Stable Immunosuppression Research Articles

Lenabasum for Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis

Spiera et al. report promising results of a small multicenter, double-blind, randomized, placebo-controlled, phase II study of lenabasum, a cannabinoid type 2 (CB2) receptor agonist, for the treatment of skin disease in patients with early diffuse cutaneous systemic sclerosis (dcSSc) on stable background immunosuppression. This study is important because it examines the effects of cannabinoid (CB) modulation in SSc, a hitherto unexplored pathway, it uses the American College of Rheumatology (ACR) Combined Response Index in Systemic Sclerosis (CRISS) index as an outcome in a 12-week as opposed to its intended use in 12-month clinical trials, and it redemonstrates the utility of obtaining skin biopsies to assess secondary outcomes in SSc clinical trials.

Self-risk assessment for patients with rheumatic disease during the COVID-19 pandemic.

Self-risk assessment for patients with rheumatic disease during the COVID-19 pandemic.

Early reduction of regulatory T cells is associated with acute rejection in liver transplantation under tacrolimus-based immunosuppression with basiliximab induction.

Regulatory T (Treg) cells are important in preventing acute rejection (AR) in solid organ transplantation, but the clinical relevance of the different kinetics early after liver transplantation (LT) in acute rejectors and non-rejectors is unclear. We analyzed peripheral blood samples of 128 LT recipients receiving basiliximab induction plus tacrolimus immunosuppression. Samples were obtained at pretransplant, D7, and D30 after LT. Frequency and phenotype of Tregs were analyzed by flow cytometry. The predictive value of Treg frequency at D7 was assessed for suspected acute rejection (SAR) and was validated for biopsy-proven AR (BPAR). We found that the frequencies of total and activated Tregs at D7 were significantly lower in recipients with SAR and BPAR. Treg was more reduced in BPARs by in vitro tacrolimus treatment in the presence of basiliximab. Moreover, an early reduction of Treg frequency in rejectors was associated with a greater increase in Treg apoptosis and further attenuated IL-2 signaling. D7 Treg frequency was an independent risk factor for SAR, which was also validated for BPAR. In conclusion, first-week peripheral blood Treg frequency correlates with AR after LT under tacrolimus-based immunosuppression, which needs to be proven in larger, geographically and clinically diverse populations.

Prevalence and Impact of De Novo Donor-Specific Antibodies During a Multicenter Immunosuppression Withdrawal Trial in Adult Liver Transplant Recipients.

The development of human leukocyte antigen (HLA) donor-specific antibody/antibodies (DSA) is not well described in liver transplant (LT) patients undergoing immunosuppression (IS) withdrawal protocols despite the allograft risk associated with de novo DSA (dnDSA). We analyzed the development of dnDSA in 69 LT patients who received calcineurin inhibitor monotherapy and were enrolled in the ITN030ST study. Of these 69 patients, 40 stable patients were randomized to IS maintenance (n = 9) or IS minimization (n = 31). Nine of the 31 IS minimization patients achieved complete withdrawal and were free of IS. Among patients who achieved stable IS monotherapy 1 year after transplantation, the prevalence of dnDSA was 18.8%. Acute rejections and the biopsy-proven findings disqualifying patients from IS withdrawal attempt were factors associated with dnDSA development (P = 0.011 and P = 0.041, respectively). Among randomized patients, dnDSA prevalence was 51.7% after IS minimization and 66.7% in IS-free patients. dnDSA prevalence in patients on IS maintenance was 44.4%. dnDSA development during IS minimization was a risk factor for acute rejection (P = 0.015). The majority of dnDSA were against HLA-DQ antigens (78.7%). Conclusion. During the first year following transplantation, acute rejections increase the risk of developing dnDSA, so dnDSA positivity should be considered for IS withdrawal eligibility; during IS minimization, dnDSA development was associated with acute rejection, which prevented further IS withdrawal attempts.

Outcomes of immunosuppression minimization and withdrawal early after liver transplantation.

The Immune Tolerance Network ITN030ST A-WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n=77) or maintenance (n=18) 1- to 2-years posttransplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; ≤Stage 2 Ishak fibrosis; and absence of rejection on biopsy. Immunosuppression withdrawal followed an 8-step reduction algorithm with ≥8weeks per level. Fifty-two of 77 subjects (67.5%) reduced to ≤50% of baseline dose, and 10 of 77 (13.0%) discontinued all immunosuppression for ≥1year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite end point (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage ≥3; or >25% decrease in glomerular filtration rate within 24months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite end point comparison was inconclusive for noninferiority of the withdrawal to the maintenance group.

