Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients

Administration of azole antifungals to tacrolimus‐treated solid organ recipients results in a major drug–drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co‐treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose‐corrected trough concentrations (C/D) between baseline and tacrolimus–azole co‐therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0–20.2) for voriconazole and 4.4 ± 2.6 (range 0.9–18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: ‐43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (‐14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus–azole interaction, but these did not permit accurate predictions in individual patients.     

Meta‐analysis of the association of oestrogen receptor‐beta gene RsaI (G/A) and AluI (A/G) polymorphisms with male infertility

A more precise assessment of association of oestrogen receptor‐beta genes RsaI(G/A) and AluI(A/G) polymorphisms with male infertility from current contradictory results is the aim of this meta‐analysis including five RsaI and six AluI studies respectively. No association was observed between infertility and RsaI or AluI. In the stratified analysis by ethnicity, increased risk was found among Caucasians with GA versus GG (OR = 2.263, 95% CI = 1.073–4.776, I² = 57.1%) and dominant model (OR = 2.117, 95% CI = 1.018–4.403, I² = 49.0%) of RsaI. It was not observed for AluI. In the stratified analysis by infertility subtypes, a reduced risk in GA of AluI was observed among azoospermia or severe oligospermia (GA versus AA: OR = 0.686, 95% CI = 0.498–0.945, I² = 21.2%; recessive model: OR = 1.403, 95% CI = 1.056–1.864, I² = 31.7%), and reduced risk was in recessive model (OR = 0.650, 95% CI = 0.446–0.948, I² = 0.0%) of subtypes, except for azoospermia or severe oligospermia. However, this finding was not observed in RsaI. The meta‐analysis showed GA and GG of AluI are possibly resistant factors for spermatogenesis dysfunction and deteriorated sperm quality.     

Risk factors for the development of invasive aspergillosis after kidney transplantation: Systematic review and meta-analysis

To investigate risk factors for invasive aspergillosis (IA) after kidney transplantation (KT), we conducted a systematic search in PubMed and EMBASE to identify studies published until June 2020. We included case-control or cohort design studies comprising KT recipients with a diagnosis of IA, defined according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria, and assessed risk factors for the development of IA. Random-effect models meta-analysis served to pool data. We identified eleven case-control studies (319 IA cases and 835 controls). There was an increased risk of IA among recipients with underlying chronic lung diseases (odds ratio [OR] = 7.26; 95% confidence interval [CI] = 1.05-50.06) and among those with diabetic nephropathy (OR = 1.65; 95% CI = 1.10-2.48). Requiring posttransplant hemodialysis (OR = 3.69; 95% CI = 2.13-6.37) or surgical reintervention (OR = 6.28; 95% CI = 1.67-23.66) were also associated with an increased risk. Moreover, a positive link was identified between IA and posttransplant bacterial infection (OR = 7.51; 95% CI = 4.37-12.91), respiratory tract viral infection (OR = 7.75; 95% CI = 1.60-37.57), cytomegalovirus infection or disease (OR = 2.67; 95% CI = 1.12-6.32), and acute graft rejection (OR = 3.01; 95% CI = 1.78-5.09). In contrast, receiving a kidney from a living donor was associated with a reduced risk (OR = 0.65; 95% CI = 0.46-0.93). KT recipients that accumulate several of these conditions should be closely monitored and a low threshold of suspicion for IA should be maintained. Future studies should explore the benefit of mold-active prophylaxis to this subgroup of KT recipients at highest risk.     

Risk factors associated with Hepatitis E virus infection in kidney transplant recipients in a single tertiary Center in the United States

BackgroundHepatitis E virus (HEV), the causative agent of hepatitis E, is a common but self-limiting disease. However, in immunosuppressed kidney transplant 47 recipients (KTRs), HEV infection can become chronic. We investigated risk factors associated with HEV infection among 271 KTRs at the Johns Hopkins Hospital transplanted between 1988 and 2012.MethodsHEV infection was defined as having positive anti-HEV IgM, anti-HEV IgG, or HEV RNA. The risk factors included: age at transplant, sex, hemodialysis/peritoneal dialysis, plasmapheresis, transfusions, community urbanization, and other socioeconomic factors. Logistic regression was used to determine independent risk factors associated with HEV infection.ResultsOut of 271 KTRs, 43 (16%) had HEV infection though not active disease. HEV infection in KTRs was associated with older age (≥45 years; OR = 4.04; 95% CI = 1.81–57 10.03; p = 0.001) and living in communities with low proportions of minorities (OR = 0.22; 95% 58 CI = 0.04–0.90; p = 0.046).ConclusionKTRs who had HEV infection may be at an increased risk of developing chronic HEV.     

