N. Thai

Effect of high-dose erythropoietin on graft function after kidney transplantation: a randomized, double-blind clinical trial.

BACKGROUND AND OBJECTIVES Delayed graft function (DGF) is associated with adverse long-term outcomes after deceased-donor kidney (DDK) transplantation. Ischemia-reperfusion injury plays a crucial role in the development of DGF. On the basis of promising animal data, this study evaluated any potential benefits of erythropoietin-alfa (EPO-α) given intra-arterially at the time of reperfusion of renal allograft on the degree of allograft function, as well as tubular cell injury measured by urinary biomarkers in the early post-transplant period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the influence of EPO-α administered intraoperatively on the outcomes of DDK transplantations performed at the study center between March 2007 and July 2009. RESULTS Seventy-two patients were randomly assigned to EPO-α (n=36) or placebo (n=36). The incidences of DGF, slow graft function, and immediate graft function did not significantly differ between the treatment and control groups (41.7% versus 47.2%, 25.0% versus 36.1%, and 33.3% versus 16.7%, respectively; P=0.24). The groups had similar levels of urinary biomarkers, including neutrophil gelatinase-associated lipocalin and IL-18 at multiple times points soon after transplantation; urinary output during the first 3 postoperative days; 1-month renal function; and BP readings, hemoglobin, and adverse effects during the first month. CONCLUSIONS This study did not show any clinically demonstrable beneficial effects of high-dose EPO-α given intra-arterially during the early reperfusion phase in DDK transplant recipients in terms of reducing the incidence of DGF or improving short-term allograft function.

Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors

OBJECTIVES We report single center experience on the outcome and toxicity of SBRT alone or in combination with surgery for inoperable primary and metastatic liver tumors between 2007 and 2014. PATIENTS AND METHODS Patients with 1-4 hepatic lesions and tumor diameter ≤9 cm received SBRT at 46.8Gy ± 3.7 in 4-6 fractions. The primary end point was local control with at least 6 months of radiographic followup, and secondary end points were toxicity and survival. RESULTS Eighty-seven assessable patients (114 lesions) completed liver SBRT for hepatoma (39) or isolated metastases (48) with a median followup of 20.3 months (range 1.9-64.1). Fourteen patients underwent liver transplant with SBRT as a bridging treatment or for tumor downsizing. Eight patients completed hepatic resections in combination with planned SBRT for unresectable tumors. Two-year local control was 96% for hepatoma and 93.8% for metastases; it was 100% for lesions ≤4 cm. Two-year overall survival was 82.3% (hepatoma) and 64.3% (metastases). No incidence of grade >2 treatment toxicity was observed. CONCLUSION In this retrospective analysis we demonstrate that liver SBRT alone or in combination with surgery is safe and effective for the treatment of isolated inoperable hepatic malignancies and provides excellent local control rates.

Kidney Transplantation in Hepatitis C-Positive Recipients: Does Type of Induction Influence Outcomes?

BACKGROUND Kidney transplantation in hepatitis C virus-seropositive (HCV+) recipients improves survival compared to staying on the waiting list. A concern for using depleting (versus nondepleting) induction agent during kidney transplantation in HCV+ recipients is the possibility that the associated enhanced immunosuppression might favor the progression of hepatitis C infection, leading to adverse outcomes. METHODS Utilizing data from the Organ Procurement and Transplant Network, we identified HCV+ patients ≥ 18 years of age who underwent deceased donor kidney (DDK) transplants from either HCV+ or HCV- donors between 1998 and 2008. Patients were divided into two groups based on the induction type they received during the transplant: depleting agent (rabbit-antithymocyte globulin or alemtuzumab) or nondepleting agent (basiliximab or daclizumab) groups. Unadjusted and adjusted graft and patient survivals (Cox regression) between the groups were compared. RESULTS A total of 3490 HCV+ DDK recipients were identified (1859 in the depleting and 1631 in the nondepleting groups). When compared to nondepleting agent, adjusted graft (hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.96-1.28, P = .16) and patient (HR 1.15, 95% CI 0.93-1.42, P = .2) survivals were similar with depleting agent induction. HCV donor seropositivity did not adversely impact either graft (HR 1.11, 95% CI 0.96-1.29, P = .17) or patient (HR 1.15, 95% CI 0.93-1.42, P = .2) outcomes. CONCLUSIONS Our analysis supports the practice of transplanting HCV+ donor kidneys into HCV+ recipients to alleviate waiting list burden. Recipient HCV positivity should not influence selection of induction agent.

