Urea cycle disorders and indications for liver transplantation.

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to convert nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and liver transplantation. The aim of this study was to describe the characteristics and indication of liver transplantation in UCD in a tertiary hospital. We performed a retrospective study of children with UCD seen in the period 2000-2021. Data was collected on clinical onset, hyperammonemia severity, evolution and liver transplantation. There were 33 patients in the study period, whose diagnosis were: ornithine transcarbamylase (OTC, n = 20, 10 females), argininosuccinate synthetase (ASS, n = 6), carbamylphosphate synthetase 1 (CPS1, n = 4), argininosuccinate lyase (ASL, n = 2) and N-acetylglutamate synthetase (NAGS, n = 1) deficiency. Thirty one were detected because of clinical symptoms (45% with neonatal onset). The other 2 were diagnosed being presymptomatic, by neonatal/family screening. Neonatal forms (n = 14) were more severe, all of them presented during the first week of life as severe hyperammonemia (mean peak 1,152 µmol/L). Seven patients died (6 at debut) and all survivors received transplantation. There was no mortality among the late forms. Of the 27 patients who did not die in the neonatal period, 16 (59%) received liver transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation. The transplant's metabolic success was accompanied by neurologic sequelae in 69%, but there was no progression of brain damage. Decision of continuous medical treatment in 11 patients appeared to be related with preserved neurodevelopment and fewer metabolic crises.

Pets for pediatric transplant recipients: To have or not to have.

Pets have many health, emotional and social benefits for children, but the risk of zoonotic infections cannot be underestimated, especially for immunosuppressed patients. We report the recommendations given by health professionals working with pediatric transplant recipients to their families regarding pet ownership. An online survey addressing zoonosis knowledge and recommendations provided by health care practitioners regarding pets was distributed to clinicians treating pediatric transplant recipients. The European Society of Pediatric Infectious Disease (ESPID) and the European Reference Network ERN-TransplantChild, which works to improve the quality of life of transplanted children, allowed the online distribution of the survey. A total of 151 practitioners from 28 countries participated in the survey. Up to 29% of the respondents had treated at least one case of zoonosis. Overall, 58% of the respondents considered that the current available evidence regarding zoonotic risk for transplanted children of having a pet is too scarce. In addition, up to 23% of the surveyed professionals recognized to be unaware or outdated. Still, 27% of the respondents would advise against buying a pet. Practitioners already owning a pet less frequently advised patients against pet ownership, whereas non-pet-owners were more keen to advise against pet ownership (p = 0.058). 61% of the participants stated that there were no institutional recommendations regarding pets in their centers/units. However, 43% of them reported therapeutic initiatives that involved animals in their centers. Infectious disease specialists were more likely to identify zoonotic agents among a list of pathogens compared to other specialists (p < 0.05). We have observed a huge heterogeneity among the recommendations that health care providers offer to families in terms of risk related to pet ownership for transplant recipients. The lack of evidence regarding these recommendations results in practitioners' recommendations based on personal experience.

Clinical outcome of SARS-CoV-2 infection in immunosuppressed children in Spain.

Limited information is available regarding SARS-CoV-2 infections in children with underlying diseases. A retrospective study of children less than 15 years old with primary or secondary immunosuppression infected with SARS-CoV-2 during March 2020 was performed. In this series, 8 immunocompromised patients with COVID-19 disease are reported, accounting for 15% of the positive cases detected in children in a reference hospital. The severity of the symptoms was mild-moderate in the majority with a predominance of febrile syndrome, with mild radiological involvement and in some cases with mild respiratory distress that required oxygen therapy. The rational and prudent management of these patients is discussed, evaluating possible treatments and options for hospitalization or outpatient follow-up.Conclusion: In our experience, monitoring of children with immunosuppression and COVID-19 disease can be performed as outpatients if close monitoring is possible. Hospitalization should be assessed when high fever, radiological involvement, and/or respiratory distress are present. What is Known: • SARS-CoV-2 infection is usually mild in children. What is New: • Outcome of immunosuppressed children with COVID-19 is generally good, with a mild-moderate course.

