Poor Graft Outcome Research Articles

POS-770 “SLOW AND STEADY MAY NOT ALWAY WIN THE RACE “ –SHORT TERM OUTCOMES OF SLOW GRAFT FUNCTION POST RENAL TRANSPLANT - A SINGLE CENTRE EXPERIENCE

It is well established that delayed graft function (DGF), traditionally defined as the requirement of dialysis within the first week of transplant, is associated with poorer graft outcomes as compared to immediate graft function (IGF). A subset of patients do not have immediate graft function, but rather have a slower decrease in serum creatinine, not requiring dialysis, termed as slow graft function. Outcomes of this group of patients have not often been studied and most studies have classified this group of patients as having Immediate graft function (IGF) for comparison with patients with DGF. Our aim was to assess short term outcomes of these patients with slow graft function and to identify risk factors, if any among the cohort. Study setting: Kasturba Medical College, Manipal, a tertiary care centre in South India providing healthcare services to a predominantly rural population Type of study: Retrospective, ObservationalStudy Period: January 2016 to April 2018 Sample Size: 70 Renal allograft recipients Slow graft function was defined as per previous studies as follows 1)Creatinine > 3 mg/dl at Post-op day 5 or > 2.5mg/dl at day 72)Creatinine >1.5 and creatinine reduction ratio (CRR) < 20% between Post-op day 1 and post-op day 3Patients with DGF were not included in this study. Demographics related to recipient and donor, biopsy-proven acute rejections, short term outcomes in terms of graft function(serum creatinine and eGFR) at 1 year and 2 years follow up were documented and analysed. The transplants were predominantly living donor ( 88.6% ) and ABO compatible ( 97.1%) with a median follow up of 30 months (IQR 25-40) . 27 out of 70 transplanted patients (38.6%) were characterized as having slow graft function (SGF) as per the definitions and criteria used from earlier studies (Table 1: Baseline characteristics) . On univariate analysis, patients with SGF had lower GFR at 1 year (p-value – 0.028), higher number of biopsy-proven acute rejections over the median follow up period ( 48.1% versus 25.5 %; p-value – 0.039). The number of transplant patients with graft dysfunction at 1 year ( eGFR <60 ml/min) and 2 years were also statistically significant (Table 2: Univariate Analysis). Donor age and donor GFR ( measured by DTPA) were not significantly associated with SGF though numerically median donor age was higher and donor GFR was lower. The subset of patients with SGF may have adverse short term outcomes as compared to those with immediate graft function. A higher incidence of biopsy-proven rejection and higher number of patients with graft dysfunction at 2 years was seen in this cohort. Long term outcomes assessment and identification of risk factors leading to SGF needs to be studied and may help to better risk stratify and manage these patients for better outcomes.

POS-718 IMPACT OF INITIAL STEROID RESPONSE ON TRANSPLANT OUTCOMES IN CHILDREN WITH STEROID RESISTANT NEPHROTIC SYNDROME

Limited data suggest that children with SRNS who were initially steroid sensitive (ISS) have an increased risk of recurrence post transplantation. ISS may be a proxy for those with circulating factor disease. There are no data on risk of transplant loss stratified by ISS. Children who received a kidney transplant between 2000 and 2019 for SRNS in 7 paediatric centres were included. Clinical data were gathered from chart reviews and transplant data were provided from ANZDATA following ethics approval. Transplant survival was estimated using the Kaplan-Meier estimator with Cox modelling used to explore predictors of survival. There were 60 children who were transplanted for SRNS, 31 (51%) male, average age at transplant 11 years (SD 4) and 39 (65%) Caucasian. At presentation, 19/60 (32%) were steroid sensitive before becoming steroid resistant. Of the ISS group, 18/19 (95%) had recurrence post-transplant, compared to 17/41 (41%) of those always steroid resistant (p=0.001). The median time to recurrence was 3 days (inter quartile range 0-12 days), with no difference between the groups (p=0.9). Full remission after recurrence was achieved in 9/18 (50%) of the ISS group and 7/17 (42%) in the always steroid resistant group (p=0.64). Overall, 5-year transplant survival was 57% (95%CI 38-85%) in the ISS group, compared to 78% (95%CI 64-95%) in the always steroid resistant group (p=0.07) (Figure 1). Initial steroid sensitivity is strongly associated with SRNS recurrence. Transplant survival for children with SRNS is poor with a non-significant trend to poorer outcomes for those with initial steroid sensitivity. Further research involving other cohorts is needed to assess if initial steroid sensitivity is associated with poorer graft outcomes.

