and 6.4 ± 3.8 (range, 0-14) and the caudal catheters stayed in place until days 8.8 ± 3.5 (range, 1-16) and 9.9 ± 5.9 (range, 3-22), respectively. No difference was found when comparing the cranial (P = .308) and caudal (P = .426) drainage periods. However, during clinical acute rejection episodes the cranial drainage period was longer in group 1 (P = .003). Three patients developed lymphoceles, 1 requiring drainage, in group 2. CONCLUSIONS: There seems to be no difference in recipient lymphatic drainage by donor nephrectomy technique. A laparoscopic procedure may be advantageous owing to shorter lymphatic drainage during clinical acute rejection episodes.

Genetic association of interleukin-2, interleukin-4, interleukin-6, transforming growth factor-ß, 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-ß), 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-ß 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-ß1-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-ß 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-ß-codon 10, IL-2-330 and IL-6-174 polymorphisms may help individualized immunosuppressive dosage regiments.

Association between genetic variants in glutathione peroxidase 1 (GPx1) gene, GPx activity and the risk of prostate cancer.

AIM: The aim of this study was to investigate the association between GPx1 Pro198Leu polymorphism with the development and progression of prostate cancer (PCa) and evaluate whether smoking status and advanced age could modify this association. METHODS: A total of 134 PCa patients and 159 healthy control subjects with serum prostate specific antigen (PSA) levels <4 ng/mL and normal digital rectal examination (DRE) findings were enrolled in this prospectively designed study. PCA patients were classified as low (T1 or T2 and N0M0 stages) and high stage disease (T3 or T4 and N0M0 or N1 or M1 stages). GPx1 Pro198Leu polymorphism was determined using polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: Compared to the carriers of Pro/Pro genotype, subjects with the variant genotypes (Pro/Leu or Leu/Leu) had significantly higher risk of PCa. The Leu/Leu genotype was correlated with lower GPx activity among both controls and PCa patients. With respect to tumor stage, Leu/Leu genotype was more frequent in patients with high stage disease than those of low stage disease. In stratified analyses, although the variant Leu/Leu genotype was significantly associated with increased risk of PCa in older age, smoking did not alter this association. CONCLUSION: The present data provide evidence that GPx1 Pro198Leu polymorphism may be associated with the development and progression of PCa and older ages may influence the association.between GPx1 Pro198Leu polymorphism and PCa.