Effectiveness of immunosuppression minimisation, conversion or withdrawal strategies in paediatric solid organ and haematopoietic stem cell transplantation: a protocol of a systematic review and meta-analysis.

INTRODUCTION: Paediatric transplantation is the only curative therapeutic procedure for several end-stage rare diseases affecting different organs and body systems, causing altogether great impact in European children's health and quality of life. Transplanted children shift their primary disease to a chronic condition of immunosuppression to avoid rejection. Longer life expectancy in children poses a greater risk of prolonged and severe side effects related to long-term immunosuppressive (IS) disabilities and secondary cancer susceptibility. The goal remains to find the best combination of IS agents that optimises allograft survival by preventing acute rejection while limiting drug toxicities. This systematic review will aim to determine the optimal IS strategy within the so-called minimisation, conversion or withdrawal strategies. METHODS AND ANALYSIS: We will search the following databases with no language restrictions: Cochrane Central Register of Controlled Trials in the Cochrane Library, OvidSP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; OvidSP Embase Classic+Embase; Ebsco CINAHL Plus, complete database; WHO International Clinical Trials Registry Platform search portal. We will include controlled and uncontrolled clinical trials along with any prospective or retrospective study that includes a universal cohort (all participants from a centre/region/city over a certain period). Cases series and cross-sectional studies are excluded. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. The outcomes included in this review are: patient survival, acute graft rejection, chronic graft rejection, diabetes, graft function, graft loss, chronic graft versus host disease, acute graft versus host disease, surgical complications, infusion complications, post-transplant lymphoproliferative disease, liver function, renal function, cognition, depression, health-related quality of life, hospitalisation, high blood pressure, low blood pressure, cancer-other, cancer-skin, cardiovascular disease, bacterial infection, Epstein-Barr infection, cytomegalovirus infection, other viral infections and growth.

Similarities and Differences in Allocation Policies for Pediatric Liver Transplantation Across the World.

OBJECTIVES: We aimed to investigate national allocation policies for pediatric liver transplantation (LT). METHOD: A survey was prepared by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Hepatology Committee in collaboration with the North American Studies of Pediatric Liver Transplantation consortium. The survey was sent to pediatric hepatologists and transplant surgeons worldwide. National data were obtained from centrally based registries. RESULTS: Replies were obtained from 15 countries from 5 of the world continents. Overall donation rate varied between 9 and 35 per million inhabitants. The number of pediatric LTs was 4 to 9 per million inhabitants younger than 18 years for 13 of the 15 respondents. In children younger than 2 years mortality on the waiting list (WL) varied between 0 and 20%. In the same age group, there were large differences in the ratio of living donor LT to deceased donor LT and in the ratio of split liver segments to whole liver. These differences were associated with possible discrepancies in WL mortality. CONCLUSIONS: Similarities but also differences between countries were detected. The described data may be of importance when trying to reduce WL mortality in the youngest children.

Pharmacokinetics of tacrolimus granules in pediatric de novo liver, kidney, and heart transplantation: The OPTION study.

Tacrolimus granules were developed for patients who are unable to swallow capsules. Therapeutic drug monitoring (TDM) is required to optimize efficacy and safety, which is based on Ctrough for tacrolimus capsules. Pharmacokinetic (PK) data for tacrolimus granules are required to establish the basis for TDM in those who are unable to swallow capsules. In this phase IV study (NCT01371331) of children undergoing liver, kidney, or heart transplantation, patients received tacrolimus granules 0.15 mg/kg twice daily; first dose was administered within 24 hours of reperfusion. PK analysis samples were collected after reperfusion, after first dose of tacrolimus (Day 1), and at steady state (Day 7; >4 days stable dose). Of the 52 transplant recipients enrolled, 38 had two evaluable PK profiles. Mean AUCtau after first dose of tacrolimus was 211, 97, and 224 hour*ng/mL in liver, kidney, and heart transplant recipients, respectively; corresponding mean AUCtau at steady state was 195, 208, and 165 hour*ng/mL. Ctrough and AUCtau were positively correlated after first dose of tacrolimus and at steady state (Pearson's coefficients: r = 0.81 and r = 0.87, respectively). This study demonstrated that Ctrough is a reliable marker for TDM in pediatric transplant recipients treated with tacrolimus granules, consistent with TDM for other tacrolimus formulations.