Post-transplant de novo non donor-specific HLA antibodies are not associated with poor graft outcome in non-sensitized pediatric recipients of kidney transplantation

While de novo donor-specific HLA antibodies (dnDSAs) have a detrimental impact on kidney graft outcome, the clinical significance of de novo non donor-specific antibodies (dnNDSAs) is more controversial. We retrospectively evaluated for Ab development and characteristics of dnNDSAs serially collected post-transplant sera and, when available, graft biopsy eluates, from 144 non-sensitized, primary pediatric kidney recipients, consecutively transplanted at a single center between 2003 and 2017, using HLA class I and class II single-antigen flow-bead assays (SAB). The results were compared with clinical-pathologic data from HLA antibody negative and HLA dnDSA-positive patients.Forty-five out of 144 patients developed dnNDSAs (31%). Among the dnNDSA-positive patients, 86% displayed one or more class I/II antibodies recognizing antigens included in the CREG/shared epitope groups that also comprise the mismatched donor HLA antigens. Despite potential pathogenicity, as suggested by their occasional presence within the graft, dnNDSAs displayed significantly lower MFI, and limited complement binding and graft homing properties, when compared with dnDSAs. In parallel, the graft survival probability was significantly lower in patients with dnDSA than in those with dnNDSA or without HLA antibodies (p < 0.005). Indeed, the dnNDSA-positive patients remaining dnDSA-negative throughout the posttransplant period did not develop clinical antibody mediated rejection and graft loss, and maintained good graft function at a median follow-up of 9 years. The biological characteristics of dnNDSAs may account for the low graft damaging capability when compared to dnDSAs.

Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system

BackgroundA lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD).MethodsAfter 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema).ResultsOur results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control.ConclusionsThese data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Post-operative assessment in patients after liver transplantation: imaging parameters associated with 1-year graft failure.

To identify post-liver transplant CT findings which predict graft failure within 1 year. We evaluated the CT scans of 202 adult liver transplants performed in our institution who underwent CT within 3 months after transplantation. We recorded CT findings of liver perfusion defect (LPD), parenchymal homogeneity, and the diameters and attenuations of the hepatic vessels. Findings were correlated to 1-year graft failure, and interobserver variability was assessed. Forty-one (20.3%) of the 202 liver grafts failed within 1 year. Graft failure was highly associated with LPD (n = 18/25, or 67%, versus 15/98, or 15%, p < 0.001), parenchymal hypoattenuation (n = 20/41, or 48.8% versus 17/161, or 10.6%, p < 0.001), and smaller diameter of portal veins (right portal vein [RPV], 10.7 ± 2.7 mm versus 14.7 ± 2.2 mm, and left portal vein [LPV], 9.8 ± 3.0 mm versus 12.4 ± 2.2 mm, p < 0.001, respectively). Of these findings, LPD (hazard ratio [HR], 5.43, p < 0.001) and small portal vein diameters (HR, RPV, 3.33, p < 0.001, and LPV, 3.13, p < 0.05) independently predicted graft failure. All the measurements showed fair to moderate interobserver agreement (0.233~0.597). For patients who have CT scan within the first 3 months of liver transplantation, findings of LPD and small portal vein diameters predict 1-year graft failure. •Failed grafts are highly associated with liver perfusion defect, hypoattenuation, and small portal vein. •Right portal vein < 11.5 mm and left portal vein < 10.0 mm were associated with poor graft outcome. •Liver perfusion defect and small portal vein diameter independently predicted graft failure.

Substituting imputation of HLA antigens for high-resolution HLA typing: Evaluation of a multiethnic population and implications for clinical decision making in transplantation.

