Three-dimensional Liver Model Application for Liver Transplantation.

BACKGROUND: Children are removed from the liver transplant waitlist because of death or progressive illness. Size mismatch accounts for 30% of organ refusal. This study aimed to demonstrate that 3-dimensional (3D) technology is a feasible and accurate adjunct to organ allocation and living donor selection process. METHODS: This prospective multicenter study included pediatric liver transplant candidates and living donors from January 2020 to February 2023. Patient-specific, 3D-printed liver models were used for anatomic planning, real-time evaluation during organ procurement, and surgical navigation. The primary outcome was to determine model accuracy. The secondary outcome was to determine the impact of outcomes in living donor hepatectomy. Study groups were analyzed using propensity score matching with a retrospective cohort. RESULTS: Twenty-eight recipients were included. The median percentage error was -0.6% for 3D models and had the highest correlation to the actual liver explant (Pearson's R = 0.96, P < 0.001) compared with other volume calculation methods. Patient and graft survival were comparable. From 41 living donors, the median percentage error of the allograft was 12.4%. The donor-matched study group had lower central line utilization (21.4% versus 75%, P = 0.045), shorter length of stay (4 versus 7 d, P = 0.003), and lower mean comprehensive complication index (3 versus 21, P = 0.014). CONCLUSIONS: Three-dimensional volume is highly correlated with actual liver explant volume and may vary across different allografts for living donation. The addition of 3D-printed liver models during the transplant evaluation and organ procurement process is a feasible and safe adjunct to the perioperative decision-making process.

The African Liver Tissue Biorepository Consortium: Capacitating Population-Appropriate Drug Metabolism, Pharmacokinetics, and Pharmacogenetics Research in Drug Discovery and Development.

Pharmaceutical companies subject all new molecular entities to a series of in vitro metabolic characterizations that guide the selection and/or design of compounds predicted to have favorable pharmacokinetic properties in humans. Current drug metabolism research is based on liver tissue predominantly obtained from people of European origin, with limited access to tissue from people of African origin. Given the interindividual and interpopulation genomic variability in genes encoding drug-metabolizing enzymes, efficacy and safety of some drugs are poorly predicted for African populations. To address this gap, we have established the first comprehensive liver tissue biorepository inclusive of people of African origin. The African Liver Tissue Biorepository Consortium currently includes three institutions in South Africa and one in Zimbabwe, with plans to expand to other African countries. The program has collected 67 liver samples as of July 2023. DNA from the donors was genotyped for 120 variants in 46 pharmacogenes and revealed variants that are uniquely found in African populations, including the low-activity, African-specific CYP2C9*5 and *8 variants relevant to the metabolism of diclofenac. Larger liver tissue samples were used to isolate primary human hepatocytes. Viability of the hepatocytes and microsomal fractions was demonstrated by the activity of selected cytochrome P450s. This resource will be used to ensure the safety and efficacy of existing and new drugs in African populations. This will be done by characterizing compounds for properties such as drug clearance, metabolite and enzyme identification, and drug-drug and drug-gene interactions. SIGNIFICANCE STATEMENT: Standard optimization of the drug metabolism of new molecular entities in the pharmaceutical industry uses subcellular fractions such as microsomes and isolated primary hepatocytes, being done mainly with tissue from donors of European origin. Pharmacogenetics research has shown that variants in genes coding for drug-metabolizing enzymes have interindividual and interpopulation differences. We established an African liver tissue biorepository that will be useful in ensuring drug discovery and development research takes into account drug responses in people of African origin.

Hyperreduced left lateral living donor liver transplant in a 4.5 kg child-A first in Africa.

BACKGROUND: Supply-demand mismatch in solid organ transplantation is particularly pronounced in small children. For liver transplantation, advanced surgical techniques for reducing deceased and living donor grafts allow access to life-saving transplantation. Living donor left lateral segment liver grafts have been successfully transplanted in small children in our center since 2013, the only program providing this service in Sub-Saharan Africa. This type of partial graft remains too large for children below 6 kg body weight and generally requires reduction. METHODS: A left lateral segment graft was reduced in situ from a directed, altruistic living donor to yield a hyperreduced left lateral segment graft. RESULTS: The donor was discharged after 6 days without complications. The recipient suffered no technical surgical complications except for an infected cut-surface biloma and biliary anastomotic stricture and remains well 9 months post-transplant. CONCLUSIONS: We report the first known case in Africa of a hyperreduced left lateral segment, ABO incompatible, living donor liver transplant in a 4,5 kg child with pediatric acute liver failure (PALF).

