Τετάρτη, 23 Οκτωβρίου 2019

Antibodies against ARHGDIB and ARHGDIB gene expression associate with kidney allograft outcome
Background. The impact of donor-specific anti-HLA antibodies (DSA) on antibody-mediated rejection (AMR) and kidney allograft failure is well established. However, the relevance of non-HLA antibodies remains unclear. Methods. We investigated 13 pretransplant non-HLA antibodies and their association with histology of AMR (AMRh) and kidney allograft failure. We included single kidney recipients (N=203) with AMRh according to the Banff 2017 classification, and matched AMRh-free controls (N=219). Non-HLA antibodies were assessed using multiplex Luminex assay. Results. Of the selected non-HLA antibodies (against agrin, APMAP, ARHGDIB, ARHGEF6, AT1R, ETAR, LMNB1, LPLUNC1, PECR, PLA2R, PRKCZ, TUBB4b, vimentin), only antibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) (adjusted MFI [aMFI]≥1000), a minor histocompatibility antigen, associated with graft failure, in univariate and multivariate models (HR=2.7;95%CI,1.3-5.4;p=0.007). There was a 19.5-fold (95%CI,6.0-63.9;p<0.0001) increased risk of graft failure in patients positive for both DSA and anti-ARHGDIB antibodies (aMFI≥1000) versus patients negative for both DSA and anti-ARHGDIB antibodies, compared to a 4.4-fold (95%CI,2.4-8.2,p<0.0001) increased risk in patients with only DSA, and a 4.1-fold (95%CI,1.4-11.7;p=0.009) increased risk in patients with only anti-ARHGDIB antibodies above 2000 aMFI. AMRh associated with increased intrarenal expression of the ARHGDIB gene. In the absence of AMRh and DSA, anti-ARHGDIB antibodies were not clearly associated with graft failure. Conclusions. The presence of pretransplant anti-ARHGDIB antibodies has an additive effect in patients with DSA on the risk of graft failure via AMRh. Other investigated non-HLA antibodies, including antibodies against AT1R, did not contribute to risk stratification and could not explain the histology of AMR in the absence of DSA. Disclosures: The authors of this manuscript have no conflicts of interest to disclose. Funding: This project is funded by The Research Foundation Flanders (F.W.O.) and the Flanders Innovation & Entrepreneurship agency (VLAIO), with a TBM project (grant n° IWT.150199; "TEMPLATE"). MN is a senior clinical investigator of The Research Foundation Flanders (F.W.O.) (1844019N) and is also funded by a C3 internal grant from the KU Leuven (grant no. C32/17/049). JC holds a fellowship grant (1196119N) from The Research Foundation Flanders (F.W.O.). Corresponding author: Maarten Naesens, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel: +32 16 34 45 80; Fax: +32 16 34 45 99, Email: maarten.naesens@kuleuven.be Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Social Determinants of Health: Going Beyond the Basics to Explore Racial Disparities in Kidney Transplantation
No abstract available
Comparison of clinical features and outcome of pediatric post-transplant lymphoproliferative disorder in recipients of small bowel allograft versus isolated liver transplantation
Background: Higher incidence of post-transplant lymphoproliferative disorder (PTLD) is reported in the pediatric small bowel transplant (SBTx) population, which may be associated with more aggressive disease and poorer outcome as compared to liver transplant (LTx) recipients. We aim to compare the characteristics and outcome of PTLD in pediatric SBTx against LTx patients at a single center. Methods: Retrospective review of pediatric SBTx and LTx patients diagnosed with PTLD from 1989-2016 was conducted. Diagnosis of PTLD was biopsy-proven based on World Health Organization histologic criteria. Treatment protocol consisted of reduction of immunosuppression (RIS), rituximab (from 2000), cytotoxic T-lymphocyte (CTL) therapy (available in 1999-2004 and from 2011), and/or chemotherapy. Results: Thirty-seven PTLD patients were included following LTx (n=23, incidence=2.8%) and SBTx (n=14, incidence=14.9%). Monomorphic PTLD made up 64% of SBTx and 43% of LTx cases. RIS alone resulted in remission in 50% of LTx patients but none of the SBTx patients (p=0.002). Poorer overall remission (57% vs 96%,p=0.004), 2-year (46% vs 91%,p=0.003) and 5-year survival rates (39% vs 90%,p=0.002) were observed in the SBTx group. Risk factors associated with mortality following PTLD were SBTx (OR 12.00,95CI:2.34-61.45;p=0.003), monomorphic