The Study Of Bloodstream Infections In Transplant Recipients And Association Between Gene Polymorphisms And Infection After Kidney Transplantation

The present study includes part1Mortality and septic shock predictors of bloodstream infections in solid organ transplantation recipients, and part2Association between gene polymorphisms and infection after kidney transplantation. In part1, a retrospective study of133episodes of BSIs documented in98SOT patients was conducted to assess potential predictors of septic shock and mortality, and a retrospective study of77episodes of BSIs were observed following43of liver transplantation to assess risk factors for mortality. To determine the distribution of pathogens and their characteristics of drug susceptibility of bloodstream infections after renal or hepatic transplantation. The predictors significantly associated with increased mortality in SOT recipients with BSIs included decreased platelet count and septic shock. The risk factors for developing septic shock in SOT with bloodstream infections were early-onset (the2nd-8th week post transplant) and polymicrobial etiology. The risk factors significantly associated with increased mortality in liver transplant recipients with BSIs are higher serum creatinine levels and septic shock. Though gram positive coccus played an important role, most infections were caused by gram negative bacteria of bloodstream infections after renal or hepatic transplantation. The antibiotic resistant rate for gram negative bacteria was very high as well as gram positive coccus.In part2, the study was conducted to determine the influence of the polymorphisms of interleukin-10(IL-113)(-511C/T)and IL-1receptor antagonist gene (IL-1RN)(86-bpVNTR) on the susceptibility to bloodstream infections within the first year after kidney transplantation, and investigate whether or not the polymorphisms of TNF β, IL-10, IL-1β and IL-1receptor antagonist (IL-lra) gene predicted the susceptibility to pneumonia within the first year after kidney transplantation. MBL2and FCN2genotypic variants were also analyzed for association with the incidence of bloodstream infections within the first year after kidney transplantation.The present work provides evidence that recipient IL-1β-511CC genotype or IL-1β-511C allele is associated with the susceptibility to bloodstream infections within the first year after kidney transplantation and that recipient TNF β gene polymorphism may be useful in predicting pneumonia. Recipient QQ+PQ genotypes of MBL25’-UTR+4and recipient Thr236Met (+6359C>T) variant of exon8of FCN2have significant impact on the risk of developing bloodstream infections after kidney transplantation. There are17figures,18tables and135references. Part1Mortality and septic shock predictors of bloodstream infections in solid organ transplantation recipientsChapter I Mortality predictors of bloodstream infections in solid organ transplantation recipientsObjective:To assess the possible predictors influencing survival among solid organ transplantation(SOT) recipients with bloodstream infections(B SIs).Methods:A retrospective study of133episodes of BSIs documented in98patients was conducted to assess potential predictors of mortality. The predictors were identified by univariate and multivariate logistic regression analyses.Results:The mean age for the98enrolled patients was42.3years(42.3±12.8years). The majority of infections were nosocomial (79.6%), and the BSIs-related mortality rate was39.8%(39of98patients). The univariate analysis identified the following variables as predictors of BSIs-related mortality:intra-abdominal/biliary focus(P=0.011), polymicrobial infectionCP<0.001), liver transplant(P=0.002), platelet count<50,000/mm3(P<0.001), Lymphocyte count<300/mm3(P=0.027), and septic shock(P<0.001). The multivariate logistic regression analysis identified platelet count<50,000/mm3and septic shock as independent predictors of mortality.Conclusion:The predictors significantly associated with increased mortality in SOT recipients with BSIs included decreased platelet count and septic shock. Although appropriate antimicrobial therapy, the BSIs-related mortality was very high. Special attention should be paid to schedule optimal strategies for BSIs control practices in a transplantation setting. Chapter Ⅱ The risk factors for septic shock in solid organ transplantation recipients with bloodstream infectionsObjective:To evaluate the risk factors for septic shock among solid organ transplant recipients with bloodstream infections.Methods:A retrospective study consists of98subjects who underwent a kidney, heart transplant, simultaneous kidney-pancreas, liver-kidney, or orthotopic liver transplantation. All episodes of bloodstream infections significant according to the CDC criteria were analyzed.Results:133episodes of bloodstream infections occurred in98patients, with39of them developing septic shock. Among39septic shock patients, bloodstream infections were due to polymicrobial in43.5%, gram-negative bloodstream infections in38.5%, gram-positive bloodstream infections in15.4%, and fungal in2.6%of patients. The lung was the most frequent source of bloodstream infections (41.8%), followed by intra-abdominal/biliary focus (24.5%). Empiric therapy was correct in72%of cases with shock. However,31(79%) patients died despite that20patients were adequate empiric antibiotic therapy. Risk factors for developing septic shock were the2nd to8th week post transplant (P=0.014), polymicrobial