Utilization of immediate extubation in a multidisciplinary pathway for pediatric liver transplantation associated with improved postoperative outcomes.

BACKGROUND: Immediate extubation is becoming more common in liver transplantation. However, limited data exist on how to identify pediatric patients with potential for successful immediate extubation and how this intervention may affect recovery. METHODS: This retrospective review evaluated patients who underwent liver transplantation from 2015 to 2021 at Children's Healthcare of Atlanta. Preoperative status and intraoperative management were evaluated and compared. Outcomes comprised thrombosis, surgical reexploration, retransplantation, as well as reintubation, high flow nasal cannula (HFNC) usage, postoperative infection, the length of stay (LOS), and mortality. RESULTS: A total of 173 patients were analyzed, with 121 patients (69.9%) extubated immediately. The extubation group had older age (median 4.0 vs 1.25 years, p = .048), lower PELD/MELD (28 vs. 34, p = .03), decreased transfusion (10.2 vs. 41.7 mL/kg, p < .001), shorter surgical time (332 vs. 392 min, p < .001), and primary abdominal closure (81% vs. 40.4%, p < .001). Immediate extubation was associated with decreased HFNC (0.21 vs. 0.71 days, p = .02), postoperative infection (9.9% vs. 26.9%, p = .007), mortality (0% vs. 5.8%, p = .036), and pediatric intensive care unit LOS (4.7 vs. 11.4 days, p < .001). The complication rate was lower in the extubation group (24.8% vs. 36.5%), but not statistically significant. CONCLUSIONS: Approximately 70% of patients were able to be successfully extubated immediately, with only 2.5% requiring reintubation. Those immediately extubated had decreased need for HFNC, lower infection rates, shorter LOS, and decreased mortality. Our results show that with proper patient selection and a multidisciplinary approach, immediate extubation allows for improved recovery without increased respiratory complications after pediatric liver transplantation.

Surgical Versus Image-Guided Interventions in the Management of Complications After Liver Transplantation.

Liver transplantation is a technically demanding surgical procedure with known complications, and the optimal approach to addressing vascular and biliary complications requires a coordinated effort between surgical and interventional radiology teams. Vascular complications involving the hepatic artery, portal vein, or hepatic veins can be characterized by their mechanism, chronicity, and timing of presentation. These factors help determine whether the optimal therapeutic approach is surgical or endovascular. Very early presentation in the perioperative period favors surgical revision, while later presentation is best addressed endovascularly. Biliary complications can be categorized as leaks or strictures, and coordinated surgical, endoscopic, and percutaneous management is needed to address these types of complications. Through advances in technique and the management of complications, outcomes after liver transplantation continue to improve.

Detailed Analysis of Simultaneous Renal and Liver Allografts in the Presence of DSA.

Liver allografts protect renal allografts from the same donor from some, but not all, preformed donor specific alloantibodies (DSA). However, the precise mechanisms of protection and the potential for more subtle alterations/injuries within the grafts resulting from DSA interactions require further study. Methods: We reevaluated allograft biopsies from simultaneous liver-kidney transplant recipients who had both allografts biopsied within 60 d of one another and within 30 d of DSA being positive in serum (positive: mean florescence intensity ≥5000). Routine histology, C4d staining, and specialized immunohistochemistry for Kupffer cells (KCs; CD163) and a C4d receptor immunoglobulin-like transcript-4 were carried out in 4 patients with 6 paired biopsies. Results: Overt antibody-mediated rejection was found in 3 of 4 renal and liver allografts. One patient had biopsy-confirmed renal and liver allograft antibody-mediated rejection despite serum clearance of DSA. All biopsies showed KC hypertrophy (minimal: 1; mild: 2; moderate: 1; severe: 2) and cytoplasmic C4d KC staining was easily detected in 2 biopsies from 2 patients; minimal and negative in 2 biopsies each. Implications of which are discussed. Control 1-y protocol liver allograft biopsies from DSA- recipients showed neither KC hypertrophy nor KC C4d staining (n = 6). Conclusions: Partial renal allograft protection by a liver allograft from the same donor may be partially mediated by phagocytosis/elimination of antibody and complement split products by KCs, as shown decades ago in controlled sensitized experimental animal experiments.

A Case of "Cryptammonia": Disseminated Cryptococcal Infection Generating Profound Hyperammonemia in a Liver Transplant Recipient.

Mycoplasma and Ureaplasma infections have been described as a cause of hyperammonemia syndrome leading to devastating neurological injury in the post-transplant period, most commonly in lung transplant recipients. The occurrence of significant hyperammonemia caused by other urease-producing organisms remains unclear. We describe a case of disseminated cryptococcosis presenting with profound hyperammonemia in a 55-year-old orthotopic liver transplant recipient. Through a process of elimination, other potential causes for hyperammonemia were excluded revealing a probable association between hyperammonemia and disseminated cryptococcosis.

Adenovirus causing hepatic abscess formation and unexplained fever in adult liver transplant recipients.

