Rejection: An Integrated Response

Nickerson, Peter; Rush, David

doi:10.1111/ajt.12365

Cited by 12 publications

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“…In conclusion, unbalanced microbial communities have been associated with dysregulated immune responses and the development of inflammatory diseases such ulcerative colitis, Crohn's disease, and asthma. Interestingly, several studies including our own recent work now demonstrate an association of cellular immune rejection with the development of IFTA , suggesting that dysregulated immune responses may also be responsible for chronic rejection. Our theory is that the loss of protective, typically predominant resident bacteria and replacement with pathogenic nonresident bacteria in the UMB is acting to increase the immune response towards the transplanted kidney.…”

Section: Discussionmentioning

confidence: 94%

“…recurrent disease, BK nephropathy) occurs in ≈25% of 1‐year surveillance transplant biopsies as well as correlating with decreased graft survival . Inflammation with histological evidence of IFTA has been correlated with increased graft loss . However, our latest data indicate that any case of histological IFTA represents a risk for immune‐mediated graft loss .…”

Section: Introductionmentioning

confidence: 88%

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Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies

Modena

Milam

Harrison

et al. 2017

American Journal of Transplantation

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An unbalanced microbiome may lead to disease by creating aberrant immune responses. A recent association of cellular rejection with the development of interstitial fibrosis and tubular atrophy (IFTA) suggests the role of immune-mediated tissue injury. We hypothesized that developing IFTA correlates with altered urinary tract microbiomes (UMBs). UMBs at two serial time points, 1 and 6-8 months post-transplant, were assessed by 16S microbial ribosomal gene sequencing in 25 patients developing biopsy-proven IFTA compared to 23 transplant patients with normal biopsies and excellent function (TX) and 20 healthy non-transplant controls (HC). Streptococcus, the dominant genera in HC males, was lower in IFTA and TX males at 1 month compared to HCs. At 6-8 months, Streptococcus was further decreased in IFTA males, but normalized in TX. IFTA males and females had increases in number of genera per sample at 6-8 months. UMB composition varied substantially between individuals in all groups. Despite the wide variation in UMBs between individuals, IFTA associated with a loss in dominant resident urinary microbes in males, and a parallel increase in non-resident, pathogenic bacteria in males and females. UMB changes may contribute to IFTA development by alteration of the host immune response.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 88%

Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies

Modena

Milam

Harrison

et al. 2017

American Journal of Transplantation

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“…Acute T cell–mediated rejection (TCMR), presenting as either AR or subclinical acute rejection (subAR, histological AR without graft dysfunction only demonstrated by surveillance biopsies), is clearly linked to a higher risk of IFTA . In a study of 797 recipients, early episodes of AR led to more fibrosis and inflammation in 1‐ and 2‐year protocol biopsies than those without an occurrence of AR.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long‐Term Outcomes

Modena

Kurian

Gaber

et al. 2016

American Journal of Transplantation

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Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/ annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.

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“…Early TCMR has been linked with the risk of development of de novo DSAs. 266 In a study of 315 consecutive renal transplants without pretransplant DSAs, there was a strong trend towards clinical rejection before de novo DSA onset. 257 Further risk factors for the development of de novo DSAs include retransplantation, and other sensitization events, such as previous pregnancy.…”

Section: Slightly Modifiable or Nonmodifiable Contributors To Dsa Occmentioning

confidence: 99%

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

et al. 2017

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Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes. COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant. The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting. 12 Department of Gastroenterology and Hepatology, Erasmus MC, University Hospital Rotterdam, the Netherlands. 13 Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Belgium.14 Abdominal Transplant Surgery, Microbiology and Immunology Department, University Hospitals KU Leuven, Belgium. 15 Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Spain. www.transplantjournal.com S1 S olid organ transplantation has evolved from an experimental procedure to an established treatment option for many types of end-stage organ failure. Both patient and graft outcomes are continuing to improve, and 1-year patient and graft survival currently exceed 80%.1,2 However, survival rates gradually decline over the long term. In kidney transplant, 5-and 10-year graft survival rates in Europe are 77% and 56%, and for liver transplant, 64% and 54% (Figures 1 and 2). 3,4 Although most European countries have seen an increase in both living and deceased donation, transplantation is not available to all who would benefit from the procedure, and there is considerable morbidity and mortality for those listed for transplant.6 Therefore, maximizing long-term graft survival and reducing the need for retransplantation is paramount, not only in improving outcomes for the recipients but also for those awaiting a graft. The improvement in outcomes is predominantly due to reduction in (Transplantation. 2017;101:S1-S41). The authors were approached by Astellas to discuss the practical implementation o...

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Rejection: An Integrated Response

Cited by 12 publications

References 10 publications

Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies

Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies

Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long‐Term Outcomes

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

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