Biopsy-proven Rejection Research Articles

Kidney transplantation during coronavirus 2019 pandemic at a large hospital in Miami.

BackgroundCoronavirus 2019 (COVID‐19) pandemic has resulted in more than 350 000 deaths worldwide. The number of kidney transplants has declined during the pandemic. We describe our deceased donor kidney transplantation (DDKT) experience during the pandemic.MethodsA retrospective study was conducted to evaluate the safety of DDKT during the COVID‐19 pandemic. Multiple preventive measures were implemented. Adult patients that underwent DDKT from 3/1/20 to 4/30/20 were included. COVID‐19 clinical manifestations from donors and recipients, and post‐transplant outcomes (COVID‐19 infections, readmissions, allograft rejection, and mortality) were obtained. The kidney transplant (KT) recipients were followed until 5/31/20.ResultsSeventy‐six patients received kidneys from 57 donors. Fever, dyspnea, and cough were reported in 1, 2, and 1 donor, respectively. Thirty‐eight (66.6%) donors were tested for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV2) prior to donation (mainly by nasopharyngeal or bronchoalveolar lavage polymerase chain reaction [PCR]) and 36 (47.3%) KT recipients were tested at the time of DDKT by nasopharyngeal PCR; all of these were negative. Our recipients were followed for a median of 63 (range: 33‐91) days. A total of 42 (55.3%) recipients were tested post‐transplant for SARS‐CoV2 by nasopharyngeal PCR including 12 patients that became symptomatic; all tests were negative except for one that was inconclusive, but it was repeated and came back negative. Forty (52.6%) KT recipients were readmitted, and 7 (9.2%) had biopsy‐proven rejection during the follow‐up. None of the KT recipients transplanted during this period died.ConclusionsOur cohort demonstrated that DDKT can be safely performed during the COVID‐19 pandemic when preventive measures are implemented.

Small Bowel Transplant—Observations from Initial Setback

Small bowel transplants are performed all over the world with acceptable success rates. Although there are isolated reports of small bowel transplants from India, a robust intestinal transplant programme similar to western countries is lacking. Our aim is to share our experience to build up on the evolving field of small bowel transplants in India. Deceased donor small bowel transplant was performed for three patients with intestinal failure, two for short gut syndrome following surgery and one for visceral myopathy. All were on preoperative total parenteral nutrition for varying periods of time (6 to 13 months). There were multiple episodes of line sepsis in all patients. Post-transplant, all received induction immunosuppression with anti-thymocyte globulin (first two patients) or alemtuzumab (3rd patient). All had systemic venous drainage and stoma. Protocol weekly intestinal biopsies were done in all patients. All died in hospital at 24, 12 and 28 days following surgery. Biopsy-proven rejection was observed in only patient who had received ABO-compatible non-identical graft (O to A). This patient subsequently developed vascular thrombosis necessitating explant of the graft. Sepsis due to multidrug resistant bacteria was the reason for mortality in the remaining two patients. Despite the absence of technical complications, successful small bowel transplant seems to be an elusive entity for the Indian transplant community.

P1612CAN THE URINARY NITRATE TO CREATININE RATIO BE USED AS A MARKER FOR KIDNEY TRANSPLANT REJECTION?

Abstract Background and Aims Early identification and treatment of kidney transplant rejection episodes is vital to limit loss of function and prolong the life of the transplanted kidney and recipient. Current practice depends on detecting a creatinine rise. A biomarker to diagnose transplant rejection, either at an earlier time point, or to inform earlier decision making to biopsy, could be transformative. Urinary nitrate concentration is elevated in renal transplant rejection. Nitrate is a nitric oxide (NO) oxidation product. Transplant rejection upregulates NO synthesis via inducible nitric oxide synthase leading to elevations in urinary nitrate concentration. Historically, assays for measurement of inorganic nitrate in biological fluids have been too time consuming to be useful in a clinical setting. We have recently validated a urinary nitrate concentration assay which could provide results in a clinically relevant timeframe. Our aim was to determine whether urinary nitrate concentration is a useful tool to predict renal transplant rejection in the context of contemporary clinical practice. Method We conducted a prospective observational study, recruiting renal transplant participants over an 18 month period. We made no alterations to the patients’ clinical care including medications, immunosuppression, diet and frequency of visits. We collected urine samples from every clinical attendance including routine attendances, unscheduled attendances for acute clinical indications, and on the day of attendance for biopsy, for those who underwent biopsy. We measured the urinary nitrate to creatinine ratio (uNCR) between patient groups including routine attendances, biopsy proven rejection and biopsy proven “no rejection”. uNCR was examined over time for those with transplant rejection. Groups were compared using a 2 tail t-test of unequal variance, for statistical significance. Results A total of 2656 samples were collected. uNCR during biopsy proven rejection, median 49 µmol/mmol, IQR 23-61, was not significantly different from that of routine samples, median 55 µmol/mmol, IQR 37-82 (p=0.56), or biopsy proven “no rejection”, median 39 µmol/mmol, IQR 21-89, (P=0.77). Overall uNCR was highly variable; median 52 µmol/mmol, IQR 31-81, with no diagnostic threshold for kidney transplant rejection. Furthermore, within-patient uNCR was highly variable over time, and thus it was not possible to produce individualised patient thresholds to identify rejection. Conclusion The urinary nitrate to creatinine ratio is not a useful biomarker for renal transplant rejection.

