Gut Microbiome Dysbiosis is Associated with Increased Mortality following Solid Organ Transplantation

Abstract Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival post-transplantation varies considerably. There is now increasing evidence that the gut microbiome is linked to the survival of hematopoietic cell transplant patients, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1,370 fecal samples from liver and renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes and virulence factors. To quantify taxonomic and metabolic dysbiosis, we analyzed 1,183 age-, sex- and BMI-matched subjects from the same population. A subset of patients were also followed longitudinally from pre- to post-transplantation. Our data show that transplant recipients suffer from gut dysbiosis—including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistant genes and virulence factors—that persist up to 20 years post-transplantation. Finally, we demonstrate that the use of immunosuppressive drugs is significantly associated with the observed dysbiosis and that the extent of dysbiosis is associated with increased post-transplant mortality.

Download Full-text

Impact of Pharmacogenetic Determinants of Tacrolimus and Mycophenolate on Adverse Events in Renal Transplant Patients

Current Drug Metabolism ◽

10.2174/1389200222666210114123349 ◽

2021 ◽

Vol 22 ◽

Author(s):

Kalluri Thishya ◽

Boddupally Sreenu ◽

Shree Bhushan Raju ◽

Vijay Kutala

Keyword(s):

Renal Transplant ◽

Adverse Events ◽

Metabolic Pathways ◽

Early Stage ◽

Maintenance Phase ◽

Solid Organ ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Post Transplantation ◽

Increased Risk

Background: Graft acceptance against immunity is one of themajor challenges in solid organ transplant. Immunosuppressive medications have effectively improved the post-transplantation outcome; however it has its own limitations. Genetic polymorphisms in drug-metabolizing enzymes have been identified as the potential targets in developing a pharmacogenetic strategy, to individualize drug dose and also in preventing the adverse events. Objective: The rationale of the study was to explore polymorphisms in tacrolimus and mycophenolate metabolic pathways that influence the adverse clinical outcomes in renal transplant recipients. Methods: A total of 255 renal transplant recipients were analyzed for the pharmacogenetic determinants of tacrolimus (CYP3A5*3, ABCB1 1236 T>C, ABCB1 2677 G>A/T, ABCB1 3435 T>C) and mycophenolate (UGT1A8*3, UGT1A9, IMPDH I, IMPDH II c.787C>T , ABCC2 -24 C>T and c.3972C>T) using Sanger sequencing. Results: Acute rejection (AR) was observed in 5.88% of the transplant recipients, whereas, acute tubular necrosis (ATNs) was observed in 7.45% of the patients, within early stage of the maintenance phase. Infections, such as urinary tract infection (UTI) and cytomegalovirus (CMV) infection were observed in 11.37% and 12.16% of the patients. The AUC of mycophenolate was significantly higher in patients with increased risk for infections. ABCC2 -24 C>T, c.3972C>T polymorphisms and ABCB1 3435 C-allele, were associated with reduced risk for infections. ABCC2 rs3740066 was associated with 2.06-fold all-cause mortality risk. CYP3A5 AG- and UGT1A9-440 CC-genotypes showed increased risk, and ABCC 3972C>T, CC-genotype showed protection against adverse events. Conclusion: Genetic variants in tacrolimus and mycophenolate metabolic pathways were found to influence the morbidity and mortality in renal transplant recipients.

