Submitted by Dr Jun Oh, Division of Ped. Nephrology, Ped. Hepatology and Ped. Transplantation, Center for Obstetrics and Pediatrics, University Medical Center Hamburg-Eppendorf

Pediatric Transplantation for Propionic Acidemia and other Non-Structural Liver Diseases

The field of liver transplantation (LT) for inborn errors of metabolism with no structural liver diseases has gained much attention over recent years, representing the fastest growing indication in the United States between 2007 and 2017 and covering 20% of pediatric transplantation (McKiernan, 2019). Within this category, the most common are urea cycle disorders (UCD), maple syrup urine disease (MSUD) and organic acidemia (OA).PA is a rare multi-systemic disorder caused by a deficiency of the mitochondrial enzyme propionyl‐CoA carboxylase. The trigger for metabolic decompensation is catabolism leading to accumulation of toxic metabolites often accompanied by lactic acidosis and hyperammonemia (Haijes, 2019). Affected patients display recurrent episodes of metabolic decompensation with subsequent risk of neurocognitive impairment, cardiomyopathy and chronic kidney failure. Even with strict dietary adherence and pharmacological therapy disease control often remains unsatisfactory. Therefore, LT has been established as a therapeutic alternative by reducing the frequency of metabolic decompensation despite a liberalization of dietary protein intake alimentary protein restriction with three major articles addressing this topic in 2020 (Alexopoulos, 2020; Curnock, 2020; Zhou, 2020).

In a recent publication from October 2020, Zhou et al. present their systematic review and meta-analysis concerning LT for PA with a total of 70 patients (Zhou, 2020). The main indications for LT were poor metabolic control (67%) and cardiomyopathy (17%). Overall patient and allograft survival were 95% and 91%, respectively. HAT (8%) among other transplant related complications were within expected ranges. The majority of 54 patients (98%) were stable from a metabolic perspective with no further metabolic crisis after LT. Data on protein intake after LT was available in 45 patients with two-third of them (66%) displaying a liberalized protein intake. Data on PA-associated cardiomyopathy was only available in a small subgroup of 11 patients. All of these 11 patients showed a reversal of their pre-existing cardiomyopathy. For another subgroup of 21 individuals available data suggested an improvement of neurodevelopmental delay in 97% after LT.

In a detailed retrospective monocentric cohort study of 14 patients by Curnock et al, patient and graft survival of 79% and 69% were satisfactory (Curnock, 2020). The number of metabolic decompensations prior to LT (median 4, range 1-30) as the main indication for LT could be reduced (median 0, range 0-5). Protein intake was liberalized in all patients after LT.  Complications including HAT (6%, 1 patient) occurred within the expected frequency compared to non-PA-LT.

Alexopoulos et al. published their results from a retrospective multicenter study including 23 patients from 10 different centers (Alexopoulos, 2020). Most patients (73.9%) in the cohort were younger than 5 years with a patient and allograft survival of 89.5% and 84.6%. No major perioperative events like HAT were reported.

The common thread between the three publications emphasizes the feasibility with comparable outcomes to LT in structural liver disease (Alexopoulos, Curnock, Zhou). Reported differences in patient and allograft are likely due to extensive span of time covered with the study by Curnock spanning the longest period including patients from 1995 (Curnock, 2020). Two of the publications present additional details about possible improvement of neurocognitive function (Curnock, 2020; Zhou, 2020).

Even though non-structural liver disease remains a heterogeneous entity in terms of specific complications and challenges, patients’ survival rates in PA can be compared to other indications in the field (Molema, 2020; Strauss, 2020). Indications for LT in patients with non-structural liver disease, such as PA, are wide-ranging: medical (metabolic decompensation), dietary (. protein-restricted diet), and neurologic (neurocognitive impairment) need to be addressed. The possible risks of a liver transplantation are often balanced against the potential benefits: (ex: patients at risk for metabolic decompensation with cumulative neurocognitive damage, early transplantation seems reasonable if not mandatory) (McKiernan, 2019; Hadzic, 2019). Patients need to be assessed on an individual basis by an experienced multidisciplinary team involving physicians experienced in pediatric liver transplantation and metabolic diseases, nurses, dieticians and particularly psychologists. All specialized centers need to share, collect and analyze their experiences with rare indications for LT including non-structural liver diseases to constantly challenge our understanding and reassess our management in this rapidly evolving field of pediatric liver transplantation.