Plasma Cell-Rich Rejection and Worse Renal Outcomes After Kidney Transplantation: Simultaneous Histologic Evidence for Both Cellular and Humoral Rejection

BACKGROUND: Kidney transplantation is the optimal therapy for end-stage renal disease, but allograft rejection is considered to be a major obstacle to transplantation success. Plasma cell-rich rejection (PCR) is morphologically distinctive and may represent variants of allograft rejection, but the data remain limited. This study aimed to compare the clinical prognoses of different types of allograft rejection with that of PCR. METHODS: Between January 2002 and December 2017, there were 325 kidney transplant recipients with or without biopsy-proven rejection were divided into T cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR), PCR, and other pathologic findings without evidence of rejection groups, and their histopathological lesions, allograft outcomes, and clinical prognoses were examined. The outcomes of interest included allograft loss and recipient survival. In addition, responses to different types of anti-PCR treatment were evaluated. RESULTS: Compared with recipients without rejection, recipients with mixed ABMR/TCMR were at greatest risk of allograft failure (adjusted hazard ratio [aHR], 3.70; 95% confidence interval [CI], 1.97-7.27), followed by those with ABMR (aHR, 3.07; 95% CI, 1.61-6.08), PCR (aHR, 3.07; 95% CI, 1.33-6.85) and TCMR (aHR, 2.47; 95% CI, 1.38-4.65). No significant difference in recipient survival after rejection was observed. Principal component analyses revealed that PCR was a morphologic type of combined cellular and humoral rejection. CONCLUSION: This study showed that PCR is associated with poorer allograft outcomes than is TCMR, but better outcomes than ABMR and mixed ABMR/TCMR. Therefore, clinical physicians need to be aware of this entity and apply more aggressive treatment strategies for kidney allograft salvage.

P1705ARE DIRECT-ACTING ANTI-VIRAL DRUGS ACCUSED OF INCREASED INCIDENCE OF HEPATOCELLULAR CARCINOMA IN ENDEMIC AREA: A PILOT STUDY