Changes in humoral immune response after SARS-CoV-2 infection in liver transplant recipients compared to immunocompetent patients

The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case–control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17–83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03–1.36), and therapy with renin–angiotensin–aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47–34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.     

Considering extended right lobe grafts as major extended donor criteria in liver transplantation is justified

The outcomes of split-liver transplantation are controversial. This study compared outcomes and morbidity after extended right lobe liver transplantation (ERLT) and whole liver transplantation (WLT) in adults. MEDLINE and Web of Science databases were searched systematically and unrestrictedly for studies on ERLT and its impact on graft and patient survival, and postoperative complications. Graft loss and patient mortality odds ratios (OR) and 95% confidence intervals (CI) were assessed by meta-analyses using Mantel–Haenszel tests with a random-effects model. Vascular and biliary complications, primary nonfunction, 3-month, 1-, and 3-year graft and patient survival, and retransplantation after ERLT and WLT were analyzed. The literature search yielded 10 594 articles. After exclusion, 22 studies (n = 75 799 adult transplant patients) were included in the analysis. ERLT was associated with lower 3-month (OR = 1.43, 95% CI = 1.09–1.89, P = 0.01), 1-year (OR = 1.46, 95% CI = 1.08–1.97, P = 0.01), and 3-year (OR = 1.37, 95% CI = 1.01–1.84, P = 0.04) graft survival. WL grafts were less associated with retransplantation (OR = 0.57; 95% CI = 0.41–0.80; P < 0.01), vascular complications (OR = 0.53, 95% CI = 0.38–0.74, P < 0.01) and biliary complications (OR = 0.67; 95% CI = 0.47–0.95; P = 0.03). Considering ERLT as major Extended Donor Criteria is justified because ERL grafts are associated with vasculobiliary complications and the need for retransplantation, and have a negative influence on graft survival.     

Organ donation video messaging: differential appeal,emotional valence,and behavioral intention

Video narratives increasingly are used to draw the public's attention to the need for more registered organ donors. We assessed the differential impact of donation messaging videos on appeal, emotional valence, and organ donation intentions in 781 non‐registered adults. Participants watched six videos (four personal narratives, one informational video without personal narrative, and one unrelated to donation) with or without sound (subtitled), randomly sequenced to minimize order effects. We assessed appeal, emotional valence, readiness to register as organ donors, and donation information‐seeking behavior. Compared to other video types, one featuring a pediatric transplant recipient (with or without sound) showed more favorable appeal (p < 0.001), generated more positive emotional valence (p < 0.01), and had the most favorable impact on organ donor willingness (p < 0.001). Ninety‐five (12%) participants clicked through to a donation website after viewing all six videos. Minority race (OR = 1.94, 95% CI = 1.20, 3.13, p = 0.006), positive change in organ donor readiness (OR = 0.26, 95% CI = 0.14, 0.48, p < 0.001), and total positive emotion (OR = 1.05, 95% CI = 1.03, 1.07, p < 0.001) were significant multivariable predictors of clicking through to the donation website. Brief, one‐min videos can have a very dramatic and positive impact on willingness to consider donation and behavioral intentions to register as an organ donor.     

Trastuzumab Beyond Progression for HER2 Positive Metastatic Breast Cancer: Progression‐Free Survival on First‐Line Therapy Predicts Overall Survival Impact