Early Enrichment and Restitution of the Peripheral Blood Treg Pool is Associated with Rejection-Free Stable Immunosuppression After Liver Transplantation

Early Enrichment and Restitution of the Peripheral Blood Treg Pool is Associated with Rejection-Free Stable Immunosuppression After Liver Transplantation

Case of Chylous Ascites: A Diagnostic Dilemma

We present a case of an 83 year-old male who is status post orthotopic liver transplant in November 2005 for alcoholic cirrhosis, presenting to Henry Ford Hospital with increasing abdominal girth. His symptoms began 2 months prior to presentation following cardiac pacemaker placement for heart block. He was hospitalized shortly after his procedure for shortness of breath and was found to have a pericardial effusion, which was thought to be inflammatory in nature and resolved with steroids. He had been following in the transplant clinic on a regular basis without issues, and was maintained on a stable immunosuppression regimen of mycophenolate and Sirolimus for several years. As part of the work up for his new-onset ascites, a paracentesis was performed. Fluid analysis demonstrated 702 WBCs with 77% lymphocytes, serum-albumin ascites gradient (SAAG) < 1.1 g/dL, total protein < 2.5 g/dL and triglycerides of 2360 mg/dL; consistent with chylous ascites. Lipase and amylase levels were within normal limits. Fungal cultures, acid-fast bacilli stains and cytology were all negative. Echocardiogram showed normal right-sided pressures with preserved ejection fraction and stable pericardial effusion. CT abdomen was unremarkable with no evidence of cirrhosis or portal hypertension. Lymphoscintigraphy study was unremarkable. Liver biopsy was performed without evidence of cirrhosis or rejection. Cardiology was consulted to determine whether the ascites was secondary to venous/lymphatic obstruction as a complication of pacemaker placement or heart failure; this was felt unlikely given preserved cardiac function and normal positioning of pacemaker leads on x-ray. Ultimately, Sirolimus was felt to be the culprit of his chylous ascites. Sirolimus was subsequently discontinued and cyclosporine was initiated with resolution of his ascites. Chylous ascites is a rare finding. It most commonly occurs in the setting of malignancy, lymphatic/vascular obstruction or cirrhosis. Less common etiologies include mycobacterial infection, congenital, inflammatory, post-operative, traumatic and medications such as calcium channel blockers and Sirolimus. Few cases of chylous ascites secondary to Sirolimus have been reported, particularly in renal transplant patients. There are no reported cases of Sirolimus-induced chylous ascites in liver transplant patients. The diagnosis is established by abdominal paracentesis, with fluid studies demonstrating a triglyceride level >200 mg/dL. SAAG and protein levels may vary. Acid-fast bacilli stain and ADA should be performed as well to rule out tuberculous ascites in those at high risk, along with amylase, lipase and standard fluid studies. Abdominal CT should be obtained to rule out pathologic lymph nodes and masses, and lymphoscintigraphy or lymphangiography can aid in detecting leakage from lymphatics and patency of the thoracic duct. Failure to identify a clear etiology following this workup should prompt an investigation into drug etiologies. Treatment is aimed at correction of the underlying etiology (or withholding the offending agent) along with therapeutic paracenteses as needed. A high protein and low fat diet with medium chain triglycerides is recommended. Occasionally, surgery may be performed for obstructive etiologies such as malignancy. Transjugular intrahepatic shunts may be performed for cirrhotic patients. There is also limited evidence for the use of orlistat, somatostatin and octreotride in the mitigation of chylous ascites.

Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission

ObjectiveTo evaluate the prevalence, duration and effect on damage accrual of the ‘Lupus Low Disease Activity State’ (LLDAS) in a monocentric cohort of patients with systemic lupus erythematosus (SLE).MethodsWe studied...