Molecular mismatch analysis for assessment of histocompatibility in transplantation requires high-resolution HLA typing. Algorithms to "guesstimate" high-resolution from low-resolution typing exist, but their accuracy remains unknown. We converted high-resolution, sequence-based, HLA typing of 310 subjects from an ethnically heterogeneous population to low-resolution equivalents and tested the ability of the NMDP HaploStats and HLA Matchmaker programs to impute/reproduce the measured high-resolution HLA type, using the more common "winner-takes-all" approach. Only 35.6% of the HaploStats imputed HLA-A, -B, -C, -DRB1, and -DQB1 haplotypes had no mistakes, and the accuracy was significantly lower for non-Caucasians (29.1%) compared to Caucasians (45.2%) (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3-0.8; P=.004). HLA Matchmaker was not able to provide high-resolution haplotypes for 45.2% of Caucasian subjects and 63.5% of non-Caucasian subjects (P=.002). Of those with an imputed result, only 10.3% of Caucasians and 4.8% of non-Caucasians had accurate 10-allele high-resolution output. Eplet analysis revealed additional, inaccurate eplets in 37% of individuals, with 22.5% showing at least 2 additional, inaccurate eplets; incorrect eplets were more common among non-Caucasians (OR, 1.8; 95% CI, 1.1-2.9; P=.018). Given this high error rate, caution should be taken before using imputation tools for clinical or research purposes, especially for non-Caucasian individuals.

Anti-Hla donor-specific antibody monitoring in pancreas transplantation: Role of protocol biopsies.

In kidney transplantation, de novo donor-specific antibodies (DSA) correlate with poor graft survival, and Consensus Guidelines recommend a protocol biopsy. In pancreas transplantation, DSA are also associated with poor graft outcomes; however, there are no recommendations on protocol biopsies. We started an antibody screening protocol on pancreas transplant patients at 0, 3, 6, 12months, and yearly. Patients with DSA or high MFI non-DSA were considered for protocol biopsies of both organs. Results: 143 pancreas recipients were screened. 84 patients had negative antibodies throughout the study, 11 patients were found to have antibodies at graft dysfunction, and 48 patients had positive antibodies at screening without acute organ dysfunction (study group). Among the 30 non-DSA patients, 9 had protocol simultaneous pancreas and kidney biopsies performed with negative results in all of them. In contrast, among the 18 DSA patients, 15 had these biopsies performed, and 47% presented with subclinical rejection of the kidney, the pancreas, or both. In addition, some of the DSA patients without a protocol biopsy presented with rejection during the first 15months of follow-up. Conclusion: We conclude that protocol biopsies of both grafts may play a role in the follow-up of pancreas transplant patients with de novo DSA appearance.

C3d-positive donor-specific antibodies have a role in pretransplant risk stratification of cross-match-positive HLA-incompatible renal transplantation: United Kingdom multicentre study.

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48months (IQR 20.47-77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37-7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56-5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

B cell-derived IL-1β and IL-6 drive homeostatic T cell recovery following lymphoablation

Abstract T cell reconstitution after lymphoablation in allograft recipients may lead to acute rejection and poor graft outcome. Using a mouse model of heart transplantation and murine anti-thymocyte globulin (mATG) we showed that while T cell recovery depends on B cells, B cell MHC expression is dispensable. The goal of this study was to investigate the role of B cell-derived IL-1β and IL-6 in T cell homeostatic reconstitution after mATG lymphoablation. The NanoString analysis showed that mATG upregulated IL-1β and IL-6 gene expression in recipient B cells. To validate NanoString findings, IL-1β and IL-6 expression was measured by intracellular flow cytometry. Following heart allograft placement and mATG treatment, B cells are the main source of IL-1β and IL-6, and these cytokines mutually regulate each other’s production. Either treatment with anti-IL-1β mAb or the use of IL-1R1 KO, caspase-1 KO and MyD88 KO recipients diminished both CD4+ and CD8+ T cell recovery along with improved heart allograft survival and decreased donor-reactive IFN-γ producing cells after mATG treatment. Similarly, in vivo IL-6 neutralization with mAb or using IL-6 KO recipients delayed CD4+ and CD8+ T cell recovery, markedly prolonged heart allograft survival and decreased donor-specific T cell responses suggesting that IL-1β and IL-6 are essential for optimal T cell recovery. Adoptive B cell transfers into μMT mice showed that B cell-derived IL-1β and IL-6 supported CD8+ T cells recovery. The absence of either IL-1R or IL-6R on CD8+ T cells markedly impaired their homeostatic recovery following mATG depletion. These findings reveal the essential role of B cell-derived IL-1β and IL-6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.