Early and Late Factors Impacting Patient and Graft Outcome in Pediatric Liver Transplantation: Summary of an ESPGHAN Monothematic Conference.

As pediatric liver transplantation comes of age, experts gathered to discuss current paradigms and define gaps in knowledge warranting research to further improve patient and graft outcomes. Identified areas ripe for collaborative research include understanding the molecular and cellular mechanisms of tolerance and the role of donor-specific antibodies, considering ways to expand donor pool, minimizing long-term side effects of immunosuppression, and fine-tuning surgical techniques to minimize biliary and vascular complications.

Conversion from Prograf to Advagraf in adolescents with stable liver transplants: comparative pharmacokinetics and 1-year follow-up.

The recommended dose of Advagraf for conversion from Prograf is considered to be 1:1 on a milligram basis. However, the long-term equivalence of Prograf and Advagraf has been questioned. The relative bioavailability of Advagraf and Prograf was evaluated in a single-center, open-label study of Prograf-to-Advagraf conversion in 20 patients, ranging in age from 12 to 18 years, who had a stable liver transplant and were receiving Prograf. After the supervised administration of Prograf for 7 days, the patients were converted to Advagraf. On days 7 and 14, serial blood samples were obtained for tacrolimus determinations. The pharmacokinetic parameters were calculated with a noncompartmental approach, and the relative bioavailability of both formulations was calculated according to standard statistical methods. Polymorphisms in cytochrome P450 3A5 (rs776746), adenosine triphosphate-binding cassette B1 (rs1045642), POR*28 (rs1057868), and POR (rs2868177) were determined with standard methods. The clinical and analytical data from a 1-year follow-up period were collected for all patients 30, 90, 180, and 360 days after conversion. The mean ratios for Cmax and AUC0-24 were 96.9 (90% confidence interval = 85.37-110.19) and 100.1 (90% confidence interval = 90.8-112.1), respectively. No relationship was found between the patients' genotypes and the pharmacokinetic tacrolimus values. During the follow-up, biochemical parameters (aspartate aminotransferase, alanine aminotransferase, bilirubin, cystatin C, and creatinine) did not change significantly; 3 patients presented with relevant clinical events, but no event was considered to be related to tacrolimus. A decrease in tacrolimus blood levels and an increase in dose/level ratios were observed 3 and 6 months after conversion, but they returned to basal levels by month 12. In conclusion, conversion from Prograf to Advagraf with a 1:1 dose equivalence is appropriate as an initial guideline. Our 1-year follow-up showed a transient decrease in tacrolimus levels, so closer monitoring of tacrolimus levels may be required after conversion.

Recomendaciones GESITRA-SEIMC/REIPI para el manejo de la infección por citomegalovirus en pacientes trasplantados de órgano sólido / GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients

La infección por citomegalovirus (CMV) constituye una complicación importante en los pacientes sometidos a trasplante de órgano sólido (TOS). En el año 2005 el Grupo de Estudio de Infección en el Trasplante (GESITRA) de la Sociedad Española de Microbiología Clínica y Enfermedades Infecciosas (SEIMC) elaboró un documento de consenso para la profilaxis y el tratamiento de la infección por CMV en pacientes sometidos a TOS. Desde entonces han sido numerosas las publicaciones que o bien han aclarado, o bien han planteado nuevas dudas respecto a los aspectos tratados en el anterior documento. Entre estos aspectos se encuentran las situaciones y poblaciones que deben recibir profilaxis y su duración, la elección de la mejor técnica para el diagnóstico y monitorización y la elección de la mejor estrategia terapéutica. Todo ello justifica la necesidad de elaborar un nuevo documento de consenso que incluya las últimas recomendaciones en el manejo de la infección por CMV post-trasplante en base a las nuevas evidencias disponibles (AU)