Abstract P046: Cardiometabolic Risk Liver Transplant Survivors

Background: Coronary heart disease (CHD) is an important cause of long-term mortality in liver transplant recipients (LTR). LTR are at increased risk for CHD-related mortality due to exposure to chronic immunosuppression contributing to cardiometabolic risk. Physical activity (PA) and nutrition are important lifestyle management tools used in clinical practice to reduce CHD risk, however, little is known about the long-term effects of these strategies in LTR. Objective: The aim of this study was to evaluate PA and diet and correlate findings with the atherogenic lipoprofile, obesity and 10-year risk of CHD. Methods: LTR (≥ 2 years post LT; stable immunosuppression) without documented CHD, diabetes, graft cirrhosis, physical limitations, and malignancy were included. PA was quantitated via International Physical Activity Questionnaire (IPAQ). Anthropometric assessment was used to obtain body mass index (BMI) and waist hip ratio (WHR). NMR Lipoprofile was used to obtain athrogenic lipoprotein concentration and size followed by generic lipid profile. Food preferences were evaluated via Olbrisch Eating Style Questionnaire and Diet History Questionnaire. CHD risk was assessed by Framingham Risk Score (FRS). Results: Of 122 subjects screened, 27 met entry criteria. Most were overweight (N=11) or obese (N=8) with mean BMI 28.5 kg/m 2 ( SD =4.05; range=20.2-37.8) and mean WHR= 0.94 (SD=0.22; range=0.65-1.85). According to IPAQ, 20 patients (75%) were sedentary. Eating style and food preference choices suggested that 23 (85.2%) were unable to control portion sizes and 14 (51.9%) preferred sugar, fat, or starches in their diet. Fasting glucose was 98.8mg/dL ( SD =14.2, range=78-133) suggesting 7 participants were “pre-diabetes” and 2 undiagnosed type 2 diabetes. Four reported smoking; of these, one was highly nicotine dependent. FRS was 7.15% (SD=6.15, ranged 7-23). While the calculated total cholesterol 166.44 (SD=34.15), HDL 55.19 (SD=15.31), LDL 84.56 (SD=26.58), and TG 143.44 (SD=76.29)(all in mg/dL) were within normal range, numbers and sizes of lipoprotein particles indicate that LTRs were at moderate risk of CHD: LDL-C 1221.48 (SD+447.31)&gt;1000 nmol/L as reference), small LDL-P 799.81 (SD=489.95) &gt;527nmol/L), LDL-size 20.89 (SD=1.12)&gt;20.5nm, Large VLDL-P 2.93 (SD=4.35) &gt;2.7 nmol/L, and VLDL size 51.07(SD=9.74) &gt;46.6 nm. PA (more time sitting) was associated with higher BMI (r=.394, P&lt;0.05) and WHR (r=.535, P&lt;0.01) but not with particle number or density. PA (MET minutes/week) was associated with WHR (r=.535, p&lt;0.01). Neither PA nor nutrition (Kcal/day) was associated with FRS. Conclusion: LTR are generally inactive and make poor dietary choices which are reflected by the obesity indices and characterized by the atherogenic lipoprofile.

EP 85. Immunosuppression in Vogt-Koyanagi-Harada-syndrome

Vogt–Koyanagi–Harada-syndrome is a rare autoimmune disease which affects organs containing large amounts of melanocytes (e.g. CNS, eyes, skin, inner ear). Relapsing uveitides and meningitides, sensorineural hearing loss and vitilligo/poliosis are typical symptomes. We describe the clinical course and difficulties of maintaining a long lasting and effective immunosuppression in Vogt–Koyanagi-syndrome. A 53-year-old female presented with relapsing uveitides and later on with visual loss and headaches. The neurological examination revealed neck stiffness and an organic brain syndrome containing severe content thought and formal thought disorders. Vitiligo was found in dermatological investigation. The cranial MRI showed a prominent contrast enhancement of the meninges. CSF-analysis revealed a pleocytosis of 200 cells/ μ l. Infectional serologies were negative. There was no serological evidence for collagenosis or malignant diseases. Due to the combination of uveitis, meningitis and vitiligo a Vogt–Koyanagi–Harada-syndrome was diagnosed. A four month lasting glucocorticoide therapy was without sufficient effect on uveitis and neuropsychological disorders. Periocular cortisone depots yielded a significant reduction of the visual loss. In the following months neither azathioprine nor methotrexate lead to decline of neuropsychological symptomes. Consequently we initiated cyclophosphamide therapy and gained complete regression of headaches and thought disorders. Unfortunately the patient was admitted with a further organic brain syndrome after six months under cyclophoshamide therapy. Due to limited therapeutical options we started intravenous immunoglobulin therapy which showed significant effectiveness. The following neurological examinations revealed a nearly complete regression of neuropsychological disorders. The case demonstrates that the rare Vogt–Koyanagi–Harada-syndrome should be considered as a differential diagnosis when the combination of uveitis, meningitis, neuropsychological disorders and vitiligo is present. Furthermore the clinical course described above revealed the difficulties of maintaining a stable and long lasting immunosuppression under glucocorticoide, azathioprine, methotrexate and cyclophophamide therapy. In our opinion after poor response of these substances an intravenous immunoglobuline therapy seems to be promising.

