A multinational survey of companion animal veterinary clinicians: How can antimicrobial stewardship guidelines be optimised for the target stakeholder?

Antimicrobial stewardship initiatives are widely regarded as a cornerstone for ameliorating the global health impact of antimicrobial resistance. Within companion animal health, such efforts have largely focused on development and dissemination of antimicrobial stewardship guidelines (ASGs). However, there have been few attempts to understand veterinarian attitudes towards and knowledge of ASGs or to determine how awareness regarding ASGs might best be increased. An online survey regarding ASGs was formulated for veterinarians who treat companion animals. The survey was distributed across 46 European and associated countries between 12 January and 30 June, 2022. In total, 2271 surveys were completed, with 64.9% of respondents (n = 1474) reporting awareness and usage of at least one ASG. Respondents from countries with greater awareness of ASGs tended to report more appropriate use of antimicrobials (Spearman's rank coefficient = 0.6084, P ≤ 0.001), with respondents from countries with country-specific ASGs tending to score highest across both awareness and appropriate use domains. Respondents prioritised guidance around antimicrobial choice (82.0%, n = 1863), duration of treatment (66.0%, n = 1499), and dosage (51.9%, n = 1179) for inclusion in future ASGs, with 78.0% (n = 1776) of respondents preferring ASGs to be integrated into their patient management system. Awareness of ASGs and their use in companion animal veterinary practice appears to be greater than previously reported, with respondents tending to report antimicrobial prescription decision making broadly in line with current clinical recommendations. However, further initiatives aimed at maximising accessibility to ASGs both within countries and individual veterinary practices are recommended.

Effects of Preheating and Sonic Delivery Techniques on the Internal Adaptation of Bulk-fill Resin Composites.

OBJECTIVE: To compare the effects of conventional (hand-placed), sonic, or preheated insertion techniques on the internal adaptation of bulk-fill resin composites. METHODS AND MATERIALS: A total of 150 freshly extracted human third molars were used to prepare standardized cylindrical occlusal cavities. Teeth were divided into five main groups according to the resin composites: 1 incremental (Clearfil Majesty Posterior [CMP]) and four paste-like bulk-fill (SonicFill 2 [SF2], VisCalor bulk [VCB], Filtek One bulk-fill restorative [FBR], and Tetric EvoCeram bulk-fill [TEB]). Each main group was divided into three subgroups according to the placement technique: conventional, preheating, and sonic delivery (n=10). In the conventional placement technique, cavities were filled manually. In the sonic insertion technique, a specific handpiece (SonicFill Handpiece; Kerr Corporation) was used. In the preheating technique, a heating device (Caps Warmer, Voco, Cuxhaven, Germany) was used to warm the resin composites before placement. Internal voids (%) of the completed restorations were calculated with microcomputed tomography. Data was analyzed with two-way analysis of variacne followed by Tukey's multiple comparisons test (α=0.05). RESULTS: All resin composites showed fewer internal gaps with preheating compared with the conventional placement (p<0.05). For all resin composites other than SF2, preheating provided fewer internal gaps than that of the sonic placement (p<0.05). Sonic placement led to fewer internal gaps compared with the conventional placement, but only for SF2 and FBR (p<0.05). For the conventional placement, the lowest gap percentage was observed with the incremental resin composite (CMP, p<0.05). Among all groups, the lowest gap percentages were observed for preheated VCB followed by sonically inserted SF2 (p<0.05). CONCLUSION: The best internal adaptation was observed in sonically inserted SF2 and preheated VCB, which were the manufacturers' recommended insertion techniques. Preheating considerably improved the internal adaptation of all resin composites, except for that of SF2.

Sinonasal teratocarcinosarcoma mimicking chronic invasive fungal disease of paranasal sinuses.

Sinonasal teratoid carcinosarcoma or teratocarcinoma is an extremely rare aggressive tumour. It usually arises in the nasal cavity and paranasal sinuses. In this study, the authors described magnetic resonance imaging and computed tomography findings from a patient with sinonasal teratocarcinoma. Computed tomography of the sinonasal teratoid carcinosarcoma can mimic paranasal fungal infections. Magnetic resonance imaging is a very useful tool for making a differential diagnosis between the sinonasal teratoid carcinosarcoma and paranasal sinusitis.