References

1. Alexopoulos SP, Matsuoka L, Hafberg E. Liver Transplantation for Propionic Acidemia: A Multicenter-linked Database Analysis. J Pediatr Gastroenterol Nutr. 2020 Feb;70(2):178-182. Read the article
2. Curnock R, Heaton ND, Vilca-Melendez H. Liver Transplantation in Children With Propionic Acidemia: Medium-Term Outcomes. Liver Transpl. 2020 Mar;26(3):419-430. Read the article
3. Hadzic N. Metabolic Indications for Pediatric Liver Transplantation: A Slow Train Coming. Liver Transpl. 2019 Jun;25(6):829-830. Read the article
4. Haijes HA, Jans JJM, Tas SY. Pathophysiology of propionic and methylmalonic acidemias. Part 1: Complications.. J Inherit Metab Dis. 2019 Sep;42(5):730-744. Read the article
5. McKiernan PJ, Ganoza A, Squires JE. Evolving Trends in Liver Transplant for Metabolic Liver Disease in the United States. Liver Transpl. 2019 Jun;25(6):911-921. Read the article
6. Molema F, Martinelli D, Hörster F. Liver and/or kidney transplantation in amino and organic acid-related inborn errors of metabolism: An overview on European data. J Inherit Metab Dis. 2020. Read the article
7. Strauss KA, Carson VJ, Soltys K. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Mol Genet Metab. 2020 Mar;129(3):193-206. Read the article
8.  Zhou GP, Jiang YZ, Wu SS. Liver Transplantation for Propionic Acidemia: Evidence from A Systematic Review and Meta-analysis. Transplantation 2020 Oct 21. Online ahead of print. Read the article

Our Communications committee was newly formed in 2019, with the purpose to enhance the electronic and social media communications from IPTA and improve the society’s visibility, using the channels that have transformed how individuals communicate with each other.

We created an IPTA Twitter handle @IPTAPedsTx that now has 325 followers! IPTA Executive Officers and Communications Committee members have been tweeting from this account. We encourage all IPTA members who are on Twitter to follow our IPTA Twitter handle. Note that the IPTA journal Pediatric Transplantation has its own handle @pedtransjrnl. The two accounts follow each other but the journal account is handled by the publisher Wiley.

We aligned our IPTA webpage to have a similar URL name. The most recent posts through our IPTA account are now automatically shown on the IPTA website home page. The Communications Committee also assisted in making enhancements to the presentation of the IPTA home page.

In Summer 2020, we expanded the Communications Committee, to include the following members:

• Pankaj Chandak, London, UK (incoming chair)
• Lyndsey Grover, Dallas, USA
• Nima Memaran, Hannover, Germany
• Kathryn Shaw, Hollywood, USA
• David Peng, Ann Arbor, USA
• Nam-Joon Yi, Seoul, Korea 

We are excited for our IPTA social media presence to grow both on Twitter and through other platforms (Facebook, Instagram, etc) and to facilitate this, we are currently exploring options of using a professional social media person to assist the voluntary Communications Committee members and the IPTA Headquarters staff.

Respectfully submitted

Vikas Dharnidharka
Chair, Communications Committee

Publishing is often difficult for less experienced researchers, especially for those who work in structures where performing research and writing of publications are not considered a priority.

Would you like help from senior IPTA members to refine your research question or review your manuscripts to increase likelihood of publication? The Publications Committee would like to invite you to participate in the Peer Mentoring Program, designed to increase access to experienced reviews. We would like to offer to participants a chance to have dialog with those experienced in the publication process prior to final submission. Responsibilities of your mentor would reviewer style feedback to you and being available for subsequent questions. Our mentors are also willing to refine language to meet standards for publication, especially for non-native English speakers. With the IPTA meeting coming up soon, you could also receive help with drafting your abstract. If you want to become a mentee, please contact Katie Tait (katie.tait@tts.org) with your research question or manuscript!

Burkhard Tönshoff, MD, PhD, is professor of pediatrics and pediatric nephrology at the University Children’s Hospital Heidelberg, Germany; Vice Chairman of the Department of Pediatrics I (General Pediatrics, Neuropediatrics, Metabolism, Gastroenterology, and Nephrology); Medical Director of the Pediatric Kidney Transplantation Program.

