Granulocyte colony-stimulating factor with or without immunosuppression reduction in neutropenic kidney transplant recipients.

INTRODUCTION: Neutropenia post-kidney transplantation is associated with adverse graft and patient outcomes. We aimed to analyze the effect of granulocyte colony-stimulating factor (G-CSF) use with and without immunosuppression reduction on graft outcomes in neutropenic recipients. METHODS: In this retrospective cohort study, we identified 120 recipients with neutropenia, within the first-year post-transplant. RESULTS: Of these, 45.0% underwent no intervention, 17.5% had immunosuppression reduced, 18.3% were only given G-CSF, and 19.2% had both interventions. Overall, 61 patients experienced the composite outcome of de-novo DSA, biopsy-proven acute rejection, and all-cause graft failure and the cumulative incidence of this outcome did not vary by any of the four interventions (p = .93). When stratifying the cohort by G-CSF use alone, those who received G-CSF were more likely to have had severe neutropenia (<500/mm3 : 51.1% vs. 12.0%, p < .001), and immunosuppression reduction (51.1% vs. 28.0%, p = .003). However, the composite outcome was not different in the G-CSF and no G-CSF cohort (53.3% vs. 49.3%, p = .67), and in a multivariate model, G-CSF use was not associated with this outcome (aHR = 1.18, 95% CI: .61-2.30). However, a trend towards higher DSA production was noted in the G-CSF cohort (87.5% vs. 62.2%) and this observation warrants prospective evaluation. CONCLUSION: Overall, we conclude that G-CSF use with or without immunosuppression reduction was not associated with graft outcomes.

Evolving Trends in Risk Profiles and Outcomes in Older Adults Undergoing Kidney Retransplantation.

BACKGROUND: In older adults (≥65), access to and outcomes following kidney transplantation (KT) have improved over the past 3 decades. It is unknown if there were parallel trends in re-KT. We characterized the trends, changing landscape, and outcomes of re-KT in older adults. METHODS: Among the 44,149 older kidney-only recipients (1995-2016) in the Scientific Registry of Transplant Recipients, we identified 1743 who underwent re-KT. We analyzed trends and outcomes (mortality, death-censored graft failure [DCGF]) by eras (1995-2002, 2003-2014, and 2015-2016) that were defined by changes to the expanded criteria donors and Kidney Donor Profile Index policies. RESULTS: Among all older kidney-only recipients during 1995-2002, 2003-2014, 2015-2016 the proportion that were re-KTs increased from 2.7% to 4.2% to 5.7%, P < 0.001, respectively. Median age at re-KT (67-68-68, P = 0.04), years on dialysis after graft failure (1.4-1.5-2.2, P = 0.003), donor age (40.0-43.0-43.5, P = 0.04), proportion with panel reactive antibody 80-100 (22.0%-32.7%-48.7%, P < 0.001), and donation after circulatory death (1.1%-13.4%-19.5%, P < 0.001) have increased. Despite this, the 3-y cumulative incidence for mortality (22.3%-19.1%-11.5%, P = 0.002) and DCGF (13.3%-10.0%-5.1%, P = 0.01) decreased over time. Compared with deceased donor retransplant recipients during 1995-2002, those during 2003-2014 and 2015-2016 had lower mortality hazard (aHR = 0.78, 95% confidence interval, 0.63-0.86 and aHR = 0.55, 95% confidence interval, 0.35-0.86, respectively). These declines were noted but not significant for DCGF and in living donor re-KTs. CONCLUSIONS: In older retransplant recipients, outcomes have improved significantly over time despite higher risk profiles; yet they represent a fraction of the KTs performed. Our results support increasing access to re-KT in older adults; however, approaches to guide the selection and management in those with graft failure need to be explored.

Relative decrease in hemoglobin and outcomes in patients undergoing kidney transplantation surgery: A retrospective cohort study.

