Geographic Disparities in Liver Allocation and Distribution in the United States: Where Are We Now?

BACKGROUND: Equitable deceased donor liver allocation and distribution has remained a heated topic in transplant medicine. Despite the establishment of numerous policies, mixed reports regarding organ allocation persist. METHODS: Patient data was obtained from the United Network for Organ Sharing liver transplant database between January 2016 and September 2017. A total of 20,190 patients were included in the analysis. Of this number, 8790 transplanted patients had a median Model for End-Stage Liver Disease (MELD) score of 25 (17-33), after a wait time of 129 (32-273) days. Patients were grouped into low MELD and high MELD regions using a score 25 as the cutoff. RESULTS: Significant differences were noted between low and high MELD regions in ethnicity (white 77.4% vs 60.4%, Hispanic 8.1% vs 24.5%; P < .001) and highest level of education (grade school 4.8% vs 8.5%, Associate/Bachelor's degree 19% vs 15.7%, P < .001), respectively. Patients in high MELD regions were more likely to be multiply listed if they had a diagnosis of hepatocellular carcinoma (12.1% vs 15%, P = .046). Wait-list mortality (4.8% vs 6%, P < .001) and wait-list time (110 [27-238] vs 156 [42-309] days, P < .001) were greater in the high MELD regions. CONCLUSIONS: These results highlight some of the existing disparities in the recently updated allocation and distribution policy of deceased donor livers. Our findings are consistent with previous work and support the liver distribution policy revision.

Portojejunostomy in Split Liver Transplantation as a Rescue Technique for Challenging Biliary Reconstruction: A Case Report.

Cadaveric split liver transplantation (SLT) is a valid option to increase the pool of cadaveric organs, obtaining 2 functioning grafts from a single donor. Typically, SLT is performed for 1 adult and 1 pediatric recipient. However, on the heels of great results achieved in living donor liver transplantation, splitting cadaveric liver into full right graft and full left graft for 2 adults has become a feasible idea. The rate of biliary complications remains the "Achilles heel" in partial graft liver transplantation, either from cadaveric or living donors. In cases of biliary complications, interventional radiology and/or endoscopic procedures are the cornerstone of management. Surgical revision is left as the last option. When surgical revision fails, retransplantation becomes the only rescue option. Herein we describe the case of a cadaveric SLT, complicated by biliary leakage in the presence of multiple bile ducts. A duct-to-duct anastomosis was not feasible. Therefore, a hepaticojejunostomy was performed and resulted in a high-output biliary leak from different sources. Given the anatomy of the biliary tree, radiologic interventional measures were not feasible to address the leak. The idea of performing a portoenterostomy to restore bilioenteric continuity proved to be successful. Portoenterostomy should not be performed in lieu of other alternatives, but rather as the last option to avoid retransplantation in cases of complicated biliary reconstruction after partial graft liver transplant.

YAP/TAZ mechano-transduction as the underlying mechanism of neuronal differentiation induced by reduced graphene oxide.

AIM: The aim of this work is the dissection of the molecular pathways underlying the differentiation effect of reduced graphene oxide (GO) materials in the absence of differentiation agents. MATERIALS & METHODS: Reduced GO is obtained either by drop casting method and heat-treated or biological reduction by the interaction between GO and wtPrxI. Cells were grown on both materials and the differentiation process studied by immunological and morphological detection. RESULTS & CONCLUSION: The results obtained indicate that both reduction methods of GO can determine the modulation of pathway involved in mechano-transduction and differentiation, by affecting YAP/TAZ localization outside the nuclei and increasing neuronal differentiation markers. This suggests that the mechano-transduction pathways are responsible for the differentiation process.

Eculizumab for Prevention of Antibody-Mediated Rejection in Blood Group-Incompatible Renal Transplantation.