He graduated from the Freiburg University School of Medicine, and completed a pediatric residency and fellowship at the University Children’s Hospital in Heidelberg, Germany. From 1992 to 1994, he served as a postdoctoral research fellow at the Division of Pediatric Nephrology and Department of Physiology, State University of New York at Stony Brook, USA with a Feodor-Lynen-research grant from the Alexander von Humboldt-Stiftung.

His current research focuses on various issues in acute and chronic kidney disease and renal transplantation, such as studies on the pharmacokinetics, efficacy and safety of novel immunosuppressive drugs in pediatric renal transplant recipients, optimization of immunosuppressive therapy by therapeutic drug monitoring and immune monitoring, prevention of infectious and other complications after renal transplantation, biomarker-guided minimization of immunosuppressive therapy and the impact of donor-specific HLA and non-HLA antibodies on graft histology and function. In the year 2009 he founded the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN; www.certain-registry.eu) as a multicenter research network and platform built on a novel, web-based registry. Other research activities focus on the pathophysiology and therapy of the nephrotic syndrome, biomarker research for acute kidney injury, the role of endothelial progenitor cells and mesenchymal stem cells in various pediatric kidney diseases and the role of the gut microbiome in solid organ transplantation.

Awards and nominations: Adalbert-Czerny-Preis der Deutschen Gesellschaft für Kinderheilkunde. Else-Kröner-Fresenius-Preis of the Arbeitsgemeinschaft Pädiatrische Nephrologie. Jürgen-Bierich-Preis of the Arbeitsgemeinschaft Pädiatrische Endokrinologie. MedidaPrix - mediendidaktischer Hochschulpreis der Gesellschaft für Medien in der Wissenschaft. Johannes-Brodehl-Preis of the Gesellschaft für Pädiatrische Nephrologie (GPN). Helmut Werner-Preis der Kinderhilfe Organtransplantation e.V. (KiO). Eurotransplant Kidney Advisory Committee. Scientific Steering Committee der DZIF Transplantationskohorte e.V. Chair, Working Group “Renal Transplantation” of the European Society for Paediatric Nephrology (ESPN) and of the German Society for Paediatric Nephrology (GPN). Co-Editor of the journal Der Nephrologe. Council of the International Pediatric Transplant Association (IPTA); 2015 - 2017 President of IPTA. Since 2018 Editor-in-Chief of the journal Pediatric Transplantation, the official journal of IPTA. Publications: 352 original and review articles, 109 book chapters and 6 books. Hirsch-index: 46.

Dear Transplant Colleagues,

The IPTA Allied Health and Nursing Professionals (AHNP) committee have compiled a professional practice survey. 

The goals of this survey are:

1. To describe the prevalence and diversity of the clinical, research and teaching practice of Allied Health (AH) and Nursing team members internationally.
2. To understand the multidisciplinary composition of transplant care teams and develop an international framework regarding professional practice.
   
3. To identify possible barriers and challenges for AH and Nursing professionals within their role, with the aim of improving and supporting AH and Nursing practice development specifically within the field of pediatric transplant.
4. To support a publication related to international AH and Nursing practice in pediatric solid organ transplantation   

If you are an Allied Health or Nursing professional (both members and non-members of IPTA): please consider completing the survey (see link below) and forwarding it to your non-IPTA colleagues.

Physicians and other members: Please share this email with your Allied Health and Nursing colleagues at your centre, and encourage them to complete the survey (You do not have to be a member of IPTA to complete this survey)

You may open the survey in your web browser by clicking the button below.

IPTA Allied Health and Nursing Survey

The survey should only take about 5-10  minutes to complete. You participation is voluntary, and all responses will be de-identified to ensure anonymity. 

We are extremely grateful for your time 

IPTA AHNP Committee

Visit www.ipta2022.org for more details

The ethics cases shared in this section off the opportunity for us to discuss the moral and ethical challenges of providing care to the pediatric community both before and after transplant.  This discussion allows us to learn from our colleagues and, hopefully, improve the care that we provide.  If you would like to share an ethics case for dissemination via the IPTA newsletter please contact me at MFreeman3@pennstatehealth.psu.edu.