Allogeneic Liver Transplantation and Subsequent Syngeneic Hepatocyte Transplantation in a Rat Model: Proof of Concept for in vivo Tissue Engineering

Objectives: Stable long-term functioning of liver cells after transplantation in humans is still not achieved successfully. A new approach for successful engraftment of liver cells may be the transplantation of syngeneic cells into an allogeneic liver graft. We therefore developed a new rat model for combined liver and liver cell transplantation (cLCTx) under stable immunosuppression. Materials and Methods: After inducing a mitotic block, liver grafts from female donor rats (Dark Agouti) were transplanted into female recipients (Lewis). In male Lewis rats, liver cell proliferation was induced with subsequent cell isolation and transplantation into female recipients after organ transplantation. Y-chromosome detection of the transplanted male cells was performed by quantitative polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FisH) with localization of transplanted cells by immunohistochemistry. Results: Immunohistochemistry demonstrated the engraftment of transplanted cells, as confirmed by FisH, showing repopulation of the liver graft with 15.6% male cells (± 1.8 SEM) at day 90. qPCR revealed 14.15% (± 5.09 SEM) male DNA at day 90. Conclusion: Engraftment of transplanted syngeneic cells after cLCTx was achieved for up to 90 days under immunosuppression. Immunohistochemistry indicated cell proliferation, and the FisH results were partly confirmed by qPCR. This new protocol in rats appears feasible for addressing long-term functioning and eventually the induction of operational tolerance in the future.

The Management of Pregnancy in Patients with Advanced Liver Disease Before and After Liver Transplantation

Pregnancy in cirrhotic women carries a significant risk of morbidity and mortality to both mother and fetus. Fetal complications include higher rates of spontaneous abortion, prematurity, and perinatal death. Maternal complications in a patient with established cirrhosis include portal hypertension, potentially life-threatening variceal hemorrhage, hepatic decompensation, postpartum hemorrhage, and splenic artery aneurysm rupture. Most of these adverse outcomes are associated with the severity of liver disease; however, physiologic hypervolemiain pregnancy leads to an additional increase in portal hypertension. Preconception liver transplantation mitigates some of these complications but also introduces added risks of hypertension/preeclampsia, gestational diabetes, and fetal growth restriction. Delaying conception by at least 1 year after transplantation minimizes fetal exposure to high doses of immunosuppressant medication and allows demonstration of good graft function prior to pregnancy. Thus, contraception counseling shortly after the transplant is imperative. Long-acting reversible contraception, which includes intrauterine devices and contraceptive implants, provides the most effective contraception for this population. Once pregnancy is planned and achieved, women need to maintain stable immunosuppression to prevent allograft rejection. Given the complexity of these patients, a multidisciplinary approach and close monitoring are essential to achieving successful outcomes.

Uncommon presentation of tuberculosis in a renal allograft recipient

Tuberculosis (TB), especially in developing countries like India, is a common infective complication after renal transplant with occurrence common in first 2 years. However, sternal TB is rare. We describe a 55-year-old female patient who after 5 years of live donor renal transplant with stable immunosuppression and graft function presented with a chest swelling and a destructive bony lytic lesion diagnosed as sternal TB with radiological and microbiological investigations. She was successfully treated with antitubercular therapy to which she spontaneously responded. This case, to the best of our knowledge, is the first reported case of sternal TB in a renal allograft recipient to be successfully managed with antitubercular therapy.

Feasibility and Benefit of Minimization and Withdrawal of Immunosuppression (IS) Early After Liver Transplantation in HCV Positive Recipients.