International Pediatric Transplant Association (IPTA) position statement supporting prioritizing pediatric recipients for deceased donor organ allocation.

A position statement of the International Pediatric Transplant Association endorsing prioritizing pediatric recipients for deceased donor organ allocation, examining the key ethical arguments that serve as the foundation for that position, and making specific policy recommendations to support prioritizing pediatric recipients for deceased donor organ allocation globally.

Human Leukocyte Antigen Typing with Sequence Specific Oligonucleotides for Renal Transplantation in South Africa.

BACKGROUND: Kidney transplants are the only curative therapeutic intervention for end-stage kidney disease (ESKD). The current organ shortage in South Africa makes recipient risk assessments and effective laboratory workup crucial to assist in better organ assignment and increase the likelihood of better transplant outcomes. HLA typing is a step in the pre-transplant workup for performing virtual crossmatches and matching donors and recipients. Sequence Specific Oligonucleotide (SSO) PCR is a relatively fast and inexpensive method for determining genotypic HLA types at a 2- to 4-digit resolution. This study aimed to validate the SSO technique for achieving a 4-digit resolution when determining HLA types to improve virtual crossmatches. METHODS: DNA was extracted from 33 samples. After PCR amplification, the samples were hybridized to oligonu-cleotide probes and the HLA A, B, C, DRB1, DQA1/B1, DRB3, DRB4, DRB5, and DPA1/B1 types were identified. These results were compared to results from external laboratories. RESULTS: The kappa coefficient calculated for the low-resolution comparison suggested a perfect agreement between the two results (p = 0.32). CONCLUSIONS: SSO was successfully validated for HLA typing in the Johannesburg kidney transplant setting. This will improve the specificity of virtual crossmatches on an automated system by matching the resolution of the HLA typing and the HLA antibody testing. Additionally, common HLA types were identified in this donor cohort. Future research into these common HLA types and haplotypes in a South African population will inform the feasibility of reintroducing HLA matching into the pretransplant workup.

Myosteatosis, the More Significant Predictor of Outcome: An Analysis of the Impact of Myosteatosis, Sarcopenia, and Sarcopenic Obesity on Liver Transplant Outcomes in Johannesburg, South Africa.

OBJECTIVES: In high-income countries, myosteatosis, sarcopenia, and obesity with sarcopenia (sarcopenic obesity) are associated with adverse outcomes after liver transplantation. In South Africa, an upper-middleincome country, we investigated the prevalence and impact of these muscle abnormalities on posttransplant outcomes in adult liver transplant recipients. MATERIALS AND METHODS: We reviewed 106 liver transplant recipients and measured muscle abnormalities on computed tomography using segmentation software. The parameters evaluated were myosteatosis by mean muscle attenuation, sarcopenia by skeletal muscle index at the third lumbar vertebra using validated cutoffs, and sarcopenic obesity as sarcopenia and a body mass index of ≥25 kg/m². The effects of these abnormalities on 1-year patient and graft survival (primary endpoint) and length of hospital and intensive care unit stay, costs, and 90-day and overall postoperative complications (secondary endpoints) were assessed. RESULTS: Most liver transplant recipients were male (n = 64, 60%). Alcoholic and/or nonalcoholic steatohepatitis were the most frequent indications for transplant (n = 38, 36%). Myosteatosis occurred in 76 patients (72%), 69 patients (65%) had sarcopenia, and 36 patients (34%) had sarcopenic obesity. One year after transplant, myosteatosis was associated with higher mortality (hazard ratio of 3.3; 95% confidence interval, 1.00-11.13; P = .049), greater risk of allograft failure (hazard ratio of 4.1; 95% confidence interval, 1.2-13.5; P = .021), and longer hospital and intensive care unit stays compared with those without myosteatosis. All patients with no body composition abnormalities were alive at 1 year compared with 69% with coexisting myosteatosis and sarcopenia. CONCLUSIONS: In our setting, liver transplant recipients with myosteatosis had a higher risk of death and allograft failure at 1 year compared with patients without body composition abnormalities.