Abstract Background and Aims Great progression in treating hepatitis C infection has been made with the new Interferon-free regimens. Reports about developing hepatocellular carcinoma after DAAs have been spotlighted. Kidney transplantation and hemodialysis are considered risk factors for developing malignancies. Here we are evaluating the prevalence of HCC after DAAs treatment in high risk population. Method This cross-sectional study was held in Urology and Nephrology Center, Mansoura University, Egypt including. Total number of 165 patients received DAAs included in this study in 2 phases. The first phase included 50 patients (12 hemodialysis and 38 kidney transplant recipients). All patients completed DAAs course as treatment for hepatitis C infection (HCV) 24 months ago. Alfa feto protein and liver ultrasound (Use of both modalities combined yielded sensitivity (99.2%) and specificity (68.3%)) was used to screening of HCC for all patients. Triphasic CT liver with 86% to 94% sensitivity was done for all hemodialysis patients and KTRs with suspicious lesions or high alfa-feto protein. Results Our patients mean age was 52.32±3.2 years with male predominance. Mean Hemodialysis duration was 48.21±12.3 months and mean kidney transplantation duration was 36.21±6.7 months. Baseline laboratory investigations: ALT: 39.17±16.3 iu/l, Albumin: 3.6±1.32 g/dl, Bilirubin: 0.54±0.21, Hemoglobin: 10.57±1.9 g/dl, AFP: 5.3±2.4 ng/ml. Baseline liver US: normal (49%), enlarged (42%) and cirrhotic (9%) (No focal lesions). Fibro scan: F0 (26%), F1 (31%), F2 (32%) and F3 (11%). None of them experienced hepatic encephalopathy attacks or bleeding varices. All hemodialysis patients received Ombitasvir/Paritaprevir/Ritonavir (OMV/PTV/RTV) regimen (3 months). Only 2 KTRs received OMV/PTV/RTV regimen (3 months), the remaining 36 KTRs received Sofosbuvir/Daclatasvir regimen (6 months). Only 1 case reported relapse within 3 month after completing treatment. The rest achieved 12-week and 24-week SVR successfully. After 2 years from completing treatment, there was significant improvement in ALT levels. Four KTRs passed to graft failure due to accelerated immunologic response (rejection episodes) and 7 KTRs showed rise of serum creatinine (biopsy-proven rejection). Mean AFP rose up to 7.6±2.4 ng/ml with no statistical difference. Three hemodialysis patients and 4 KTRs showed rise in alfa-feto protein above normal values (10ng/dl). Four out of them exceeded 500ng/ml (1 HD and 3 KTRs). Abdominal US revealed: no change (39 patients), enlargement (6 patients) and cirrhosis (5 patients). Suspicious mass was found in 11 patients. Triphasic CT then was done for all hemodialysis patients and 9 KTRs. Regarding hemodialysis, 1 patient was diagnosed as HCC based on increased enhancement by Triphasic CT and alfa-fetoprotein was >500 ng/ml. Regarding KTRs, HCC was diagnosed in 2 patients and liver metastasis secondary to lymphoma was diagnosed in 1 case. The other patients with suspicious lesions (5 patients) showed uniform enhancement by Triphasic CT suggesting benign lesions. So, we have 3 (6%) out of 50 patients has been diagnosed as HCC after DAAs. By retrieval of their data, HCV duration was over 10 years and the liver was cirrhotic or enlarged with cirrhotic changes by ultrasound. Baseline ALT was slightly high without significant improvement after treatment. Also, baseline alfa-feto protein was high. The 3 patients were F2 or F3. Conclusion Hepatocellular carcinoma incidence after Direct-acting anti-virals is related mostly to the poor condition of the patients at baseline not to the drug itself and HCC in such cases could be considered as a part of disease progression not a drug complication.

P1624TORQUE TENO VIRUS FOR RISK STRATIFICATION OF GRAFT REJECTION AND INFECTION IN KIDNEY TRANSPLANT RECIPIENTS - A PROSPECTIVE OBSERVATIONAL TRIAL

Abstract Background and Aims The non-pathogenic and ubiquitous Torque Teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. This prospective observational trial was designed to assess the potential of TTV load for risk prediction of both, infection and rejection in the first year after transplantation. The objective of this trial was to provide TTV cut-off level to define an optimal TTV range as a basis for a randomised controlled interventional trial to test the efficacy of TTV-guided immunosuppression. Method Within this trial (DRKS00012335) all 386 adult (≥18 years of age) consecutive kidney graft recipients transplanted at the Medical University Vienna, Austria, between January 1st 2016 and June 31st 2018. were subjected to longitudinal per protocol TTV monitoring. In total 3265 TTV measurements were taken and 71 biopsy proven graft rejections (defined by BANFF classification) and 472 clinically relevant infections were documented in the first year post-transplant. After reaching steady state at the end of post-transplant month 3, peripheral TTV plasma load was analyzed in the context of subsequent rejection and infection by rt-PCR. Results Patients with allograft rejection had lower levels of TTV compared to patients without rejection (median 3.5x106 c/mL, IQR 1.7x105-1.3x108 c/ml vs. median 2.5x108 c/mL, IQR 5.8x106-9.3x108 c/mL; P = .028) in subsequent biopsies. TTV load in individuals experiencing an infectious event in the subsequent observation period was higher compared to patients without infection (median 3.9x108 c/mL, IQR 7.9x106-3.3x109 c/mL vs. median 2.6x107 c/mL, IQR 1.3x106-9.2x108 c/mL; P < .001). Of note, TTV was quantified several weeks before rejection diagnosis and infection onset. Each log increase in TTV load decreased the odds for rejection by 22% (OR 0.78, 95% CI 0.62-0.97; P = .027) and increased the odds for infection by 11% (OR 1.11, 95% CI 1.06-1.15; P < .001). The association of TTV and infection and rejection, respectively was not altered by confounding or effect modification. A TTV load between 106 and 108 copies/mL was defined as optimal range to minimize the risk for rejection and infection. Conclusion These data support the initiation of an interventional trial assessing the efficacy of TTV-guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients.

