A Hemodynamic Study to Evaluate the Buffer Response in Cirrhotic Patients Undergoing Liver Transplantation

The physiological regulation of the liver blood flow is a result of a reciprocal portal vein and hepatic artery flow relationship. This mechanism is defined as the hepatic arterial buffer response (HABR). This study was addressed to investigate whether HABR is maintained in denervated grafts in liver transplant recipients. Portal blood flow (PBF) and hepatic arterial resistance index (PI) were measured 6 months after transplantation using Doppler. In each patient we consecutively measured the vasodilator (Ensure Plus PO versus placebo) and vasoconstrictor (isosorbide dinitrate 5 mg SL versus placebo) stimuli. The meal ingestion caused a significant increase of both parameters, PBF (from 1495±260 to 2069±250 mL/min, P<0.05) and PI (from 0.7±0.2 to 0.8±0.2, P<0.05). By contrast, isosorbide dinitrate reduced PBF (from 1660±270 to 1397±250 mL/min, P<0.05) and PI (from 0.7±0.2 to 0.5±0.2, P<0.05). We show that PBF and PI are reciprocally modified with the administration of vasoconstrictor and vasodilator stimuli. These results suggest the persistence of the HABR in a denervated human model, suggesting that this mechanism is independent of the regulation from the autonomic nervous system.

Long-Term Outcome of Liver Transplantation in HIV-1-Positive Patients: 15-Year Follow-Up

Liver transplantation (LT) for patients with human immunodeficiency virus type-1 (HIV-1) infection has been associated with poor outcome. However, after the introduction of the highly active antiretroviral therapy, short-term patient survival after LT has improved significantly. We examined the long-term outcome of HIV-1-positive patients who underwent LT. Medical records were analysed in nine HIV-1-positive LT patients who underwent LT from August 1998 to May 2012. Eight were known to be HIV-1 positive at the time of listing for LT and had end-stage liver disease (ESLD) due to hepatitis C. One patient had primary biliary cirrhosis, and primary HIV-1 infection was found at the date of LT. Seven of the nine patients remain alive to date. So far, three have survived more than 12 years after LT. The overall patient survival rate for both five and 10 years is 77.8%. Four patients experienced acute rejection and six acquired biopsy-confirmed HCV recurrence. HIV-1 replication was effectively blocked during follow-up in all patients. We conclude that long-term survival of HIV-1-positive patients after LT can be achieved. Our study suggests that LT can offer an effective treatment option in selected HIV-1 infected patients with ESLD.

Low-Dose Valganciclovir for CMV Prophylaxis after Lung Transplantation

Purpose. Cytomegalovirus (CMV) remains an important pathogen following solid organ transplantation (SOT). Universal prophylaxis for CMV is adopted by most centers after lung transplantation. Various combinations studied for CMV prophylaxis include intravenous and oral ganciclovirs, oral valganciclovir, and CMV immunoglobulins. We present our experience with a low-dose of oral valganciclovir for CMV prophylaxis following lung transplantation. Methods and Materials. Our center started using 450 mg of daily oral valganciclovir for CMV prophylaxis in lung transplant recipients in Jan, 2001. A retrospective chart analysis of patients who underwent lung transplantation from January 2001 to December 2006 was done. Of 46 patients, 4 were excluded as they died within 30 days of transplant from postop complications. The mean age at transplant was 64 years, mostly single lung transplants (36/6) with a male-to-female ratio of 25/17. COPD was the most common reason for transplant (65%), and the serological CMV status of donors (D) and recipients (R) was as follows: D+/R+ 28, D+/R− 5, D−/R+ 5, and D−/R− 4. Valganciclovir was given for a total of 6 months posttransplant except for D−/R+ patients who received it for 12 months. Results. Five patients (12%) developed CMV disease with an average followup of 26 months. Only 2 (4.7%) developed CMV disease within six months of completing valganciclovir prophylaxis. This incidence is not significantly different from the best-reported results of CMV prophylaxis in lung transplant recipients. The remaining 3 patients developed the disease later in their course, one as late as 32 months posttransplant. The main side effects noted include leucopenia, neutropenia, and GI disturbances. However, the number of patients who had to temporarily stop or discontinue the medication (9.5%) was significantly lower than that reported in previous studies. Conclusions. Our experience suggests that low-dose valganciclovir is an effective method of prophylaxis for CMV disease in high-risk patients. It is a simple regimen that seems to have a better side effect profile and to improve patient compliance.