Improving Poor Outcomes of Children With Biliary Atresia in South Africa by Early Referral to Centralized Units.

Biliary atresia (BA) is a progressive fibrosing cholangiopathy of infancy, the most common cause of cholestatic jaundice in infants and the top indication for liver transplantation in children. Kasai portoenterostomy (KPE) when successful may delay the requirement for liver transplantation, which in the majority offers the only cure. Good outcomes demand early surgical intervention, appropriate management of liver cirrhosis, and in most cases, liver transplantation. These parameters were audited of children with BA treated at the Steve Biko Academic Hospital (SBAH) in Pretoria, South Africa. Methods: All children with BA who were managed at SBAH between June 2007 and July 2018 were included. Parameters measured centered on patient demographics, timing of referral and surgical intervention, immediate and long-term outcomes of surgery, and follow-up management. Results: Of 104 children treated, 94 (90%) were KPE naive. Only 23/86 (26%) of children were referred before 60 days of life and 42/86 (49%) after 120 days. Median time to surgical assessment and surgery was 4 (IQR 1-70) and 5 (IQR 1-27) days post presentation, respectively. The median age at KPE was 91 days (IQR 28-165), with only 4/41 (12%) of KPEs performed before 60 days of life. Of those with recorded outcomes, 12/33 (36%) achieved resolution of jaundice. Only a third of the cohort were referred for transplantation. Conclusion: Children with BA have poor outcomes in the public health sector in South Africa. Late referrals, delayed diagnostics, advanced age at KPE with low drainage rates, poor follow-up, and low transplant rates account for low survival. Early referral to units offering expert intervention at all stages of care, including transplantation, would offer the best outcomes.

Minding the gap-Providing quality transplant care for South African children with acute liver failure.

Pediatric ALF is rare but life-threatening and may require urgent transplantation. In low and middle-income countries, access to transplantation is limited, deceased organ donation rates are low, and data on outcomes scarce. The Wits Donald Gordon Medical Centre, in Johannesburg, is one of only two centers in South Africa that perform pediatric liver transplant. We describe the etiology, clinical presentation, and outcomes of children undergoing liver transplant for ALF at our center over the past 14 years. We performed a retrospective chart review of all children undergoing liver transplantation for ALF from November 2005 to September 2019. Recipient data included demographics, clinical and biochemical characteristics pretransplant, post-operative complications, and survival. We conducted descriptive data analysis and used the Kaplan-Meier method for survival analysis. We performed 182 primary pediatric liver transplants. Of these, 27 (15%) were for ALF, mostly from acute hepatitis A infection (11/27;41%). Just over half of the grafts were from living donors (15/27;56%), and five grafts (5/27;19%) were ABO-incompatible. The most frequent post-transplant complications were biliary leaks (9/27;33%). There were two cases of hepatic artery thrombosis (2/27;7%), one of whom required re-transplantation. Unadjusted patient and graft survival at one and 3 years were the same, at 81% (95% CI 61%-92%) and 78% (95% CI 57%-89%), respectively. At WDGMC, our outcomes for children who undergo liver transplantation for ALF are excellent. We found workable solutions that effectively addressed our pervasive organ shortages without compromising patient outcomes.

Liver Transplant for Nonresectable Colorectal Cancer Liver Metastases in South Africa: A Single-Center Case Series.

