The Elephant in the Transplant Room: Personhood

A recent study and related editorial discuss the ethics and utilization of transplantation for children with intellectual disability.

In the study by Wightman et al, the researchers performed a retrospective cohort analysis of children receiving a first kidney, liver, or heart-alone transplant in the United Network for Organ Sharing dataset from 2008 to 2017. Key findings:

  • Definite intellectual disability accounted for 594 of 6747 (9%) first pediatric kidney-alone, 318 of 4566 (7%) first pediatric liver-alone, and 324 of 3722 (9%) first pediatric heart-alone transplant recipients. 
  • Children with intellectual disability account for 7%-9% of pediatric transplant recipients with comparable long-term outcomes to other pediatric recipients.
  • The article had a number of limitations including a lack of a standardized assessment of cognitive development.

In the editorial, the author “opposes the absolute exclusion of patients with intellectual disability and end-stage organ disease from transplantation waitlists provided that the candidates are expected to gain a predefined minimum benefit threshold of life-years and quality-adjusted-life years. Intellectual disability is one of many factors that should be considered in determining transplant eligibility and each candidate should have an individualized interdisciplinary assessment.”

In this commentary, it is noted that “the vast majority (85%) of individuals classified as having intellectual disability are able to live independently with minimum levels of support.” While the author would exclude those in a persistent vegetative state and those who were minimally conscious, otherwise he advocates “the candidate with intellectual disability should be given equal priority for organ transplantation.”

My view: The suitability for transplantation of individuals with intellectual disability centers on the issue of personhood; those who meet the threshold of personhood should be eligible to receive organ transplants without discrimination.  Wikipedia-Personhood: “Defining personhood is a controversial topic in philosophy and law and is closely tied with legal and political concepts of citizenship, equality, and liberty.”

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Good Results with Liver Transplantation Using Hepatitis C Livers

The advent of highly-effective therapy for hepatitis C has led to the use of hepatitis C-infected livers for organ transplantation.

H Bohorquez et al. Liver Transplantation 2021; 27: 548-557. Liver Transplantation Using Hepatitis C Virus–Viremic Donors Into Hepatitis C Virus–Aviremic Recipients as Standard of Care

Methods: The authors would utilize livers from donors with hepatitis C if they had a “normal gross appearance or, in cases in which a liver biopsy was indicated, acceptable histology less than grade 2 inflammation and less than stage 2 fibrosis (Batts-Ludwig classification)”

Key findings:

  • 292 patients, 61 rHCV− received DNAT+ livers (study group), and 231 rHCV− received DNAT− (aviremic donors [nuclear acid test‐negative donors]) (2018-2019)
  • 1‐year post‐LT patient and graft survival were similar between groups
  • In the study group, 4 patients died, and 1 patient required retransplantation within the first year post‐LT (all unrelated to HCV)
  • 51 patients completed DAA treatment, all achieving sustained virologic response for 12 or more weeks (SVR‐12) (one required re-treatment)

Given the limited organ availability, using livers from donors with hepatitis C has the potential to reduce waitlist times and waitlist mortality.

My take: Liver transplantation with hepatitis C has become bidirectional; livers are being received by those with liver failure due to hepatitis C and failed livers are being replaced by donors infected with hepatitis C.

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Cool Perfusion –Better Liver Transplant Outcomes

R van Rijn et al. NEJM 2021; 384: 1391-1401. Hypothermic Machine Perfusion in Liver Transplantation — A Randomized Trial

Background: Nonanastomotic biliary strictures are a major complication after liver transplantation, and ischemia–reperfusion injury is a key mechanism in their development. Although static cold preservation provides some protection against injury, preclinical studies have shown that a short period of hypothermic oxygenated machine perfusion restores mitochondrial function and reduces damage.

Methods: In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial).

Key points:

  • Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group, risk ratio, 0.36
  •  Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group; risk ratio, 0.43
  • Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers; risk ratio, 0.61

My take: Hypothermic oxygenated machine perfusion led to lower risk of nonanastomotic biliary strictures

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Suboptimal Transitions: Pediatric to Adult Care

Two recent articles delve into the topic of Pediatric to Adult Care Transition.

M Katz et al. J Pediatr (Epub head of publication) 2021. African American Pediatric Liver Transplant Recipients Have an Increased Risk of Death After Transferring to Adult Healthcare (Thanks to a friend who shared this reference & congratulations to my Emory colleagues and senior author Nitika Gupta on this publication)

This retrospective study examined 101 patients between 1990 and 2015. 64 had long-term followup data available.