histology (OR 10.63,95CI:1.88-60.25;p=0.008), multi-site involvement (OR 6.38,95CI:1.35-30.14;p=0.019) and tumor involvement of allograft (OR 5.33,95CI:1.14-24.90;p=0.033). Introduction of CTL therapy was associated with improved survival. Conclusion: Majority of PTLD following pediatric SBTx are of monomorphic subtype and associated with poorer outcome as compared to LTx patients. RIS is inadequate as a single strategy in managing PTLD in SBTx and prompt escalation to rituximab and/or CTL is recommended. ORCID: Fang Kuan Chiou: 0000-0003-4777-0267 Disclosure: The authors declare no conflicts of interest Funding: None to declare Corresponding Author: Dr. Girish Gupte, Consultant Paediatric Hepatologist Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham B4 6NH, United Kingdom; Tel no: + 44 121 333 8255; Fax no: + 44 121 333 8251, Email id: girishgupte@nhs.net Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Does Racial Disparity in Kidney Transplant Wait-listing Persist After Accounting for Social Determinants of Health?
Background: African Americans have lower rates of kidney transplantation (KT) compared to Whites, even after adjusting for demographic and medical factors. In this study, we examined whether racial disparity in KT wait-listing persists after adjusting for social determinants of health (e.g. cultural, psychosocial, knowledge). Methods: We prospectively followed a cohort of 1055 patients who were evaluated for KT between 3/10-10/12 and followed through 8/18. Participants completed a semi-structured telephone interview shortly after their first KT evaluation appointment. We used Wilcoxon rank-sum and Pearson chi-square tests to examine race differences in the baseline characteristics. We then assessed racial differences in the probability of wait-listing while accounting for all predictors using cumulative incidence curves and Fine & Gray proportional subdistribution hazards models. Results: There were significant differences in the baseline characteristics between non-Hispanic African Americans (AA) and non-Hispanic Whites (WH). AA were 25% less likely (95% confidence interval, 0.60-0.96) to be wait-listed than WH even after adjusting for medical factors and social determinants of health. In addition, being older, having lower income, public insurance, more comorbidities, and being on dialysis decreased the probability of wait-listing while having more social support and transplant knowledge increased the probability of wait-listing. Conclusion: Racial disparity in kidney transplant wait-listing persisted even after adjusting for medical factors and social determinants of health, suggesting the need to identify novel factors that impact racial disparity in transplant wait-listing. Developing interventions targeting cultural and psychosocial factors may enhance equity in access to transplantation. ORCID ID: https://orcid.org/0000-0001-9893-9937 Disclosure:The authors of this manuscript declare no financial conflict of interest. Funding:This research is supported in part by NIDDK Grants #R01DK081325 and R01DK101715; and, by the National Institutes of Health through Grant Number UL1 TR001857. Corresponding author: Yue-Harn Ng, MD, MSC 04-2785, 1 University of New Mexico, Albuquerque NM 87131, Telephone number: 505-272-0407, Email address: YNg@salud.unm.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Patients with Persistently Low MELD-Na Scores Continue to be at Risk of Liver Related Death
Background: The vast majority of patients with cirrhosis have low Model for End Stage Liver Disease-Sodium (MELD-Na) scores, however the ability for the MELD-Na score to predict patient outcomes at low scores is unclear. Methods: Adult patients in a multicenter, Chicago-wide database of medical records with ICD-9 codes of cirrhosis and without a history of hepatocellular carcinoma were included. Records were linked with the state death registry and death certificates were manually reviewed. Deaths were classified as "liver related", "nonliver related", and "nondescript" as adjudicated by a panel comprised of a transplant surgeon, a hepatologist, and an internist. A sensitivity analysis was performed where patients with hepatocellular carcinoma were included. Results: Among 7922 identified patients, 3999 patients had MELD-Na scores that were never higher than 15. In total, 2137 (27%) patients