Antibody-mediated rejection (AMR) is one of the leading causes of allograft failure especially in patients undergoing ABO-incompatible (ABOi) renal transplantation. We hypothesized that complement inhibition with eculizumab, a C5 inhibitor, would protect against AMR and maintain graft function in ABOi renal transplant recipients. Four patients undergoing living donor kidney transplant from ABOi donors were treated with a 9-week eculizumab course without therapeutic plasma exchange, intravenous immunoglobulin, or splenectomy. All patients had successful transplants and have normal graft function at the time of last follow-up. There were no cases of AMR or acute cellular rejection. Of note, 2 patients were transplanted despite persistent ABO antibody titers of 1:32, conventionally considered a contraindication to proceed in standard protocols. Eculizumab is a promising option to prevent AMR with ABOi renal transplantation without the need for splenectomy, post-transplant therapeutic plasma exchange, and intravenous immunoglobulin. Future multicenter studies are needed to determine long-term efficacy and safety.

Emergency Kidney Transplantation in Recipients With Iliocaval Thrombosis Using Splenic Vessel Anastomosis After Splenectomy: A Case Series.

BACKGROUND: The external iliac vein is the standard site used for venous anastomosis in kidney transplantation. When a pre-transplantation diagnosis of iliocaval thrombosis is established, a different and suitable venous drainage for the renal outflow must be identified for successful transplant. METHODS: We report 4 cases of kidney transplantation, performed from 2004 to 2016, in recipients presenting with thrombosis of the inferior vena cava and iliac system needing, because of the lack of access for dialysis, urgent kidney transplantations. The splenic vessels were used in all cases for the graft's vascular anastomosis after splenectomy. RESULTS: Kidney transplantation after splenectomy, with anastomosis of the renal vessels to the splenic ones, was completed in all 4 patients. All of the cases were technically successful with good renal function on discharge. During the follow-up, no graft losses were registered as due to thrombotic event or inadequate renal venous outflow. A normal vascular inflow and outflow was confirmed by means of follow-up ultrasound. Two grafts were lost at 31 months and 91 months, both to noncompliance with immunosuppressive therapy. The other 2 are currently functioning well. Notably, the kidney's position in the left upper quadrant has not caused technical difficulties in urologic reconstruction. CONCLUSIONS: In our experience, kidney transplantation using splenic vessels for vascular anastomosis is technically feasible and very useful in the setting of complete iliocaval thrombosis.

PPARs in Neurodegenerative and Neuroinflammatory Pathways.

BACKGROUND: PPARs are lipid sensors activated by dietary lipids or their metabolites, mainly fatty acids and eicosanoids, that play critical roles in CNS biology, since brain has a very high lipid content and has the higher energetic metabolism in the body. METHODS: In neurodegenerative diseases in addition to metabolic impairment, also neuroinflammation is observed and PPARs are also closely linked to inflammatory processes. Several studies have revealed a complicated relationship between the innate immune response and tissue metabolism. RESULTS: In the brain, during pathological conditions, an alteration in metabolic status occurs, particularly involving glucose utilization and production, a condition which is generally related to metabolic changes. CONCLUSION: Taking into account the high expression of PPARs in the brain, this review will focus on the role of these transcription factors in CNS diseases.

Roles of PPAR transcription factors in the energetic metabolic switch occurring during adult neurogenesis.

PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation. Although it has been demonstrated that PPARs play important roles in determining NSCs fate, less is known about their function in regulating NSCs metabolism during differentiation. In order to identify the metabolic events, controlled by PPARs, occurring during neuronal precursor differentiation, the glucose and lipid metabolism was followed in a recognized model of neuronal differentiation in vitro, the SH-SY5Y neuroblastoma cell line. Moreover, PPARs distribution were also followed in situ in adult mouse brains. The concept of adult neurogenesis becomes relevant especially in view of those disorders in which a loss of neurons is described, such as Alzheimer disease, Parkinson disease, brain injuries and other neurological disorders. Elucidating the crucial steps in energetic metabolism and the involvement of PPARγ in NSC neuronal fate (lineage) may be useful for the future design of preventive and/or therapeutic interventions.

Influenza virus surveillance in Argentina during the 2012 season: antigenic characterization, genetic analysis and antiviral susceptibility.

