Introduction: Noninvasive biomarkers that reflect tubular health and allow early recognition of accelerated graft fibrosis development are warranted. Serum uromodulin (sUmod) and urinary epidermal growth factor (uEGF) originate from kidney tubules and may reflect functional nephron mass. The aim of this study was to investigate the associations between sUmod and uEGF with measured glomerular filtration rate (mGFR) and kidney allograft interstitial fibrosis percentage (IF%) score. Methods: sUmod and uEGF measurements, mGFR by iohexol-clearance and kidney allograft biopsies were obtained from kidney transplant recipients (KTRs) included in the Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial at 8 weeks (baseline) and at 1 year after transplantation (end of study). Associations were analyzed with univariable and multivariable linear regression. Results: Ninety patients at baseline and 48 patients at end of study had complete study variable assessments. uEGF normalized to urinary creatinine (uEGF/Cr) was associated with mGFR both at baseline (standardized β-coefficient [Std. β-coeff] = 0.457 [p = <0.001]) and at end of study (Std. β-coeff = 0.637 [p = <0.001]). sUmod was only associated with mGFR at end of study (Std. β-coeff = 0.443 [p = 0.002]). uEGF/Cr, sUmod, and mGFR were associated with graft IF% score both at baseline (Std. β-coeff = −0.349 [p = 0.001], −0.274 [p = 0.009] and −0.289 [p = 0.006], respectively) and at end of study (Std. β-coeff = −0.365 [p = 0.011], −0.347 [p = 0.016] and −0.405 [p = 0.004], respectively). The results remained largely unchanged in multivariable analysis. Conclusion: uEGF/Cr and sUmod were associated with mGFR and graft IF% score. Our results indicate a possible role of uEGF/Cr and sUmod in the follow-up of KTRs.

Rationale & ObjectiveDeterioration of kidney graft function is associated with accelerated cellular senescence. Marine n-3 polyunsaturated fatty acids (PUFAs) have favorable properties that may counteract cellular senescence development and damage caused by the senescence-associated secretory phenotype (SASP) secretome. Our objective was to investigate the potential effects of marine n-3 PUFA supplementation on the SASP secretome in kidney transplant recipients.Study DesignExploratory substudy of the Omega-3 Fatty Acids in Renal Transplantation trial.Setting & ParticipantsAdult kidney transplant recipients with a functional kidney graft (defined as having an estimated glomerular filtration rate of>30mL/min/1.73m2) 8 weeks after engraftment were included in this study conducted in Norway.Analytical ApproachThe intervention consisted of 2.6g of a marine n-3 PUFA or olive oil (placebo) daily for 44 weeks. The outcome was a predefined panel of SASP components in the plasma and urine.ResultsA total of 132 patients were enrolled in the Omega-3 Fatty Acids in Renal Transplantation trial, and 66 patients were allocated to receive either the study drug or placebo. The intervention with the marine n-3 PUFA was associated with reduced plasma levels of granulocyte colony-stimulating factor, interleukin 1α, macrophage inflammatory protein 1α, matrix metalloproteinase (MMP)-1, and MMP-13 compared with the intervention in the control group.LimitationsPost hoc analysis.ConclusionsThe results suggest that marine n-3 PUFA supplementation has mitigating effects on the plasma SASP components granulocyte colony-stimulating factor, interleukin 1α, macrophage inflammatory protein 1α, MMP-1, and MMP-13 in kidney transplant recipients. Future studies with kidney transplant recipients in maintenance phase, combined with an evaluation of cellular senescence markers in kidney transplant biopsies, are needed to further elucidate the potential antisenescent effect of marine n-3 PUFAs. This trial is registered as NCT01744067.