died during the study period with higher mortality rates for the patients in the high MELD-Na group (19.4 (41.6%) vs 4.1 (12.6%) per 100 person years, p<0.001). . The high MELD-Na group died of a liver related cause in 1142/1632 (70%) as compared to 240/505 (47.5%) deaths in the low MELD-Na group. There was no difference in the distribution of subcategory of liver related death between low and high MELD-Na groups. Among subclassification of liver related deaths, the most common cause of death was ‘Infectious’ in both groups. Conclusions: Despite persistently low MELD-Na scores, patients with cirrhosis still experience high rates of liver related mortality. Funding: Drs. Atiemo and Mazumder were supported by NIH grant T32DK077662 PI MM Abecassis. Disclosures: The authors declare no conflicts of interest Corresponding author: Daniela P Ladner, MD, MPH, FACS, dladner@nm.org, Associate Professor of Surgery, Department of Surgery, Division of Organ Transplantation, Director Northwestern University Transplant Outcomes Research Collaborative (NUTORC), Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, 676 North Saint Clair St., Suite 1900, Chicago, Illinois 60611, Phone: 312-695-1703, Fax: 312-695-9194 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Incidence and Risk Factors of Obesity in Childhood Solid-Organ Transplant Recipients
Background: Obesity is a significant public health concern; however, the incidence post solid-organ transplantation is not well reported. Methods: This study determined the incidence and risk factors of obesity among pediatric solid-organ transplant recipients (heart, lung, liver, kidney, multiorgan) at Hospital for Sick Children (2002-2011), excluding prevalent obesity. Follow-up occurred from transplantation until development of obesity, last follow-up or end of study. Incidence of obesity was determined overall, by baseline BMI and organ groups. Risk factors were assessed using Cox proportional-hazards regression. Results: Among 410 (55% male) children, median transplant age was 8.9 (interquartile range [IQR]:1.0-14.5) years. Median follow-up time was 3.6 (IQR:1.5-6.4) years. Incidence of obesity was 65.2 (95% confidence interval [CI]:52.7-80.4) per 1000 person-years. Overweight recipients had a higher incidence, 190.4 (95% CI:114.8-315.8) per 1000 person-years, than nonoverweight recipients, 56.1 (95% CI:44.3-71.1). Cumulative incidence 5-years posttransplant was 24.1%. Kidney relative to heart recipients had the highest risk (3.13 adjusted hazard ratio [aHR]; 95% CI:1.53-6.40) for obesity. Lung and liver recipients had similar rates to heart recipients. Those with higher baseline BMI (z-score; 1.72 aHR; 95% CI:1.39-2.14), overweight status (2.63 HR; 95% CI:1.71-4.04) and younger transplant age (years; 1.18 aHR; 95% CI:1.12-1.25) were at highest risk of obesity. Higher cumulative steroid dosage (per 10mg/kg) was associated with increased risk of obesity after adjustment. Conclusions: Among all transplanted children at Hospital for Sick Children, 25% developed obesity within 5-years posttransplant. Kidney recipients, younger children, those overweight at transplant, and those with higher cumulative steroid use (per 10mg/kg) were at greatest risk. Early screening and intervention for obesity are important preventative strategies. Funding: Dr. Rulan S. Parekh received funding from the Transplant & Regenerative Medicine Centre (TRMC) Catalyst Grant at The Hospital for Sick Children, Ashley's Angels Catwalk, and the Canadian Institutes of Health Research (CIHR) for the completion of this study. This research was undertaken, in part, thanks to funding from the Canada Research Chairs program. Disclosures: The authors declare no conflicts of interest. Authorship Statement: B.C.B., T.M.B., J.V-R., and R.S.P. participated in the study design. B.C.B., A.S., J.V-R., and R.C. participated in the data abstraction. B.C.B., T.M.B., and R.S.P participated in the data analysis. B.C.B. and R.S.P. drafted the manuscript. All authors read and approved the final manuscript. Corresponding Author: Dr. Rulan S. Parekh, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, rulan.parekh@sickkids.ca. (416) 813-7654 x 328042 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Effects of intraoperative fluid balance during liver transplantation on postoperative acute kidney injury: an observational cohort study.