Memory T Cells in Transplantation: Old Challenges Define New Directions

Immunologic memory is the ability of adaptive immune system to quickly and specifically recognize previously encountered antigens and initiate an effector response. Alloreactive memory cells can mount rapid and robust responses to the transplanted organ resulting in allograft injury. Thus preexisting humoral or cellular memory alloresponses are typically associated with poor graft outcomes in experimental and clinical transplantation. While both B and T lymphocytes exhibit memory responses, this review discusses recent updates on the biology of memory T cells and their relevance to the field of transplantation. Three major areas of focus are the emergence and characterization of tissue resident memory T cells, manipulation of T cell metabolic pathways, and the latest promising approaches to targeting detrimental T cell memory in the settings of organ transplantation.

Early graft losses in paired kidney exchange: Experience from 10years of the National Kidney Registry.

Cooperative kidney paired donation (KPD) networks account for an increasing proportion of all living donor kidney transplants in the United States. There are sparse data on the rate of primary nonfunction (PNF) losses and their consequences within KPD networks. We studied National Kidney Registry (NKR) transplants (February 14, 2009 to December 31, 2017) and quantified PNF, graft loss within 30days of transplantation, and graft losses in the first-year posttransplant and assessed potential risk factors. Of 2364 transplants, there were 38 grafts (1.6%) lost within the first year, 13 (0.5%) with PNF. When compared to functioning grafts, there were no clinically significant differences in blood type compatibility, degree of HLA mismatch, number of veins/arteries, cold ischemia, and travel times. Of 13 PNF cases, 2 were due to early venous thrombosis, 2 to arterial thrombosis, and 2 to failure of desensitization and development of antibody-mediated rejection (AMR). Given the low rate of PNF, the NKR created a policy to allocate chain-end kidneys to recipients with PNF following event review and attributable to surgical issues of donor nephrectomy. It is expected that demonstration of low incidence of poor early graft outcomes and the presence of a "safety net" would further encourage program participation in national KPD.

Plasma cell-rich rejection – The enigma revisited: Case report

Plasma cell-rich rejection (PCRR) is a morphological pattern of rejection characterized by the presence of plasma cells constituting at least 10% of the cellular infiltrate. Clinical characteristics, therapeutic options, and its position in the Banff Classification for Allograft Rejection have not been clearly defined. Although morphologically discussed in close association with cellular rejection, histopathological advances and better availability of C4d helped us to understand the close relationship with the antibody-mediated rejection. T helper cell 2 predominant cellular infiltration has been identified in recent studies. Rational choices of drugs such as bortezomib have not shown outcomes as expected in various clinical trials. Newer therapeutic options directed at TH2 cytokines which are being tested in other disorders may open up new avenues of therapy. We discuss two cases of PCRR with varied presentation, one early and the other very late in the course of transplantation. Both of our patients had poor graft outcomes despite therapy.

When rubber meets the road: how innate features of adaptive immune cells play critical roles in transplant alloimmunity.

Studies on adaptive cells have largely focused on features that are specific to adaptive immunity. However, adaptive cells utilize innate cell features to modulate their responses, and this area of T and B-cell biology is understudied. This review will highlight recent work done to understand how innate features of adaptive immune cells modulate alloimmunity. Over the past year, research has shown that T-cell-expressed danger-associated molecular patterns, Toll-like receptors, complement receptors, and Fc receptors regulate T-cell alloimmunity in a cell-intrinsic manner. Further, IL-17 and p40 of IL-12 have been implicated in the migration of T cells into allografts. Lastly, innate B cells, specifically B1 cells, have been shown to produce clinically relevant autoantibody associated with poor graft outcome. These data provide evidence that innate features are utilized by adaptive immune cells to control adaptive alloimmunity.