Abstract Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available (AU)

Peculiaridades del manejo de la infección por citomegalovirus en el trasplante de órgano sólido en pacientes pediátricos / Special considerations in the management of cytomegalovirus infection in pediatric solid organ transplant recipients

Durante años, ganciclovir intravenoso ha sido el tratamiento recomendado para la enfermedad por citomegalovirus (CMV) en pacientes trasplantados. En los últimos años, valganciclovir oral ha mostrado una similar respuesta frente a CMV que ganciclovir intravenoso, por lo que puede ser utilizado alternativamente a ganciclovir en pacientes con enfermedad no grave. La terapia secuencial con ganciclovir seguido de valganciclovir, tras iniciarse la mejoría clínica, reduce costes y evita hospitalizaciones prolongadas, lo que supone un beneficio para los pacientes. La duración óptima del tratamiento irá guiada por la respuesta clínica y los controles virológicos (PCR o antigenemia), manteniéndose hasta que éstos sean negativos. Algunos grupos utilizan profilaxis secundaria ante la presencia de factores de riesgo de recidiva de la enfermedad por CMV. Reducir la intensidad de la inmunosupresión o complementar la terapia antiviral con inmunoglobulinas son medidas a considerar en casos graves o en grandes inmunodeprimidos. No hay datos firmes acerca del mejor tratamiento alternativo ante la evidencia de CMV resistente a ganciclovir. Las decisiones terapéuticas deberán sustentarse en el estudio genotípico de resistencias, el estado inmune del paciente y en la gravedad de la enfermedad. El tratamiento consiste en foscarnet solo o con ganciclovir en las formas más graves y en mutaciones de alta resistencia, o en el incremento de las dosis de ganciclovir en las formas clínicas o de resistencia más benignas. No hay datos concluyentes acerca de antivirales alternativos o de terapia complementaria con inhibidores de mTOR. Se ensayan diversas vacunas frente a CMV con resultados preclínicos esperanzadores (AU)

In pediatric patients, the main risk factor for the development of post-transplantation cytomegalovirus (CMV) is the absence of specific immunity to the virus in the pretransplantation period. CMV infection has become less of a problem in pediatric solid organ transplant (SOT) recipients mainly due to the availability of sensitive diagnostic techniques, the development of prevention strategies, and the possibility of starting effective antiviral treatments. Both polymerase chain reaction (PCR) techniques and pp65 antigenemia have proved to be effective in the diagnosis and monitoring of children with CMV infection. However, in some types of transplantation, such as lung transplantation, CMV infection continues to be an important risk factor for mortality or retransplantation in D+/R-1 patients. Prophylaxis with ganciclovir followed by valganciclovir for between 3 and 6 months is recommended over preemptive therapy. In the treatment of CMV disease, the use of ganciclovir is recommended until a negative weekly result of PCR or pp65 antigenemia is obtained. The total duration of treatment, both in viral syndrome and organ disease, is the same as in adults. Treatment can be completed by substituting intravenous ganciclovir for oral treatment in older children and adolescents (AU)

GESITRA-SEIMC/REIPI recommendations for the management of cytomegalovirus infection in solid-organ transplant patients.

Cytomegalovirus infection remains a major complication of solid organ transplantation. In 2005 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, numerous publications have clarified or questioned the aspects covered in the previous document. These aspects include the situations and populations who must receive prophylaxis and its duration, the selection of the best diagnosis and monitoring technique and the best therapeutic strategy. For these reasons, we have developed new consensus guidelines to include the latest recommendations on post-transplant CMV management based on new evidence available.

[Special considerations in the management of cytomegalovirus infection in pediatric solid organ transplant recipients]. / Peculiaridades del manejo de la infección por citomegalovirus en el trasplante de órgano sólido de pacientes pediátricos.