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

Outcome of ABO Blood Type–Incompatible Living-Related Donor Kidney Transplantation Under a Contemporary Immunosuppression Strategy in Japan

BackgroundBecause of the serious donor shortage in Japan, there is an increasing need for ABO blood type–incompatible kidney transplantation (ABOi-KT) in living-related donor kidney transplantation. We evaluated the outcomes of ABOi-KT performed at our hospitals using a contemporary immunosuppression strategy with low-dose rituximab. Patients and MethodsBetween June 2006 and April 2019, 107 patients underwent living-related donor kidney transplantation at our hospitals. The patients were divided into ABO-compatible (ABOc) and ABOi groups. The basic immunosuppression regimen differed between the 2 groups in the use of low-dose rituximab and therapeutic apheresis in the ABOi group. We compared graft survival, patient survival, rejection, viral infection, and posttransplant renal function between the 2 groups. ResultsOf 107 recipients, 37 (35%) underwent ABOi-KT. The 5-year graft survival rates in the ABOc and ABOi group were 91% and 100%, respectively. The Kaplan-Meier analyses showed no difference in graft survival (P = .168) or patient survival (P = .873) between the groups. Biopsy-proven rejection in the ABOc and ABOi groups was observed in 13 (19%) and 7 (19%) patients, respectively (P = .965), and viral infection was observed in 21 (30%) and 10 (27%) patients (P = .747), respectively. Renal function by estimated glomerular filtration rate from 1 week to 5 years after transplantation was similar in both groups. ConclusionsThe outcomes of ABOi-KT with low-dose rituximab were comparable with those of ABOc-KT at our hospitals. ABOi-KT with proper immunosuppression may be an option to help resolve the severe donor shortage in Japan.

Early Steroid Withdrawal Protocol With Basiliximab and Rituximab in ABO-Incompatible Kidney Transplant Recipients

ObjectivesCorticosteroids remain an important component of immunosuppressive regimens in high-risk kidney transplants. In this study, we investigated the efficacy of early steroid withdrawal with basiliximab and rituximab in ABO–blood type incompatible (ABO-i) recipients of kidney transplants. MethodsBetween 2008 and 2019, 15 patients underwent ABO-i kidney transplantation. Seven of the 15 patients were treated with a steroid maintenance protocol and the remaining 8 with an early steroid withdrawal protocol. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone (MP), with basiliximab administered as induction therapy. Rituximab was administered as a single 200-mg dose 1 to 4 weeks before kidney transplantation. Two to 4 sessions of either double-filtration plasmapheresis or regular plasmapheresis or both were performed to remove anti-AB antibodies before transplantation. During surgery, MP was administered at a dose of 500 mg; thereafter, the dosage was tapered rapidly, and the drug was discontinued on day 14 post transplant. ResultsIn the steroid maintenance group, 2 patients experienced acute antibody-mediated rejection (AMR). One patient with severe AMR had graft loss on postoperative day 4. Patient and graft survival rates in the steroid maintenance group were 100% and 86%, respectively. MP was successfully withdrawn in the steroid withdrawal group. In this group, there was no biopsy-proven rejection. Patient and graft survival rates were 100%, and when last measured, serum creatinine level ± SD was 1.6 ± 0.8 mg/dL. ConclusionsOur protocol successfully enabled the early withdrawal of steroids in recipients of ABO-i grafts; however, further follow-up is necessary to confirm our results.

Health literacy and its association with adherence in pediatric liver transplant recipients and their parents.

Non-adherence to pediatric regimens is a common concern. Low health literacy is correlated with poor outcomes in adults but is understudied in pediatrics. The current project aimed to determine the relationship between health literacy, adherence, and outcomes in pediatric liver transplant recipients. Hypotheses included a) parent and patient health literacy would be positively correlated; and b) low patient and/or parent health literacy would be negatively correlated with adherence and health outcomes. Eligible participants were recruited during routine follow-up visits in a pediatric liver transplant clinic. Parents and patients (>13years old) completed 2 measures of health literacy. Patients ≥18years completed health literacy measures without corresponding parent surveys. Adherence variables and health outcomes were obtained from medical records. Seventy-nine patients across two sites completed the study. Variance in classification of health literacy between measures was observed; however, most parents (82%-100%) scored within an "adequate literacy" range. More adolescents scored in lower health literacy ranges relative to the parents. Markers of SES were positively correlated with health literacy. Parent health literacy was negatively associated with biopsy-proven rejection episodes and the number of hospitalizations; however, it was not associated with measures of tacrolimus adherence. There were no relationships observed between parent and adolescent health literacy. Health literacy is an important consideration in managing patient care; however, available measures demonstrate variability in capturing the skills of patients. Effective communication strategies may ameliorate admittedly small, but negative, impacts of limited health literacy on outcomes.

Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside.

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P<.5) from a discovery cohort of HLA antibody-negative, endothelial cell crossmatch-positive sera obtained from 12 cardiac allograft recipients at the time of biopsy-proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n=477 no rejection; n=69 rejection) identified 18 non-HLA antibodies associated with rejection (P<.1) including 4 newly identified non-HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non-HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non-HLA antigens synergize with HLA donor-specific antibodies and significantly increase the odds of rejection (P<.1). The non-HLA panel was validated using an independent adult cardiac transplant cohort (n=21 no rejection; n=42 rejection, >1R) with an area under the curve of 0.87 (P<.05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection.

Relationship between 2-Hour Tacrolimus Concentrations and Clinical Outcomes in Long Term Kidney Transplantation.

Background: Tacrolimus is routinely monitored using trough concentrations, however, recent data have suggested that area under the curve (AUC) provides better correlation with toxicity and efficacy. Area under the curve is cumbersome to measure, but studies have demonstrated that surrogate time points such as 2-hour concentrations are well correlated with AUC. Methods: This is a single center, retrospective study of adult kidney transplant recipients with 2-hour tacrolimus concentrations measured over three years post-transplant. The primary outcome was to determine the difference in serum creatinine (Scr) in those with 2-hour tacrolimus concentrations greater than 20 ng/mL versus those less than or equal to 20 ng/mL. Results: A total of 150 kidney transplant recipients were included. The mean Scr and glomerular filtration rate were 1.49 ± 1.01 mg/dL and 59 ± 23.2 mL/min/1.73 m2, respectively, for the entire cohort. The rate of donor specific antibody formation was 2% and 8% experienced biopsy-proven rejection. The rate of cytomegalovirus viremia was 2% and BK viremia was 13%. There was no significant difference in kidney function over 36 months for the groups specified a priori. Conclusions: Long-term outcomes of maintaining tacrolimus 2-hour concentrations over 20 ng/mL is favorable with minimal opportunistic infections.

Assessment of Mycophenolic Acid Levels on Biopsy Proven Rejection and Adverse Effects in Pediatric Heart Transplant Recipients

Therapeutic ranges of Mycophenolic Acid (MPA) concentrations have not been established in pediatric heart transplant recipients. There are limited data supporting are under the concentration-time curve (AUC) in adult heart transplant on outcomes such as rejection, but AUC monitoring may be not be feasible in clinical practice. The purpose of our study is to evaluate the relationship between mycophenolic acid (MPA) trough levels and incidence of biopsy proven rejection and adverse effects in pediatric heart transplant patients. A single-center retrospective chart review was performed on patients receiving heart transplant between Jan 2011 and Dec 2015. Patients included for analysis were ≤18 years at transplant and received maintenance immunosuppression with tacrolimus, mycophenolate, and a corticosteroid. Endomyocardial biopsy grades up to one-year post transplant and simultaneous MPA levels were recorded. Patients with acute cellular rejection scores of 2R or 3R or immunopathologic evidence of antibody mediated rejection were considered as biopsy proven acute rejection (BPAR). Leukopenia, gastrointestinal side effects, and mycophenolate dose decreases were also recorded. A total of 47 patients were included in the final analysis. There were no significant differences in baseline demographics between patients who had BPAR and those who did not. Overall 24% of patients had at least 1 incidence of BPAR after heart transplant. The mean MPA trough levels between the group of patients with rejection (2.4 ug/mL +/- 1.62) and those without rejection (2.46 ug/mL +/- 1.74) was not significantly different (p=0.38). Mean MPA trough levels also were also not consistent when examining rejection by time from transplant. Only examining by individual MPA trough levels on biopsy days did we observe a significantly lower MPA trough 1.6 ug/mL +/- 1.05 in those with rejection versus those without 2.5 ug/mL +/- 1.69 (p=0.02). The mean MPA level associated with a dose decrease due to an adverse effect between these two groups was not significant. MPA trough levels may have a relationship with incidence of biopsy proven rejection or with incidence of adverse events within one-year post transplant in this population. Controlled prospective studies with are warranted to further evaluate this potential relationship.