The activity and circulation of influenza viruses in Argentina was studied during 2012 as part of the Argentinean Surveillance for Influenza and other Respiratory Viruses, in the context of Global Influenza Surveillance. The antigenicity and molecular characteristics of haemagglutinins (HA) of circulating influenza A and B viruses were analysed to assess the emergence of virus variants. Susceptibility to oseltamivir and zanamivir was evaluated by enzymatic assay and results were backed-up by sequencing of the neuraminidase (NA) genes. During the 2012 season, influenza virus circulation in Argentina was detected from weeks 24 to 51. The HA sequences of the studied A(H1N1)pdm09 subtype viruses segregated in a different genetic group compared to those identified during the 2009 pandemic, although they were still closely related antigenically to the vaccine virus A/California/07/2009. The HA sequences of the A(H3N2) viruses analysed fell into the A/Victoria/208/2009 clade, genetic group 3C. A mixed circulation of virus variants belonging to B/Victoria and B/Yamagata lineages was detected, with B/Victoria being dominant. All viruses tested were sensitive to oseltamivir and zanamivir except one. This isolate, an A(H1N1)pdm09 virus possessing the substitution NA-N295S, showed highly reduced inhibition by oseltamivir and reduced inhibition by zanamivir. Virological and epidemiological surveillance remains critical for detection of evolving influenza viruses.

Monitoring of reversible boronic acid-diol interactions by fluorine NMR spectroscopy in aqueous media.

Recognition and sensing of various biologically relevant species using boronic acid-based chemosensors have become increasingly popular over the last few years. Herein, we describe a new convenient method for monitoring boronic acid-diol interactions in aqueous media based on (19)F NMR spectroscopy with fluorinated boronic acid probes.

Pregnant women infected with pandemic influenza A(H1N1)pdm09 virus showed differential immune response correlated with disease severity.

BACKGROUND: During pregnancy, immunological and hormonal alterations place women at increased risk for influenza-related severe illnesses including hospitalization and death. Although A(H1N1) pdm09 infection resulted in increased disease severity in pregnant women, the precise mechanisms responsible for this risk have yet to be established. OBJECTIVES: The present study was aimed to investigate the role of host chemokines and cytokine profiles in A(H1N1) pdm09 infection regarding disease severity in pregnant women. STUDY DESIGN: This retrospective survey examined 41 pregnant women with confirmed A(H1N1) pdm09 infection. Of them, 12 died (D), 29 survived (S), and 17 remained uninfected and served as controls (C). Antiviral response was evaluated for IFN-ß expression and gene expression profiles of cytokines (TNF-α, IL-6, IL-12, TGF-ß) and chemokines (IL-8, RANTES, MCP-1, IP-10), and the viral Matrix (M1) gene was quantified and normalized using the housekeeping gene product ß-actin mRNA. RESULTS: Higher IL-8 and TNF-α mRNA expression were found in D and S compared with C, while IL-6 showed higher expression in D. Interestingly, these results were associated with a decrease in the anti-inflammatory response of TGF-ß mRNA and IFN-ß. These alterations would lead to an imbalance in the immune response of those patients. CONCLUSIONS: Pregnancy-related reductions in IFN-ß and TGF-ß expression levels and elevated levels of pro-inflammatory cytokines could explain the increased severity of infection and death of pregnant women. These findings may help improve the understanding of the high susceptibility and disease severity to influenza virus infection during pregnancy.

A novel and personalized rehabilitation program for obese kidney transplant recipients.

INTRODUCTION: Physical rehabilitation programs for kidney transplant recipients are not routinely personalized to patients' physical and emotional health, which could result in a potentially limited health impact, shorter-term participation, and an overall low success rate. MATERIALS AND METHODS: We conducted an internal review board-approved randomized prospective study involving a 12-month supervised multidisciplinary rehabilitation program (GH method) initiated after kidney transplantation in obese recipients (body mass index >30). The new method incorporates 3 major components: physical exercise, behavioral interventions, and nutritional guidance. We compared 9 patients who underwent supervised rehabilitation with 8 patients who underwent standard care. Patients were followed up after the start of the intervention, and multiple assessments were performed. RESULTS: The adherence to training and follow-up was 100% in the intervention group, compared with 25% at 12 months in the control group. There was a trend for a higher glomerular filtration rate in the intervention group compared with the control group (55.5 ± 18.6 mL/min/1.73 m(2) vs 38.8 ± 18.9 mL/min/1.73 m(2), P = .06). The quality of life (SF-36) mean score improved more in the intervention group compared with the control group (583 ± 13 vs 436 ± 22, P = .008). There was a significantly higher employment rate in the intervention group, 77.7% at 12 months compared with 12.5% in the control group (P = .02). CONCLUSIONS: Our preliminary results suggest that this comprehensive approach to physical rehabilitation can improve adherence, kidney function, quality of life, and employment rate for obese patients after kidney transplantation.