Trastuzumab beyond first progression in the metastatic setting has been adopted based on limited data suggesting improved outcomes compared to second‐line chemotherapy alone although predictive factors for preferential benefit remain elusive. We conducted a retrospective review of all patients receiving trastuzumab for HER2 + metastatic disease between Jan 1, 1999–June 15, 2011. Univariate and time to event analyses described treatment and survival patterns. Median duration of each line of therapy and overall survival times for covariates, including treatment era (pre versus post Jan 1, 2005), lines of trastuzumab‐based therapy (1 versus 2 versus 3 + ), first‐line chemotherapy partner (docetaxel/paclitaxel versus other) and median exposure to first‐line trastuzumab‐based therapy (=/> versus < cohort median) were estimated. A total of 119 patients received a median of two lines of trastuzumab‐based therapy (range 1–8). Median overall survival was 21.8 months (95% CI = 14.5–27.1 m), by era was 15.6 m (95% CI = 9.7–24.8 m) versus 26.1 m (95% CI = 20.0–39.3 m; p = 0.11) and by lines of trastuzumab‐based therapy received was 10.6 m (95% CI = 5.3–17.4 m) versus 13.9 m (95% CI = 9.5–27.6 m) versus 32.5 m (95% CI = 25–49.4 m) (p = 0.0014). Median overall survival was significantly longer for those receiving taxanes with trastuzumab compared to other first line partners (26.1 m, 95% CI = 17.8–31.4 m versus 14.5 m, 95% CI = 9.4–21.9 m, p = 0.02). Median overall survival with duration of first‐line trastuzumab‐based therapy =/> cohort median was 31.9 m (95% CI = 26.2–52.2 m) versus 10.3 m for shorter durations (95% CI = 6.9–15.6 m; p < 0.0001). Our observations support progression‐free survival on first‐line trastuzumab‐based therapy as a clinically relevant predictive factor for overall survival benefit with the adoption of a trastuzumab beyond progression treatment strategy.     

Association of Herpes simplex virus I&II infections with rs187084 SNP of TLR9 and male infertility

Since TLR9 recognises unmethylated CpG motifs in viral DNA, its polymorphisms may contribute to the susceptibility to Herpes simplex virus I&II infection. In the present study, to evaluate the role of rs187084 SNP (single nucleotide polymorphism) of TLR9 in Herpes simplex virus I&II infection and male infertility, 103 infertile and 27 fertile blood and semen samples were analysed. We assessed the micro and macro properties of semen specimens and the presence of HSV immunoglobulins. Tetra-primer ARMS PCR was used to detect SNP and to investigate the genotype distribution of TLR9-rs187084 SNPs, and the correlation between polymorphisms of TLR9 gene and male infertility. Moreover, the odds ratio (OR) and 95% confidence intervals were used to estimate the strength of the association. Based on our finding, a significant correlation was observed between HSV infection, agglutination and polymorphism (TT) under dominant (OR = 1.28, 95% CI = 0.94–1.75) and recessive (OR = 0.44, 95% CI = 0.21–0.94) models for the data, which was complied with Hardy–Weinberg equilibrium (HWE) (OR = 2.91, 95% CI = 1.02–8.30). The result showed a significant association between HSV IgM and agglutination in HSV infection (p < .001), and in addition, there were associations between alleles so that rs187084 SNP might be considered as a risk factor for the incidence of HSV infection.     

Exploration of the association between chronic periodontal disease and erectile dysfunction from a population‐based view point

Several cross‐sectional studies have indicated an association between chronic periodontal disease (CPD) and cardiovascular disease and metabolic syndrome. Erectile dysfunction (ED) also shares pathological mechanisms with these diseases. Using a nationwide population‐based data set, we examined the association between ED and CPD and assessed the effect of dental extraction (DE) on ED prevalence in different aged CPD populations in Taiwan. We identified 5105 patients with ED and randomly selected 10 210 patients as controls. Of these patients, 2617 (17.09%) were diagnosed with CPD according to the index data: 1196 (23.43%) in the ED group and 1421 (13.92%) in the control group. After adjusting for comorbid factors, patients with ED were more likely to have been diagnosed with prior CPD than controls (OR = 1.79, 95% CI = 1.64–1.96, P < 0.001). Moreover, the association was much stronger in the populations aged less than 30 years (OR = 2.13, 95% CI = 1.23–3.70, P < 0.001) and more than 59 years (OR = 2.27, 95% CI = 1.99–2.59, P < 0.001). Dental extraction seems to attenuate damage to the penile endothelial beds caused by CPD‐related inflammation and overcame the process of ED in the middle‐aged and older populations.     

Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics

Most calcineurin inhibitor (CNI)‐based protocols reduce blood trough goals approximately 2–3 months post‐transplant in clinically stable kidney transplant recipients. The CNI target trough level to prevent rejection, after reduction, is unknown. Using a multivariate Cox proportional hazards model, we determined the association of time‐varying tacrolimus (TAC) trough levels with acute rejection (AR) occurring in the first 6 months post‐transplant, but specifically we assessed this association after 3 months. A total of 1930 patients received TAC‐based immunosuppression prior to AR in a prospective study. Of the 151 (7.8%) who developed AR, 47 developed AR after 3 months post‐transplant. In an adjusted time‐varying multivariate model, each 1 ng/ml decrease in TAC trough levels was associated with a 7.2% increased risk of AR [hazards ratio (HR) = 1.07, 95% confidence interval (CI) (1.01, 1.14) P = 0.03] in the first 6 months. There was an additional 23% increased risk of AR with each 1 ng/ml decrease in the TAC trough levels in months 3–6 [HR = 1.23, 95% CI (1.06, 1.43) P = 0.008]. In conclusion, lower TAC trough levels were significantly associated with increased risk of AR in the first 6 months post‐transplant with additional risk of AR between months 3 and 6 post‐transplant. The timing and practice of TAC dose reduction should be personalized based on the individual's risk factors.     