BACKGROUND: Recent surgical literature suggests that a relative decrease in hemoglobin (ΔHb) is predictive of adverse outcomes regardless of the absolute level. We aimed to examine the association between perioperative ΔHb and kidney transplantation (KT) outcomes. METHODS: This was a retrospective cohort study of transplant recipients, where ΔHb = [Hb0- Hb1Hb0]x 100 (Hb0 = hemoglobin pre-KT and Hb1 = lowest hemoglobin 24-h post-KT). The main outcome of interest was immediate graft function (IGF). RESULTS: Of the 899 eligible patients, 38% experienced IGF, and ΔHb was associated with 36% lower odds of IGF. Also, ΔHb was associated with higher all-cause graft failure and longer length of stay but not death-censored graft failure or mortality. ΔHb ≥30% was the threshold beyond which the odds of IGF were significantly lower even if Hb1 was ≥7 g/dL. CONCLUSION: ΔHb is associated with inferior outcomes independent of Hb1; whether it can be used to guide transfusion practices should be explored.

Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts.

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

Pretransplant Recipient Circulating CD4+CD127lo/- Tumor Necrosis Factor Receptor 2+ Regulatory T Cells: A Surrogate of Regulatory T Cell-Suppressive Function and Predictor of Delayed and Slow Graft Function After Kidney Transplantation.

BACKGROUND: Delayed graft function (DGF) and slow graft function (SGF) are ischemia-reperfusion-associated acute kidney injuries (AKI) that decrease long-term graft survival after kidney transplantation. Regulatory T (Treg) cells are protective in murine AKI, and their suppressive function predictive of AKI in kidney transplantation. The conventional Treg cell function coculture assay is however time-consuming and labor intensive. We sought a simpler alternative to measure Treg cell function and predict AKI. METHODS: In this prospective observational cohort study, pretransplant recipient circulating CD4+CD25+CD127lo/- and CD4+CD127lo/- tumor necrosis factor receptor 2 (TNFR2)+ Treg cells were measured by flow cytometry in 76 deceased donor kidney transplant recipients (DGF, n = 18; SGF, n = 34; immediate graft function [IGF], n = 24). In a subset of 37 recipients, pretransplant circulating Treg cell-suppressive function was also quantified by measuring the suppression of autologous effector T-cell proliferation by Treg cell in coculture. RESULTS: The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P < 0.01). In receiver operating characteristic curves, percentage and absolute number of CD4+CD127lo/-TNFR2+ Treg cell predicted DGF from non-DGF (IGF + SGF) with area under the curves of 0.75 and 0.77, respectively, and also AKI (DGF + SGF) from IGF with area under the curves of 0.76 and 0.72, respectively (P < 0.01). Prediction of AKI (DGF + SGF) from IGF remained significant in multivariate logistic regression accounting for cold ischemic time, donor age, previous transplant, and pretransplant dialysis modality. CONCLUSIONS: Pretransplant recipient circulating CD4+CD127lo/-TNFR2+ Treg cell is potentially a simpler alternative to Treg cell function as a pretransplant recipient immune marker for AKI (DGF + SGF), independent from donor and organ procurement characteristics.

Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial.

IMPORTANCE: BK virus infection is a significant complication of modern immunosuppression used in kidney transplantation. Viral reactivation occurs first in the urine (BK viruria) and is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies. OBJECTIVE: To determine if levofloxacin can prevent BK viruria in kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled randomized trial involving 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers between December 2011 and June 2013. INTERVENTIONS: Participants were randomly assigned to receive a 3-month course of levofloxacin (500 mg/d; n = 76) or placebo (n = 78) starting within 5 days after transplantation. MAIN OUTCOMES AND MEASURES: The primary outcome was time to occurrence of BK viruria (detected using quantitative real-time polymerase chain reaction) within the first year after transplantation. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival. RESULTS: The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51-1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76-49.95). CONCLUSIONS AND RELEVANCE: Among kidney transplant recipients, a 3-month course of levofloxacin initiated early following transplantation did not prevent BK viruria. Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance. These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01353339.

Quinolone prophylaxis for the prevention of BK virus infection in kidney transplantation: study protocol for a randomized controlled trial.