In pediatric patients, the main risk factor for the development of post-transplantation cytomegalovirus (CMV) is the absence of specific immunity to the virus in the pretransplantation period. CMV infection has become less of a problem in pediatric solid organ transplant (SOT) recipients mainly due to the availability of sensitive diagnostic techniques, the development of prevention strategies, and the possibility of starting effective antiviral treatments. Both polymerase chain reaction (PCR) techniques and pp65 antigenemia have proved to be effective in the diagnosis and monitoring of children with CMV infection. However, in some types of transplantation, such as lung transplantation, CMV infection continues to be an important risk factor for mortality or retransplantation in D+/R(-1) patients. Prophylaxis with ganciclovir followed by valganciclovir for between 3 and 6 months is recommended over preemptive therapy. In the treatment of CMV disease, the use of ganciclovir is recommended until a negative weekly result of PCR or pp65 antigenemia is obtained. The total duration of treatment, both in viral syndrome and organ disease, is the same as in adults. Treatment can be completed by substituting intravenous ganciclovir for oral treatment in older children and adolescents.

Recurrence of bile salt export pump deficiency after liver transplantation.

Severe bile salt export pump (BSEP) deficiency is a hereditary cholestatic condition that starts in infancy and leads to end-stage liver disease. Three children who underwent orthotopic liver transplantation for severe BSEP deficiency had post-transplantation episodes of cholestatic dysfunction that mimicked the original disease. Remission of all episodes was achieved by intensifying the immunosuppressive regimen. The phenotypic recurrence of the disease correlated with the presence of circulating high-titer antibodies against BSEP that inhibit transport by BSEP in vitro. When administered to rats, these antibodies targeted the bile canaliculi and impaired bile acid secretion.

Efficacy and safety of valganciclovir in liver-transplanted children infected with Epstein-Barr virus.

Epstein-Barr virus (EBV) infection after liver transplantation (LT) is associated with increased risk of posttransplant lymphoproliferative disorder (PTLD). Lowering immunosuppression is the current method to prevent PTLD in LT children with a high viral load. The aim of this study was to assess the efficacy and safety of valganciclovir (VGCV) in children with EBV infection after LT. Forty-seven children showing detectable EBV-DNA (72% asymptomatic) were treated with VGCV (520 mg/sqm twice daily) with no immunosuppression decrease (except in 4 cases). VGCV treatment started 17 months (median) after the onset of EBV infection. A 30-day treatment applied to 26 patients led to undetectable EBV-DNA in 11/32 courses (34.3%), with 82% relapsing. A long VGCV treatment (median: 8 months) achieved undetectable EBV-DNA in 20/42 (47.6%), 60% of whom maintained response off therapy. There were no new PTLD cases. Symptoms worsened in 1 (2.1%) in whom PTLD was suspected but not confirmed in liver and jejunum biopsies. Factors associated with achievement of undetectable EBV-DNA were a longer time from LT and a lower rate of intervening infections in comparison with nonresponders. The safety profile for VGCV was excellent. Graft rejection occurred in 6%. In conclusion, in 47 LT children with a sustained increased EBV load treated with VGCV and unchanged immunosuppression, PTLD was suspected in 1 child (2.1%). A viral load decrease could be achieved as EBV-DNA was undetectable in 47% of patients under prolonged treatment.

Efficacy and safety of peginterferon-alpha2b and ribavirin combination therapy in children with chronic hepatitis C infection.