Exploratory use of cardiovascular magnetic resonance imaging in liver transplantation: a one-stop shop for preoperative cardiohepatic evaluation.

Background Preoperative cardiovascular risk stratification in orthotopic liver transplantation candidates has proven challenging due to limitations of current noninvasive modalities. Additionally, the preoperative workup is logistically cumbersome and expensive given the need for separate cardiac, vascular, and abdominal imaging. We evaluated the feasibility of a “one-stop shop” in a magnetic resonance suite, performing assessment of cardiac structure, function, and viability, along with simultaneous evaluation of thoracoabdominal vasculature and liver anatomy. Methods In this pilot study, patients underwent steady-state free precession sequences and stress cardiac magnetic resonance (CMR), thoracoabdominal magnetic resonance angiography, and abdominal magnetic resonance imaging (MRI) on a standard MRI scanner. Pharmacologic stress was performed using regadenoson, adenosine, or dobutamine. Viability was assessed using late gadolinium enhancement. Results Over 2 years, 51 of 77 liver transplant candidates (mean age, 56 years; 35% female; mean Model for End-stage Liver Disease score, 10.8; range, 6–40) underwent MRI. All referred patients completed standard dynamic CMR, 98% completed stress CMR, 82% completed late gadolinium enhancement for viability, 94% completed liver MRI, and 88% completed magnetic resonance angiography. The mean duration of the entire study was 72 min, and 45 patients were able to complete the entire examination. Among all 51 patients, 4 required follow-up coronary angiography (3 for evidence of ischemia on perfusion CMR and 1 for postoperative ischemia), and none had flow-limiting coronary disease. Nine proceeded to orthotopic liver transplantation (mean 74 days to transplantation after MRI). There were six ascertained mortalities in the nontransplant group and one death in the transplanted group. Explant pathology confirmed 100% detection/exclusion of hepatocellular carcinoma. No complications during CMR examination were encountered. Conclusions In this proof-of-concept study, it appears feasible to perform a comprehensive, efficient, and safe preoperative liver transplant imaging in a CMR suite—a one-stop shop, even in seriously ill patients.

Cardio-hepatic risk assessment by CMR imaging in liver transplant candidates

The preoperative workup of orthotopic liver transplantation (OLT) patients is practically complex given the need for multiple imaging modalities. We recently demonstrated in our proof‐of‐concept study the value of a one‐stop‐shop approach using cardiovascular MRI (CMR) to address this complex problem. However, this approach requires further validation in a larger cohort, as detection of hepatocellular carcinoma (HCC) as well as cardiovascular risk assessment is critically important in these patients. We hypothesized that coronary risk assessment and HCC detectability is acceptable using the one‐stop‐shop CMR approach.

Cardio-hepatic risk assessment by CMR in liver transplant candidates; advancing beyond a proof of concept

Background The pre-operative workup of orthotopic liver transpantation (OLT) patents is practically complex given the need for separate cardiac, vascular, and abdominal imaging. Precise diagnosis and staging of hepatocellular carcinoma (HCC) is crucial in the selection and timing orthotopic liver transplantation (OLT) in cirrhotic pts. We have recently demonstrated in our ‘Proof of Concept’ study in determining the short term value of a ‘One Stop Shop’ approach combining the attributes of a nuclear stress, echocardiogram and abdominal MRI into one single, same day, pre-op CMR evaluation. However, this approach requires further validation, as detection of HCC as well as cardiovascular risk assessment is critically important in these pts. We hypothesize in this intermediate term and larger study that CAD assessment and HCC detectability is independent of whether the study is performed as part of a larger One Stop Shop CMR or as a traditional focused MRI.