BACKGROUND: BK virus infection has emerged as a major complication in kidney transplantation leading to a significant reduction in graft survival. There are currently no proven strategies to prevent or treat BK virus infection. Quinolone antibiotics, such as levofloxacin, have demonstrated activity against BK virus. We hypothesize that administration of a quinolone antibiotic, when given early post-transplantation, will prevent the establishment of BK viral replication in the urine and thus prevent systemic BK virus infection. METHODS/DESIGN: The aim of this pilot trial is to assess the efficacy, safety and feasibility of a 3-month course of levofloxacin in the kidney transplant population. This is a multicenter, randomized, double-blind, placebo-controlled trial with two parallel arms conducted in 11 Canadian kidney transplant centers. A total of 154 patients with end-stage renal disease undergoing kidney transplantation will be randomized to receive a 3-month course of levofloxacin or placebo starting in the early post-transplant period. Levofloxacin will be administered at 500 mg po daily with dose adjustments based on kidney function. The primary outcome will be the time to occurrence of BK viruria within the first year post-transplantation. Secondary outcomes include BK viremia, measures of safety (adverse events, resistant infections,Clostridium difficile-associated diarrhea), measures of feasibility (proportion of transplanted patients recruited into the trial), proportion of patients adherent to the protocol, patient drop-out and loss to follow-up,and use of quinolone antibiotics outside of the trial protocol. DISCUSSION: Results from this pilot study will provide vital information to design and conduct a large, multicenter trial to determine if quinolone therapy decreases clinically meaningful outcomes in kidney transplantation. If levofloxacin significantly reduces BK viruria and urine viral loads in kidney transplantation, it will provide important justification to progress to the larger trial. If the full trial shows that levofloxacin significantly reduces BK infection and improves outcomes, its use in kidney transplantation will be strongly endorsed given the lack of proven therapies for this condition. TRIAL REGISTRATION: This trial was funded by the Canadian Institutes of Health Research (grant number:222493) and is registered at ClinicalTrials.gov (NCT01353339).

Simultaneous liver and kidney transplants: optimizing use of this double resource.

Simultaneous liver and kidney transplantation is a life saving procedure for patients with combined liver and kidney failure; however, it remains controversial because of the need to balance individual patient need versus resource allocation. As waiting lists for transplantation become longer and patients become increasingly ill, there will be greater numbers of patients referred for liver and kidney transplantation. Acute kidney injury even requiring dialysis may potentially be reversible making combined transplant decisions difficult. Similarly, selected compensated cirrhotic patients with renal failure may be managed with renal transplant alone. Shared multicenter experience or clinical trials or both will be required to refine our ability to optimally manage these patients with combined liver and kidney dysfunction.

Association of preoperative parameters with postoperative mortality and long-term survival after liver transplantation.

BACKGROUND: The ability of Child-Turcotte-Pugh (CTP) or Model for End-Stage Liver Disease (MELD) scores to predict recipient survival after liver transplantation is controversial. This analysis aims to identify preoperative parameters that might be associated with early postoperative mortality and long-term survival after liver transplantation. METHODS: We studied a total of 15 parameters, using both univariate and multivariate models, among adults who underwent primary liver transplantation. RESULTS: A total of 458 primary adult liver transplants were performed. Fifty-seven (12.44%) patients died during the first 3 postoperative months and composed the early mortality group. The remaining 401 patients composed the long-term patient survival group. The parameters that were identified through univariate analysis to be associated with early postoperative mortality were CTP score, MELD score, bilirubin, creatinine, international normalized ratio and warm ischemia time (WIT). In all multivariate models, WIT retained its statistical significance. The 10-year long-term survival was 65%. The parameters that were identified to be independent predictors of long-term survival were the recipient's sex (improved survival in women, p = 0.005), diagnosis of hepatocellular cancer (p=0.015) and recipient's age (p=0.024). CONCLUSION: Either CTP or MELD score, in conjunction with WIT, might have a role in predicting early postoperative mortality after liver transplantation, whereas the recipient's sex and the absence of hepatocellular cancer are associated with improved long-term survival.

Reduction of cyclosporine following the introduction of everolimus in maintenance heart transplant recipients: a pilot study.

Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C(0) 5-10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C(0) and C(2), respectively. Mean cGFR was 68.9 +/- 14.5 ml/min at baseline and 61.6 +/- 11.5 ml/min at week 48 (P = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease

Long-term immunosuppression with anti-CD25 monoclonal antibodies in heart transplant patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD), a frequent and serious complication after heart transplantation, is associated with increased mortality. Current strategies include dose reduction or conversion from calcineurin inhibitors (CNIs) to either mycophenolate mofetil and/or rapamycin, with variable results and side-effect profiles. METHODS: We evaluated the effectiveness of long-term anti-CD25 monoclonal antibody (MAb)-based immunosuppression in 17 adult heart transplant recipients with CKD at 10 +/- 5 years post-transplant. Seven patients had previously been switched to rapamycin but had untreatable side-effects and 10 patients were still on a CNI. The latter were matched with 10 control heart transplant patients whose renal function had remained stable over a similar post-transplant follow-up period, on CNI. RESULTS: Anti-CD25 MAb were given over 13 +/- 10 months and were well tolerated with CD25 saturation monitoring (target <2% expression). Side-effects secondary to rapamycin resolved in 6 patients. The slope change of the creatinine clearance improved in patients in whom CNIs were discontinued (+0.335 ml/min/month vs -0.124 ml/min/month in controls, p = 0.03). Four patients died. Three died after 2, 6 and 7 months of follow-up, respectively, with the following diagnoses: acute renal failure (the patient refused dialysis); acute rejection (the patient had refused protocol endomyocardial biopsy); and perforated diverticulitis. The fourth patient died of pneumonia, 3 months after conversion from anti-CD25 MAb to rapamycin, because of poor venous access. CONCLUSIONS: The use of long-term anti-CD25 MAb therapy as a potential replacement for CNI- and rapamycin-based immunosuppression is feasible. It is crucial that rejection surveillance be intensified. A randomized, controlled trial is required to confirm the benefits and safety of this strategy.

Management of chronic allograft nephropathy: a systematic review.

Despite improving immunosuppressive protocols in renal transplantation, chronic allograft nephropathy (CAN) remains a major impediment to long-term graft survival. The optimal immunosuppressive regimen for a patient with CAN is unknown. The aim of this study is to evaluate the various immunosuppressive management strategies of biopsy-proven CAN and of chronic allograft dysfunction (CAD) (no biopsy). A systematic review of randomized trials (n = 12 trials with 635 patients) was conducted. Studies included patients who were >6 mo post-transplant. All patients were on a calcineurin inhibitor (CNI), most often cyclosporine, and were randomized to convert to mycophenolate mofetil (MMF), tacrolimus, or sirolimus (Rapa) or to add azathioprine, MMF or Rapa to their current regimen. Follow-up time was 6 to 36 mo. The outcome measures evaluated were renal function in 11 of 12 studies and repeat renal biopsy results in one study. The methodological quality scores of the trials were generally low, using the Jadad scale (median value 2/5). Results varied between studies but suggested that CNI withdrawal is safe and that conversion to MMF or Rapa may be beneficial. The incidence of adverse effects ranged from 0% to 68% between the studies, and medication withdrawal occurred in 0% to 24% of patients. The review did not result in a consensus regarding the management of CAN and CAD. Further studies are required to determine the best therapeutic option for patients with CAD and CAN.

20-year follow-up results of a randomized controlled trial comparing antilymphocyte globulin induction to no induction in renal transplant patients.

BACKGROUND: The purpose of this study was to determine the impact of antilymphocyte globulin (ALG)-induction on long-term outcomes of postrenal transplantation. METHODS: Between January 1985 and January 1986, 123 consecutive renal transplants from deceased donors were performed at a single institution. Patients were randomized into two groups: group 1 (n=63, 40+/-10 year) received cyclosporine (CsA), prednisone, and azathioprine; and group 2 (n=60, 36+/-9 year) received ALG-induction, CsA, and prednisone and delayed initiation (45-90 days posttransplantation) of azathioprine if the CsA dose was less than 4 mg/kg per day. Target CsA trough levels were 150 to 250 ng/mL. Cytomegalovirus prophylaxis was not used. Human leukocyte antigen matching (2.4+/-1.1 vs. 2.6+/-1.2) and cold ischemia time (38+/-8 hr vs. 39+/-9 hr) did not differ. RESULTS: The incidence of acute rejection was lower in group 2 (28% vs. 75%, P<0.0001). The incidence of cytomegalovirus infection was 10% in group 1 and 18% in group 2 (P=0.41). The incidence of cancer was 22.2% in group 1 and 11.7% in group 2 (P=0.53) and the incidence of lymphoma did not differ (3% vs. 5%, P=0.77). Patient and graft survival in groups 1 and 2 at 1, 10, and 20 years were 100%/79% vs. 100%/93%, 83%/56% vs. 88%/51%, and 64%/43% vs. 54%/47%, respectively (log-rank test, P=0.18 and P=0.078). CONCLUSION: The use of ALG-induction resulted in a lower incidence of acute rejection and improved graft survival during the first year postrenal transplantation. Patient and graft survival at 20-year follow-up was not affected by ALG-induction.

