Unexplained fever after pancreas transplantation.

BACKGROUND: Fever occurs frequently early after pancreas transplant, however, the exact cause is often undetermined. Limited data are available on pancreas recipients experiencing unexplained, noninfectious fever. This study aims to characterize unexplained fever (UF) in pancreas recipients and its effect on patient and graft outcomes. METHODS: We performed a retrospective cohort study of UF among consecutive pancreas or simultaneous pancreas-kidney transplant recipients from 1 January 2011 to 31 August 2015. Classification of UF was based on the absence of positive cultures, radiologic findings, and other diagnostic features of infection or rejection. RESULTS: Twenty-three of 92 (25%) patients experienced UF. The UF episode first occurred at a mean of 31 ± 17 days post-transplant and accounted for 34 admissions with an average length of stay of 5.1 ± 3.4 days. Intravenous corticosteroid was administered following confirmation of negative diagnostic tests in 77% of patients, with fever resolution occurring in all. No differences were seen in rates of biopsy-proven rejection, graft loss, death, or documented infections compared to UF-free patients during the first-year post-transplant. CONCLUSION: UF is a common cause for readmission following pancreas transplantation. While the etiology of UF remains difficult to identify, UF occurrence was not associated with adverse outcomes during the first-year post-transplant.

Combined lung and liver transplantation: analysis of a single-center experience.

Patients with end-stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung-liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single-center CLLT series. Eight consecutive CLLT performed during 2009-2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 ± 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n = 3), idiopathic pulmonary fibrosis (n = 2), α1-antitrypsin deficiency (AATD) (n = 1) and pulmonary hypertension (n = 2). Liver indications were CF (n = 3), hepatitis C (n = 2), AATD (n = 1), cryptogenic (n = 1), and cardiac/congestive (n = 1). Urgency was reflected by median lung allocation score (LAS) of 41 (36.0-89.0) and median predicted FEV1 of 25.7%. Median donor age was 25 (20-58) years with median cold ischemia times of 147 minutes and 6.1 hours for lung and liver, respectively. Overall patient survival at 30 days, 90 days and 1 year was 87.5%, 75.0% and 71.4% respectively. One patient had evidence of acute lung rejection, and no patients had liver allograft rejection. Early postoperative mortalities (90 days) were caused by sepsis in 2 recipients who exhibited the highest LAS of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1-year. Median length of stay was 25 days (7-181). Complications requiring operative intervention included bile duct ischemia (n = 1) and bile leak (n = 1), ischemia of the bronchial anastomosis (n = 1), and necrotizing pancreatitis with duodenal perforation (n = 1). This series reflects a large single-center CLLT experience. Sepsis is the most common cause of death. The procedure should be considered for candidates with LAS < 50.

BK virus-associated nephropathy in sirolimus-treated renal transplant patients: incidence, course, and clinical outcomes.

BACKGROUND: Because the course of polyoma virus-associated nephropathy (PVAN) has not been evaluated in a large cohort of patients receiving sirolimus (SRL)-based regimens, we have herein presented the incidence, clinical characteristics, and outcomes of 378 renal transplant recipients treated with SRL-based immunosuppression. METHODS: This retrospective single center study evaluated 344 kidney alone (KTX) and 34 simultaneous pancreas-kidney (SPK) transplantations performed between June 2000 and December 2004. RESULTS: At a mean follow-up of 43.3 months, six kidney (1.7%) and three kidney-pancreas (9.0%) transplanted patients displayed biopsy-proven PVAN. The mean time to diagnosis after transplantation was 18.2 months (range: 3.5-31.1 months), with a higher incidence among patients exposed (4.23%) versus not exposed to rabbit antithymocyte globulin (rATG; 0.53%; P=0.019) or SPK (9.0%) versus KTX (1.7%) recipients (odds ratio: 5.43; confidence interval: 1.29-22.8; P=0.038). Despite treatment with cidofovir, reduced immunosuppression and maintenance therapy with no agents other than SRL (C0=10.2+/-2.7 ng/dL) plus modest doses of prednisone (< or =5 mg), five patients (55.5%) experienced renal allograft failure. No rejection episodes were documented during the PVAN treatment and pancreatic function continued to be excellent among the SPK patients. CONCLUSIONS: Patients treated with SRL-based immunosuppression showed an incidence at the lower end of the range described with various other contemporaneous immunosuppressive regimens and with other cohorts not undergoing BK virus polymerase chain reaction surveillance. Exposure to rATG and SPK transplantation represented risk factors for the occurrence of PVAN, which showed a pernicious course despite withdrawal of calcineurin antagonists and/or mycophenolate mofetil.

Janus kinase 3: a novel target for selective transplant immunosupression.