Renal Autotransplantation in a Patient with Bilateral Renal Artery Stenosis Secondary to Takayasu Arteritis.

Involvement of the renal artery is common in Takayasu arteritis. We, herein, present on a patient with Takayasu arteritis causing severe renal failure and a successful auto-transplantation. This case shows that early diagnosis and immediate appropriate interventions are life-saving in patients with Takayasu arteritis. Renal auto-transplantation performed in selected cases increases dialysis-free survival.

Species distribution, genetic diversity and antimicrobial susceptibility of Campylobacter isolates recovered from the preputial cavity of healthy rams in Turkey.

AIMS: Campylobacter sp. are important causes of reproductive disease in ruminants worldwide. Although healthy bulls are well-known carriers for infection of cows, the role of rams as a potential source for infecting ewes is unclear. This study aimed to determine prevalence, species distribution, genetic diversity and antimicrobial susceptibility profiles of Campylobacter sp. isolated from the preputial cavity of healthy rams. METHODS AND RESULTS: The material of this prospective study comprised 191 swab samples taken from the preputial cavity of healthy rams. Enrichment and membrane filtration were employed for the isolation of Campylobacter. Presumptive isolates were confirmed as Campylobacter by phenotypic and molecular tests. 16S rRNA gene sequence analysis was used for the definitive identification of the isolates at species level, and genotyping was performed using pulsed-field gel electrophoresis (PFGE). The susceptibility of the Campylobacter sp. isolates to various antibiotics was determined by the disk diffusion test. In all, 27 of the 191 (14·13%) swab samples were found to be positive for Campylobacter sp. (28 isolates were recovered in total). Per phenotypic and genotypic analyses, one isolate was identified as Campylobacter mucosalis and the remaining 27 isolates were identified as Campylobacter sputorum bv. faecalis. The PFGE analysis of the C. sputorum biovar faecalis isolates produced 17 clusters and 24 different pulsotypes, indicating high genetic heterogeneity. All 28 isolates were found to be susceptible to all of the antibiotics tested. CONCLUSIONS: Healthy rams may be an important reservoir of different Campylobacter species in the preputium. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated for the first time that healthy rams can carry different Campylobacter sp. including genetically diverse C. sputorum bv. faecalis and C. mucosalis in the preputial cavity. Further investigation on the potential implication of this finding on sheep reproductive health (e.g. infectious infertility, and abortion) and overall epidemiology of Campylobacter may be warranted.

Oral health related quality of life and disease severity in autoimmune bullous diseases.

BACKGROUND: There is an increased risk of long-term dental and periodontal disease in autoimmune bullous diseases (AIBD). AIMS: In this cross-sectional study, we aimed to determine whether the oral health-related quality of life status (OHRQoL) was associated with disease severity and activity in patients with AIBD. SUBJECTS AND METHODS: 67 patients with AIBD were enrolled in this study. Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) was used to evaluate the disease severity. The score was categorized as a significant course (≥17) and moderate course (<17). Oral health impact profile-14 (OHIP-14) questionnaire was filled to assess the OHRQoL. Self-reported oral health status and oral lesion related pain score were also evaluated in the study group. RESULTS: OHIP-14 score was significantly higher in active patients (42.28 ± 13.66) than inactive patients (29.08 ± 12.25) (P = 0.004) and it was correlated with the pain score (6.33 ± 2.78; r = 0.409, P = 0.013). Furthermore, OHIP-14 score was higher in patients with a significant disease course (45.18 ± 15.08) (P = 0.010) than in patients with a moderate course (36.09 ± 9.73). CONCLUSIONS: OHRQoL may be useful in the disease management and treatment. Since it can be affected by both presence of oral erosions and disease severity, a collaboration between dermatologists and dentists could be crucial to the disease management in AIBD.

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.

Nocturnal blood pressure dipping is similar in rheumatoid arthritis patients as compared to a normal population.

OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder which further doubles the risk of developing cardiovascular disease. Some studies suggest that in RA patients, the prevalence of hypertension increases due to prednisolone use, clinical status, genetic factors, and physical inactivity. On the other hand, dipper and non-dipper status in RA patients compared to non-RA subjects has not been investigated to our knowledge. Purpose of the study is to investigate whether non-dipper status is more deteriorated in RA patients. METHODS: Sixty-five RA patients and 61 age-sex-matched control patients were evaluated in this cross-sectional study. Patients were classified according to 24-h ambulatory blood pressure monitoring results. Patients with previous hypertension diagnosis, coronary artery disease, and abnormal kidney function were excluded. RESULTS: Mean age of the study sample was 53.7 ± 12.3 years and 40.5% were male. There was no significant difference between groups in terms of basic demographic characteristics. Leukocyte counts (p = 0.001), neutrophil counts (p = 0.001), and red cell distribution width (p = 0.000) were significantly higher in the RA group. ABPM results indicate no significant difference between RA patients and the control group in terms of daytime systolic and diastolic blood pressure, nighttime systolic and diastolic blood pressure, and average systolic and diastolic blood pressure results (p > 0.05). There was no statistical difference regarding the non-dipper status of patient groups (p = 0.412). Nocturnal blood pressure dipping was significantly similar between groups (p = 0.980). CONCLUSION: In conclusion, RA patients have similar values in terms of nocturnal blood pressure dipping and hypertension diagnosis as compared to normal population.

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.

The identification of Meyerozyma guilliermondii from blood cultures and surveillance samples in a university hospital in Northeast Turkey: A ten-year survey.

Meyerozyma (Pichia) guilliermondii exists in human skin and mucosal surface microflora. It can cause severe fungal infections like candidemia, which is an opportunistic pathogen. One hundred and forty-one M. guilliermondii isolates, consisting of 122 blood culture isolates, belonging to 126 patients; 13 total parenteral nutrition solution isolates; and two rectal swab isolates were identified according to carbohydrate assimilation reactions in a university hospital in Turkey between January 2006 and December 2015. Following Candida albicans (34.0%) and C. parapsilosis (21.2%), the third yeast species most commonly isolated from blood cultures in the Farabi Hospital was M. guilliermondii (20.6%). The patients were hospitalised in 27 different departments. A total of 50% of the patients were in pediatric departments, 49.2% were in intensive care units, and 17.2% were in haematology-oncology departments. Molecular identification of the isolates was performed using DNA sequence analysis of ribosomal ITS gene regions and IGS amplification-AluI fingerprinting (IGSAF). With molecular identification, 140 isolates were identified as M. guilliermondii and one isolate was identified as Candida membranifaciens. It was observed that the ITS1 region specifically helps in identifying these species. It was demonstrated that biochemical and molecular methods were 99.3% consistent in identifying M. guilliermondii. The Wild-Type (WT) Minimum Inhibitory Concentrations (MICs) distribution of fluconazole, voriconazole, itraconazole, and flucytosine were determined using the Sensititre YeastOne YO2V system after 24h of incubation. One M. guilliermondii strain was determined to be non-WT for fluconazole, voriconazole, itraconazole and flucytosine. In total, three M. guilliermondii strains, for fluconazole, were determined to be non-WT in this study.

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.

Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software.

INTRODUCTION: High rates of panel-reactive antibody (PRA) may decrease the chance of kidney transplantation and may result in long waiting periods before transplantation. The calculated PRA (cPRA) is performed based on unacceptable HLA antigens. These antigens are identified by a program that was created based on the antibodies that developed against the HLA antigens circulating in serum and on the risk of binding of these antibodies to antigens. The antigen profile of the population and antigen frequencies can be measured, and more realistic cPRA positivity rates may be obtained using this method. MATERIALS AND METHODS: We developed a program based on the HLA antigens of 494 blood donors in 2 European Federation for Immunogenetics-accredited Tissue Typing Laboratories in Turkey. Next-generation sequencing-based tissue typing (HLA-A, -B, -C, -DR, -DQ, 4 digits) of the samples was performed. The PRA screening test was performed on 380 patients who were waiting for organ transplant from a cadaver in Istanbul Faculty of Medicine. The single antigen bead assay testing was performed to identify the antibody profiles on 48 hypersensitized patients. RESULTS: The PRA testing results using the current methods were 44.6% ± 18.5%, and the cPRA rate was 86.2% ± 5.1%. The mean PRA positivity of the sensitized patients using the current methods was 44.6%; however, the rate was 86.2% using the cPRA. DISCUSSION: cPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. CONCLUSION: In principal, implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match, particularly for hypersensitized patients, by the creation of an unacceptable mismatch program using cPRA software.