Relationship between early proteinuria and long term outcome of kidney transplanted patients from different decades of donor age

BackgroundProteinuria after kidney transplantation portends a worse graft survival. However the magnitude of proteinuria related to patient and graft survival and its correlation with donor and recipient characteristics are poorly explored.MethodsThis study investigated the impact of post transplant proteinuria in the first year in 1127 kidney transplants analyzing the impact of different donor ages. Proteinuria cut off was set at 0.5 g/day.ResultsTransplants with proteinuria > 0.5 g/day correlated with poor graft and patient outcome in all donor age groups. In addition, 6-month-1-year proteinuria increase was significantly associated with graft outcome, especially with donors > 60 years old (p < 0.05; Odd Ratio 1.8). 1-year graft function (eGFR < or ≥ 44 ml/min) had similar impact to proteinuria (≥ 0.5 g/day) on graft failure (Hazard Ratio 2.77 vs Hazard Ratio 2.46). Low-grade proteinuria (0.2–0.5 g/day) demonstrated a trend for worse graft survival with increasing donor age. Also in kidney-paired analysis proteinuria ≥0.5 effect was more significant with donors > 50 years old (Odd Ratio 2.3).ConclusionsPost-transplant proteinuria was increasingly harmful with older donor age. Proteinuria ≥0.5 g/day correlates with worse outcomes in all transplanted patients. Prognostic value of proteinuria and eGFR for graft and patient survival was comparable and these two variables remain significant risk factors even in a multivariate model that take into consideration the most important clinical variables (donor age, rejection, delayed graft function and cytomegalovirus viremia among others).

Prediction of kidney transplant outcome based on different DGF definitions in Chinese deceased donation

BackgroundDelayed graft function (DGF) is an important complication of kidney transplantation and can be diagnosed according to different definitions. DGF has been suggested to be associated with the long-term outcome of kidney transplantation surgery. However, the best DGF definition for predicting renal transplant outcomes in Chinese donations after cardiac death (DCDs) remains to be determined.MethodA total of 372 DCD kidney transplant recipients from June 2013 to July 2017 in the First Affiliated Hospital of Xi’an Jiaotong University were included in this retrospective study to compare 6 different DGF definitions. The relationships of the DGF definitions with transplant outcome were analyzed, including graft loss (GL) and death-censored graft loss (death-censored GL). Renal function indicators, including one-year estimated glomerular filtration rate (eGFR) and three-year eGFR, and were compared between different DGF groups.ResultsThe incidence of DGF varied from 4.19 to 35.22% according to the different DGF diagnoses. All DGF definitions were significantly associated with three-year GL as well as death-censored GL. DGF based on requirement of hemodialysis within the first week had the best predictive value for GL (AUC 0.77), and DGF based on sCr variation during the first 3 days post-transplant had the best predictive value for three-year death-censored GL (AUC 0.79). Combination of the 48-h sCr reduction ratio and classical DGF can improve the AUC for GL (AUC 0.85) as well as the predictive accuracy for death-censored GL (83.3%).ConclusionDGF was an independent risk factor for poor transplant outcome. The combination of need for hemodialysis within the first week and the 48-h serum creatinine reduction rate has a better predictive value for patient and poor graft outcome.

Mobile medication manager application to improve adherence with immunosuppressive therapy in renal transplant recipients: A randomized controlled trial.