BACKGROUND: Interferon (IFN)-alpha2b plus ribavirin is approved for treatment of hepatitis C in children; however, little is known about efficacy and tolerability of pegylated IFN (PEG-IFN)-alpha2b in this population. The objective of this study was to test the efficacy and safety of PEG-IFN-alpha2b plus ribavirin in children with chronic hepatitis C. METHODS: Thirty children 3-16 years of age who had detectable hepatitis C virus (HCV) RNA for >or=3 years after exposure and elevated alanine aminotransferase values received PEG-IFN-alpha2b 1.0 microg/kg/wk plus ribavirin 15 mg/kg/d for 24 weeks (genotype 2/3) or 48 weeks (genotype 1/4). The primary endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) at week 24 of follow-up. RESULTS: SVR was achieved in 50% of patients (3/3 genotype 3; 12/27 genotype 1/4). At week 12, 52% of patients were HCV RNA negative and 72% had a >2 log10 decrease in viral load, compared with baseline; 87% and 71% of these patients, respectively, attained an SVR. Therapy was discontinued in 3 patients as a result of adverse events. No patient required ribavirin dose reduction; PEG-IFN-alpha2b dose was reduced in 23% of patients to manage neutropenia. CONCLUSIONS: Combination therapy with PEG-IFN-alpha2b and ribavirin treatment was effective in children with chronic hepatitis C. Virologic status at week 12 identified future responders and nonresponders. PEG-IFN-alpha2b and ribavirin were reasonably well tolerated, with no unexpected or permanent adverse effects. Further studies are needed to identify the optimum treatment regimen for this patient population.

Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1.

Farnesoid X receptor (FXR) is a transcription factor that controls bile acid homeostasis. The phenotype of Fxr null mice is characterized by hypercholanaemia, impaired secretion of bile acids and failure to thrive. Human disorders with these characteristics include FIC1 disease (caused by mutations in ATP8B1, which encodes a putative aminophospholipid translocase, FIC1, whose function in bile handling is unknown) and bile salt export pump (BSEP) disease (caused by mutation in ABCB11, which encodes BSEP, the primary canalicular bile salt export pump). We investigated the possibility of hepatic down-regulation of FXR in FIC1 disease and BSEP disease. Three siblings with this phenotype, born to consanguine parents, were initially studied. The children were demonstrated to be compound heterozygotes for missense and nonsense mutations in ATP8B1. Expression of specific genes in liver was analysed, comparing one of these siblings with a child homozygous for missense mutation in ABCB11, as well as with a child having idiopathic cholestatic liver disease, a child with extrahepatic biliary atresia and a normal organ donor. The expression of two main FXR isoforms was specifically decreased in the liver of the FIC1 disease patient. A consistent and concomitant reduction in messenger RNA levels of FXR targets, such as BSEP and small heterodimer partner, was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in FIC1-disease liver. Of note was that several genes involved in synthesis, conjugation and transport of bile acids were down-regulated. A cluster of genes involved in lipid metabolism was also differentially expressed. Our findings suggest that hepatic down-regulation of FXR contributes to the severe cholestasis of FIC1 disease.

Bipartición hepática / Hepatic bipartition

La bipartición hepática representa en la actualidad un procedimiento de elección para el trasplante hepático de donante cadáver. La escasez del número de donantes existentes y el constante incremento en el número de receptores avalan este hecho. La realización de este procedimiento obliga a un riguroso protocolo de selección del donante, a una cuidadosa logística en la donación con el objetivo de no prolongar los tiempos de isquemia y al establecimiento de un consenso entre los dos equipos que van a realizar los dos implantes, a efectos de atender sus necesidades en función de la situación del receptor y las características anatómicas, y poder realizar una lógica repartición de los pedículos vasculobiliares. Dos procedimientos técnicos han sido descritos: procedimiento ex vivo e in situ. Este último está asociado con una menor incidencia de complicaciones quirúrgicas, hemorragia postoperatoria, trombosis de las reconstrucciones vasculares realizadas, complicaciones biliares y necrosis de áreas hepáticas. Si bien la bipartición hepática para un receptor adulto y otro pediátrico está claramente justificada, más dificultades existen para su realización con dos receptores adultos. Sólo debe plantearse ser efectuado con dos adultos de bajo peso, en donde el volumen hepático a implantar sea el adecuado. Los resultados obtenidos con la bipartición hepática confirman el gran beneficio para los programas pediátricos en función de la reducción de su lista de espera y las mínimas consecuencias en términos de complicaciones postoperatorias o pérdidas de injertos para los programas de adultos. (AU)