High rate of unemployment after kidney transplantation: analysis of the United network for organ sharing database.

INTRODUCTION: Despite an increased quality of life after transplant, in the United States, recipients participate less in employment compared to the general population. Employment after kidney transplantation is an important marker of clinically significant individual health recovery. Furthermore, it has been shown that employment status in the post-transplant period has a strong and independent association with patient and graft survival. MATERIALS AND METHODS: Using the United Network for Organ Sharing (UNOS) database, we identified all adults (between 18 and 64 years of age) who underwent kidney transplantation between 2004 and 2011. Patients with a stable renal allograft function and with full 1-, 3-, and 5-year follow-up were included. For recipients of multiple transplants, the most recent transplant was considered the target transplant. The data collected included employment rate after kidney transplantation in recipients employed and unemployed before transplant. The employment data were stratified for insurance payer (private, Medicaid, and Medicare). The results of categorical variables are reported as percentages. Comparisons between groups for categorical data were performed using the χ(2) test with Yates continuity correction or Fisher test when appropriate. RESULTS: The UNOS database available for this study included a total of 100,521 patients. The employment rate at the time of transplant was 23.1% (n = 23,225) under private insurance and 10% (n = 10,032) under public insurance (Medicaid and Medicare, P < .01, compared to private insurance). Over a total of 29,809 recipients analyzed, alive and with stable renal allograft function who were working at time of transplantation, the employment rate was 47% (n = 14,010), 44% (n = 13,115), and 43% (n = 12,817) at 1, 3, and 5 years after transplant under private insurance and 16% (n = 4769), 14% (n = 4173), and 12% (n = 3567), respectively, under public insurance (P < .01, compared to private insurance). Over a total of 46,363 recipients alive and with stable renal function who were not working at time of transplant, the employment rate was 5.3% (n = 2457), 5.6% (n = 2596), and 6.2% (n = 2874) at 1, 3, and 5 years after transplant under private insurance and 6.5% (n = 3013), 7.8% (n = 3616), and 7.5% (n = 3477), respectively, under public insurance (P < .01, compared to private insurance). CONCLUSION: The employment rates at the time of transplant in the United States are generally low, although privately insured patients are significantly more likely than patient with public insurance to have employment. Only a portion of these patients returns to work after transplantation. For the patients unemployed at the time of transplantation, the chance to find a job afterward is quite low even in privately insured patients. A concerted effort should be made by the transplant community to improve the ability of successful kidney transplant recipients to return to work or find a new employment. It had been shown that employment status in the post-transplant period has a strong and independent association with the graft and recipient survival.

Cerebellar abscess caused by Listeria monocytogenes in a liver transplant patient.

Brain abscesses are a rare but serious complication and have been documented in transplant recipients. Aspergillus is by far the most frequent etiology of post-transplant brain abscesses. Bacteria, apart from Nocardia, have a low association with brain abscesses in transplant recipients. We report herein the case of a 52-year-old man who had undergone orthotopic liver transplantation (OLT) for end-stage liver disease and hepatocellular carcinoma secondary to chronic hepatitis, and who developed a cerebellar abscess (CA) from Listeria monocytogenes. Three months after transplantation, he presented with a 1-week history of headache and vomiting. Computed tomography scan of the brain revealed a space-occupying lesion in the right cerebellum, which was further confirmed by magnetic resonance imaging. Emergency surgery was planned because of pressure effect on the surrounding structures. The patient recovered smoothly from the surgery. To our knowledge, no reports of Listeria CA following OLT have been published in the English literature. This case shows that, although extremely rare, L. monocytogenes may cause CA in liver transplant recipients, and clinicians should be aware of this, so that prompt diagnosis and treatment can be instituted before serious brain damage can occur.

Unconventional extrahepatic neovascularization after transplant hepatic artery thrombosis: a case report.

