Risk of myeloid neoplasms after solid organ transplantation

Solid organ transplant recipients have elevated cancer risks, owing in part to pharmacologic immunosuppression. However, little is known about risks for hematologic malignancies of myeloid origin. We linked the US Scientific Registry of Transplant Recipients with 15 population-based cancer registries to ascertain cancer occurrence among 207 859 solid organ transplants (1987–2009). Solid organ transplant recipients had a significantly elevated risk for myeloid neoplasms, with standardized incidence ratios (SIRs) of 4.6 (95% confidence interval 3.8–5.6; N=101) for myelodysplastic syndromes (MDS), 2.7 (2.2–3.2; N=125) for acute myeloid leukemia (AML), 2.3 (1.6–3.2; N=36) for chronic myeloid leukemia and 7.2 (5.4–9.3; N=57) for polycythemia vera. SIRs were highest among younger individuals and varied by time since transplantation and organ type (Poisson regression P<0.05 for all comparisons). Azathioprine for initial maintenance immunosuppression increased risk for MDS (P=0.0002) and AML (2–5 years after transplantation, P=0.0163). Overall survival following AML/MDS among transplant recipients was inferior to that of similar patients reported to US cancer registries (log-rank P<0.0001). Our novel finding of increased risks for specific myeloid neoplasms after solid organ transplantation supports a role for immune dysfunction in myeloid neoplasm etiology. The increased risks and inferior survival should heighten clinician awareness of myeloid neoplasms during follow-up of transplant recipients.

Epigenetics:Time to translate into transplantation

Substantial progress has been made in identifying genetic loci associated with multifactorial disorders, including variants that seem to impact outcomes following solid organ transplantation. Despite these advances, much of the heritability and susceptibility to chronic disease processes remains unexplained. Epigenetic modifications may exert their effect independently or complementary to genetic variants. Epigenetic modifications can change gene expression without altering the DNA sequence. These modifications are dynamic, potentially heritable, and can be induced by environmental stimuli or drugs. The impact of epigenetic phenomena on the outcomes of organ transplantation is currently poorly understood. Epigenetic modifications can occur during periods of illness; these may persist and potentially influence allograft outcomes. Epigenetic mechanisms influence the activation, proliferation, and differentiation of the immune cells involved in allograft rejection. The donor's epigenome may also impact transplant survival, and initial research has demonstrated that peritransplant conditions induce rapid epigenetic modification within the allograft. Further research will help to define the importance of epigenetic modifications in transplantation. This will potentially lead to the identification of useful biomarkers and the development of novel pharmacotherapies. This review explores the nature of epigenetic modification in disease and the emerging evidence for epigenetic influences on allograft survival.

Donor type microchimerism is an infrequent event following liver transplantation and is not associated with graft acceptance

Donor-type microchimerism, the presence of a minority population of donor-derived haematopoietic cells following solid organ transplantation, has been postulated as a mechanism for induction of donor-specific graft tolerance. The stability, frequency, and relevance of microchimerism with respect to long-term outcome, however, remains uncertain. Using a polymerase chain reaction (PCR)-based method of microsatellite analysis of highly polymorphic short tandem repeat sequences (STRs) to detect donor-type cells, DNA from 11 patients was analyzed prospectively at specific time points for 12 months following liver transplantation, and from a further six patients retrospectively 2 years after liver transplantation. Using a panel of STRs, transient peripheral blood donor microchimerism was detected in 2 of 11 patients at a single time-point following transplantation, but persistent evidence of donor-derived cells was not observed during the study period. Analysis of DNA extracted from skin and duodenum in two patients likewise failed to show donor-type cells at these sites. None of the six patients in the retrospective arm showed donor microchimerism, resulting in an overall detection rate of 1.58%. These results suggest that donor microchimerism following liver transplantation is an infrequent event, and that the generation of graft tolerance is independent of microchimerism.

A HuGE Review and Meta-Analyses of Genetic Associations in New Onset Diabetes after Kidney Transplantation

PURPOSE: New onset diabetes after transplantation (NODAT) is a serious complication following solid organ transplantation. There is a genetic contribution to NODAT and we have conducted comprehensive meta-analysis of available genetic data in kidney transplant populations.

METHODS: Relevant articles investigating the association between genetic markers and NODAT were identified by searching PubMed, Web of Science and Google Scholar. SNPs described in a minimum of three studies were included for analysis using a random effects model. The association between identified variants and NODAT was calculated at the per-study level to generate overall significance values and effect sizes.

RESULTS: Searching the literature returned 4,147 citations. Within the 36 eligible articles identified, 18 genetic variants from 12 genes were considered for analysis. Of these, three were significantly associated with NODAT by meta-analysis at the 5% level of significance; CDKAL1 rs10946398 p = 0.006 OR = 1.43, 95% CI = 1.11-1.85 (n = 696 individuals), KCNQ1 rs2237892 p = 0.007 OR = 1.43, 95% CI = 1.10-1.86 (n = 1,270 individuals), and TCF7L2 rs7903146 p = 0.01 OR = 1.41, 95% CI = 1.07-1.85 (n = 2,967 individuals).