MHC Disparate Resting B Cells Are Tolerogenic in the Absence of Alloantigen-Expressing Dendritic Cells

Resting B cell (rB) populations have been shown to tolerize to soluble proteins and to minor-H but not to MHC alloantigens. We speculated that the reason for failing to tolerize to MHC alloantigen is that the few remaining dendritic cells (DCs) contaminating purified rB cell populations efficiently activate MHC allospecific T cells which are present at a higher frequency than T cells specific for minor-H alloantigen and soluble proteins. We established that MHC disparate rB cells are indeed tolerogenic when devoid of DC populations, as parental strain mice showed delayed skin graft rejection when infused with rB cells from mice in which MHC class I alloantigen was specifically targeted to T and B cells (CD2- transgenic mice). In contrast, treatment of parental strain mice with allogeneic rB cells purified from MHC- transgenic mice, in which is ubiquitously expressed, including DCs, induced accelerated graft rejection. We also showed that adding only 5,000 expressing DCs to CD2- rB cells abrogated the tolerogenic effect. Surprisingly, allogeneic rB cells prolonged graft survival in -primed mice. Thus, MHC disparate rB cells are tolerogenic and their failure to delay graft rejection can be explained by contaminating allogeneic DCs.

A Review of Long-Term Mechanical Circulatory Support as Destination Therapy: Evolving Paradigms for Treatment of Advanced Heart Failure

Left ventricular assist devices as long-term mechanical circulatory support are increasingly utilized as an option for medically refractory advanced heart failure. Rapid advances in this field, from pulsatile paracorporeal flow pumps to now more advanced intracorporeal continuous flow devices, have led to more wide spread use of device therapy. Several trials have now confirmed the survival benefits of ventricular assist devices, not only as a method for bridging patients waiting on the transplant list, but also as an evolving paradigm of destination therapy. Significant improvements in quality of life and functional status have been reported in patients receiving these devices. Survival outcomes with this therapy continue to improve, and long term durability of newer generation devices remains yet to be discerned. Comparative data to heart transplantation remains scarce. This paper will focus on the historical development of ventricular assist device therapy for advanced heart failure, review major trials of destination therapy, and look at comparative literature in the modern era to cardiac transplantation.

Effects of Rituximab on the Development of Viral and Fungal Infections in Renal Transplant Recipients

Background. Rituximab is becoming increasingly utilized in renal transplant recipients; however, its association with infections remains unclear. Methods. We reviewed the incidence of viral and fungal infections in kidney transplant recipients treated with () or without () rituximab (RTX) in addition to standard immunosuppression. Results. Infections occurred in 134 (30%) patients, with a greater proportion in RTX versus no RTX patients (47% versus 28%; ). Viral infections occurred in 44% and 27% of RTX and no RTX patients, respectively (). This was largely driven by the frequency of BK viremia and noncytomegalovirus/non-BK viruses in RTX patients (27% versus 13% () and 15% versus 2% (), resp.). Fungal infections also occurred more often in RTX patients (11% versus 3 %; ). Multivariate analysis revealed deceased donor recipient (odds ratio = 2.5; ) and rituximab exposure (odds ratio = 2.2; ) as independent risk factors for infection. Older patients, deceased donor recipients, those on dialysis longer, and those with delayed graft function tended to be at a greater risk for infections following rituximab. Conclusions. Rituximab is associated with an increased incidence of viral and fungal infections in kidney transplantation. Additional preventative measures and/or monitoring infectious complications may be warranted in those receiving rituximab.

Tacrolimus Dose Modification in Hematopoietic Cell Transplant Recipients Following a Change in Therapy from Fluconazole to Voriconazole

Antifungal therapy with voriconazole or fluconazole in combination with the calcineurin inhibitor tacrolimus exhibits significant CYP3A4 drug interaction potential in allogeneic hematopoietic cell transplant (HCT) recipients. The package insert for voriconazole has dosing recommendations for tacrolimus when voriconazole is started, but these do not apply to patients already receiving fluconazole therapy. The purpose of this retrospective study is to estimate appropriate dose modification of tacrolimus following a change in therapy from fluconazole to voriconazole. We performed a retrospective case-series analysis of five patients. The mean steady-state concentration/dose (C/D) ratio of tacrolimus increased from 413 (range, 255–642) to 850 (range, 670–953) following a switch from fluconazole to voriconazole (). This data represents a mean 2-fold increase in C/D ratios following the switch, indicating that the dose of tacrolimus may be most accurately reduced by approximately 50% following this switch in therapy. This provides some guidance for practitioners to estimate dose adjustments but will require close pharmacokinetic monitoring and adjustments on an individual patient basis.