We applaud the initiative by Dr. Yee Khong and colleagues in this issue of the journal, to collect more data on placental pathology in solid organ transplant recipients and to share these data between national registries. Additionally, we agree that this area of research should receive more attention. However, there are many other areas that also deserve increased attention. In general, there is a lack of knowledge regarding numbers of missed abortions in this population—both with respect to the mother being on immunosuppressive medication during pregnancy and also with respect to fathers being on immunosuppression at time of conception.1 Another unanswered question is whether immunosuppression used during pregnancy may affect maturation of the immune system to the unborn child? It is well known that breast-feeding can boost a baby’s immune system but still many transplant centers recommend organ-transplanted mothers not to breast-feed. Systematic long-term follow-up of offspring should perhaps be initiated? Lately there have been several publications on pregnancies following uterus transplantations. This is a totally new “ball-game” and seems to be increasingly accepted as infertility treatment for women with absolute uterine factor infertility.2,3 This is a field within transplantation that also definitely will need increased attention. So, in our article, we recommended pregnancy management to be performed by a Nephrologist or transplant physician, a Midwife, and an Obstetrician.4 This should be regarded as a minimum standard and not necessarily the optimal way to do it. Large transplant centers might consider a more ambitious approach, in which several groups of relevant health personnel should be invited to join the pregnancy management teams. As we are entering a new decade, we believe that the Transplant Society should consider revision of current guidelines to include more ambitious goals for preconception counseling and pregnancy management, stress patient involvement in decisions regarding reproductive health, and point out areas of research that needs to be addressed.5

Background High levels of plasma marine n-3 fatty acids (n-3FAs) are associated with improved patient and graft survival in renal transplant recipients (RTRs). The aim of this study was to evaluate the utility of a new food frequency questionnaire (FFQ) to estimate marine n-3FA consumption in future epidemiological research. Methods We developed an FFQ with a simple design of 10 questions to assess intake of marine sources of n-3FAs. RTRs included in the recent ORENTRA trial (n = 132) completed the study FFQ at the baseline visit eight weeks after engraftment and at the end of study visit one year post-transplant. We measured the reference biomarker plasma phospholipid (PL) marine n-3FA levels by gas chromatography at the same time points to evaluate association and degree of agreement between FFQ based marine n-3FA consumption estimates and the biomarker. Results The median plasma PL marine n-3FA level was 6.0 weight percentage (wt)% (interquartile range [IQR] 4.7 to 7.3) at baseline and 6.3 wt% (IQR 4.8 to 7.4) at end of study. Median FFQ based marine n-3FA consumption estimates were 22.8 g/month (IQR 13.0 to 34.0) at baseline and 20.3 g/month (IQR 14.5 to 32.3) at end of study. FFQ based marine n-3FA consumption estimates showed a moderate correlation with plasma PL marine n-3FA levels at baseline (Spearman’s correlation coefficient rs = 0.43, p<0.001) and a stronger correlation at end of study (rs = 0.62, p<0.001). Bland Altman plots showed a reasonable degree of agreement between the two methods at both time points. Conclusions Marine n-3FA consumption estimates based on the FFQ showed a moderate correlation with the reference biomarker plasma PL marine n-3FA levels. The FFQ might be useful in epidemiological studies where resources are limited.

Resting heart rate (rHR) and heart rate variability (HRV) are non-invasive measurements that predict the risk of sudden cardiac death (SCD). Marine n-3 polyunsaturated fatty acid (PUFA) supplementation may decrease rHR, increase HRV, and reduce the risk of SCD. To date, no studies have investigated the effect of marine n-3 PUFA on HRV in renal transplant recipients. In a randomized controlled trial, 132 renal transplant recipients were randomized to receive either three 1 g capsules of marine n-3 PUFA, each containing 460 mg/g EPA and 380 mg/g DHA, or control (olive oil) for 44 weeks. HRV was calculated in the time and frequency domains during a conventional cardiovascular reflex test (response to standing, deep breathing, and Valsalva maneuver) and during 2 min of resting in the supine position. There was no significant effect of marine n-3 PUFA supplementation on time-domain HRV compared with controls. rHR decreased 3.1 bpm (± 13.1) for patients receiving marine n-3 PUFA compared to 0.8 (± 11.0) in controls (p = 0.28). In the frequency domain HRV analyses, there was a significant change in response to standing in both high and low frequency measures, 2.9 (p = 0.04, 95% CI (1.1;8)) and 2.7 (p = 0.04, 95% CI (1.1;6.5)), respectively. In conclusion, 44 weeks of supplemental marine n-3 PUFAs in renal transplant recipients significantly improved the cardiac autonomic function, assessed by measuring HRV during conventional cardiovascular reflex tests.