Download Full-text

Cytomegalovirus in Solid Organ Transplant Recipients: Clinical Updates, Challenges and Future Directions

Current Pharmaceutical Design ◽

10.2174/1381612826666200531152901 ◽

2020 ◽

Vol 26 (28) ◽

pp. 3497-3506

Author(s):

Raymund R. Razonable

Keyword(s):

Organ Transplantation ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ ◽

Transplant Recipients ◽

Cmv Infection ◽

Future Directions ◽

Prevention And Treatment ◽

Solid Organ Transplant Recipients

Cytomegalovirus is the classic opportunistic infection after solid organ transplantation. This review will discuss updates and future directions in the diagnosis, prevention and treatment of CMV infection in solid organ transplant recipients. Antiviral prophylaxis and pre-emptive therapy are the mainstays of CMV prevention, but they should not be mutually exclusive and each strategy should be considered depending on a specific situation. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is emphasized as a major factor that should pave the way for an individualized approach to prevention. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management, and strategies for managing drug-resistant CMV infection are enumerated. There is increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, and their potential role in optimizing CMV prevention and treatment efforts is discussed.

Download Full-text

Exploring the Epidemiology of Cancer after Solid Organ Transplantation (EpCOT): an observational cohort study

BMJ Open ◽

10.1136/bmjopen-2020-043731 ◽

2021 ◽

Vol 11 (4) ◽

pp. e043731

Author(s):

Adnan Sharif ◽

Javeria Peracha ◽

David Winter ◽

Raoul Reulen ◽

Mike Hawkins

Keyword(s):

Organ Transplantation ◽

Record Linkage ◽

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Study Cohort ◽

Solid Organ ◽

Post Transplantation ◽

Increased Risk ◽

Risk Of Cancer

IntroductionSolid organ transplant patients are counselled regarding increased risk of cancer (principally due to their need for lifelong immunosuppression) and it ranks as one of their biggest self-reported worries. Post-transplantation cancer is common, associated with increased healthcare costs and emerging as a leading cause of post-transplant mortality. However, epidemiology of cancer post-transplantation remains poorly understood, with limitations including translating data from different countries and national data being siloed across different registries and/or data warehouses.Methods and analysisStudy methodology for Epidemiology of Cancer after Solid Organ Transplantation involves record linkage between the UK Transplant Registry (from NHS Blood and Transplant), Hospital Episode Statistics (for secondary care episodes from NHS Digital), National Cancer Registry (from cancer registration data hosted by Public Health England) and the National Death Registry (from NHS Digital). Deterministic record linkage will be conducted by NHS Digital, with a fully anonymised linked dataset available for analysis by the research team. The study cohort will consist of up to 85 410 solid organ transplant recipients,who underwent a solid organ transplant in England between 1 January 1985 and 31 December 2015, with up-to-date outcome data.Ethics and disseminationThis study has been approved by the Confidentiality Advisory Group (reference: 16/CAG/0121), Research Ethics Committee (reference: 15/YH/0320) and Institutional Review Board (reference: RRK5471). The results of this study will be presented at national and international conferences, and manuscripts with results will be submitted for publication in high-impact peer-reviewed journals. The information produced will also be used to develop national evidence-based clinical guidelines to inform risk stratification to enable risk-based clinical follow-up.Trial registration numberNCT02991105.

Download Full-text

Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution

Annals of Hematology ◽

10.1007/s00277-007-0298-2 ◽

2007 ◽

Vol 86 (8) ◽

pp. 599-607 ◽

Cited By ~ 94

Author(s):

Sylvain Choquet ◽

Stephan Oertel ◽

Veronique LeBlond ◽

Hanno Riess ◽

Nathalie Varoqueaux ◽

...

Keyword(s):

Organ Transplantation ◽

Lymphoproliferative Disorder ◽

Solid Organ Transplantation ◽

Solid Organ ◽

Post Transplantation

Download Full-text

Viral Enteritis in Solid-Organ Transplantation

Viruses ◽

10.3390/v13102019 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2019

Author(s):

Anum Abbas ◽

Andrea J. Zimmer ◽

Diana Florescu

Keyword(s):