Effect of Granulocyte Colony-Stimulating Factor on Acute Cellular Rejection in Lung Transplant Recipients

Neutropenia is a known complication after lung transplantation either related to infection or as a side effect of medication. Granulocyte colony-stimulating factor (G-CSF) is an option for treating neutropenia in lung transplant recipients. Acute cellular rejection (ACR) is a common complication after lung transplantation, especially in the first year post-transplantation. The purpose of this study was to assess whether there is an association between the use of G-CSF and the incidence of ACR. Data on lung transplant recipients from May 2007 to November 2018 was reviewed. Patients who received at least one dose of G-CSF were identified and compared with patients without a history of therapy. Baseline characteristics, episodes of G-CSF administration, and biopsy proven rejections were collected. The rates of ACR in the study groups were calculated and compared. Multivariate Poisson regression was used to adjust for confounding variables which included the number of immunosuppressive agents, presence of respiratory viral infections, and presence of donor specific antibodies. Eighty-two patients were studied. 19 (23%) received G-CSF. There were no significant differences in baseline characteristics between the study groups. The rate of ACR for the G-CSF group was 0.12 event/month in the 3 months after G-CSF administration (95% CI, 0.06 - 0.24) and 0.06 event/month all other times (95% CI, 0.02 - 0.14). The rate of ACR for the control group was 0.05 event/month (95% CI, 0.04 - 0.08). There was a significant difference between the rates of ACR in the G-CSF group in the 3 months after G-CSF administration versus the control group (P = 0.033), but not for the other time periods (P = 0.897). G-CSF administration was found to be associated with a significant short-term increased risk of ACR in lung transplant recipients.

Combined AlloSure and AlloMap Testing in Multi-Organ Heart Transplantation Rejection Surveillance

AlloSure test is a non-invasive blood test designed to detect the presence of donor cell-free DNA in the recipients blood as a measure of the probability of rejection in heart transplant recipients. The result is displayed as a percent of donor-derived cell-free DNA (dd-cfDNA) in the totalcell-free DNA (cfDNA). Recommended threshold of 0.2% dd-cfDNA has been predictive of low likelihood of rejection. There is no data looking at its value and validation in multi-organ transplant. We aimed to study this area by reviewing our transplant database. All patients who received more than one solid organ transplant at our center and had AlloSure testing were included. Study outcomes included one year survival, rejection grade 2R or more, and hemodynamically significant graft dysfunction. There were (7) patients included in the study, average AlloSure score was 0.93% ±0.61% with an average AlloMap score of 33.8±2.14. Four patients (57.1%) had heart and kidney transplant, 3 patients (42.9%) had heart and liver transplantation. Average AlloSure score for heart/kidney transplant recipients was 0.52±0.17% with an average AlloMap score of 33.6±2.28. The while average AlloSure score for heart/liver transplant recipients was 1.21±0.55% mean AlloMap score of 33.93±2.32. None of our patients had graft dysfunction or biopsy-proven rejection >=2R. Survival rate was 100% for the first year in our patients CONCLUSION: AlloSure levels were higher in heart-liver vs. heart-kidney recipients, and in both cohorts higher than the 0.2% threshold recommended for heart transplant prediction of rejection, however did not predict rejection. In our cohort, while AlloMap scores were consistent in both groups, (33.93±2.32 vs. 33.6±2.28 respectively). Elevated AlloSure was not predictive of rejection in multiorgan heart transplant recipients.

Cytomegalovirus Infections are Frequent after Heart Transplantation but Do Not Increase the Risk of Biopsy-Proven Allograft Rejection in the Modern Era

Our aim was to analyze the clinical impact of CMV infections on the risk of allograft rejection. We conducted a single-center retrospective study including patients transplanted between January 2012 and December 2016 who had at least one endomyocardial biopsy (EMB) during follow-up. Patients at high risk of CMV infections (D+/R-) received valganciclovir prophylaxis for 3 months, those at intermediate risk (R +) were treated according to a preemptive strategy (viral replication threshold: 10,000 IU / mL). Protocol monitoring included 13 B.M. per patient in the first year. Allograft rejection was defined as ≥ 1R1B acute cellular rejection or ≥ pAMR1 antibody-mediated rejection according to international guidelines. The impact of CMV infection, defined as a viral replication ≥ 10,000 IU / mL, on the risk of allograft rejection was analyzed using a mixed effects logistic regression. 399 patients met the inclusion criteria, including 60 patients D+/ R-, 256 R+ and 72 D+/R. All patients received an induction therapy and a triple basal immunosuppression. We observed a dynamic risk of infection during the first year according to the baseline CMV serology (Figure 1A). CMV infections were diagnosed in more than half of the patients (Figure 1B). 140 patients (35%) had at least one episode of biopsy-proven rejection. In univariable analyses, CMV infections were not associated with an increased risk of rejection in month following infection (0R=1.03, 95%CI=0.6-1.7, p=0.91). After adjustment for the presence of DSA, the number of HLA AB-DR-DQ mismatches, recipient age and time post-transplant, CMV infections were not associated with the risk of rejection in month following infection (OR=0.9, 95%CI=0.5-1.5, p=0.61). Different timing post-infection have been evaluated but were not associated with rejection. CMV infections were common after heart transplantation but were not associated with the risk of allograft rejection.