Introduction Development of cardiovascular (CV) disease due to unwanted side effects of immunosuppression is common following renal transplantation. Tacrolimus (Tac) is known to have negative impact on CV risk factors. In this setting, high-dose fish oil supplementation may have beneficial effects on both renal function and CV risk profile. However, it is not known if administration of fish oil affects Tac concentrations. The aim of the present study was to investigate the potential effects of fish oil on once-daily Tac pharmacokinetics in renal transplant recipients. Methods A single center prospective study was conducted. Fifteen stable renal transplant recipients receiving once-daily tacrolimus (Advagraf®), mycophenolate and a steroid-based immunosuppression were included in the study. Two 8-hr pharmacokinetic investigations were performed before and after 4 weeks of fish oil administration (2.55 g/day). Tac dosing remained unchanged during the treatment period. Standard non-compartmental methods were used to determine pharmacokinetic parameters and the European Medicines Agency guidelines for bioequivalence studies to assess the possible pharmacokinetic interaction. Results Twelve patients, median age 59 years (range 28-75) provided 2 evaluable pharmacokinetic Tac profiles. Concomitant administration of fish oil induced a 25 ± 30% increase in tacrolimus AUC0-8 (P< 0.01). The bioequivalence criteria were not fulfilled; the mean before:after AUC0-8 and Cmax ratios were 1.22 (90% CI: 1.08-1.37) and 1.20 (90% CI: 1.11-1.30), respectively. Tac trough concentrations also tended to increase from 5.5 ± 1.2 μg/L before to 6.3 ± 1.8 μg/L after administration of fish oil (P=0.19). Conclusions In renal transplant recipients, fish oil administration significantly increased the exposure of once-daily Tac. It is therefore advisable and warranted to closely monitor Tac concentrations following initiation and discontinuation of high-dose fish oil supplementation.

Objective: High consumption of trans-fatty acids (TFAs) is associated with increased mortality. Design and methods: Observational cohort study of 1.988 Norwegian renal transplant recipients with a median follow-up time of 9.6 years. We assessed multivariable adjusted associations between plasma levels of industrial and ruminant TFAs with patient and graft survival. Plasma phospholipid fatty acid levels were determined by gas chromatography at 10 weeks after transplantation. Results: During follow-up, there were 595 deaths, and 805 grafts were lost. Plasma industrial TFA levels dropped from 0.3 wt% in years 1999-2004 to reach a plateau of 0.2 wt% from year 2005 and beyond, whereas plasma levels of ruminant TFAs remained stable throughout the study period. In the former era (years 1999 to 2004, n = 902), we found multivariable adjusted associations between plasma industrial TFA levels and mortality (hazard ratio 4.44, P = .02) and graft loss (hazard ratio 4.22, P=.01). In the latter era (years 2005 to 2011, n=1,086), there were no associations between plasma industrial TFA levels and patient or graft survival. Plasma ruminant TFAs were not associated with mortality or graft loss in either eras. Conclusion: In this Norwegian transplant cohort, plasma industrial TFA levels dropped from around 0.3 wt% in the former era to 0.2 wt % in the latter era. While plasma industrial TFA was significantly associated with survival in the former era, no associations were found with survival in the latter era. This finding suggests that lowering industrial TFA consumption from modest to low levels could possibly influence health beneficially after renal transplantation. (C) 2018 by the National Kidney Foundation, Inc. All rights reserved.