Adenovirus infection is commonly associated with self-limited respiratory and gastrointestinal illnesses. However, infection in immunocompromised individuals, such as transplant recipients, can cause severe life-threatening illness including pneumonitis, hemorrhagic cystitis, nephritis, hepatitis, and enterocolitis. In orthotopic liver transplant recipients, adenovirus viremia can cause hepatitis leading to marked transaminitis, allograft loss, and death. Although hepatic abscesses mediated by adenovirus have been described in other immunosuppressed patient populations, it has very rarely been described in liver transplant recipients. Here, we report two adult cases of hepatic abscesses following liver transplantation secondary to adenovirus infection and describe the successful treatment of these patients. Adenovirus should be considered as an uncommon etiology of hepatic abscess and unexplained fevers in adults following liver transplantation.

Racial, Ethnic, and Socioeconomic Disparities in Web-Based Patient Portal Usage Among Kidney and Liver Transplant Recipients: Cross-Sectional Study.

BACKGROUND: Kidney and liver transplant recipients must manage a complex care regimen after kidney transplant. Although the use of Web-based patient portals is known to improve patient-provider communication and health outcomes in chronic disease populations by helping patients manage posttransplant care, disparities in access to and use of portals have been reported. Little is known about portal usage and disparities among kidney and liver transplant recipients. OBJECTIVE: The aim of this study was to examine patient racial/ethnic, socioeconomic, and clinical characteristics associated with portal usage among kidney and liver transplant recipients. METHODS: The study included all adult kidney and liver transplant recipients (n=710) at a large academic transplant center in the Southeastern United States between March 2014 and November 2016. Electronic medical record data were linked with Cerner portal usage data. Patient portal use was defined as any portal activity (vs no activity) recorded in the Cerner Web-based portal, including viewing of health records, lab results, medication lists, and the use of secure messaging. Multivariable log-binomial regression was used to determine the patient demographic, clinical, and socioeconomic characteristics associated with portal usage, stratified by organ. RESULTS: Among 710 transplant recipients (n=455 kidney, n=255 liver), 55.4% (252/455) of kidney recipients and 48.2% (123/255) of liver recipients used the patient portal. Black patients were less likely to use the portal versus white patients among both kidney (57% black vs 74% white) and liver (28% black vs 55% white) transplant recipients. In adjusted multivariable analyses, kidney transplant recipients were more likely to use the portal if they had higher education; among liver recipients, patients who were white versus black and had higher education were more likely to use the portal. CONCLUSIONS: Despite studies showing that patient portals have the potential to benefit transplant recipients as a tool for health management, racial and socioeconomic disparities should be considered before widespread implementation. Transplant centers should include portal training and support to all patients to encourage use, given its potential to improve outcomes.

Corticosteroids and methotrexate as adjuvants to costimulation blockade in non-human primate renal transplantation.

Belatacept, the CD28-B7 costimulation pathway inhibitor, has been approved as a calcineurin inhibitor (CNI) alternative in kidney transplantation. Although costimulation blockade (CoB) allows for CNI avoidance, it is associated with increased rates of early rejection, prompting a search for agents to pair with belatacept. Methotrexate (MTX) is an antimetabolite that has been found to be complimentary with abatacept, a lower affinity CD28-B7-specific analogue of belatacept, in the treatment of rheumatoid arthritis (RA). We examined whether this synergy would extend to prevention of kidney allograft rejection. Rhesus macaques underwent kidney transplantation treated with abatacept maintenance therapy with either a steroid taper, MTX, or both. The combination of abatacept maintenance with steroids prolonged graft survival compared to untreated historical controls and previous reports of abatacept monotherapy. The addition of MTX did not provide additional benefit. These data demonstrate that abatacept with adjuvant therapy may delay the onset of acute rejection, but fail to show synergy between abatacept and MTX beyond that of steroids. These findings indicate that MTX is unlikely to be a suitable adjuvant to CoB in kidney transplantation, but also suggest that with further modification, a CoB regimen used for advanced RA may suffice for RA patients requiring kidney transplantation.

Pancreas transplantation in unconventional recipients.

PURPOSE OF REVIEW: Advances in surgical technique and immunosuppression have significantly improved outcomes after pancreas transplantation, and as a result pancreas transplants increasingly are being performed for indications other than type 1 diabetes mellitus. This review summarizes the current literature on pancreas transplantation in unconventional recipient populations. RECENT FINDINGS: An increasing body of work suggests that pancreas transplantation can be performed with good outcomes in patients with type 2 diabetes mellitus and those 50 years of age and older. Obesity appears detrimental to patient and pancreas graft survival, and bariatric surgery prior to transplantation may be of increasing interest and relevance. There are limited data yielding mixed outcomes on pancreas transplantation in patients with HIV or hepatitis C virus. However, rapidly improving antiviral therapies are prolonging survival in patients with HIV and chronic hepatitis C virus infections and may increase the number of candidates available for pancreas transplantation in these populations in the future. SUMMARY: Despite limited literature in these patient populations, pancreas transplantation may be a viable treatment option for endocrine pancreas failure in appropriately selected patients regardless of disease cause or age.