Michael Freeman, MD, MA, Co-Chair, Ethics Committee

Ethics Case Report

The patient in question was a 17 year- old young man with familial FSGS who transferred care to our institution shortly after starting hemodialysis.  During his time on hemodialysis he routinely attended all hemodialysis sessions.  In considering other markers of adherence, he demonstrated sub-optimal phosphorus control but good volume regulation and blood pressure control between hemodialysis sessions. Unfortunately, our relationship with the patient’s family was often adversarial, with the blame for any deviation in optimal measures of his end-stage kidney disease treatment being attributed to the poor provision of medical care. He was subsequently transplanted via a living unrelated donor.

In the post-transplant setting, the patient demonstrated widely variable tacrolimus levels.  This raised concerns that he may be non-adherent to his medication.  All such non-adherence was denied by the patient and the patient’s family.  He continued to demonstrate marked variability and was subsequently transitioned from immediate release to extended release forms of tacrolimus in an attempt to improve adherence, address any first-order elimination pharmacokinetic effects and to allow the sustained usage of a single pharmaceutical preparation.  Despite these efforts he continued to require extensive escalation of his tacrolimus XR dose, eventually reaching a dose of 30 mg daily.  During this dose escalation we performed a clinical version of pharmacokinetic studies including trough levels, observed medication administration and 1 and 3 hour post-drug administration levels that reached a peak of only 10 ng/dL, confirming a degree of hypermetabolism.

Despite these efforts, the patient continued to demonstrate substantial variability in tacrolimus levels inthe home setting and would frequently exhibit undetectable tacrolimus levels. During hospitalizations he would often require dose reductions, although did not exhibit frank tacrolimus toxicity.  He subsequently developed stage 2B ACR by Banff criteria.  Following treatment of his acute cellular rejection he was transitioned to belatecept for ongoing immunosuppression.  He received these infusions as scheduled without missing doses.  Throughout this time there has been strong clinical suspicion that non-adherence played a role in this patient’s difficult course.  He and his family have continued to deny any non-adherence at any time.  Continued discussion of this issue caused significant friction with the patient and his family, making ongoing interactions emotionally challenging for transplant staff.

Bias, assessment of adherence and the dilemma of transplant care

Was this patient non-adherent? The strong suspicion of the clinical team continues to be that, yes, the patient was non-adherent to at least a degree.  That having been said, it was also likely that the patient’s status as a hyper-metabolizer of tacrolimus may have contributed to increased perception that the patient was non-adherent.  Continued discussions around this issue increased conflict with the patient and his family, which in turn may have impeded our ability to reach a therapeutic alliance with them to address any non-adherence that may be present.

Unfortunately, our ability to accurately assess which of our patients are non-adherent is not absolute.  When biomarkers, such as drug levels or serum phosphorus concentrations are used, what we perceive is the degree of deviation from our goal, not the degree of non-adherence.  Patients with substantial physiologic variation may be deemed to be less non-adherent, while those who demonstrate consistency in spot checks of laboratory values may have their broader non-adherence missed. Studies in children have suggested that non-adherence to treatment recommendations is widespread and we likely consider many patients to be adherent who are otherwise not.¹ Similarly our perception of non-adherence is not free of bias, whether it is driven by personal characteristics, such as a poor relationship with a patient or family, or broader systemic causes of implicit bias such as non-majority status.²

Given the inherent scarcity of donor organs, we continue to have obligations to be good stewards make thoughtful and compassionate assessments of our patient’s expected degree of adherence in the post-transplant setting.  However, this must also be undertaken with a great deal of humility and acknowledgment of our imperfections while doing so.

1. See [Fine RN, Becker Y, De Geest S, Eisen H, Ettenger R, Evans R, Rudow DL, McKay D, Neu A, Nevins T, Reyes J. Nonadherence consensus conference summary report. American Journal of Transplantation. 2009 Jan;9(1):35-41] and [Chua AN, Warady BA. Adherence of pediatric patients to automated peritoneal dialysis. Pediatric Nephrology. 2011 May 1;26(5):789-93.] as examples.
2. See [Pabst S, Bertram A, Zimmermann T, Schiffer M, de Zwaan M. Physician reported adherence to immunosuppressants in renal transplant patients: prevalence, agreement, and correlates. Journal of psychosomatic research. 2015 Nov 1;79(5):364-71.] as an example.