Liver neovascularization preserves hepatic function and improves survival in the setting of post-transplant hepatic artery thrombosis (HAT). In this report, we have presented a unique case of a neovascularized liver after subclinical HAT in a 46-year-old liver transplant patient in whom a collateral supply was recruited from three unconventional sources: The right colic, right intercostal, and right inferior adrenal arteries. We propose systematic angiographic evaluation of all potential sources of collateral vessel formation for patients with HAT to accurately assess patient risk and determine the need for further intervention or revascularization.

Prospective qualitative and quantitative non-invasive evaluation of intestinal acute GVHD by contrast-enhanced ultrasound sonography.

Intestinal acute GVHD (I-aGVHD) is a life-threatening complication after allografting. Non-invasive bed-side procedures to evaluate extension and treatment response are still lacking. We hypothesized that, during I-aGVHD, contrast-enhanced ultrasound sonography (CEUS) could detect microcirculation changes (MVC) of the bowel wall (BW) and help to monitor treatment response. We prospectively employed CEUS in 83 consecutive patients. Of these, 14 patients with biopsy-proven intestinal GVHD (I-GVHD) were defined as the study group, whereas 16 patients with biopsy-proven stomach GVHD (U-GVHD) without intestinal symptoms, 6 normal volunteers and 4 patients with neutropenic enterocolitis were defined as the control group. All patients were evaluated with both standard ultrasonography (US) and CEUS at the onset of intestinal symptoms, during clinical follow-up and at flare of symptoms. Standard US revealed BW thickening of multiple intestinal segments, useful to determine the extension of GVHD. CEUS showed MVC, which correlated with GVHD activity, treatment response, and predicted flare of intestinal symptoms. US and CEUS findings were superimposable at diagnosis and in remission. CEUS was, however, more sensitive and specific to identify subclinical activity in patients with clinical relevant improvement. These findings were not observed in the control groups. CEUS is a non-invasive, easily reproducible bed-side tool useful to monitor I-aGVHD.

The use of bortezomib as a rescue treatment for acute antibody-mediated rejection: report of three cases and review of literature.

Antibody-mediated rejection (AMR) typically occurs early after transplantation in approximately 5%-7% of recipients. The literature reports suggest that 12%-37% of kidney transplant recipients with acute AMR do not respond to treatment and eventually lose their grafts. The proteasome inhibitor bortezomib is currently approved by the Food and Drug Administration for the treatment of multiple myeloma. It has been demonstrated both in vitro and in vivo to possess apoptotic properties against mature plasma cells. Herein we have described a series of 3 patients with positive cross-matches who developed early AMR after kidney transplantation. Bortezomib rescue treatment was administered after the patients failed to respond to plasmapheresis/intravenous immunoglobulin and splenectomy. All 3 patients responded with full, durable recovery of renal function. In conclusion, bortezomib is useful to treat refractory AMR after kidney transplantation.

Circulation of West Nile virus lineage 1 and 2 during an outbreak in Italy.

In 2011, from 26 September to 16 October, a small outbreak of West Nile virus (WNV) disease occurred on the island of Sardinia (Italy). According to the national case definition, six cases with acute neurological disease were confirmed in hospitalized patients, and four of them died; one of these was only 34 years old. In two case, WNV RNA was detected in urine, suggesting renal involvement. Sequence analysis showed lineage 1 and 2 circulation.

The role of splenectomy in the setting of refractory humoral rejection after kidney transplantation.

Living donor kidney transplantation remains the best option for presensitized recipients to avoid excessive time on the waiting list. However, the possibility for a positive crossmatch with a potential living donor is high. A desensitization protocol may be required to avoid antibody-mediated rejection (AMR). Current protocols are not always effective to prevent AMR and in some cases fail to convert subjects to a negative crossmatch before transplantation. From March 2006 to January 2011, the 11 presensitized patients who displayed AMR after living donor kidney transplantation underwent splenectomy as a rescue procedure due to failure of standard rejection treatments. Splenectomy was considered to be effective in six recipients who normalized their renal function without the need for other immunomodulating therapy. Our analysis suggested that splenectomy can be successfully performed alone or in association with other treatments like bortezomib or rituximab to overcome severe AMR.