Genetic polymorphism in hOGG1 is associated with triple-negative breast cancer risk in Chinese Han women

8-hydroxy-2′-deoxyguanine (8-OHdG), a typical product of oxidative stress-induced DNA damage, can cause a G–T transversion during DNA replication if it is not removed. Human 8-oxoguanine glycosylase 1 (hOGG1), a key DNA repair gene, recognizes and excises 8-OHdG from damaged DNA accurately; however, a c.977C>G (Ser326Cys) polymorphism in hOGG1 can inhibit the gene's ability to remove 8-OHdG. The aim of present study was to investigate the association between the c.977C>G polymorphism in hOGG1 and the risk of breast cancer in Chinese Han women. We used high-resolution melting and sequencing to analyze the genotypes of 630 patients with sporadic breast cancer patients and 777 healthy controls. We also performed risk-stratified subgroup analyses to determine the association between the c.977C>G polymorphism and other characteristics of breast cancer subgroups. Breast cancer patients and healthy controls did not have significantly different of c.977C/G genotypes (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.82–1.49, p = 0.57) and c.977G/G genotypes (OR = 1.34, 95% CI = 0.97–1.84, p = 0.09). However, the c.977G/G genotype was especially prevalent in breast cancer patients who were younger than 55 years (OR = 1.58, 95% CI = 1.05–2.39, p = 0.04), were premenopausal status (OR = 1.87, 95% CI = 1.14–3.06, p = 0.02), had triple-negative disease (OR = 2.14, 95% CI = 1.06–4.29, p = 0.04), or p53-positive disease (OR = 1.56, 95% CI = 1.14–2.12, p = 0.005). These findings suggest that the c.977C>G polymorphism in hOGG1 is associated with an increased risk of breast cancer in Chinese Han women who are younger than 55 years, premenopausal, triple-negative, or p53-positive subgroups.     

Association between granzyme B and perforin I polymorphisms and allograft outcomes in Hispanic kidney transplant recipients

Granzyme B (GZMB) and perforin 1 gene (PRF1) are key effector molecules of cytotoxic T lymphocytes, in causing acute and chronic solid organ transplant rejection. In this study, we analyzed the impact of GZMB and PRF1 polymorphism on kidney allograft outcomes. In all, 527 de novo kidney Hispanic allograft recipients were genotyped for PRF1 (rs10999426, rs35947132) and GZMB (rs8192917, rs7144366). PRF1 (rs10999426, rs35947132) G alleles and GG genotypes were negatively associated with allograft rejection, demonstrating protection against allograft rejection (OR = 0.61, p = 0.005 for rs1099946; OR = 0.4, p = 0.01 for rs 35947132). On the other hand, the GA heterozygosity of PRF1 was found marginally associated with the rejection group (OR = 1.53, p = 0.05 for rs10999426; OR = 2.24, p = 0.07 for rs35947132). There was a significant increase in allograft survival in time period studied for the PRF1 (rs10999426) GG genotype, while the GA heterozygosity was associated with graft failure. We found no association for polymorphic markers in GZMB gene with allograft rejection. Survival was significantly improved for patients who were homozygous TT for the GZMB (rs8192917) (TT vs. CC/TT, p = 0.041). The result suggests that PRF1 and GZMB gene polymorphisms may determine the incidence of acute rejection or graft survival among Hispanic allograft recipients.     

Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label,single‐arm,one‐way crossover study

There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.     