Is Early Steroid Withdrawal Feasible in Sensitized Elderly Kidney Transplant Recipients?: Abstract# B963

B963 Is Early Steroid Withdrawal Feasible in Sensitized Elderly Kidney Transplant Recipients? K. Sureshkumar,1 B. Chopra,1 N. Thai,2 R. Marcus.1 1Nephrology and Hypertension, Allegheny General Hospital, Pittsburgh, PA; 2Abdominal Transplantation, Allegheny General Hospital, Pittsburgh, PA. Sensitized kidney transplant recipients (KTRs) are considered high immune risk and generally are maintained on steroids by many transplant centers. Older KTRs could be more vulnerable to the adverse consequences of enhanced immunosuppression. We aimed to look at the impact of early steroid withdrawal (ESW) compared to chronic steroid maintenance (CSM) on the outcomes in older KTRs with varying levels of HLA sensitization. Utilizing UNOS database, we identifi ed patients ≥60 years of age who underwent deceased donor kidney (DDK) transplantation from 2000 to 2008 after receiving antibody induction followed by maintenance immunosuppression with calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF) with or without steroids. Patients were divided into three classes based on peak panel reactive antibody (PRA) titers: 0-30%, 31-60% and >60%. Adjusted over all graft and death-censored graft failure risks as well as patient death risks for ESW vs. CSM were assessed for each PRA class using Cox model. There were 10,979 patients included in the study distributed according to PRA class as follows: 0-30%, n= 8924 (ESW = 2341, CSM = 6583); 31-60%, n= 1022 (ESW= 247, CSM = 775); >60%, n= 1033 (ESW = 173, CSM= 860). Graft failure and patient death risks for ESW vs. CSM groups stratifi ed by PRA class are shown in the table. Adjusted overall graft failure risk Adjusted death-censored graft failure risk Adjusted patient death risk PRA class HR 95% CI HR 95% CI HR 95% CI 0-30% 0.78** 0.68-0.88 0.79* 0.69-0.91 0.70** 0.61-0.82 31-60% 0.96 0.68-1.40 0.96 0.65-1.43 0.83 0.55-1.27 >60% 1.35 0.92-1.96 1.40 0.92-2.08 1.32 0.84-2.04 * = p, 0.001; ** = p<0.001 In summary, our analysis showed that steroid can be safely withdrawn early from sensitized DDK transplant recipients ≥60 years old that received induction therapy and were maintained on a CNI/MMF based regimen. In the 0-30% PRA group, enhanced immunosuppression with CSM could be contributing to adverse graft and patient outcomes. In the high PRA groups, ESW did not result in signifi cant adverse graft and patient outcomes suggesting that any risk of immunological graft injury with ESW in these groups is offset by adverse consequences of CSM. Our results favor ESW in older DDK transplant recipients regardless of the level of HLA sensitization. Abstract# B964 Long-Term Outcome of a Prospective Randomized Trial of Conversion From Tacrolimus to Sirolimus Treatment After Renal Transplantation. A. El-Agroudy,1 S. Alarrayed,1 S. Ghareeb,1 E. Farid,2 H. Alhellow,3 S. Abdulla.3 1Nephrology and Transplant Department, Salmaniya Medical Complex, Manama, Bahrain; 2Immunology, Salmaniya Medical Complex, Manama, Bahrain; 3Transplant Surgery, Salmaniya Medical Complex, Manama, Bahrain. Background/Aim: Calcineurin inhibitors improve acute rejection rates and short-term graft survival in renal transplantation, but their continuous use may be deleterious. We report a prospective, open-label, randomized study to evaluate the safety and effi cacy of converting patients with stable renal function from Tacrolimus (Tac) based regimen to a Sirolimus (SRL)-based regimen after kidney transplantation. Methods: Fifty eight renal allograft recipients who were eligible to the study, 6 months posttransplant and receiving tacrolimus, were randomly assigned to continue Tac (n=29) or convert from to SRL (n=29). We evaluated the 3-year outcomes including patient and graft survival, graft function and safety profi le. Results: Over a mean follow-up period of approximately 3 yr, patient survival was 93.1% in the SRL group and 100% in the Tac group (p = 0.04), and graft survival was was 89.7% in the SRL group and 100% in the Tac group (p = 0.04). However, the SRL group had signifi cantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. During the followup, 4 (13.8%) patients in the SRL group and 3 (10.3%) in the Tac group (p = 0.5) developed biopsy proven acute rejection (BPAR). Mean urinary protein excretion was similar at baseline but increased signifi cantly after SRL conversion. Diastolic blood pressure was signifi cantly lower in patients who eliminated tacrolimus (p = 0.03). Mean hemoglobin concentrations decreased after SRL conversion and remained signifi cantly lower from 12 months to 36 months ( p = 0.01). At 36 months, the mean serum cholesterol and triglyceride levels increased signifi cantly in the sirolimus group, and 24% of the patients in the tacrolimus arm were taking lipid-lowering medications, compared to 58% of the patients in the sirolimus arm (p < 0.0001). Conclusions: This study shows