Key findings:

  • African Americans had higher rates of death after transfer than patients of other races (44% mor-
    tality vs 16%, representing 67% of all cases of death; P = .032)
  • 18 of the 64 (28%) died. Of those 18 deaths, 4 (22%) occurred within the first 2 years after transfer, and 10 (55%)
    within 5 years of transfer.
  • There was a high rate of medication nonadherence in patients who died. ” Death in our cohort was typically caused by chronic rejection and graft failure, with a high frequency of severe infections or bleeding events ultimately causing a patient to die.”
  • The average age of transplant in deceased patients was 15. Transplantation in teenage years could be a risk factor as well.
  • The authors note that “the years directly after transfer of care from pediatrics to adult medicine are high risk for death and poor patient outcomes. Racial disparities seen in pediatric medicine also hold true after transfer to adulthood.”

H Pearlstein et al. JPGN 2021; 72: 563-568. Predicting Suboptimal Transitions in Adolescents with Inflammatory Bowel Disease

This retrospective study with 104 subjects defined suboptimal transition as “either a return to pediatric care or requiring care escalation within 1 year of transfer.

Key findings:

  • 37 (36%) were determined to have a suboptimal transition.
  • Risk factors: mental health diagnosis (OR 4.15), medication non-adherence (OR 5.15), public insurance (OR 6.60), and higher Physician Global Assessment score at time of transition (OR 6.64).

Comments: This is a small study and included only 26 patients receiving public insurance, which the authors considered as a proxy measure of socioeconomic status.

My take: These studies show the difficulties and potential deadly outcomes that face these young adults during transition from pediatrics to adult care. In many cases, medication non-adherence is a key factor and can be affected by access to care, insurance coverage, and mental health. Most young adults with serious medical problems probably would benefit from keeping their parents actively involved in their care.

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March 30,2021. Washington D.C. Thanks to Seth for this picture.

Liver Shorts: Delisting Transplant Candidates, Albumin Infusions for Cirrhosis, Terlipresin & Liver Learning System

KL Karunungan et al. Liver Transplantation 20021: 27: 200-208. Impact of Payer Status on Delisting Among Liver Transplant Candidates in the United States

This was a retrospective study which relied on large national databases.

  • The 1‐year cumulative incidence of delisting was 9.0% (95% confidence interval [CI], 8.3%‐9.8%) for patients with private insurance, 10.7% (95% CI, 9.9%‐11.6%) for Medicare, and 10.7% (95% CI, 9.8%‐11.6%) for Medicaid
  • Medicare (HR, 1.20; 95% CI, 1.17‐1.24; P < 0.001) and Medicaid (HR, 1.20; 95% CI, 1.16‐1.24; P < 0.001) were independently associated with an increased hazard of death or deterioration compared with private insurance.
  • The article highlights regional variation in payor coverage and change in watilist death or deterioration from 2002-2018 (Figure 1)
  • Higher levels of education and employment were protective against waitlist mortality and deterioration
  • Female sex was a risk factor for delisting which may be in part to body size as women are more likely to have an organ declined as a result of small stature

L China et al. NEJM 2021; 384: 808-17. A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis This was the ATTIRE trial; somehow ATTIRE is an acronym to allude to “Albumin to Prevent Infection in Chronic Liver Failure.” This trial was a multicenter, randomized controlled study.

“In patients hospitalized with decompensated cirrhosis, [daily] albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care.” The standard of care included giving albumin under specific circumstances: large volume paracentesis, spontaneous bacterial peritonitis, or hepatorenal syndrome. Infusions (20% albumin) were infused at a rate of 100 mL/hr. In addition, the albumin group, which received 10 times as much albumin as the standard group, had more severe or life-threatening adverse events, especially pulmonary edema or fluid overload.

F Wong et al. NEJM 2021; 384: 818-828. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome In this multicenter, randomized controlled study, terlipressin was associated with improved renal function -reversal of HRS occurred in 32% compared to 17% in placebo group; however, it was associated with increased serious adverse events (eg. respiratory failure) and increased death (51% vs 45% in placebo group).

ER Perito et al. JPGN 2021; 72: 417-424. A Learning Health System for Pediatric Liver Transplant: The Starzl Network for Excellence in Pediatric Transplantation The Starzl Network for Excellence in Pediatric Transplantation (SNEPT) is the first multicenter effort by pediatric liver transplant teams. Its goal is to establish and share evidence-based care to improve liver transplantation outcomes. If successful, SNEPT should be to liver transplantation as ImproveCareNow network is for pediatric inflammatory bowel disease.