The ITN030ST prospective study examines the potential for early development of tolerance; clinical benefits of IS minimization as measured by complications of long-term IS; and the course of recurrent HCV disease in liver transplant recipients. Methods: This randomized study enrolled 130 HCV subjects prior to transplantation. 37 were randomized at a mean of 16 +/- 4 months post-transplant to withdrawal (n=30) or maintenance (n=7). Randomization eligibility criteria included stable IS monotherapy, acceptable kidney and liver function, and acceptable biopsy findings including Ishak ≤2. IS withdrawal followed an 8-level reduction algorithm with ≥ 8 weeks per level. Subjects tolerated considerable minimization of IS (Table 1). 17% reached operational tolerance and 63% reduced to half of baseline dose. Acute rejection and/or abnormal liver tests were generally reversed with reinstitution of calcineurin inhibitors with or without anti-metabolites; only 4 subjects required corticosteroids.Table 1: IS Withdrawal Success (N=30)The primary composite endpoint (death or graft loss; grade 4 secondary malignancy or opportunistic infection; stage ≥3 fibrosis; or GFR < 90 mL/min/1.732 and 25% decrease in GFR within 24 months of randomization) occurred in 4 of 5 (80.0%) and 4 of 24 (16.7%) evaluable subjects in the maintenance and withdrawal groups respectively (p=0.01). The 2 groups did not differ in HCV viral load or fibrosis progression. GFR decrease was noted in 2 of 5 evaluable maintenance subjects and 2 of 24 evaluable withdrawal subjects. In this study, monotherapy, daily dosing, significant minimization, and operational tolerance (17%) were achievable in HCV recipients without compromise of allograft function. Rejection was generally reversed by adjustment in IS monotherapy. Early minimization may be associated with clinical benefits, specifically improvement and/or stabilization of GFR.

Neohybrid Liver Graft - a Novel Concept of in Vivo Tissue-Engineering

Objectives: Liver transplantation (LTx) is the standard therapy for end-stage liver disease, even though long-term survival is still affected by serious side-effects of immunosuppression. Liver cell transplantation (LCT), a possible alternative to LTx, still has not shown long-lasting clinical success. We developed a novel concept for in vivo tissue-engineering based on the combination of orthotopic LTx and transplantation of autologous liver cells isolated from the patient's own diseased liver: the Neohybrid Liver Graft. Autologous hepatocytes and hepatic progenitor cells (hPC) may repopulate the allogeneic liver using the graft as biological matrix. This could eventually lead to an entirely syngeneic liver and operational tolerance. Materials and methods: Aim of this study was to investigate the feasibility of the Neohybrid Liver Graft concept in the Dark Agouti/Lewis rat model under stable immunosuppression. Therefore, we performed orthotopic LTx with Retrorsin-pretreated liver grafts from female donors (Dark Agouti) into female recipients (Lewis). Afterwards, syngeneic hepatocytes and hPCs were isolated from 2AAF/PH -preconditioned male Lewis rats and combined liver cells (cLCT) were transplanted into the recipient's spleen. Animals were sacrificed at four different time-points (day 8, 15, 30, 90) after LTx. In order to analyse the degree of cell engraftment and repopulation, Y-chromosome detection of transplanted male cells was performed by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) for the SRY gene and by Fluorescence in-situ Hybridisation (FisH-typing). Immunohistochemical analyses of hPC specific markers (OV6, CK18, AFP and EpCam) in correlation with proliferation stains (PCNA, Ki67, BrdU) were used to identify transplanted cells. Results: Correlating immunohistochemical results, hPC specific markers and proliferation stains demonstrated engraftment of transplanted cells with increasing quantity during follow-up. FisH-typing confirmed successful repopulation of the liver graft at day 8 with 8.1% ± 4.0% SEM and day 90 with 23.0% ± 3.8% SEM after combined cLCT and LTx. Validating these results by qRT-PCR using a standard curve, proportion of SRY-positive DNA and absolute weight of each sample were calculated. Collected data for 3 animals showed 0% SRY-positive DNA at day 8, but 16.4% ± 7.9% SD SRY-positive DNA at day 90. Conclusion: We could proof successful engraftment of transplanted cells as well as repopulation of the allograft after combined LTx and cLCT with growing efficiency during follow-up. Histological analyses indicated a continuous cell proliferation activity and FisH-typing results were partly confirmed by qRT-PCR calculating absolute weight of SRY-positive DNA of liver samples. Influence of hPCs on engraftment and proliferation of transplanted hepatocytes are under evaluation, especially with respect to minimization of immunosuppression and induction of tolerance. This new concept for in vivo tissue-engineering could enable repopulation of liver allografts with autologous cells from the patient's own liver to generate a Neohybrid Liver Graft.

