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The relevance of most genetic polymorphisms beyond CYP3A5*1on tacrolimus disposition remains unclear. We constructed a predictive mixed model for tacrolimus dose-corrected trough concentration (C0/dose) at months 3, 12 and 24 after transplantation in a retrospective cohort of 766 predominantly Causasian adult renal recipients (n=2042 trough concentrations). All patients were genotyped for 32 single-nucleotide polymorphisms with a proven or possible relevance to tacrolimus disposition based on the previous studies. Of these, ABCB1, ABCC2, OATP1B1, COMT, FMO, PPARAand APOA5were analyzed as (functional) diplotype groups. Predictors of C0/dose were CYP3A5*1, hematocrit, age, CYP3A4*22, use of concomitant CYP3A4 inhibitor or inducer, ALT, estimated glomerular filtration rate, tacrolimus formulation (once vs twice daily), ABCB1diplotype and time after transplantation. The effect of ABCB1diplotype was small but strongly accentuated in CYP3A4*22carriers and non-existent in CYP3A5 expressors. ABCC2diplotype had a limited effect on C0/dose that was only statistically significant in CYP3A5 non-expressors.

Allograft outcome depends on a range of factors, including donor age, the allo-immune response, ischemia–reperfusion injury, and interstitial fibrosis of the allograft. Changes in the epigenome, and in DNA methylation in particular, have been implicated in each of these processes, in either the kidney or other organ systems. This review provides a primer for DNA methylation analyses and a discussion of the strengths and weaknesses of current studies, but it is also a perspective for future DNA methylation research in kidney transplantation. We present exciting prospects for leveraging DNA methylation analyses as a tool in kidney biology research, and as a diagnostic or prognostic marker for predicting allograft quality and success. Topics discussed include DNA methylation changes in aging and in response to hypoxia and oxidative stress upon ischemia–reperfusion injury. Moreover, emerging evidence suggests that DNA methylation contributes to organ fibrosis and that systemic DNA methylation alterations correlate with the rate of kidney function decline in patients with chronic kidney disease and end-stage renal failure. Monitoring or targeting the epigenome could therefore reveal novel therapeutic approaches in transplantation and open up paths to biomarker discovery and targeted therapy.

Allograft outcome depends on a range of factors, including donor age, the allo‐immune response, ischemia–reperfusion injury, and interstitial fibrosis of the allograft. Changes in the epigenome, and in DNA methylation in particular, have been implicated in each of these processes, in either the kidney or other organ systems. This review provides a primer for DNA methylation analyses and a discussion of the strengths and weaknesses of current studies, but it is also a perspective for future DNA methylation research in kidney transplantation. We present exciting prospects for leveraging DNA methylation analyses as a tool in kidney biology research, and as a diagnostic or prognostic marker for predicting allograft quality and success. Topics discussed include DNA methylation changes in aging and in response to hypoxia and oxidative stress upon ischemia–reperfusion injury. Moreover, emerging evidence suggests that DNA methylation contributes to organ fibrosis and that systemic DNA methylation alterations correlate with the rate of kidney function decline in patients with chronic kidney disease and end‐stage renal failure. Monitoring or targeting the epigenome could therefore reveal novel therapeutic approaches in transplantation and open up paths to biomarker discovery and targeted therapy. This review highlights how DNA methylation research can provide novel insights into the mechanisms of kidney transplant failure by pointing out major discoveries in related research fields, including senescence, ischemia, the immune response, fibrosis, and chronic kidney disease.

This study shows the effect of a genetic variation in the immunoglobulin G receptor on respiratory infections and survival.

Chronic rejection remains the most important complication after lung transplantation (LTx). There is mounting evidence that both rheumatoid arthritis and chronic rejection share similar inflammatory mechanisms. As genetic variants in the FCGR2Agene that encodes the immunoglobulin gamma receptor (IgGR) have been identified in rheumatoid arthritis, we investigated the relationship between a genetic variant in the IgGR gene and chronic rejection and mortality after LTx. Recipient DNA from blood or explant lung tissue of 418 LTx recipients was evaluated for the IgGR (rs12746613) polymorphism. Multivariate analysis was carried out, correcting for several co-variants. In total, 216 patients had the CC-genotype (52%), 137 had the CT-genotype (33%) and 65 had the TT-genotype (15%). Univariate analysis demonstrated higher mortality in the TT-genotype compared with both other genotypes (p < 0.0001). Multivariate analysis showed that the TT-genotype had worse survival compared with the CC-genotype (hazard ratio [HR] = 2.26, p = 0.0002) but no significance was observed in the CT-genotype (HR = 1.32, p = 0.18). No difference was seen for chronic rejection. The TT-genotype demonstrated more respiratory infections (total, p = 0.037; per patient, p = 0.0022) compared with the other genotypes. A genetic variant in the IgGR is associated with higher mortality and more respiratory infections, although not with increased prevalence of chronic rejection, after LTx.

Focuses on the prevention and combating of corrupt activities in South Africa. Definition of gratification; Interpretation of the Section 2 of Act 12 of 2004; Offences of corruption.