Here’s A Bad Idea-Alcohol Consumption on the Day of Liver Transplantation

Yes –there is a retrospective study describing outcomes for patients who consume alchohol on the day of liver transplantation: J Ursic-Bedoya et al. Liver Transplantation 2021; 27: 34-42. Alcohol Consumption the Day of Liver Transplantation for Alcohol‐Associated Liver Disease Does Not Affect Long‐Term Survival: A Case‐Control Study

This study had 42 patients who had alcohol detectable in blood and/or urine matched with 84 controls among patients who received liver transplantation for alcohol-associated liver disease (ALD); this study had a median follow-up of 12.9 years..

Key findings:

  • Long‐term survival was not different between the groups; however, rates of recurrent cirrhosis and cirrhosis‐related deaths were more frequent in the alcohol consumption group
  • Relapse to any alcohol consumption rate was higher in the case group (59.5%) than in the control group (38.1%, odds ratio 2.44; CI95% = [1.13; 5.27]), but sustained excessive consumption was not significantly different between the groups (33.3% versus 29.8% in case and control groups respectively, χ2 = 0.68). 

My take: Yikes.! Fortunately, alcohol consumption is not a significant factor in pediatric liver disease. For adult hepatologists, this study highlights the need for patient support due to the frequency of alcohol relapse.

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Chicago at Sunrise

Liver Shorts -March 2021. Neonatal liver disease, Hepatitis-Associated Aplastic Anemia & Two

S Kemme et al. JPGN 2021; 72: 194-201. Outcomes of Severe Seronegative Hepatitis-associated Aplastic Anemia: A Pediatric Case Series This small case series (n=4) with HAAA found that this condition was poorly responsive to steroids, azathioprine and tacrolimus; however, Anti-Thymocyte Globulin (ATG) was associated with sustained biochemical remission of the hepatitis. Two patients underwent hematopoietic stem cell transplantation. All patients had extensive investigations. All had evidence of systemic hyperinflammation (with markedly-elevated ferritin and soluble IL-2 R levels) and CD8+ T cell predominant liver tissue infiltration.

C Potter. JPGN Reports 2021; 1: e031. doi: 10.1097/PG9.0000000000000031. Full text: The Role of a NICU Hepatology Consult Service in Assessing Liver Dysfunction in the Premature Infant This was a retrospective observational study of 157 consecutive babies were evaluated by a single hepatologist. The approach outlined by this study:

  1. Workup: In the well and stable premature with elevated DB, “aminotransferases, AP, GGT, glucose, T4, TSH, UC, urine CMV PCR, and US with Doppler evaluation should be obtained…Coagulation studies in well babies with other evidence of good synthetic function are not necessary.” Empiric ursodeoxycholic acid may be given with weekly evaluation.
  2. Genetic testing: “Genetic panels are indicated in babies with no obvious risk factors after the first tier of studies…In critically ill babies with multisystem disease, critical whole exome sequencing (WES) is faster and provides broader results.”
  3. Sepsis: Babies with sudden increase in DB and ALT should be evaluated for sepsis (including urosepsis) and CMV.
  4. Nutritional support: Infants should be “supported with MCT and vitamin supplementation.”
  5. Severe liver disease: “Babies with coagulopathy and marked elevation of aminotransferases who have multiorgan failure in the first few days of life need to be evaluated for perinatal complications, severe metabolic disease, and gestational alloimmune liver disease (GALD). In this period, ischemic shock or infectious disease is much more common than primary liver disease, but the presentations can overlap.”
  6. Liver biopsy: “Liver biopsy should be pursued in babies whose cholestasis is not improving and the diagnosis is unclear.”
  7. Etiology: Infection, genetic disease, cardiac dysfunction, large heme loads, and hypothyroidism are common causes of liver dysfunction in the NICU. Common findings included trisomy 21-associated liver dysfunction (n=12), and thyroid disease. 6 patients had type 2 Abenathy shunts -only one required closure. Two patients had biliary atresia. Other liver diseases identified included GALD (n=2), PFIC2, Alagille, Alpha-one-antitrypsin, Cystic Fibrosis, and Niemann-Pick.

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Wahid N et al. AASLD 2020, Abstract 153. Summary from GI & Hepatology News: Liver-related deaths decline after Medicaid-expansion under ACA. “Beginning around 2015, liver-related deaths began to decline in expansion states by a mean of –0.6%, while they continued on an upward trajectory in the nonexpansion states…“It’s a no-brainer that the lack of insurance accessibility for the most vulnerable people in the United States meant that they were dying of cirrhosis instead of being transplanted,” said Elliot Benjamin Tapper, MD, of the University of Michigan, Ann Arbor.”