Solid Organ Transplantation ◽

Organ Transplant ◽

Solid Organ Transplant ◽

Solid Organ ◽

Transplant Recipients ◽

Post Transplantation ◽

Organ Transplant Recipients ◽

Increased Risk ◽

Viral Enteritis ◽

Solid Organ Transplant Recipients

Solid organ transplant recipients are at increased risk for infections due to chronic immunosuppression. Diarrhea is a commonly encountered problem post transplantation, with infectious causes of diarrhea being a frequent complication. Viral infections/enteritides in solid organ transplant recipients often result from frequently encountered pathogens in this population such as cytomegalovirus, adenovirus, and norovirus. However, several emerging viral pathogens are increasingly being recognized as more sensitive diagnostic techniques become available. Treatment is often limited to supportive care and reduction in immunosuppression, though antiviral therapies mayplay a role in the treatment in certain diseases. Viral enteritis is an important entity that contributes to morbidity and mortality in transplant recipients.

Download Full-text

Solid Organ Transplantation in HIV-Infected Individuals

10.1093/med/9780190493097.003.0025 ◽

2017 ◽

Author(s):

Eurides Lopes ◽

Jennifer Husson

Keyword(s):

Organ Transplantation ◽

Opportunistic Infections ◽

Solid Organ Transplantation ◽

Team Approach ◽

Solid Organ ◽

Hiv Disease ◽

Transplant Recipients ◽

Post Transplant ◽

Liver And Kidney ◽

Infectious Disease Specialists

End-organ disease has become a major cause of morbidity and mortality in HIV-infected patients due to increased life expectancy, increasing the demand for organ transplantation in these patients. The care of HIV-infected transplant recipients warrants a multidisciplinary team approach, including the transplant team, pharmacists, infectious disease specialists, nurses, and patients and their families. The immunosuppression of HIV-infected recipients post-transplant does not appear to further advance HIV disease. The post-transplant risk for HIV-infected recipients of opportunistic infections does not appear to be increased by immunosuppression. However, the overall rate of infections is high, and it is even higher in hepatitis C virus (HCV) co-infected transplant recipients. HIV/HCV co-infected recipients have worse outcomes compared to both liver and kidney HIV-infected recipients.

Download Full-text

Beyond Cytomegalovirus and Epstein-Barr Virus: a Review of Viruses Composing the Blood Virome of Solid Organ Transplant and Hematopoietic Stem Cell Transplant Recipients

Clinical Microbiology Reviews ◽

10.1128/cmr.00027-20 ◽

2020 ◽

Vol 33 (4) ◽

Cited By ~ 1

Author(s):

Marie-Céline Zanella ◽

Samuel Cordey ◽

Laurent Kaiser

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Clinical Significance ◽

Viral Infections ◽

Solid Organ Transplantation ◽

High Morbidity ◽

Solid Organ ◽

Cell Transplant ◽

Transplant Recipients ◽

Hematopoietic Stem

SUMMARY Viral primary infections and reactivations are common complications in patients after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) and are associated with high morbidity and mortality. Among these patients, viral infections are frequently associated with viremia. Beyond the usual well-known viruses that are part of the routine clinical management of transplant recipients, numerous other viral signatures or genomes can be identified in the blood of these patients. The identification of novel viral species and variants by metagenomic next-generation sequencing has opened up a new field of investigation and new paradigms. Thus, there is a need to thoroughly describe the state of knowledge in this field with a review of all viral infections that should be scrutinized in high-risk populations. Here, we review the eukaryotic DNA and RNA viruses identified in blood, plasma, or serum samples of pediatric and adult SOT/HSCT recipients and the prevalence of their detection, with a particular focus on recently identified viruses and those for which their potential association with disease remains to be investigated, such as members of the Polyomaviridae, Anelloviridae, Flaviviridae, and Astroviridae families. Current knowledge of the clinical significance of these viral infections with associated viremia among transplant recipients is also discussed. To ensure a comprehensive description in these two populations, individuals described as healthy (mostly blood donors) are considered for comparative purposes. The list of viruses that should be on the clinicians’ radar is certainly incomplete and will expand, but the challenge is to identify those of possible clinical significance.

Download Full-text