OBJECTIVES: Publication in 2013 of the first Secondary Cancer cohort study returned attention to liver transplant for nonresectable colorectal cancer, demonstrating excellent outcomes for a procedure that was historically contraindicated. The Wits Donald Gordon Medical Centre in Johannesburg, South Africa, hosts the largest liver transplant program in sub-Saharan Africa. The persistent shortage of deceased donor organs in our setting has compelled us to innovate solutions unique to our context, which allows us to perform as many transplants as possible and maximize our resource utilization. Therefore, we initiated a research study to transplant organs in patients with nonresectable colorectal carcinoma with expanded criteria using marginal deceased donor organs that would otherwise have been discarded. MATERIALS AND METHODS: Institutional Review Board approval was obtained for this study. We used criteria from the 2013 Secondary Cancer cohort study to determine eligibility of patients with nonresectable colorectal carcinoma for liver transplant. Unlike the study from 2013, we utilized expanded criteria and marginal liver allografts for transplant. RESULTS: Five patients have undergone liver transplant for nonresectable colorectal carcinoma. At a median follow-up of 36 months (range, 10-52 months), 4 of the 5 (80%) patients are alive. The patient who died had progressive disease on chemotherapy pretransplant and was the only patient who tested positive for the Kirsten rat sarcoma viral oncogene homolog mutant. Recurrence occurred in all patients at a median time of 6 months after transplant (range, 3-13 months). CONCLUSIONS: To our knowledge, this is the only published case series of patients undergoing liver transplant for nonresectable colorectal carcinoma in Africa and is internationally unique in its use of expanded criteria and marginal grafts for this type of transplant. Despite the use of such grafts in our recipients, thus far, these outcomes align with those of the 2013 Secondary Cancer cohort studies from Norway.

Successful ABO-incompatible living donor liver transplant for acute liver failure secondary to Hodgkin's Lymphoma in a child.

We present a case of pediatric ALF, secondary to hepatic HL, who underwent a successful ABOi living donor liver transplant. We believe this is the first such case reported in academic literature. HL with liver involvement is extremely rare and is not considered an indication for transplantation. The 12-year-old, male patient presented with a viral illness prodrome, and parvovirus was detected in pre-transplant laboratory cultures. He received an ABOi living donor liver graft followed by a course of plasma exchange and rituximab after which standard immunosuppression was used. The HL was diagnosed on hepatic biopsy post-transplant. Subsequently, the patient commenced six cycles of R-CHOP chemotherapy. During chemotherapy, we stopped tacrolimus and mycophenolate mofetil. Immunosuppression was maintained with corticosteroids in-between cycles. The patient is alive and reports good quality of life 1-year post-transplant. The HL is in remission. During the post-operative period, the patient experienced four episodes of neutropenia, a bile leak, and gram-negative sepsis. One episode of acute rejection has been treated. Although we did not initially transplant the patient for ALF secondary to HL, its subsequent diagnosis and the patient's response to management raises many issues that warrant consideration. While the findings from a single case cannot be generalized, this could be a "proof of concept" for liver transplantation in hepatic HL. We hope it will facilitate discussions and potentially expand therapeutic options available to this very small group patients.

Contemporary outcomes of the pediatric kidney transplant program in Johannesburg, South Africa, between 2004 and 2017: Better or not-And which way forward?

BACKGROUND: Outcomes for the pediatric kidney transplant program in Johannesburg (1984-2003) were found to be suboptimal. In this study, we compared (a) early (era 1:1984-2003) to contemporary (era 2:2004-2017) outcomes and (b) compared contemporary outcomes between the public and private sector hospitals in our program. METHODS: We conducted a retrospective record review of all pediatric (<18 years) KA transplants performed in our kidney transplant program at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and Wits Donald Gordon Medical Centre (WDGMC) from 2004 to 2017. We collected the following data per site: number of recipients, transplants performed, mean follow-up time, and grafts lost; per recipient: age at time of transplant, sex, self-reported population group; transplant history; donor type; etiology of ESKD; recipient and graft survival. Outcomes for era 1 were based on data published on our kidney transplant program, based at CMJAH. RESULTS: At CMJAH (public sector), there was no improvement in recipient and graft survival over time. In the contemporary analysis, 1-, 5-, and 10-year recipient survival, as % (95% CI) was 93 (84-97); 76 (64-84); 59 (44-70) for CMJAH, and 98 (90-99); 95 (86-99); 82 (54-94) for WDGMC (private sector). Similarly, 1-, 5- and 10-year graft survival was 75 (63-84); 55 (42-66); 36 (24-49) for CMJAH, and 96 (87-99); 84 (73-91); 64 (48-76) at WDGMC. CONCLUSION: Contemporary outcomes for the pediatric kidney transplant program at WDGMC are comparable to outcomes achieved in middle- and high-income settings. However, outcomes at CMJAH are suboptimal, reflecting numerous health system, infrastructural and human resource challenges.

Blood stream infections in children in the first year after liver transplantation at Wits Donald Gordon Medical Centre, South Africa.