Cell Transplantation and “Stem Cell Therapy” in the Treatment of Myopathies: Many Promises in Mice, Few Realities in Humans

Myopathies produce deficits in skeletal muscle function and, in some cases, progressive and irreversible loss of skeletal muscles. The transplantation of myogenic cells, that is, cells able to differentiate into myofibers, is an experimental strategy for the potential treatment of some of these diseases. The objectives pursued by the transplantation of these cells are essentially three: (a) the fusion with the patient’s myofibers to obtain the expression of therapeutic proteins into them, (b) the neoformation of new functional myofibers in skeletal muscles that were too degenerated by the progressive degeneration, and (c) the formation of a new pool of healthy donor-derived satellite cells. Although the repertoire of myogenic cells appears to have expanded in recent years, myoblasts are the only cells that have been demonstrated to engraft in humans. The present work aims to make a comprehensive review of the subject, from its beginnings to recent advances, including the preclinical experience in different animal models and recent clinical findings.

Sicker Patients for Liver Transplantation: Meld, Meld Sodium, and Integrated Meld’s Prognostic Accuracy in the Assessment of Posttransplantation Events at a Single Center from Argentina

Background. MELD or MELD sodium promotes sicker patients for earlier liver transplantation (LT); the balance between pre- and post-LT outcomes is still controversial. Aim. To compare MELD and related scores’ risk assessment of short-term morbidity and mortality after LT. Methods. We included only transplanted cirrhotic patients from 6/2005 to 6/2010 (). Immediate pre-LT MELD, integrated MELD (iMELD), and two MELD sodium formulas “MELD Na1” and “MELDNa2” were calculated. Results. Pre-LT scores for nonsurvivors were higher than those for survivors: MELD (28 ± 8 versus 22 ± 7, ), MELD Na1 (33 ± 8 versus 27 ± 10, ), and iMELD (51 ± 6 versus 46 ± 8, ). Patient survival assessment was performed by AUROC analysis (95% CI): MELD 0.694 (0.56–0.82; ), MELD Na1 0.682 (0.56–0.79; ), MELD Na2 0.651 (0.54–0.76; ), and iMELD 0.698 (0.593–0.80; ). Patients with MELD ≥25 points had longer intensive care stay (mean 10 versus 7 days, ) and longer mechanical ventilatory support (5.4 versus 1.9 days, ). Conclusions. The addition of serum sodium to MELD does not improve assessment of mortality after LT. Patients with higher MELD may preclude higher morbidity after transplantation.

Double-Glide Method Using Cathereep Protective Sheet As a Substitute in Descemet's Stripping Automated Endothelial Keratoplasty

Purpose. For the insertion of the donor graft in Descemet's stripping automated endothelial keratoplasty (DSAEK), the double-glide method using a Busin glide and intraocular lens (IOL) glide concomitantly has been shown to be effective. The aim of this report is to evaluate the results for the double-glide method using Cathereep (Nichiban, Tokyo, Japan), a protective sheet made of polyurethane film for medical use, as a substitute for an IOL glide. Materials and Methods. The subjects were 10 eyes of 10 patients with bullous keratopathy. The DSAEK operation was performed, and the double-glide method was used for the donor graft insertion. During the operation, an IOL glide was used for the 5 eyes, and the Cathereep protection sheet was used for the remaining 5 eyes. We trimmed approximately 5 mm wide strips from the nonadhesive area surrounding the Cathereep protection sheet. Results. The donor graft was inserted equally easily with the Cathereep protective sheet and IOL glides and improvement of visual acuity was noted in both groups significantly. A favorable postoperative course was obtained with no perioperative complications including endothelial damage. Conclusions. Cathereep protective sheet can be used as a substitute for an IOL glide for double-glide method in DSAEK.