Biomarkers for kidney transplant rejection.

The immune management of organ transplant recipients is imperfect. Beyond general dosing guidelines for immunosuppressive agents and clinical diagnostic tests for rejection or infection, there are few objective tools to determine the aggregate status of a patient's alloimmune response or protective immune capacity. The lack of prognostic precision significantly contributes to patient morbidity and reduces long-term allograft survival after kidney transplantation. Noninvasive biomarkers that could serve as predictive tools or surrogate end points for rejection might help clinicians individualize immunosuppression and allow for early intervention, ideally prior to clinically evident organ dysfunction. Although the growing understanding of organ rejection has provided numerous candidate biomarkers, none has been confirmed in robust validation studies as sufficiently useful to guide clinical practice independent of traditional clinical methods. In this Review, the general characteristics of biomarkers and surrogate end points; current biomarkers under active clinical investigation; and the prominent barriers to the translation of biomarkers into clinical practice are discussed.

Chemokines and their receptors in human renal allotransplantation.

BACKGROUND: Chemokines and their receptors play a critical role in leukocyte trafficking, and inhibition of select chemokines has been shown to attenuate kidney disease and allograft rejection in animal models. Therefore, we evaluated chemokine and chemokine receptor transcripts in human renal allograft biopsies, correlating transcript levels with clinical course and immunohistochemical analysis to relate chemokine expression to relevant clinical human disease phenotypes. METHODS: Renal biopsies were grouped as postreperfusion (n=10), stable function (n=10), subclinical (n=10) or acute rejection (n=17), or calcineurin inhibitor nephrotoxicity (n=9) based on clinical presentation and histopathologic assessment. Using quantitative real-time polymerase chain reaction analysis, chemokine transcripts were assessed relative to transcript levels in preprocurement biopsies from live donor kidneys (n=15). RESULTS: Transcripts from several inflammatory chemokines (CCL3, CCL5, CXCL9, CXCL10, and CXCL11) and chemokine receptors (CCR5, CCR7, and CXCR3) were significantly increased in allografts with subclinical and clinical acute rejection, indicating a strong polarization toward a T-helper 1 effector phenotype during rejection. These transcripts also distinguished acutely rejecting allografts from allografts with nonrejection causes of renal dysfunction. Biopsies from patients with stable function without histologic evidence of rejection had increased chemokine transcript levels that were qualitatively similar but quantitatively reduced compared with rejecting allografts. CONCLUSIONS: This comprehensive evaluation of chemokines and their receptors in human renal transplantation defines associations between chemokine expression and clinical phenotypes, may have diagnostic utility, and highlights relevant pathways for therapeutic intervention.

Regulation of the rat follicle-stimulating hormone beta-subunit promoter by activin.

FSH is controlled by a variety of positive and negative stimuli, and the unique FSHbeta-subunit is a major target for this regulation. Activin is a key modulator of FSHbeta transcription and hormone secretion. The signal transduction pathway leading to FSH expression was previously unknown. Here, we show that the transcription factors Smad3 and Smad4 mediate activin-stimulated activity of the rat FSHbeta promoter in a pituitary-derived cell line, LbetaT2. Cells were transiently transfected with the rat FSHbeta promoter fused to a luciferase reporter gene (-338rFSHbeta-Luc), and a minimal activin-responsive region was identified. Transfection of Smad3, but not the highly related Smad2, led to a ligand-independent stimulation of the FSHbeta promoter activity. As expected, activin caused an additional increase of luciferase expression, which was blocked by cotreatment with follistatin. Although Smad4 alone had no effect on FSHbeta transcription, it significantly augmented Smad3 and activin-mediated stimulation of the promoter. A palindromic consensus Smad-binding element in the proximal promoter was found to bind Smad4, and elimination of the region resulted in a loss of activin-mediated FSHbeta transcription. The activin signaling pathway is conserved in a number of cells, but FSHbeta expression is restricted to gonadotropes. A pituitary-specific transcription factor necessary for activin-dependent induction of the FSHbeta promoter has been identified that permits FSHbeta expression in nongonadotrope cells. Pitx2 is a member of Pitx subfamily of bicoid-related homeodomain factors that is required for pituitary development and is present in the adult pituitary. This factor was transfected into LbetaT2 cells, where it caused up-regulation of basal and activin-mediated FSHbeta promoter activity. Furthermore, cotransfection of Pitx2c with Smad3 in kidney-derived TSA cells resulted in activin-regulated FSHbeta response, suggesting its important role in tissue-restricted regulation of FSHbeta by activin. A Pitx2c binding site was identified within the proximal promoter, and elimination of this region also resulted in a loss of activin-regulated FSHbeta promoter activity. Taken together, these studies suggest that the regulation of FSHbeta is dependent on activin-mediated signaling factors in concert with pituitary-derived nuclear regulatory proteins.