etiology (P=0.001), intra-abdominal/biliary focus (P=0.011), and liver transplant (P=0.002) Only the2nd to8th week post transplant and polymicrobial etiology were significant in multivariate analysis.Conclusions:Our study revealed that risk factors for developing septic shock in SOT with bloodstream infections were early-onset (the2nd-8th week post transplant) and polymicrobial etiology. Chapter III The Risk Factors for Mortality in Deceased Donor Liver Transplant Recipients with Bloodstream InfectionsObjective:More data on the risk factors for mortality in liver transplant recipients with bloodstream infections (BSIs) are needed. From January2002to January2012, a retrospective analysis of BSIs in deceased donor liver transplant was reviewed.Methods:During the retrospective study period,135deceased donor liver transplants were performed, and77episodes of BSIs were observed following43of them to assess risk factors for mortality. Risk factors were identified by univariate and multivariate logistic regression analysis.Results:Forty-three of the recipients (31.9%) developed BSIs. The median age for these patients was45.1years(45.1±14.1years). The majority of infections were nosocomial (97.7%), and more than half were polymicrobial(53.5%). There were24deaths in these recipients (55.8%). The univariate analysis identified the following variables as the risk factors for BSIs-related mortality:Polymicrobial{P=0.029), platelet count<50,000/mm3(P=0.02), creatinine>1.5mg/dL (P=0.008), and septic shock(P<0.001). Multivariate logistic regression showed that the independent risk factors for mortality are creatinine>1.5mg/dL and septic shock.Conclusion:The risk factors significantly associated with increased mortality in deceased donor liver transplant recipients with BSIs are higher serum creatinine levels and septic shock. Although appropriate antimicrobial treatment, BSIs accompanied by septic shock or higher serum creatinine levels are associated with high mortality rates. It is therefore essential to pay special attention to protection of renal function and effective control measures to reduce the incidence of BSIs. Chapter IV Distribution of pathogen and resistance of BSIs after renal or hepatic transplantation:A clinical anylasis of21Objective:To determine the distribution of pathogens and their characteristics of drug susceptibility of bloodstream infections after renal or hepatic transplantation, and to provide evidence for clinical anti-infection treatments.Methods:Retrospective analysis to the pathogens and their drug susceptibility characteristics was carried out. These pathogens were isolated from the samples that came from patients with bloodstream infections after renal or hepatic transplantation from2008to2010.Results:The main pathogens were gram negative bacteria (62.5%), and the next ones were gram positive bacteria (37.5%). The most common gram negative bacilli were Escherichia coli. While for gram positive bacteria, the main bacilli were Staphylococcus aureus. The gram negative bacteria were relatively sensitive to carbapenem and quinolone. The gram positive bacteria were sensitive to glycopeptides and oxazolidone.Conclusions:Though gram positive coccus played an important role, most infections were caused by gram negative bacteria of bloodstream infections after renal or hepatic transplantation. The antibiotic resistant rate for gram negative bacteria was very high as well as gram positive coccus. Part2Association between gene polymorphisms and infection after kidney transplantationChapter I Genetic association of interleukin-1βand its receptor antagonist gene polymorphisms with susceptibility to bloodstream infections in kidney transplant recipientsObjective:Bloodstream infections remain significant causes of morbidity and mortality after kidney transplantation. No study has investigated the association of IL-1cluster gene polymorphism with susceptibility to bloodstream infections in kidney transplant recipients so far. The present study was therefore, conducted to determine the influence of the polymorphisms of interleukin-1β (IL-1β)(-511C/T)and IL-1receptor antagonist gene (IL-1RN)(86-bpVNTR) on the susceptibility to bloodstream infections within the first year after kidney transplantation.Methods:Subjects comprised21kidney transplant recipients with bloodstream infections and60noninfected kidney transplant recipients. Genomic DNA from these81kidney transplant recipients was extracted routinely from peripheral blood leukocytes. The region containing the Aval polymorphic site at position-511of IL-1β gene was amplified by polymerase chain reaction(PCR) and subsequently digested with AvaI restriction enzyme. The polymorphic regions within intron2of IL-1RN containing variable numbers of a tandem repeat (VNTR) of86base pairs were amplified by means of PCR.Results:A higher presence of IL-1β-511CC genotype and IL-1β-511C allele in the recipients with bloodstream infections than in the noninfected recipients (P=0.023and P=0.015, respectively) was found. In contrast, the current study failed to show any significant difference, either in genotypic or allelic frequency for the IL-1RN polymorphism regarding the incidence of bloodstream infections (P=0.508and P=0.507, respectively). After adjusting, recipient IL-1β-511CC genotype (OR 4.400,95%CI=1.517-12.759, P=0.006) and recipient IL-1β-511C allele (OR=2.444,95%CI=1.172-5.100, P=0.015) predicted independently the risk for bloodstream infections within the first