Preliminary Results of a Phase II Trial of Montelukast for the Treatment of Bronchiolitis Obliterans Syndrome After HSCT

Bronchiolitis obliterans syndrome (BOS) after allogeneic HSCT is a deadly manifestation of cGVHD. Current treatments are inferior and yield transient responses with published overall survival of 44% at 2 years. Although the pathogenesis of BOS after HSCT is unknown, a similar disease, BOS after lung transplant is associated with elevated leukotriene levels. We present preliminary results from a prospective, open label, phase II trial testing the efficacy of montelukast, a leukotriene inhibitor, for the treatment of BOS after HSCT. BOS diagnostic criteria included: FEV1<75%, FEV1/VC < 0.7 or air trapping on CT and RV>120% or RV/TLC>120% in the absence of infection and presence of another cGVHD manifestation. Subjects had stable or declining FEV1 on stable or decreasing immunosuppression. Twenty patients have been enrolled. One withdrew prior to treatment and one withdrew after study medication initiation; 16/20 patients have reached the primary endpoint (6 months) on study medication (10 mg qhs). Study participants age ranged from 15-64 years, 12/20 female, with baseline FEV1 from 24 to 73% predicted. All patients met criteria for response on the clinical trial with less than 15% decline in FEV1 % predicted at the primary endpoint. FEV1 increased 5-13% predicted in 5 participants, remained stable in 6 (change <5%), and declined 5-13% in 5. Comparison of patient pre-study FEV1 decline to on-study FEV1 values was generated using the slope of FEV1 volume vs. days post-transplant. The difference in pre- and primary endpoint slope revealed: 14/16 improvement and 2/16 decline. Six minute walk test demonstrated that 4/16 patients had significant increases in walk distance that exceeded the minimally important difference, 2 of which had declining FEV1%. 2/20 had a significant decline in walk test accompanied by a decline in FEV1% predicted. Of 10 patients eligible for the 2 year endpoint, 7/10 are alive with 2 patients with durable FEV1 improvements from baseline (FEV1+ 6%, +14%), 2 stable (FEV1 0%, +1%), 3 with decline from baseline (FEV1 -4%, -4%, -8%). Montelukast was well-tolerated with only one grade II probable attributable adverse event (insomnia) during the six-month collection period. These findings suggest that montelukast is a promising therapy for BOS after allogeneic HSCT.

123 SIROLIMUS-BASED IMMUNOSUPPRESION IS ASSOCIATED WITH INCREASED SURVIVAL AFTER LIVER TRANSPLANTATION FOR HEPATO-CELLULAR CARCINOMA

Liver transplantation is an important treatment option for selected patients with nonresectable hepatocellular carcinoma (HCC). Several reports have suggested a lower risk of posttransplant tumor recurrence with the use of sirolimus and a higher one with calcineurin inhibitors, but the selection of an ideal immunosuppression protocol is still a matter of debate. The aim of this study was to define the immunosuppression associated with the best survival after liver transplantation for HCC. It was based on the Scientific Registry of Transplant Recipients and included 2,491 adult recipients of isolated liver transplantation for HCC and 12,167 for non-HCC diagnoses between March 2002 and March 2009. All patients remained on stable maintenance immunosuppression protocols for at least 6 months posttransplant. In a multivariate analysis, only anti-CD25 antibody induction and sirolimus-based maintenance therapy were associated with improved survivals after transplantation for HCC (hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.45-0.9, P < 0.01; HR 0.53, 95%CI: 0.31-0.92, P< 0.05, respectively). The other studied drugs, including calcineurin inhibitors, did not demonstrate a significant impact. In an effort to understand whether the observed effects were due to a direct impact of the drug on tumor or more on liver transplant in general, we conducted a similar analysis on non-HCC patients. Although anti-CD25 induction was again associated with a trend toward improved survival, sirolimus showed a trend toward lower rates of survival in non-HCC recipients, confirming the specificity of its beneficial impact to cancer patients.Conclusion: According to these data, sirolimus-based immunosuppression has unique posttransplant effects on HCC patients that lead to improved survival. (HEPATOLOGY 2010;51:1237-1243.)