Best single time points to predict the area-under-the-curve in long-term heart transplant patients taking mycophenolate mofetil in combination with cyclosporine or tacrolimus.

BACKGROUND: The use of C2 levels for therapeutic drug monitoring (TDM) of cyclosporine microemulsion (CsA) has been clinically validated. Routine TDM of tacrolimus and mycophenolate mofetil (MMF) is based on trough (C0) levels and side effects, respectively. The purpose of the present study was to determine the best single time points to assess the area-under-the-curve (AUC(0-12 hours)) in long-term heart transplant patients being treated with MMF in combination with CsA or tacrolimus. METHODS: We studied the AUC(0-12 hours) in long-term (>1 year), adult heart transplant patients being treated with CsA and MMF (14 patients) and with tacrolimus and MMF (9 patients). RESULTS: C2 is the best surrogate (r2 = 0.87) of CsA AUC(0-12 hours). Tacrolimus C1 (r2 = 0.78), C2 (r2 = 0.83), C3 (r2 = 0.89) and C4 (r2 = 0.92) correlate better than C0 (r2 = 0.51) with the AUC(0-12 hours). When MMF is combined with CsA, there is poor correlation (r2) of MPA at all measured time points (C0 = 0.49, C2 = 0.09, C3 = 0.23, C4 = 0.44, and C6 = 0.60). When MMF is combined with tacrolimus, MPA C2 (r2 = 0.72), C4 (r2 = 0.86), C6 (r2 = 0.85), and C8 (r2 = 0.93) are better surrogates of the AUC(0-12 hours) compared with C0 (r2 = 0.69). CONCLUSION: Our results suggest that in long-term heart transplant patients, the calcineurin inhibitor used in combination with MMF affects the correlation between MPA single time points and the AUC(0-12 hours). Future studies should determine the clinical benefit of TDM of tacrolimus and MPA with C2 or C4 compared with C0 and determine the therapeutic ranges. As for CsA-treated patients, CsA TDM should be performed with C2, and the TDM of MMF may be clinically irrelevant.

Tricuspid regurgitation after cardiac transplantation: how many biopsies are too many?

BACKGROUND: Tricuspid regurgitation (TR) is common in patients after orthotopic cardiac transplantation (OHT). Endomyocardial biopsy (EMB) used to monitor for rejection may be a cause of TR. The purpose of this study was to identify a correlation between the severity of TR and the number of EMBs. METHODS: We studied 101 patients with OHT at our institution between May 1987 and August 2001. The number of EMBs performed in each patient was determined. Data on technique of anastomosis, liver and renal function, ejection fraction, and pulmonary artery pressure were also extracted. Echocardiography reports were reviewed to determine the presence and severity of TR. Symptoms of right heart failure were assessed by the amount of diuretic intake. RESULTS: Twenty-five (25%) of 101 patients had evidence of severe TR, whereas 76 (75%) had non-severe TR. Multivariate analysis identified EMB as the only independent predictor of the severity of TR (p < 0.0001). At last follow-up, 60% of patients with more than 31 EMBs had developed severe TR, whereas none of the patients with less than 18 EMBs had severe TR. Of the 25 patients who had severe TR, 15 (61%) needed high doses of daily diuretics, and 4 (16%) required tricuspid valve replacement. CONCLUSIONS: The development of TR after OHT is in large part due to EMBs used to monitor for rejection. There is a direct correlation between the number of EMBs and the severity of TR. We suggest a cutoff of less than 31 EMBs to reduce the risk of severe TR.