Transplant InternationalVolume 30, Issue S2 p. 165-346 Brief OralsFree Access Brief Orals First published: 24 September 2017 https://doi.org/10.1111/tri.13050Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume30, IssueS2Special Issue: Abstracts of the 18th Congress of the European Society for Organ Transplantation, 24-27 September 2017, Barcelona, SpainSeptember 2017Pages 165-346 RelatedInformation

OBJECTIVE:Marine n-3 polyunsaturated fatty acids (PUFAs) exert potential anti-inflammatory effects and might improve long-term outcomes after renal transplantation. We assessed associations between plasma phospholipid levels of marine n-3 PUFAs and plasma inflammatory biomarkers 10 weeks after renal transplantation.DESIGN:Cross-sectional single-center study.SUBJECTS:A study population of 861 renal transplant recipients transplanted at Oslo University Hospital between 2007 and 2011.METHODS AND MAIN OUTCOME MEASURE:Plasma phospholipid fatty acids were determined by gas chromatography. Marine n-3 PUFA levels were defined as the sum of eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid levels in weight percentage of total plasma phospholipid fatty acids. Plasma inflammatory biomarkers were measured by enzyme immunoassays. We used multivariable linear regression analysis to assess associations between levels of marine n-3 PUFAs and inflammatory biomarkers in plasma.RESULTS:Plasma marine n-3 PUFA levels were inversely associated with plasma levels of proinflammatory biomarkers soluble tumor necrosis factor receptor 1 (standardized regression coefficient -0.11, P < .001) and interleukin-6 (standardized regression coefficient -0.09, P = .01). In contrast, there was no association between plasma levels of marine n-3 PUFAs and the anti-inflammatory mediator interleukin-10.CONCLUSIONS:In this renal transplant cohort, inverse associations between plasma levels of marine n-3 PUFAs and markers of inflammation were demonstrated.

OBJECTIVE(S) We assessed associations between plasma levels of polyunsaturated fatty acids (PUFAs) and degree of inflammation and interstitial fibrosis in transplanted kidneys. DESIGN The design of the study was single center cohort study. SUBJECTS A study population of 156 patients who received a kidney transplant at Oslo University Hospital during 2010. MAIN OUTCOME MEASURE Kidney transplant biopsies were obtained at 2 months and 1 year after transplantation. Degree of inflammation and interstitial fibrosis in the cortex of transplanted kidneys were estimated semi-quantitatively. Plasma phospholipid fatty acids levels were measured in a stable phase 2 months posttransplant. We used multivariate linear regression to assess associations between plasma levels of PUFAs and degree of inflammation and interstitial fibrosis at 2 months and 1 year postoperatively and change in degree of interstitial fibrosis during the first year after transplantation, adjusting for inflammation and fibrosis risk factors. RESULTS Higher plasma marine n-3 PUFA levels were associated with less development of interstitial fibrosis in the kidney transplant (unstandardized β-coefficient -1.12, standardized β-coefficient -0.18, P = .03) during the first year after transplantation. Plasma levels of alpha linoleic acid, linoleic acid, and arachidonic acid were not associated with development of interstitial fibrosis. No associations were found between plasma levels of PUFAs and inflammation inside fibrotic areas or outside fibrotic areas in the kidney transplant at neither 2 months nor 1 year postoperatively. Linolenic acid levels in plasma were positively associated with change in renal function during the first year after transplantation. CONCLUSION The inverse association between plasma marine n-3 PUFA levels and development of interstitial fibrosis during the first year after kidney transplantation suggests that marine fatty acid consumption might halt progression of fibrosis.

Transplant InternationalVolume 30, Issue S2 p. 165-346 Brief OralsFree Access Brief Orals First published: 24 September 2017 https://doi.org/10.1111/tri.13050Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume30, IssueS2Special Issue: Abstracts of the 18th Congress of the European Society for Organ Transplantation, 24-27 September 2017, Barcelona, SpainSeptember 2017Pages 165-346 RelatedInformation