Conversion to belatacept within 1-year of renal transplantation in a diverse cohort including patients with donor-specific antibodies.

Early conversion from a calcineurin inhibitor to belatacept has the potential to improve long-term renal allograft function; however, there remains limited experience with this strategy among African Americans and patients with preformed donor-specific antibodies (DSA). To examine these subgroups, we performed a single-center review of kidney transplant recipients converted to belatacept within 1-year of transplant between 01/2011 and 10/2017. All patients received lymphocyte-depleting induction with maintenance tacrolimus and mycophenolate +/- corticosteroids. Patients were switched to belatacept for clinical indication and followed from date of conversion until allograft failure or study conclusion. The primary endpoint at 1-year was a composite of allograft loss, biopsy proven rejection, de novo DSA formation, proteinuria, and declining renal function. Thirty-two patients were included in the review. The majority were African American, and 28.1% had DSA at transplant. Patient and allograft survival at 1-year was 96.9% and 93.8%, respectively, and estimated glomerular filtration rate improved from 41.9 to 58.4mL/min. No African Americans or patients with pretreatment DSA developed rejection or allograft failure within 1-year. The only clinical variable correlated with suboptimal allograft function was baseline weight ≥80kg (OR=6.2; 95% CI, 1.2-32.3). Early conversion to belatacept appears safe for select patients with DSA and African Americans receiving lymphocyte-depleting induction.

SAT-339 Low Dose Induction Immunotherapy with Anti Human T-lymphocyte Immunoglobulin (Grafalon) in High Risk Renal transplantation – A Real-world, Single Centre Experience from India

The current armamentarium of rabbit polyclonals includes thymoglobulin and Grafalon. The experience with the latter has been quite limited as until recently it was not available in India. In addition, its dose and duration are controversial, differs center-wise, and is based on scarce clinical data. The objective of this study was to assess the safety and efficacy of Grafalon induction in live related high-risk kidney transplant patients. (history of blood transfusions, HLA mismatch> 3). This was a single-center, prospective, observational study of 54 renal transplant patients who received Grafalon as induction therapy. All patients underwent living donor kidney transplantation. Pre-transplant CDC and flow crossmatch were negative in all. Grafalon was administered at an average dose of 6.0 mg/kg body weight, as a single dose infusion through peripheral intravenous line over 3 hours on day 0. Tacrolimus, MMF and prednisolone constituted maintenance immunosuppression in all patients. These patients were followed up twice a week for 1 month, once a week for 2nd month and once in 15 days for the 3rd month and thereafter once a month. At each visit, they were evaluated clinically as well subjected to laboratory investigations. Tacrolimus levels were monitored twice a week for the first week, once a week for the first month and thereafter once a month. Microsoft Excel was used to analyse the data. All of the patients tolerated Grafalon infusion well and there were no major infusion reactions or fever requiring temporary stoppage or cessation of the drug. Seven patients (13%) developed biopsy proven acute rejection. Majority of them were mild grade cellular rejections and responded well to steroids with good recovery of renal function. At a mean follow up of 10.65+5.4months, patient survival was 100% and graft survival was 100%. Infection episodes were seen in 7 patients with UTI (n=6) being the commonest cause. There were no documented CMV or BK virus infections. Post-transplant, day 1 serum creatinine was 4.89+2.78 mg/dL which reduced to 1.44 ± 0.8mg/dL (n=49, p<0.0001) at day 10 and 1.24 ± 0.35 mg/dl (n=34, p<0.0001) at day 30. Grafalon (6mg/kg) is associated with an acceptable efficacy and safety profile in renal transplantation. Larger studies are necessary to confirm the findings.