that tacrolimus-MMF-prednisone produces better graft and patient survival compared to CNI-free regimen using sirolimus-MMFprednisone. The sirolimus-based regimens were not associated with improved outcomes for kidney transplantation patients. B964 Long-Term Outcome of a Prospective Randomized Trial of Conversion From Tacrolimus to Sirolimus Treatment After Renal Transplantation. A. El-Agroudy,1 S. Alarrayed,1 S. Ghareeb,1 E. Farid,2 H. Alhellow,3 S. Abdulla.3 1Nephrology and Transplant Department, Salmaniya Medical Complex, Manama, Bahrain; 2Immunology, Salmaniya Medical Complex, Manama, Bahrain; 3Transplant Surgery, Salmaniya Medical Complex, Manama, Bahrain. Background/Aim: Calcineurin inhibitors improve acute rejection rates and short-term graft survival in renal transplantation, but their continuous use may be deleterious. We report a prospective, open-label, randomized study to evaluate the safety and effi cacy of converting patients with stable renal function from Tacrolimus (Tac) based regimen to a Sirolimus (SRL)-based regimen after kidney transplantation. Methods: Fifty eight renal allograft recipients who were eligible to the study, 6 months posttransplant and receiving tacrolimus, were randomly assigned to continue Tac (n=29) or convert from to SRL (n=29). We evaluated the 3-year outcomes including patient and graft survival, graft function and safety profi le. Results: Over a mean follow-up period of approximately 3 yr, patient survival was 93.1% in the SRL group and 100% in the Tac group (p = 0.04), and graft survival was was 89.7% in the SRL group and 100% in the Tac group (p = 0.04). However, the SRL group had signifi cantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. During the followup, 4 (13.8%) patients in the SRL group and 3 (10.3%) in the Tac group (p = 0.5) developed biopsy proven acute rejection (BPAR). Mean urinary protein excretion was similar at baseline but increased signifi cantly after SRL conversion. Diastolic blood pressure was signifi cantly lower in patients who eliminated tacrolimus (p = 0.03). Mean hemoglobin concentrations decreased after SRL conversion and remained signifi cantly lower from 12 months to 36 months ( p = 0.01). At 36 months, the mean serum cholesterol and triglyceride levels increased signifi cantly in the sirolimus group, and 24% of the patients in the tacrolimus arm were taking lipid-lowering medications, compared to 58% of the patients in the sirolimus arm (p < 0.0001). Conclusions: This study shows that tacrolimus-MMF-prednisone produces better graft and patient survival compared to CNI-free regimen using sirolimus-MMFprednisone. The sirolimus-based regimens were not associated with improved outcomes for kidney transplantation patients. Abstract# B965 Limited Sampling Strategies for Predicting Tacrolimus Exposure With Once Daily Extended Formulation in Kidney Transplant Recipients and Optimal Pre-Dosing Schedule. S. Narumi,1 Y. Watarai,1 N. Goto,1 T. Hiramutsu,1 M. Tsujita,1 T. Yamamoto,1 A. Takeda,1 K. Morozumi,1 A. Katayama,2 T. Kobayashi,3 K. Uchida.4 1Nagoya Daini Red Cross Hospital, Nagoya, Aichi, Japan; 2Masuko Memorial Hospital, Nagoya, Aichi, Japan; 3Nagoya University Graduate School of Med, Nagoya, Aichi, Japan; 4Aichi Medical School, Nagoya, Aichi, Japan. Pharmacokinetics (PK) and optimal dosing of tacrolimus extended-release formulation (TACER)re not well evaluated. We have validated the use of single and limited sampling strategies to estimate tacrolimus exposure with TACER. Patients and Methods: Thirty-three Living-donor kidney transplant recipients were prospectively involved in PK-study measuring tacrolimus area under curve profi les (TAC-AUC) 0-24 by 9 points sampling following the trapezoidal rule at 1, 2 and 3 weeks after transplant. All recipients received 0.2mg/day of TACER 7 days before transplant, followed by mycophenolate mofetile (MMF), prednisolone and basiliximab after transplant. Targeted trough level of tacrolimus was 8-10ng/ml in the fi rst month, 6-8ng/ml until 3 months and 4-6ng/ml thereafter. MMF was started with 1250mg bid and reduced to 750mg bid at 2 weeks after transplant. 1) Optimal predosing schedule, 2) clinical effi ciency and CNI toxicity evaluated by protocol biopsy at 6 and 12 months after transplant, 3) Correlation between single sampling/limited sampling strategies and measured TAC-AUC 0-24 were evaluated respectively. Results: 1) With a mean observation of 45 months (40-53), patients and graft survival are 100%. 2) Subclinical and clinical T cell mediated rejection were observed in 2(6.1%) and 2(6.1%). 3) CNI toxicity were observed in 7(21.2%) by protocol biopsies and mean eGFR maintained above 50ml/min/1.73m2 at 3 years after transplant. 4) Trough level of tacrolimus did not correlated with AUC0-24 (R=0.79), nor other single sampling data. Limited sampling strategy principles well correlated with AUC 0-24 as shown in Table1. B965 Limited Sampling Strategies for Predicting Tacrolimus Exposu