BackgroundNonadherence to immunosuppressive therapy after renal transplantation is associated with poor graft outcomes. We aimed to evaluate whether the use of the Adhere4U mobile medication manager application could improve adherence among renal transplant recipients ≥1 year posttransplantation. Adhere4U can provide medication reminders, monitor medication use, and provide information on immunosuppressants.MethodsWe conducted a prospective randomized controlled study to compare the rate of nonadherence to index immunosuppressant (tacrolimus or cyclosporine) in a group using the Adhere4U app (mobile group) and in another group receiving conventional care (control group). The primary outcome was the nonadherence rate, which was evaluated using an electronic medication event monitoring system during the 6-month intervention period. Our secondary outcome included self-reported adherence using the Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS) and the visual analog scale (VAS) based on a 4-week recall on days 28, 90, and 180. Longitudinal data of repeated measures of self-rated adherence were analyzed using generalized estimating equations (GEE) to compare the between-group difference in adherence change over time.ResultsBetween November 2013 and May 2015, 138 renal transplant recipients were randomly allocated to the control (n = 67) or the mobile group (n = 71). The overall nonadherence rate over the 6-month study period by electronic monitoring was 63.6%, with no between-group difference [mobile group, 65.0% (n = 39/60); control group, 62.1% (n = 36/58); odds ratio 1.14; 95% confidence interval 0.53–2.40; p = 0.89]. Self-rated nonadherence assessed using the BAASIS and VAS at baseline was 53.7% and 51.5%, respectively. Although the self-rated nonadherence by BAASIS of the mobile group was lower than the control group throughout the study period, there was no between-group difference in the change of nonadherence over time (χ2 = 2.82, df = 3, p = 0.42 by logistic GEE). There also was no significant between-group difference in the nonadherence by VAS (χ2 = 1.71, df = 3, p = 0.63 by logistic GEE) over time. The main limitation of this study was the low rate of patient engagement with the app among the mobile group. The rate of app use was 47.6% (31/65) at 28 days, 33.9% (19/56) at 90 days, and 11.5% (6/52) at 180 days.ConclusionsThe Adhere4U application did not improve adherence to immunosuppressive therapy. Our evidence is limited by the high rate of attrition. Further studies on strategies to facilitate patient engagement with mobile interventions are warranted.

Preoperative echocardiographic evaluation of cardiac systolic and diastolic function in liver transplant recipients with diabetes mellitus: a propensity-score matched analysis.

BackgroundDiabetes mellitus (DM) increases risk of heart failure. It has been shown that diabetes leads to DM-cardiomyopathy, characterized by systolic and diastolic dysfunction. Pre-transplant diastolic dysfunction, has been associated with poor graft outcome and mortality. We assessed the hypothesis that end-stage liver disease (ESLD) patients with diabetes (DM-ESLD), have more advanced cardiac systolic and diastolic dysfunction, compared to ESLD patients without diabetes (Non DM-ESLD).MethodsWe retrospectively evaluated preoperative echocardiography of 1,319 consecutive liver transplant recipients (1,007 Non DM-ESLD vs. 312 DM-ESLD [23.7%]) January 2012–May 2016. Systolic and diastolic indices, such as left ventricular ejection fraction, transmital E/A ratio, tissue doppler s’, e’ velocity, and E/e’ ratio (index of left ventricular end-diastolic pressure), were compared using 1:2 propensity-score matching.ResultsDM-ESLD patients showed no differences in systolic indices of left ventricular ejection fraction and s’ velocity, whereas diastolic indices of E/A ratio ≤ 1 (49.0% vs. 40.2% P = 0.014), e’ velocity (median = 7.0 vs. 7.4 cm/s, P < 0.001) and E/e’ ratio (10.9 ± 3.2 vs. 10.1 ± 3.0, P < 0.001), showed worse diastolic function compare with Non DM-ESLD patients, respectively.ConclusionsDM-ESLD patients suffer higher degree of diastolic dysfunction compared with Non DM-ESLD patients. Based on this, careful preoperative screening for diastolic dysfunction in DM-ESLD patients is encouraged, because poor transplant outcomes have been noted in patients with preoperative diastolic dysfunction.

Defining a threshold for tacrolimus intra-patient variability associated with late acute cellular rejection in paediatric kidney transplant recipients.

Late acute cellular rejection (LACR) is associated with poorer graft outcomes and non-adherence. Non-adherence to tacrolimus can be indirectly assessed by the intra-patient variability (IPV) of tacrolimus trough levels. The threshold of IPV associated with rejection is not known. We conducted a case-control study comparing 25 patients with biopsy-proven LACR against 25 stable controls matched for age group, primary diagnosis and time post-transplant. IPV was calculated using coefficient of variance (CV) and mean absolute deviation (MAD) using tacrolimus levels in the preceding 12months. We also assessed the percentage time for tacrolimus levels <4μg/L (Tac < 4) and the concentration/weight-adjusted dose (C/D) ratio as a proxy marker of tacrolimus metaboliser status. LACR patients had higher CV (median, IQR 44%, 36-61% v. 24%, 19-35%, p< 0.0001) and higher MAD (33%, 25-48% v. 19%, 15-26%, p< 0.0001). The MAD was less affected by outlying tacrolimus results. Receiver operating curve analysis of the MAD resulted in a sensitivity of 76% and specificity of 76% at a threshold of 26% (AUC 0.85, p< 0.05). LACR patients had more Tac < 4 (50% v. 26%, p< 0.05). There was no difference in C/D suggesting that good IPV can be maintained in fast metabolisers. Patients with LACR had significantly increased creatinine at 12-month follow-up despite treatment (108 v. 5umol/L increase from baseline) and four patients lost their allograft. Monitoring of tacrolimus IPV using the MAD may be a clinical marker for LACR. A threshold IPV of 26% can potentially be used as a therapeutic target pending further validation studies.