Existing immunosuppressants inhibit lymphocyte activation and T cell cytokine signal transduction pathways, reducing the rate of acute rejection episodes to < 10%. However, the widespread tissue distribution of their molecular targets engenders pleiotropic toxicities. One strategy to address this problem seeks to identify compounds that selectively inhibit a target restricted in distribution to the lymphoid system. Janus kinase (Jak) 3 is such a molecule; it mediates signal transduction via the gamma common chain of lymphokine surface receptors. Disruption of this lymphoid-restricted enzyme would not be predicted to produce collateral damage in other organ systems. Development of selective Jak3 inhibitors has been difficult due to crossreactivity with its homologue, Jak2. In contrast to all other putative antagonists, which are discussed in detail herein, one Jak3 inhibitor, NC1153, shows at least 40-fold greater selective inhibition for Jak3 than for Jak2, is robustly synergistic with calcineurin antagonists, and, either alone or in combination with cyclosporin, produces no adverse effects in rodents preconditioned to be at heightened risk for nephrotoxicity, bone marrow suppression, or altered lipid metabolism.

The selective use of basiliximab versus thymoglobulin in combination with sirolimus for cadaveric renal transplant recipients at low risk versus high risk for delayed graft function.

BACKGROUND: We previously reported that the use of basiliximab together with sirolimus permits a window of recovery from delayed graft function before the introduction of reduced-dose cyclosporine. The present study reviews our experience with the substitution of thymoglobulin for basiliximab as induction therapy for recipients at increased risk for early acute rejection episodes. METHODS: We retrospectively reviewed 145 cadaveric renal allograft recipients who received either basiliximab (n=115) or thymoglobulin (n=30) in combination with sirolimus and prednisone, followed by delayed introduction of reduced doses of cyclosporine. Recipients were stratified as high immune responders if they were African American, a retransplant recipient, or a recipient with a panel-reactive antibody greater than 50%. All other recipients were considered low immune responders. RESULTS: Basiliximab-treated high immune responders exhibited a higher incidence of acute rejection episodes (26%) than either basiliximab-treated low immune responders (10%, P=0.04) or thymoglobulin-treated high immune responders (3%, P=0.01). The median time to initiation of cyclosporine was 12 days; cyclosporine was initiated when the serum creatinine level was 2.5 mg/dL or less. Patients with early return of renal function displayed a lower incidence of acute rejection episodes than those with later recovery of function (P=0.003). High immune responders treated with basiliximab expressed a higher mean serum creatinine level at 3 months (P<0.01), 6 months (P=0.02) and 12 months (P=0.01) than either low immune responders treated with basiliximab or high immune responders treated with thymoglobulin. CONCLUSION: A strategy combining sirolimus with basiliximab for low-immunologic risk recipients and thymoglobulin for high-risk recipients leads to prompt recovery of renal function with a low risk of acute rejection episodes.

Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations.

This study correlated the dynamic effects of sirolimus (rapamycin; RAPA) and cyclosporine (CsA) alone versus in combination to produce renal dysfunction, myelosuppression, or hyperlipidemia, with their corresponding blood and tissue concentrations. After salt-depleted rats were treated with RAPA (0.4 to 6.4 mg/kg per d) and/or CsA (2.5 to 20.0 mg/kg per d) for 14 d, the GFR, lipid levels, bone marrow cellularity, and CsA/RAPA concentrations in whole blood versus liver or renal tissues were measured, and the median effect model was used to discern the type of drug interactions. Compared with vehicle controls (1.98 +/- 0.34 ml/min), GFR values were reduced only by large doses of drug monotherapy, namely RAPA (3.2 mg/kg per d = 1.2 +/- 0.02 ml/min or 6.4 mg/kg per d = 1.3 +/- 0.2 ml/min; both P < 0.01) or CsA (10.0 mg/kg per d = 1.2 +/- 0.1 ml/min or 20.0 mg/kg per d = 0.8 +/- 0.4 ml/min; both P < 0.01). In contrast, hosts that were treated with smaller doses of CsA/RAPA combinations showed more pronounced effects in reduction of GFR values: 2.5/0.4 mg/kg per d, modestly (1.5 +/- 0.5 ml/min; P < 0.01); 5.0/0.8 mg/kg per d, moderately (0.23 +/- 0.01 ml/min; P < 0.001); and higher-dose groups, markedly. The exacerbation of renal dysfunction seemed to be due to a pharmacokinetic interaction of RAPA to greatly increase CsA concentrations in whole blood and, particularly, in kidney tissue. In contrast, the pharmacodynamic effects of CsA to potentiate two RAPA-mediated toxicities-myelosuppression and increased serum cholesterol/low-density lipoprotein cholesterol-occurred independently of pharmacokinetic interactions. RAPA aggravates CsA-induced renal dysfunction owing to a pharmacokinetic interaction, whereas CsA produces a pharmacodynamic effect that augments RAPA-induced myelosuppression and hyperlipidemia.