W-M Choi et al. Clin Gastroenterol Hepatol 2021; 19: 246-258. Effects of Tenofovir vs Entecavir on Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection: A Systematic Review and Meta-analysis “In a meta-analysis of studies of patients with chronic HBV infection, we found that TDF treatment was associated with a significantly lower (20%) risk of HCC than entecavir treatment. Randomized trials are needed to support this finding.” This analysis comprised 15 studies (61,787 patients; 16,101 patients given TDF and 45,686 given entecavir).

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New Information on Hepatic Artery Thrombosis in Pediatric Liver Transplantation & COVID-19 Vaccine Timeline

NE Ebel et al. J Pediatr 2020; 226: 195-201. Decreased Incidence of Hepatic Artery Thrombosis in Pediatric Liver Transplantation Using Technical Variant Grafts: Report of the Society of Pediatric Liver Transplantation Experience

This study used multicenter data from the Society of Pediatric Liver Transplantation on first-time pediatric (aged <18 years) liver transplant recipients (n = 3801) in the US and Canada (1995-2016).

Key findings:

  • 7.4% developed HAT within the first 90 days of transplantation.
  • Of those who were retransplanted, 20.7% developed recurrent HAT.
  • Those less than 1 year had the highest risk OR 1.20).
  • Lower Risk for HAT:
    • Recipients with split, reduced, or living donor grafts had decreased odds of HAT (OR, 0.59; P < .001 compared with whole grafts)
    • Adolescents aged 11-17 years (OR, 0.53; P = .03).
  • HAT increased risk of graft failure and mortality:
    • Fifty percent of children who developed HAT developed graft failure within the first 90 days of transplantation (adjusted hazard ratio, 11.87; 95% CI, 9.02-15.62)
    • Mortality risk (w/in 90 days after transplantation): adjusted hazard ratio, 6.18 (95% CI, 4.01-9.53).

The finding that split grafts had lower rates of HAT may be related to the fact that these grafts more typically come from larger donors with larger vessels. Historically, split grafts had been described as a risk factor for HAT. The authors note that high-performing centers with the lowest incidence of HAT “also tend to have high rates of living and split transplants, suggesting that surgical expertise may play a role in the decreased risk of HAT in select recipients with technical variant grafts.”

Increased rates of HAT among those who were retransplanted, in some, could be related to thrombophilic conditions; thus, consideration of anticoagulation protocol could be needed

My take: Continued efforts are needed to reduce HAT due to its impact on liver transplantation outcomes. One of the biggest risk factors is age. While this would seem to be a nonmodifiable factor, improving recognition and treatment of biliary atresia could help.

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Online Aspen Webinar (Part 7) -Liver Organ Allocation

Below I’ve included a few slides and some notes from recent Aspen Webinars; my notes may have errors of omission or transcription.

Key Points:

  • The new allocation policy tries to make liver organ allocation more equitable in terms of disease acuity at time of transplantation and access to allografts
  • The changes, based on some preliminary data, appear to improve the likelihood of children receiving needed organs. Dr. Bondoc specifically cited the work of Dr. John Bucuvalas in pointing out some of the systemic ways that the previous system disadvantaged children.
    • Infants are at the greatest risk on the wait list.  Yet, successful transplantation in children could be beneficial for many decades
    • PELD underestimates mortality risk
    • 25% of pediatric donors have historically gone to adults


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More School Advice for Organ Transplant Recipients, Plus Another Benefit of the Influenza Vaccine

Link to PDF (from Pediatric Infectious Disease Society:

FAQs Regarding Return to School for Children after Solid Organ Transplant in the United States During the COVID-19 Pandemic

Some excerpts:

Are pediatric SOT recipients at higher risk for getting COVID-19 compared with other children?
Children of any age can get COVID-19, but they seem to have milder disease than adults. Pediatric SOT recipients do not seem to get COVID-19 more often than other children.

If infected with COVID-19, are pediatric SOT recipients at higher risk for developing severe disease or complications?

Based on experience with other viruses, and from reports of COVID-19 in adult SOT patients, there are a few things that may increase the risk of severe COVID-19. These include:
1) Having undergone transplantation in the last 3-6 months
2) Receiving high doses of immunosuppression (such as for treatment of rejection)
3) Having other medical problems such as diabetes, obesity, or certain lung conditions (refer to CDC website under Helpful Resources for more details)
It is not known if the above factors also put children with SOT at risk. In fact, of all the reports among pediatric SOT recipients with COVID-19 published so far, the majority have had mild symptoms and recovered.

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