Association between Aortic Calcification, Cardiovascular Events, and Mortality in Kidney and Pancreas-Kidney Transplant Recipients

Background: Cardiovascular (CV) disease is the leading cause of death in kidney and simultaneous pancreas-kidney (SPK) transplant recipients. Assessing abdominal aortic calcification (AAC), using lateral spine x-rays and the Kaupilla 24-point AAC (0–24) score, may identify transplant recipients at higher CV risk. Methods: Between the years 2000 and 2015, 413 kidney and 213 SPK first transplant recipients were scored for AAC at time of transplant and then followed for CV events (coronary heart, cerebrovascular, or peripheral vascular disease), graft-loss, and all-cause mortality. Results: The mean age was 44 ± 12 years (SD) with 275 (44%) having AAC (26% moderate: 1–7 and 18% high: ≥8). After a median of 65 months (IQR 29–107 months), 46 recipients experienced CV events, 59 died, and 80 suffered graft loss. For each point increase in AAC, the unadjusted hazard ratios (HR) for CV events and mortality were 1.11 (95% CI 1.07–1.15) and 1.11 (1.08–1.15). These were similar after adjusting for age, gender, smoking, transplant type, dialysis vintage, and diabetes: aHR 1.07 (95% CI 1.02–1.12) and 1.09 (1.04–1.13). For recipients with high versus no AAC, the unadjusted and fully-adjusted HRs for CV events were 5.90 (2.90–12.02) and 3.51 (1.54–8.00), for deaths 5.39 (3.00–9.68) and 3.38 (1.71–6.70), and for graft loss 1.30 (0.75–2.28) and 1.94 (1.04–3.27) in age and smoking history-adjusted analyses. Conclusion: Kidney and SPK transplant recipients with high AAC have 3-fold higher CV and mortality risk and poorer graft outcomes than recipients without AAC. AAC scoring may be useful in assessing and targeted risk-lowering strategies.

Impact of CYP3A5 Genetic Polymorphism on Intrapatient Variability of Tacrolimus Exposure in Chinese Kidney Transplant Recipients

BackgroundAlthough high tacrolimus (FK) intrapatient variability (IPV) was shown to be associated with poor graft outcome in kidney transplant recipients (KTRs), it is uncertain whether there is any association between the CYP3A5 genotype and IPV of FK concentrations. Instead of trough level, we use calculated abbreviated AUC0-12 to investigate the impact of CYP3A5 genetic polymorphism on IPV of FK pharmacokinetics. MethodsWe conducted a retrospective, single-center study of 86 adult Chinese KTRs with known CYP3A5 genotype. Coefficient of variation (CV) was used for the quantification of FK IPV. CV of dose-normalized FK AUC0-12 was calculated and was compared between the CYP3A5 expresser group and nonexpresser group. ResultsForty-one patients (47.7%) were classified as CYP3A5 expressers while 45 were nonexpressers. No significant differences in the baseline characteristics were found between expressers and nonexpressers. CYP3A5 expressers required 1.8 times higher FK dose compared with the nonexpressers. There was no significant difference in the FK CV between CYP3A5 expressers (18.2 ± 7.5%) and nonexpressers (16.7 ± 5.7%) (P = .31). ConclusionThe IPV of FK exposure was not associated with CYP3A5 genotype in stable KTRs. Further studies should focus on other factors such as medication nonadherence, which may explain FK IPV.