Improved 24-Hour Blood Pressure Control With Sirolimus Versus Calcineurin Inhibitor Based Immunosuppression in Renal Transplant Recipients

Introduction Calcineurin inhibitors (CNI) have brought dramatic improvements in early renal allograft survival. However, CNI are associated with posttransplant hypertension (PTHTN), a risk factor for mortality from cardiovascular disease and graft failure. Sirolimus (SRL) is emerging as an alternative to CNI. SRL effects on blood pressure (BP) in humans are unclear. We compared the prevalence of PTHTN among patients receiving SRL as maintenance immunosuppression with a group receiving CNI by using 24-hour ambulatory BP (AMBP). AMBP has been shown to predict cardiovascular events and progression of kidney disease better than casual office BP measurements in chronic kidney disease (CKD) patients. Methods Renal transplant recipients with office hypertension (defined as BP > 130/80 or on antihypertensive medications), receiving stable immunosuppression and displaying consistent serum creatinine values for ≥6 months were eligible. We enrolled the first 40 patients to consent. Office BP was measured twice using a BP-Tru machine. AMBP was then analyzed for systolic BP (SBP), diastolic BP (DBP), and nocturnal blood pressure fall (NF; “dipping”). Patients were placed in the SRL group ( n = 18) and the CNI group ( n = 20) based on their maintenance immunosuppressive protocol. Two patients were excluded because of incomplete data. All patients received mycophenolate mofetil, and 14/38, maintenance steroids. We collected, demographics as well as type and date of renal allograft, medications, comorbidities, CKD stage, proteinuria, and plasma creatinine at the time of study enrollment. Results Patients in the SRL group displayed lower 24-hour SBP than the CNI group (128.0 ± 10.8 vs 137.7 ± 14; P = .029). Nightime MAP, nightime SBP, and nighttime DBP were all lower in the SRL group. NF did not reach significance between the SRL and CNI groups (44% vs 15%; P = .074). Patient demographics and number of antihypertensive medications did not differ. Conclusion The lower 24-hour SBP seen in the SRL group by AMBP may lead to improved cardiovascular and renal outcomes over time. Long-term patient follow-up will be needed to clarify the effect of the lower 24-hour SBP.

Sirolimus‐based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma†

Liver transplantation is an important treatment option for selected patients with nonresectable hepatocellular carcinoma (HCC). Several reports have suggested a lower risk of posttransplant tumor recurrence with the use of sirolimus and a higher one with calcineurin inhibitors, but the selection of an ideal immunosuppression protocol is still a matter of debate. The aim of this study was to define the immunosuppression associated with the best survival after liver transplantation for HCC. It was based on the Scientific Registry of Transplant Recipients and included 2,491 adult recipients of isolated liver transplantation for HCC and 12,167 for non-HCC diagnoses between March 2002 and March 2009. All patients remained on stable maintenance immunosuppression protocols for at least 6 months posttransplant. In a multivariate analysis, only anti-CD25 antibody induction and sirolimus-based maintenance therapy were associated with improved survivals after transplantation for HCC (hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.45-0.9, P < or = 0.01; HR 0.53, 95% CI: 0.31-0.92, P < or = 0.05, respectively). The other studied drugs, including calcineurin inhibitors, did not demonstrate a significant impact. In an effort to understand whether the observed effects were due to a direct impact of the drug on tumor or more on liver transplant in general, we conducted a similar analysis on non-HCC patients. Although anti-CD25 induction was again associated with a trend toward improved survival, sirolimus showed a trend toward lower rates of survival in non-HCC recipients, confirming the specificity of its beneficial impact to cancer patients. According to these data, sirolimus-based immunosuppression has unique posttransplant effects on HCC patients that lead to improved survival.

Fluctuation in ventricular sensing leading to underdetection of ventricular fibrillation in a patient with cardiac sarcoidosis

In this case report, we describe markedly fluctuating ventricular sensing through an implantable cardioverter defibrillator (ICD) over a period of 29 months in a patient with cardiac sarcoidosis. We conclude that the fluctuations in the measured R wave are the result of waxing and waning inflammation associated with sarcoid activity. The patient had a stable medical course throughout the time period studied, including stable immunosuppression and stable electrolytes. We believe this is an example of an important complication of ICD implants in patients with cardiac sarcoidosis and that frequent sensing evaluations are prudent in these patients.