Is the detection of hepatocellular carcinoma in liver transplantation candidates impaired using a dedicated CMR stress test as a 'one-stop-shop'? a pathological correlation study

Background Precise diagnosis and staging of hepatocellular carcinoma (HCC) is crucial in the selection and timing of orthotopic liver transplantation (OLT) patients, especially cirrhotics. The preoperative workup of OLT patients is logistically cumbersome and expensive given the need for separate cardiac, vascular, and abdominal imaging. We have recently demonstrated the value of a ‘one-stop-shop’ approach combining the attributes of a nuclear stress, echocardiogram and abdominal MRI into one single preop CMR evaluation. However, this approach requires further validation as accurate detection of HCC is critically important. Hypothesis: HCC detectability is independent of whether the study is performed as part of a larger onestop-shop CMR or as a traditional focused MRI. Objective: We evaluated the ‘detectability’ of HCC using cardiac MRI for pre-operative evaluation of OLT candidates in a CMR suite performing assessment of cardiac structure, function and viability, along with simultaneous evaluation of thoracoabdominal vasculature and liver anatomy and compared with histopathology in explanted livers.

Influence of maintenance steroids on the outcomes in deceased-donor kidney transplant recipients exposed to prolonged pretransplantation dialysis.

BACKGROUND Pre-transplant dialysis duration exerts a graded negative influence on outcomes after kidney transplantation. Higher immune reactivity associated with prolonged dialysis with consequent increased acute rejection could be contributory. METHODS Using the Organ Procurement and Transplant Network/United Network of Organ Sharing database, we identified patients ≥ 18 years of age who received deceased-donor kidney (DDK) transplants from 2000 to 2008 after being on maintenance dialysis for ≥ 4 years. Patients received induction therapy with rabbit antithymocyte globulin (r-ATG), alemtuzumab, or an interleukin-2 receptor blocker (IL-2B) and were discharged on calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF)-based immunosuppression with or without steroid. Unadjusted and adjusted graft/patient survivals were compared in steroid versus no-steroid groups by induction type. RESULTS A total of 14,459 patients were identified, of which 7,684 received r-ATG (steroid, 6,098; no-steroid, 1,586), 1,292 alemtuzumab (steroid, 362; no-steroid, 930), and 5,483 an IL-2B agent (steroid, 5,107; no-steroid, 376). Adjusted graft survivals were similar for steroid versus no-steroid groups in r-ATG (hazard ratio [HR] 1.10, 95% confidence interval (CI) 0.96-1.26, P = .16), alemtuzumab (HR 0.88, 95% CI 0.65-1.19; P = .40), and IL-2B (HR 0.91, 95% CI 0.73-1.13; P = .38) groups. Adjusted patient survival for steroid versus no-steroid groups was inferior in r-ATG (HR 1.41, 95% CI 1.17-1.71; P < .001) but similar in alemtuzumab (HR 1.05, 95% CI 0.70-1.59; P = .80) and IL-2B (HR 1.17, 95% CI 0.86-1.58; P = .32) groups. CONCLUSIONS Our analysis failed to show a graft survival benefit for the addition of steroid to a CNI/MMF-based immunosuppression after induction with r-ATG, alemtuzumab, or an IL-2B agent in DDK recipients exposed to prolonged pretransplantation dialysis.