year after kidney transplantation.Conclusion:The present work provides evidence that recipient IL-1β-511CC genotype or IL-1β-511C allele is associated with the susceptibility to bloodstream infections within the first year after kidney transplantation. These results suggest that genotyping data may allow more accurate prediction of bloodstream infections and the design of strategies to protect the most vulnerable patients. Chapter Ⅱ Genetic association of tumor necrosis factor β, interleukin-10and interleukin-1gene cluster polymorphism with susceptibility to pneumonia in kidney transplant recipientsObjective:Pneumonia remains a significant cause of morbidity and mortality after kidney transplantation. The present study was therefore, conducted to investigate whether or not the polymorphisms of TNF β, IL-10, IL-1β and IL-1receptor antagonist (IL-lra) gene predicted the susceptibility to pneumonia within the first year after kidney transplantation.Methods:Subjects comprised33kidney transplant recipients with pneumonia and63non-infected kidney transplant recipients. Genomic DNA from these96kidney transplant recipients was extracted from peripheral blood leukocytes. The regions containing the Ncol polymorphic site at position+252of TNF β gene, the RsaI polymorphic site at position-592of IL-10gene and the Aval polymorphic site at position-511of IL-1β gene were amplified by polymerase chain reaction(PCR) and subsequently digested with Ncol, RsaI and Aval restriction enzyme, respectively. The polymorphic regions within intron2of IL-lra gene (IL-1RN) containing variable numbers of a tandem repeat (VNTR) of86base pairs, were amplified by PCR.Results:Individual locus analysis showed that recipient IL-10, IL-1β and IL-1RN polymorphisms were not associated with the presence of pneumonia (P=0.589,0.940and0.286, respectively). However, compared with GG genotype, recipient TNF β+252AA+AG genotype was significantly associated with susceptibility to pneumonia (P=0.006). After adjusting for age of45years or older, recipient TNF β+252AA+AG (OR=5.366,95%confidence intervals (CI)=1.470-19.589, P0.011) independently predicted the risk for pneumonia within the first year after kidney transplantation.Conclusion:These results suggested that recipient TNF β gene polymorphism may be useful in predicting pneumonia hence identifying individuals that could benefit from preventive treatment and a less potent immunosuppression regimen. Chapter III Mannose-binding lectin gene polymorphisms influence the susceptibility to bloodstream infections in kidney transplant recipientsObjective:Mannose-binding lectin (MBL) is a C-type lectin that interacts with carbohydrate structures on microbial surfaces. Polymorphisms at the promoter and exon1of the MBL2gene are responsible for low serum levels of MBL and have been shown to play an important role in an increased risk of post-transplant infections. MBL2genotypic variants were analyzed for association with the incidence of bloodstream infections within the first year after kidney transplantation.Methods:We prospectively analyzed81kidney transplant recipients. A total of6well-known functional Single-nucleotide polymorphisms(SNPs) in the MBL2gene of the recipients were determined by gene sequencing. The events of bloodstream infections were collected prospectively.Results:Multivariate analyses only found an association of recipient QQ+PQ genotypes of MBL25’-UTR+4with the incidence of bloodstream infections (OR=3.677,95%confidence intervals (CI)=1.127-11.998, P=0.031) as compared to PP genotypes of MBL25’-UTR+4. No differences were found according to other5polymorphisms in the MBL2gene.Conclusion:Recipient QQ+PQ genotypes of MBL25’-UTR+4have significant impact on the risk of developing bloodstream infections after kidney transplantation. Chapter IV Gene polymorphisms of ficolin-2predict bloodstream infections risk after kidney transplantationObjective:Ficolin-2interacts with N-acetylglucosamine on microbial surfaces and has similarities in structure and function to Mannose-binding lectin (MBL). Polymorphisms in the promoter region and exon8of the ficolin-2(FCN2) gene are responsible for differences in ficolin-2serum levels and have been shown to play an important role in an increased risk of post-transplant infections. We assessed the relationship between these polymorphic genes and bloodstream infections within the first year after kidney transplantation, in relation to major risk factors.Methods:We prospectively analyzed81kidney transplant recipients. A total of5well-known functional Single-nucleotide polymorphisms(SNPs) in the FCN2gene of the recipients were determined by gene sequencing. Bloodstream infections events were collected prospectively. FCN2genotypic variants were analyzed for association with the incidence of bloodstream infections within the first year after kidney transplantation.Results:Univariate analysis found-986G/A variant of promoter region(P=0.016) and Thr236Met (+6359OT) variant of exon8(P=0.016) are associated with the incidence of bloodstream infections. Multivariate analysis only found an association of recipient Thr236Met (+6359C>T) variant of exon8with the incidence of bloodstream infections (OR=4.917,95%confidence intervals (CI)=1.229-19.667, P=0.024). No differences were found according to other3polymorphisms in the FCN2gene.Conclusion:Recipient Thr236Met (+6359C>T) variant of exon8are major determinants of the risk of developing bloodstream infections after kidney transplantation.