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.

Maternal and fetal Doppler velocimetry in women diagnosed with fear of childbirth.

AIM: This study aimed to investigate maternal and fetal Doppler flow parameters in term pregnant women diagnosed with fear of childbirth (FOC). MATERIALS AND METHODS: Women between 20 and 40 years with full-term singleton pregnancies (≥37 gestational weeks) were included in the study. All patients were questioned with Turkish form of Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ) version A. Women with W-DEQ scores ≥85 were defined as FOC. Forty women diagnosed with FOC (FOC group) and 45 women with W-DEQ scores <85 (control group) underwent Doppler waveform analysis and the pulsatility index (PI) and resistance index (RI) values for uterine, umbilical, and mid cerebral arteries were recorded. RESULTS: Both groups had similar PI and RI values for umbilical and mid cerebral arteries (P > 0.05). However, PI and RI values for both right and left uterine arteries were higher in FOC group than control group (P < 0.05, for right uterine artery PI; P< 0.001, for left uterine artery RI; and P< 0.01, for others). CONCLUSION: It may be suggested that the presence of FOC in term pregnant women seems to have a negative effect on uterine blood flow parameters. When diagnosed with FOC, the women should be referred to a specialist for psychoeducation and psychosomatic support to decrease her fear and to minimize the negative impact of fear on the fetus.

DETERMINATION OF VOLUME OVERLOAD BY BIOELECTRICAL IMPEDANCE ANALYSIS AND NT-PROBNP IN DIABETIC PRE-DIALYSIS PATIENTS.

INTRODUCTION: Diabetic chronic kidney disease has more fatal clinical progresses and this situation can be related to volume overload, which is seen more commonly in diabetic chronic kidney disease patients than in non-diabetic chronic kidney disease patients. Therefore, we examined the effect of diabetes mellitus on volume overload in newly diagnosed stage 5 chronic kidney disease patients whose volume overloads were not showing signs of improvement from renal replacement therapy. METHOD: One hundred and five patients (46 diabetic, 59 non-diabetic) with end-stage chronic kidney disease, who had glomerular filtration rate (GFR) under 15 mL/min for at least three months were enrolled in this prospective study. We determined the body volume overload and configuration using a bioimpedance device. NT-proBNP levels were recorded. RESULTS: There was a statistically significant difference between diabetic and non-diabetic groups according to overhydration (OH, p=0.003), extracellular water (ECW, p=0.045), intracellular water (ICW, p<0.001) and OH/ECW (p=0.003). In addition, there was a statistically significant difference between groups in terms of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP levels, p=0.008). DISCUSSION: We compared diabetic and non-diabetic end-stage chronic kidney disease patients who were not in renal replacement therapy yet. We found more volume overload and extracellular fluid volume in the diabetic group.

Maternal/neonatal vitamin D deficiency: a risk factor for bronchopulmonary dysplasia in preterms?

OBJECTIVE: The objective of this study was to investigate the possible association between maternal/neonatal 25-hydroxy vitamin D (25-OHD) levels and development of bronchopulmonary dysplasia. STUDY DESIGN: One hundred and thirty-two preterm infants ⩽32 weeks of gestation who were diagnosed with respiratory distress syndrome were enrolled. 25-OHD levels were determined in maternal/neonatal blood samples that were obtained at the time of admission to the neonatal intensive care unit. RESULT: A total of 100 infants were included and 31 (31%) developed bronchopulmonary dysplasia (BPD). Both maternal and neonatal 25-OHD levels in the BPD group were significantly lower compared with those in the no-BPD group (P=0.0001). A positive correlation was detected between maternal and neonatal 25-OHD levels. All of the infants with BPD had a 25-OHD level <10 ng ml(-1), which represented severe deficiency. Univariate logistic regression analysis revealed that maternal/neonatal vitamin D levels were a significant predictor of BPD (odds ratio (OR): 0.76 and 0.61, respectively, P<0.001). CONCLUSION: We demonstrated for the first time that lower maternal and neonatal vitamin 25-OHD levels were associated with BPD development in preterm infants. However, further studies with larger sample sizes are needed to delineate the possible link between vitamin D deficiency and BPD.

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.