Children who undergo liver transplantation and subsequently develop BSI are at risk for adverse outcomes. Research from high-income settings contrasts the dearth of information from transplant centers in low- and middle-income countries, such as South Africa. Therefore, this study from Johannesburg aimed to describe the clinical and demographic profile of children undergoing liver transplantation, and determine the incidence and pattern of BSI and associated risk factors for BSI during the first year after liver transplant. Pediatric liver transplants performed from 2005 to 2014 were reviewed. Descriptive analyses summarized donor, recipient, and post-transplant infection characteristics. Association between BSI and sex, cause of liver failure, age, nutritional status, PELD/MELD score, graft type, biliary complications, and acute rejection was determined by Fisher's exact test; and association with length of stay by Cox proportional hazards regression analysis. Survival estimates were determined by the Kaplan-Meier method. Sixty-five children received one transplant and four had repeat transplants, totaling 69 procedures. Twenty-nine BSI occurred in 19/69 (28%) procedures, mostly due to gram-negative organisms, namely Klebsiella species. Risk for BSI was independently associated with biliary atresia (44% BSI in BA compared to 17% in non-BA transplants; P = .014) and post-operative biliary complications (55% BSI in transplants with biliary complications compared to 15% in those without; P = .0013). One-year recipient and graft survival was 78% (CI 67%-86%) and 77% (CI 65%-85%), respectively. In Johannesburg, incident BSI, mostly from gram-negative bacteria, were associated with biliary atresia and post-operative biliary complications in children undergoing liver transplantation.

HIV and Solid Organ Transplantation: Where Are we Now.

PURPOSE OF REVIEW: We review the international evolution of HIV and solid organ transplantation over 30 years. We emphasise recent developments in solid organ transplantation from HIV-infected to HIV-uninfected individuals, and their implications. RECENT FINDINGS: In 2017, Johannesburg, South Africa, a life-saving partial liver transplant from an HIV-infected mother to her HIV-uninfected child was performed. This procedure laid the foundation not only for consideration of HIV-infected individuals as living donors, but also for the possibility that HIV-uninfected individuals could receive organs from HIV-infected donors. Recent advances in this field are inclusion of HIV-infected individuals as living organ donors and the possibility of offering HIV-uninfected individuals organs from HIV-infected donors who are well-controlled on combination antiretroviral therapy (cART). The large number of HIV-infected individuals on cART is an unutilised source of otherwise eligible living organ donors. HIV-positive-to-HIV-negative organ transplantation has become a reality, providing possible new therapeutic options to address extreme organ shortages.

Needs must: living donor liver transplantation from an HIV-positive mother to her HIV-negative child in Johannesburg, South Africa.

The world's first living donor liver transplant from an HIV-positive mother to her HIV-negative child, performed by our team in Johannesburg, South Africa (SA) in 2017, was necessitated by disease profile and health system challenges. In our country, we have a major shortage of donor organs, which compels us to consider innovative solutions to save lives. Simultaneously, the transition of the HIV pandemic, from a death sentence to a chronic illness with excellent survival on treatment required us to rethink our policies regarding HIV infection and living donor liver transplantation . Although HIV infection in the donor is internationally considered an absolute contraindication for transplant to an HIV-negative recipient, there have been a very small number of unintentional transplants from HIV-positive deceased donors to HIV-negative recipients. These transplant recipients do well on antiretroviral medication and their graft survival is not compromised. We have had a number of HIV-positive parents in our setting express a desire to be living liver donors for their critically ill children. Declining these parents as living donors has become increasingly unjustifiable given the very small deceased donor pool in SA; and because many of these parents are virally suppressed and would otherwise fulfil our eligibility criteria as living donors. This paper discusses the evolution of HIV and transplantation in SA, highlights some of the primary ethical considerations for us when embarking on this case and considers the new ethical issues that have arisen since we undertook this transplant.

Living donor liver transplant from an HIV-positive mother to her HIV-negative child: opening up new therapeutic options.