Daily fluid intake and outcomes in kidney recipients: post hoc analysis from the randomized ABCAN trial

Generous and even excessive fluid intake is routinely recommended to kidney transplant recipients despite minimal evidence to support this practice. We hypothesized that increased fluid intake, ascertained by 24‐h urine volume output, may adversely affect graft outcomes as it would impose an extra workload on a limited number of nephrons. Kidney transplant recipients who were randomized to losartan vs. placebo in the Angiotensin II Blockade for Chronic Allograft Nephropathy (ABCAN) trial (n = 153) underwent baseline, five‐yr biopsies, and annual iothalamate glomerular filtration rate assessment. Recipients with higher urine volume at randomization had higher urinary sodium and also higher urinary protein. The proportion using diuretics or CNI based regimens were similar across urinary volume tertiles. The highest urinary volume tertile (>2.56 L/d) did not predict the development of interstitial volume doubling or end‐stage renal disease (ESRD) from interstitial fibrosis/tubular atrophy (OR = 3.52, 95% CI 0.4, 31.24, p = 0.26), interstitial volume doubling or all‐cause ESRD (OR = 7.04, 95% CI 0.66, 74.87, p = 0.11), and was not associated with the conventional endpoint of doubling serum creatinine, all‐cause ESRD, or death (OR = 0.89, 95% CI 0.21, 3.71, p = 0.87). These results suggest that the current practice of liberal fluid intake may not be beneficial in low risk and mostly Caucasian transplant recipients.     

Post-transplant eosinophilic gastrointestinal disorders and lymphoproliferative disorder in pediatric liver transplant recipients on tacrolimus

AimTo examine and characterize post-transplant eosinophilic gastrointestinal disorders (PTEGID) and post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients.MethodsThis is a single center retrospective study of all liver transplant recipients aged 0–18 years from 1999 to 2019 who received tacrolimus as their primary immunosuppressant. Demographic data and clinical/laboratory data including PTEGID, PTLD, liver transplant types, Epstein-Barr virus status, and blood eosinophil count were reviewed. Analysis was done with logistic regression and Mann-Whitney U test.ResultsNinety-eight pediatric liver transplant recipients were included with median age at transplantation of 3.3 years (IQR: 1.1–9.3). The major indication for transplantation was biliary atresia, 51 (52%) cases. Eight (8%) children had PTLD and 14 (14%) had PTEGID. Receiving liver transplantation at an age of ≤1 year was associated with developing PTEGID (OR = 11.9, 95% CI = 3.5–45.6, p < 0.001). Additionally, eosinophilic count of ≥500/μL was associated with having PTLD (OR = 10.7, 95% CI = 1.8–206.0, p = 0.030) as well as having at least one liver rejection (OR = 2.8, 95% CI = 1.2–7.0, p = 0.024). The frequency of food-induced anaphylaxis significantly increased post-transplantation (p = 0.023).ConclusionsPTEGID and PTLD are common in this cohort and are associated with certain risk factors that help screen children to improve recipient survival. Further studies are needed to evaluate the clinical benefits of these findings.     

Genetic polymorphisms in IL‐2, IL‐10, TGF‐β1, and IL‐2RB and acute rejection in renal transplant patients

Acute rejection (AR) remains a concern for kidney transplantation. Cytokines are key mediators in the induction and effector phases of all immune and inflammatory responses. Single nucleotide polymorphisms (SNPs) in cytokines and their receptors may relate to AR. We investigated the relation between AR and SNPs in the genes encoding for IL‐2(–330G>T), IL‐10(?592C>A and ?1082G>A), TGF‐β1(915G>C), and IL‐2RB(rs228942 C>A and rs228953 C>T) in 325 renal transplant patients during the first year after transplantation. The overall incidence of AR was 15.4%. In multivariate analysis, only the use of induction therapy was correlated with AR (odds ratio 1.9; 95% confidence interval 1.1–3.7; p = 0.04). No statistically significant associations between the SNPs studied and AR were observed. SNPs in the investigated cytokines and their receptors were not associated with the risk of AR. Genotyping patients for these SNPs is unlikely to aid the clinician in adjusting the immunosuppressive therapy for individual patients.     

Association of HLA mismatch and MTOR inhibitor regimens with malignancy and mortality after kidney transplantation