CONCLUSION: Evaluating cumulative evidence for SNPs associated with NODAT in kidney transplant recipients has revealed three SNPs associated with NODAT. An adequately powered, dense genome-wide association study will provide more information using a carefully defined NODAT phenotype.

Impact of ATP-binding cassette, subfamily B, member 1 pharmacogenetics on tacrolimus-associated nephrotoxicity and dosage requirements in paediatric patients with liver transplant

Importance of the field: Tacrolimus is the most commonly used immunosuppressive agent following solid-organ transplantation in children. Its clinical use, however, is complicated by side effects (mainly nephrotoxicity), narrow therapeutic index and pharmacokinetic variability which can result in an increased risk of treatment failure or toxicity. Studies examining inter-individual differences in the expression of the ABCB1 (ATP-binding cassette, subfamily B, member 1) gene (which encodes the drug transporter, P-gp) and its genetic polymorphisms have attempted to elucidate variations in tacrolimus response and disposition in children.

Donor identification and consent for deceased organ donation: summary of NICE guidance.

Organ donation plays a major role in the management of patients with single organ failure of the kidneys, liver, pancreas, heart, or lung, or with combined organ failure of heart and lung (such as in cystic fibrosis) or of kidney and pancreas (such as in diabetes). A shortage of transplant organs has resulted in long waits for transplantation. Currently about 500 people in the United Kingdom die each year because of a shortage of donated organs,1 and at 31 March 2011 almost 7000 patients were waiting for a kidney transplant1 and would be having costly dialysis with serious morbidity and impact on quality of life. This shortage of organs is partly the result of relatively low numbers of road traffic deaths (lower than in many countries) but is also the result of inefficiencies in the donor identification and consent processes. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on improving donor identification and consent rates for deceased organ donation.2

Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation

The lack of suitable donors for all solid-organ transplant programs is exacerbated in lung transplantation by the low utilization of potential donor lungs, due primarily to donor lung injury and dysfunction, including pulmonary edema. The current studies were designed to determine if intravenous clinical-grade human mesenchymal stem (stromal) cells (hMSCs) would be effective in restoring alveolar fluid clearance (AFC) in the human ex vivo lung perfusion model, using lungs that had been deemed unsuitable for transplantation and had been subjected to prolonged ischemic time. The human lungs were perfused with 5% albumin in a balanced electrolyte solution and oxygenated with continuous positive airway pressure. Baseline AFC was measured in the control lobe and if AFC was impaired (defined as

How Critical Care Nurses' Role and Education Affect Organ Donation

Organ and tissue dysfunction and failure cause high mortality rates around the world. Tissue and organs transplantation is an established, cost-effective, life-saving treatment for patients with organ failure. However, there is a large gap between the need for and the supply of donor organs. Acute and critical care nurses have a central role in the organ donation process, from identifying and assessing potential donors and supporting their families to involvement in logistics. Nurses with an in-depth knowledge of donation understand its clinical and technical aspects as well as the moral and legal considerations. Nurses have a major role to play in tackling organ and tissue shortages. Such a role cannot be adequately performed if nurses are not fully educated about donation and transplant. Such education could be incorporated into mandatory training and completed by all nurses.

Association of Functional Heme Oxygenase-1 Gene Promoter Polymorphism with Renal Transplantation Outcomes

Heme oxygenase-1 (HO-1) is a cytoprotective molecule and increased expression in experimental transplant models correlates with reduced graft injury. A functional dinucleotide repeat (GT)n polymorphism, within the HO-1 promoter, regulates gene expression; a short number of repeats (S-allele

Is screening for Factor V Leiden and Prothrombin G20210A Mutations in Renal Transplantation worthwhile? Results of a large single-center U.K. study

This single center study is the largest series of renal transplant recipients and donors screened for the commonest prothrombotic genotypes. A total of 562 transplant recipients and 457 kidney donors were genotyped for the factor V Leiden and prothrombin G20210A mutations. The prevalence of heterozygous factor V Leiden was 3.4% and 2.6% and prothrombin G20210A was 2.0% and 1.1% in recipients and donors, respectively, similar frequencies to that of the general U.K. population. The 30-day and 1-year graft survival rates in recipients with thrombophilic mutations were 93% and 93%, compared with 88% and 82% in patients without these mutations (log-rank P =0.34). Thrombophilia in recipients (odds ratio 0.55; confidence interval 0.06-2.29; P =0.56) or in donors (odds ratio 1.53; confidence interval 0.27-5.74; P =0.46) did not correlate with graft loss at 30 days after transplantation. In contrast to recent reports, this study did not demonstrate an association between thrombophilia and renal allograft loss, and routine screening is not recommended.