OBJECTIVE: Transplant a liver from an HIV-positive mother to her HIV-negative child to save the child's life. DESIGN: A unique case of living donor liver transplantation from an HIV-positive mother to her HIV-negative child in South Africa. Two aspects of this case are ground-breaking. First, it involves living donation by someone who is HIV-positive and second it involves controlled transplant of an organ from an HIV-positive donor into an HIV-negative recipient, with the potential to prevent infection in the recipient. METHODS: Standard surgical procedure for living donor liver transplantation at our centre was followed. HIV-prophylaxis was administered preoperatively. Extensive, ultrasensitive HIV testing, over and above standard diagnostic assays, was undertaken to investigate recipient serostatus and is ongoing. RESULTS: Both mother and child are well, over 1 year posttransplantation. HIV seroconversion in our recipient was detected with serological testing at day 43 posttransplant. However, a decline in HIV antibody titres approaching undetectable levels is now being observed. No plasma, or cell-associated HIV-1 DNA has been detected in the recipient at any time-point since transplant. CONCLUSION: This case potentially opens up a new living liver donor pool which might have clinical relevance in countries where there is a high burden of HIV and a limited number of deceased donor organs or limited access to transplantation. However, our recipient's HIV status is equivocal at present and additional investigation regarding seroconversion events in this unique profile is ongoing.

Takotsubo cardiomyopathy post liver transplantation.

A patient with end-stage liver disease developed stress-induced Takotsubo cardiomyopathy post liver transplantation, with haemodynamic instability requiring a left ventricular assist device. We discuss the diagnosis and management of this condition.

Favourable outcomes for the first 10 years of kidney and pancreas transplantation at Wits Donald Gordon Medical Centre, Johannesburg, South Africa.

BACKGROUND: It is important for centres participating in transplantation in South Africa (SA) to audit their outcomes. Wits Donald Gordon Medical Centre (WDGMC), Johannesburg, SA, opened a transplant unit in 2004. The first 10 years of kidney and pancreas transplantation were reviewed to determine outcomes in respect of recipient and graft survival. METHODS: A retrospective review was conducted of all kidney-alone and simultaneous kidney-pancreas (SKP) transplants performed at WDGMC from 1 January 2004 to 31 December 2013, with follow-up to 31 December 2014 to ensure at least 1 year of survival data. Information was accessed using the transplant registers and clinical records in the transplant clinic at WDGMC. The Kaplan-Meier method was used to estimate 1-, 5- and 10-year recipient and graft survival rates for primary (first graft) kidney-alone and SKP transplants. RESULTS: The overall 10-year recipient and graft survival rates were 80.4% and 66.8%, respectively, for kidney-alone transplantation. In the kidney-alone group, children tended towards better recipient and graft survival compared with adults, but this was not statistically significant. In adults, recipient survival was significantly better for living than deceased donor type. Recipient and graft survival were significantly lower in black Africans than in the white (largest proportion in the sample) reference group. For SKP transplants, the 10-year recipient survival rate was 84.7%, while kidney and pancreas graft survival rates were 73.1% and 43.2%, respectively. CONCLUSION: Outcomes of the first 10 years of kidney and pancreas transplantation at WDGMC compare favourably with local and international survival data.

Pre-resection gastric bypass reduces post-resection body mass index but not liver disease in short bowel syndrome.

BACKGROUND: Obese patients developing short bowel syndrome (SBS) maintain a higher body mass index (BMI) and have increased risk of hepatobiliary complications. Our aim was to determine the effect of pre-resection gastric bypass (GBP) on SBS outcome. METHODS: We reviewed 136 adults with SBS: 69 patients with initial BMI < 35 were controls; 43 patients with BMI > 35 were the obese group; and 24 patients had undergone GBP before SBS. RESULTS: BMI at 1, 2, and 5 years was similar in control and GBP groups, whereas obese patients had a persistently increased BMI. Eight (33%) of the GBP patients had a pre-resection BMI > 35, but post-SBS BMI was similar to those <35. Obese patients were more likely to wean off PN (47% vs 20% control and 12% GBP, P < .05). Radiographic fatty liver tended to be higher in the GBP group (54% vs 19% control and 35% obese). End-stage liver disease occurred more frequently in obese and GBP patients (30% and 33% vs 13%, P < .05). CONCLUSIONS: Pre-resection GBP prevents the nutritional benefits of obesity but does not eliminate the increased risk of hepatobiliary disease in obese SBS patients. This occurs independent of pre-SBS BMI suggesting the importance of GBP itself or history of obesity rather than weight loss.