BackgroundThe association of mammalian target of rapamycin inhibitors (MTORI) with malignancies and mortality in kidney transplant recipients (KTR) with different degrees of human leukocyte antigen mismatch (HLA-mm) at transplant has not been previously studied.MethodsOur observational cohort study included 166, 256 adult KTRs in 2000–2018. Immunosuppression in the first post-transplant year were MTORIs in 13,056 (7.85%) and non-MTORIs in 153,200 (92.15%). We used Cox multivariable regression models to determine the cause-specific hazard ratio (HRcs) of non-melanoma skin cancer (NMSC),solid organ malignancies (SOM)] and all-cause death (death_ac); and the HR of the composite outcomes of NMSC or death_ac and SOM or death_ac associated with MTORI versus non-MTORI regimens in the overall study sample and the 0, 1–3, and 4–6 HLA-A, B and DR mm subgroups.ResultsNMSC risk was lower with MTORI than non-MTORI in all HLA-mm subgroups [(0 mm, HRcs = 0.67; 95% CI = 0.46–0.97, 1–3 mm, HRcs = 0.73; 95% CI = 0.61–0.87, 4–6 mm, HRcs = 0.69; 95% CI = 0.62–0.76)]. SOM risks were similar between regimens in the 0 HLA mm subgroup (HRcs = 1.10 (95% CI = 0.78–1.57) and lower with MTORI than non-MTORI in the 1–3, and 4–6 HLA-mm subgroups, [(HR = 0.84; (95% CI = 0.71–0.99), and (HR = 0.86; 95% CI = 0.78–0.94); respectively]. Risks of death_ac and composite outcomes (NMSC or death_ac and SOM or death_ac) were higher with MTORI than non-MTORI in almost all HLA-mm subgroups.ConclusionMTORIs are associated with protection from NMSC and SOM in almost all HLA-mm subgroups ca; however, their association with increased all-cause mortality in adult kidney transplant recipients needs further investigation.     

CAG‐repeat polymorphisms in the polymerase γ gene and male infertility: a meta‐analysis

CAG‐repeat in the polymerase γ (POLG) gene encoding polymerase γ for mitochondria is important to spermatogenesis. Compared with a few researchers who raised alteration of CAG‐repeat‐affected male reproductive ability, others did not find the association between CAG‐repeat polymorphisms and male infertility. Therefore, a comprehensive meta‐analysis is necessary to determine the association; 13 case–control studies were screened out using keywords search. From these studies, characteristics were extracted for conducting meta‐analysis. Odds ratio (OR) and 95% confidence interval (CI) were used to describe the results; the results indicated that CAG‐repeat allele was not a risk factor to male infertility (pooled OR = 1.03, 95% CI: 0.79–1.34, P = 0.828). Four different genetic comparisons also demonstrated a negative result: heterozygote comparison (not 10/10 versus 10/10. Pooled OR = 0.99, 95% CI: 0.77–1.27, P = 0.948), homozygote comparison (not 10/not 10 versus 10/10. Pooled OR = 1.08, 95% CI: 0.56–2.06, P = 0.816), the recessive genetic comparison (not 10/not 10 versus not 10/10 + 10/10. Pooled OR = 1.07, 95% CI: 0.58–1.95, P = 0.829) and the dominant genetic comparison (not 10/not 10 + not 10/10 versus 10/10. Pooled OR = 0.97, 95% CI: 0.72–1.29, P = 0.804); based on current researches, this meta‐analysis demonstrated no apparent association between POLG‐CAG‐repeat and male infertility. Similarly, CAG‐repeat was not a sensitive site to male infertility.     

CYP1A2, CYP2D6, GSTM1, GSTP1, and GSTT1 gene polymorphisms in patients with bladder cancer in a Turkish population

Genetic differences in the metabolism of xenobiotics have recently been suggested as modifiers of individual susceptibility to bladder cancer (BC). The objective of this study was to investigate the relationship between bladder tumor and variants of cytochrome p450 1A2 (CYP1A2) 734 C → A, cytochrome p450 2D6 (CYP2D6) 1934 G → A, glutathione S-transferase M1, (GSTM1 null), glutathione S-transferase T1 (GSTT1 null), and glutathione S-transferase P1 (GSTP1) I105 V. We investigated the distribution of these polymorphisms in 135 BC patients and in 128 age and sex-matched cancer-free controls. The polymorphisms were analyzed using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay and the multiplex PCR method. Genotype and allele frequencies and their associations with BC risk, demographic factors, smoking status, and tumor stage were investigated. The prevalence of GSTT1 null genotype in cases was 23%, compared with 7% in the control group (OR = 3.94, 95% CI = 1.70–9.38, P = 0.001). There was no association between the studied polymorphisms of CYP1A2, CYP2D6, GSTM1, and GSTP1 genes and BC. There was an association between smoking status and BC. These data seem to indicate that GSTT1 gene polymorphism may be associated with BC in the Turkish population studied. Further studies will be needed to clarify the role of such variation in determining susceptibility to BC.