Background: Liver transplant recipients suffer many postoperative complications. Few studies evaluated the effects of fluid management on these complications. We conducted a retrospective cohort study to evaluate the association between intraoperative fluid balance and postoperative acute kidney injury (AKI) and other postoperative complications. Methods: We included consecutive adult liver transplant recipients who had their surgery between July 2008 and December 2017. Our exposure was intraoperative fluid balance and our primary outcome was the grade of acute kidney injury (AKI) at 48 hours after surgery. Our secondary outcomes were the grade of AKI at 7 days, the need for postoperative renal replacement therapy (RRT), postoperative red blood cells transfusions, time to extubation, time to discharge from the intensive care unit (ICU) and one-year survival. Every analysis was adjusted for potential confounders. Results: We included 532 transplantations in 492 patients. We observed no effect of fluid balance on either 48-hour AKI, 7-day AKI or on the need for postoperative RRT after adjustments for confounders. A higher fluid balance increased the time to extubation, to ICU discharge and increased the risk of dying (hazard ratio = 1.19 [1.06, 1.33]). Conclusions: We observed no association between intraoperative fluid balance and postoperative AKI. Fluid balance was associated with a longer time to first extubation, longer time to ICU discharge and lower survival. This study provides insight that might inform the design of a clinical trial on fluid management strategies in this population. DISCLOSURES: The authors declare that they have no competing interests. FUNDING: This work was funded by the Fondation du CHUM (“Don d’organes et transplantation” program). Dr Chassé is a recipient of a Career Award Junior 1 from the Fonds de la Recherche du Québec – Santé. Corresponding author:François Martin Carrier, MD MSc , Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), 900, rue St-Denis, porte S03-434, Montréal (Québec) H2X 0A9, Email: francois.martin.carrier@umontreal.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Wide variation in the percentage of donation after circulatory death donors across donor service areas – a potential target for improvement
Background: Substantial differences exist in the clinical characteristics of donors across the 58 donor services areas (DSAs). Organ procurement organization (OPO) performance metrics incorporate organs donated after circulatory determination of death (DCDD) donors, but do not measure potential DCDD donors. Methods: Using 2011-2016 UNOS data, we examined the variability in DCDD donors/all deceased donors (%DCDD) across DSAs. We supplemented UNOS data with CDC death records and OPO statistics to characterize underlying process and system factors that may correlate with donors and utilization. Results: Among 52,184 deceased donors, the %DCDD varied widely across DSAs, with a median of 15.1% (IQR [9.3%, 20.9%]; range 0.0-32.0%). The %DCDD had a modest positive correlation with 4 DSA factors: median match MELD, proportion of white deaths out of total deaths, kidney center competition, and %DCDD livers by a local transplant center (all Spearman coefficients 0.289-0.464), and negative correlation with 1 factor: mean kidney waiting time (Spearman coefficient -0.388). Adjusting for correlated variables in linear regression explained 46.3% of the variability in %DCDD. Conclusions: Donor pool demographics, waitlist metrics, center competition and DCDD utilization explain only a portion of the variability of DCDD donors. This requires further studies and policy changes to encourage consideration of all possible organ donors. Author Disclosure Statement: The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. Funding: ES is supported by NIH grant (T32-DK07006-44). Name and Address of Corresponding Author: Elizabeth M. Sonnenberg, Hospital of the University of Pennsylvania, 5 Silverstein, Philadelphia, PA 19104, Email: elizabeth.sonnenberg@uphs.upenn.edu, Cell: 215-796-8026 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Long term graft survival and graft function following pregnancy in kidney transplant recipients: a systematic review and meta-analysis