IPTA is excited to introduce this compilation of clinical practice guidelines, guidelines, consensus papers and position statements with relevance to pediatric solid organ transplantation. This extensive catalogue, sorted by topic, contains the reference information, sponsoring organization(s) and – most importantly – online access to the full text of the publication. It is fully accessible to anyone with an active IPTA membership. You can access this Catalogue by clicking the button below.

IPTA Catalogue of guidelines and position statements

In addition, we invite all IPTA members to submit suggestions for inclusion using the link provided.

Click here to submit suggestions

The International Pediatric Transplant Association believes that it is important to represent the international community of members and the patients and the families they serve. By broadening our reach into advocacy, we can advance the cause of children and youth who stand to benefit from transplantation worldwide.

The International Advocacy group has the intention to survey the existing landscape of allocation for pediatric transplantation, define an ethical mandate for pediatric priority in deceased donor allocation to pediatric recipients, and determine an optimal path forward to execute this mandate on an international scale. 

Please respond to this survey link in order to provide information to help us define allocation practices for children worldwide! Thank you for your care of children and your involvement in the IPTA.

Click here for survey

La Asociación Internacional de Trasplantes Pediátricos (IPTA) cree que es importante representar a la comunidad internacional de miembros, pacientes y familias a las que sirve. Al ampliar alcance a la abogacía, promovemos la causa de los niños y jóvenes que se beneficiarán de trasplantes en el mundo.

El grupo de Abogacía Internacional intenta estudiar el panorama actual de asignación de órganos para trasplantes pediátricos, definir un mandato ético para la prioridad pediátrica en la asignación de donantes fallecidos a recipientes pediátricos y determinar un camino óptimo para ejecutar este mandato a escala internacional.

¡Por favor llene este cuestionario para ayudar definir las prácticas de asignación de órganos pediátricos mundialmente! Gracias por cuidar de los niños y su participación en la IPTA.

Por favor complete el cuestionario

Dr. Debra Lefkowitz is a pediatric transplant psychologist at The Children’s Hospital of Philadelphia (USA).  She is currently is the Psychosocial Director for the Pediatric Transplant Center and the Clinical Director of the Pediatric Health and Behavior Program, and serves as the psychology and Transplant Center representative to the hospital’s Ethics Committee.  She is also an Associate Professor of Clinical Psychology at the Perelman School of Medicine at the University of Pennsylvania.

Dr. Lefkowitz received her doctorate in psychology from Rutgers University, and completed a predoctoral internship and postdoctoral fellowship in Pediatric Psychology from Children’s Hospital Boston and Harvard Medical School. Since coming to CHOP in 2003, Dr. Lefkowitz has been actively involved in the national and international transplant community. She is currently on the council of the Allied Health and Nursing and Ethics Committees of the International Pediatric Transplant Association (IPTA), and from 2015-2019, was an IPTA Councilor.  Dr. Lefkowitz presents often about psychosocial and ethical issues in pediatric transplantation. 

Dr. Jo Wray is a senior research fellow and health psychologist at Great Ormond Street Hospital for Children, London and an Associate Professor at the Institute of Cardiovascular Science, UCL.  She was previously a consultant health psychologist at the Royal Brompton and Harefield NHS Foundation Trust, where she was the first psychologist to be appointed at Harefield Hospital in 1988. At that time Harefield had one of the largest cardiothoracic transplant programmes in the world and she set up and led both a programme of psychosocial research and a clinical service with the paediatric transplant programme as well as undertaking research with adult transplant patients. In 2001 the Harefield paediatric transplant programme merged with that of Great Ormond Street and for the next few years she worked across both sites, seeing patients as part of the clinical service and continuing with her transplant research.  In recent years she has also been involved in research with the liver transplant team at Birmingham Children’s Hospital and with the renal transplant team at Great Ormond Street.

She has been actively involved with the International Pediatric Transplant Association (IPTA) since 2005 and has been a member of the Membership (2005-2007), Allied Health (2007 – present time) and Publications (2009-2011) committees. She was the Allied Health Representative on the IPTA Council from 2011-2015, during which time she co-led a programme of manuscript writing which resulted in a series of seven articles about the psychosocial aspects of the transplant journey for children and families.  Her research has been published and presented widely, including at every IPTA conference since its inception.   In 2013 she was awarded the IPTA Distinguished Allied Health Professional Award.