SAT-325 ASSOCIATION OF CYP3A5 POLYMORPHISM WITH TACROLIMUS LEVELS AND GRAFT OUTCOMES IN INDIAN KIDNEY TRANSPLANT RECIPIENTS

Tacrolimus which is the sheet anchor of post-transplant immunosuppression has a narrow therapeutic index. It is imperative to achieve therapeutic tacrolimus levels for optimum graft survival as sub-optimal levels can predispose to graft rejections and toxic levels pose a risk of nephrotoxicity. The inter-individual variations in the pharmacokinetics of tacrolimus can be in part attributed to polymorphism in Cytochrome P450 (CYP) enzymes. The expressor [CYP3A5*1/*1] status leads to faster metabolism of tacrolimus than that in non- expressors [CYP3A5*3/*3]. Although it is well known that these differences in genotype affect tacrolimus levels, but their effect on long term graft outcome is equivocal. It is not proven that knowing the genotype pre-transplant and adjusting the induction dose accordingly improves graft outcomes. We aim to evaluate the association of CYP3A5 genotypes on tacrolimus trough levels and graft outcomes in adult and pediatric kidney transplant recipients. In this single-center study, consecutive kidney transplant recipients, both pediatric and adults, on tacrolimus therapy for atleast 3 months were enrolled. Genotyping was done using PCR-RFLP for CYP3A5 *1/*1, [expressors] *1/*3,[intermediate expressors] *3/*3 [non -expressors] polymorphisms., and patients were divided into these 3 groups. These groups were analyzed with retrospectively available data for differences in dose-adjusted tacrolimus levels at 1,3,12 months and graft outcomes - acute biopsy-proven rejection, chronic rejection, chronic allograft dysfunction, new-onset proteinuria, eGFR at 1,3,12 months and at last followup available, and graft loss. All groups received 0.1mg/kg/day dose of tacrolimus on day 0 of transplant and then the levels were modified according to subsequent trough tacrolimus levels. Out of 142 patients, 26% were females. Median age 48yrs, 11/142 had age <18 yrs. 16% were expressors[CYP3A5 *1/*1], 40.6% were intermediate[CYP3A5*1/*3], 43.4% were non-expressors[CYP3A5*3/*3]. Dose adjusted tacrolimus trough levels were significantly higher in non-expressors at 1 month [p=0.001], 3 months [p=0.015], 12 months [p=0.018]. Acute biopsy proven rejections were more in expressors [31.4%vs 22.6% p =0.042]. Also, chronic rejections were more in expressors [21%vs 6.53% p = 0.044] Non-expressors had higher incidence of chronic allograft dysfunction [48.4% vs 25.2% p=0.0004]. After being started with 0.1mg/kg/day of tacrolimus, expressors requied more dose escalations to reach therapeutic targets - median 3[0-6] vs 0[0-3] p =0.04. Non-expressors required more dose reductions to achieve targets - median 7[4-13] vs 2.5[0-16] p=0.02. The prevalence of non-expressors [CYP3A5 *3/*3] was 43.4% in Indian transplant recipients. When started at 0.1mg/kg/day dose, expressors had higher rates of subtherapeutic levels requiring more dose-escalation, while non-expressors required dose reductions due to supratherapeutic levels. Graft rejections both acute and chronic were more common in the expressors while non-expressors were at a higher risk of chronic allograft dysfunction. Our data support the use of pretransplant CYP3A5 genotyping to facilitate the individualization of tacrolimus dosing. Genotype guided dosing from the day of transplantation can improve graft outcomes by reducing nephrotoxicity [due to high doses] and rejections [due to suboptimal doses].

Management of BK viremia is associated with a lower risk of subsequent cytomegalovirus infection in kidney transplant recipients.

The risk of subsequent cytomegalovirus infection (CMV) in kidney transplant recipients (KTR) after diagnosis of BK polyomavirus viremia (BKV) is unclear, and current evidence is conflicting. We reviewed all KTR transplanted at our institution between 1/1/2005 and 12/31/2015. Follow-up began 3months after transplantation to avoid confounding effects of prophylaxis. Clinically significant BKV, defined as detectable BK viremia >1000copies/mL via molecular diagnostic testing (PCR), was treated as a time-varying exposure with 1-year follow-up. This viral load cutoff was chosen to ensure a more homogenous population that would be considered to have clinically significant BK viremia that necessitated management via immunosuppressive modification. Patients were then screened for subsequent CMV infection. 2435 RTX recipients met inclusion criteria; of these, 314 developed BKV during follow-up (BK+). Lymphocyte depletion, tacrolimus maintenance, and biopsy-proven rejection were significantly higher in the BK+ group. BK+ was associated with lower risk of subsequent CMV infection (BK+ HR 0.45, 95% CI 0.22-0.94, P=.03, relative risk reduction 55%). When adjusted for significant confounding factors, CMV incidence remained reduced in the BK+ population (HR 0.47, 95% CI 0.22-0.98, P=.04). This large series of KTR demonstrates that BKV is associated with lower risk of subsequent CMV infection.