Background: The incidence of pregnancy in kidney transplant (KT) recipients is increasing. Studies report that the incidence of graft loss (GL) during pregnancy is low, but less data is available on long-term effects of pregnancy on the graft. Methods: Therefore, we performed a meta-analysis and systematic review on GL and graft function, measured by serum creatinine (SCr), after pregnancy in KT recipients, stratified in years postpartum. Furthermore, we included studies of nulliparous KT recipients Results: Our search yielded 38 studies on GL and 18 studies on SCr. The pooled incidence of GL was 9.4 % within 2 years post pregnancy, 9.2% within 2 to 5 years, 22.3% within 5 to 10 years and 38,5% more than ten years postpartum. In addition, our data show that, in case of graft survival, SCr remains stable over the years. Only within 2 years postpartum Δ SCr was marginally higher (0.18 mg/dL, 95%CI [0.05-0.32], p = 0.01). Furthermore, no differences in GL was observed in 10 studies comparing GL post pregnancy with nulliparous controls. Systematic review of the literature showed that mainly pre pregnancy proteinuria, hypertension and high SCr are risk factors for GL. Conclusions: Overall, these data show that pregnancy after KT has no effect on long-term graft survival and only a possible effect on graft function within 2 years postpartum. This might be due to publication bias. No significant differences were observed between pre and postpartum SCr at longer follow-up intervals. * Authors contributed equally The authors declare no conflicts of interest. There are no financial disclosures. Corresponding author: Marleen van Buren, Erasmus Medical Center, RG-5, Department of Internal Medicine, Section Nephrology & Transplantation, P/O Box 2040, 3000 CA Rotterdam, The Netherlands. m.c.vanburen@erasmusmc.nl This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
USE OF DE-NOVO mTOR INHIBITORS IN HYPERSENSITZED KIDNEY TRASPLANT RECIPIENTS: EXPERIENCE FROM CLINICAL PRACTICE
BACKGROUND: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients, due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with Calcineurin Inhibitor (CNI) have excluded hypersensitized recipients from enrollment. METHODS: To shed light on this issue, we examined 71 consecutive patients with a baseline cPRA ≥ 50% that underwent kidney transplantation from June 2013 to December 2016 in our Unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively Mycophenolic Acid (MPA, n=38) or mTORi (either everolimus or sirolimus, n=33, target trough levels 3-8 ng/ml). RESULTS: Demographic and immunological risk profiles were similar and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection [Hazard Ratio (HR)(Confidence Interval) 0.32 (0.11-0.90), P=0.031 at univariable analysis, and 0.34 (0.11-0.95), P=0.040 at multivariable analysis]. There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de-novo DSAs. Tacrolimus trough levels along the first year were not different between groups (12-month levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/ml for MPA and mTORi group respectively, P=0.277). CONCLUSIONS: This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate. CONFLICT OF INTEREST STATEMENT: DC has received speaker fees from Novartis and travel support from Astellas and Novartis. PVA has received travel support from Astellas, Novartis, Chiesi, Sandoz and speaker fees from Alexion and Mallinkrodt. GJP has received travel support from Sandoz. NE has received travel support from Novartis, Astellas and Chiesi. IR received speaker fees from Novartis and travel support from Sandoz, Pfizer y Astellas. JMC has had consultancy agreements with Pfizer, Wyeth, Novartis and Roche; has received research funding from Pfizer and Novartis; and has been a scientific advisor or board member for Novartis and Pfizer and has received lecture fees from Alexion. FD has received research grants and speaker fees from Astellas, Neovii, Novartis, Pfizer, Teva, Transplant Biomedicals. FO has received speaker fees from Novartis, Sanofi and Neovii and travel support from Novartis. AMJ, ENM, EDSA, FC, MS, JVT, JM and MJR reported no conflict of interest. FUNDING: none CORRESPONDING AUTHOR: Fritz Diekmann, fdiekman@clinic.cat - Carrer Villaroel 170, Barcelona, 08023, Spain. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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