Early experience with two-dose daclizumab in the prevention of acute rejection in cardiac transplantation.

BACKGROUND: Daclizumab is a human monoclonal antibody that binds to the interleukin-2 receptor. It has been used as induction therapy in heart transplantation with repeated administrations over several weeks. At our institution, we use a two-dose regimen of daclizumab based on its extended half-life. We sought to determine the incidence of acute rejection with 2-dose daclizumab in cardiac transplantation. METHODS: Eighteen consecutive heart transplants performed at a single center were analyzed retrospectively. Patients received daclizumab (2 mg/kg) within 8 h of cardiac transplantation and a second dose (1 mg/kg) 2 wk thereafter. Maintenance immunosupression included mycophenolate mofetil, prednisone and either cyclosporine or tacrolimus, based on side-effect profile. The endpoint was the incidence of acute rejection as defined by a histologic grade >2 according to the classification of the International Society of Heart and Lung Transplantation. RESULTS: Four patients had acute rejections (all were 3A) during the first 3 months post-transplantation. All four patients had rejection at the first biopsy and only two had rejection thereafter. None of the rejections were hemodynamically significant and no patients were hospitalized. All except one rejection was seen in the context of low 2-h cyclosporine levels. The two-dose regimen was easier to administer on an outpatient basis and resulted in lower cost. CONCLUSIONS: This preliminary report suggests that induction therapy with a two-dose regimen of daclizumab appears to be safe and well tolerated in patients undergoing cardiac transplantation.

Relationship between endomyocardial biopsy score and cyclosporine 2-h post-dose levels (C) in heart transplant patients receiving anti-thymocyte globulin induction.

BACKGROUND: Cyclosporine (CsA) 2-h post-dose levels (C(2)) correlate better with the area-under-the-curve compared with trough levels. The purpose of this study was to determine the relationship between C(2) and endomyocardial biopsy (EMB) score in heart transplant patients receiving anti-thymocyte globulin (ATG)-induction. METHODS: We reviewed 517 EMB performed during the first year in 39 adult heart transplant patients receiving ATG-induction, corticosteroids, mycophenolate mofetil and CsA. C(2) obtained on the day of EMB was related to the International Society for Heart and Lung Transplantation classification (score /=3A). Furthermore, EMB were related to C(2) (ng/mL), sorted according to the lower recommended range in liver (0-3 months: 850; 4-6 months: 700; 7-12 months: 500) or renal transplantation (0-1 month: 1500; 2-3 months: 1200; 4-6 months: 1000; 7-12 months: 800). RESULTS: Overall, C(2) did not significantly differ in patients with EMB /=3A. However, during the first month, EMB /=3A (750 ng/mL vs. 530 ng/mL). When C(2) were sorted according to the lower recommended range in liver or renal transplantation, no significant difference was observed when EMB was /=3A. CONCLUSIONS: In heart transplant patients receiving ATG-induction, C(2) did not significantly differ according to EMB /=3A. No significant relationship was found between EMB score and C(2) based on the lower recommended range in liver or renal transplantation. However, mean C(2) >750 ng/mL appears to be associated with a lower rejection score during the first month.

Veno-atrial bypass for the operative treatment of septic gas gangrene secondary to delayed hepatic artery thrombosis.

The occurrence of late hepatic artery thrombosis after orthotopic liver transplantation can result in gas gangrene of the graft. This clinical scenario has the potential to be rapidly fatal as a result of fulminant hepatic failure, sepsis and multiple-organ-failure syndrome. Emergency operative intervention is indicated to remove the septic source and replace the failed liver. In this report, both cases demonstrated rapid deterioration within 24 h from the onset of symptoms, in spite of maximum supportive care. Intra-operative handling of the gangrenous graft resulted in hemodynamic instability and a technically unfeasible hepatectomy. The use of extra-corporeal veno-atrial bypass, by isolating the septic source, allowed for graft hepatectomy and successful re-transplantation in the second of these reported cases.