Stevens-Johnson syndrome/toxic epidermal necrolysis in an orthotopic liver transplant recipient: a case report.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare spectrum of acute, mucocutaneous drug reactions characterized by epidermal necrosis of the skin and mucous membranes with progressive multiorgan failure. Cutaneous presentation of SJS/TEN is similar to that of acute graft-versus-host disease, creating a diagnostic dilemma in solid-organ transplant recipients presenting with diffuse, erythematous eruptions, skin sloughing, and systemic sequelae, reflective of both diseases. This case report details a 48-year-old woman post-orthotopic liver transplantation (OLT) who developed a diffuse, painful, morbilliform rash with progressive desquamation, along with corresponding pathological analysis indicative of SJS/TEN. There are few documented reports of SJS/TEN in solid-organ transplant recipients, and this case illustrates successful intervention and resolution of SJS/TEN in an OLT recipient while managing intraabdominal sepsis and an episode of acute rejection. Despite its rarity, prompt diagnosis of SJS/TEN and the implementation of tailored therapeutic strategies are crucial in the care of solid-organ transplant recipients.

Selecting DCD Recipients Using Predictive Indices.

Donation after circulatory death (DCD) allografts might represent one of the largest untapped sources of liver allografts. Our aim was to identify independent recipient risk factors that predict mortality in DCD allograft recipients to preselect optimal candidates for successful transplantation. Furthermore, we compared the application of our newly constructed DCD Recipient Selector Index (RSI) score to previously developed models to determine superiority in predicting recipient survival. Methods: Using the Organ Procurement and Transplantation Network database, we performed univariate and multivariate retrospective analyses on 4228 DCD liver allograft recipients. Results: We identified 8 significant factors and incorporated them into the weighted RSI to predict 3-mo survival following DCD liver transplantation with a C-statistic of 0.6971. The most significant recipient risk factors were recipient serum sodium levels >150 mEq/L at transplant, recipient albumin <2.0 g/dL at transplant, and a history of portal vein thrombosis. Because Model for End-Stage Liver Disease (MELD) score components were included as individual predictors, the DCD RSI predicts survival independently of MELD. Upon comparison with 3 previous recipient risk scores-Balance of Risk, Renal Risk Index, Patient-Survival Outcomes Following Liver Transplantation-the DCD RSI was determined to be superior at selecting optimal candidates pre-DCD transplantation, yielding a C-statistic of 0.6971. Conclusions: After verifying the performance of predictive indices for selection of DCD recipients, the DCD RSI is best used to preselect patients for optimized outcomes after DCD transplantation. This can increase utilization of DCD donors by improving outcomes.

Ureteral stricture after pediatric kidney transplantation: Is there a role for percutaneous antegrade ureteroplasty?

INTRODUCTION: Ureteral obstruction following pediatric kidney transplantation occurs in 5-8% of cases. We describe our experience with percutaneous antegrade ureteroplasty for the treatment of ureteral stricture in pediatric kidney transplant patients. METHODS: We retrospectively reviewed all pediatric kidney transplantation patients who presented with ureteral stricture and underwent percutaneous antegrade ureteroplasty at our institution from July 2009 to July 2021. Variables included patient demographics, timing of presentation, location and extent of stricture, ureteroplasty technique and clinical outcomes. Our primary outcome was persistent obstruction of the kidney transplant. RESULTS: Twelve patients met inclusion criteria (4.2% of all transplants). Median age at time of ureteroplasty was 11.5 years (range: 3-17.5 years). Median time from kidney transplantation to ureteroplasty was 3 months. Patency was maintained in 50% of patients. Seven patients (58.3%) required additional surgery. Four patients developed vesicoureteral reflux. Patients with persistent obstruction had a longer time from transplant to ureteroplasty compared to those who achieved patency (19.3 vs 1.3 months, p = 0.0163). Of those treated within 6 months after transplantation, two patients (25%) required surgery for persistent obstruction (p = 0.06). All patients treated >1 year after transplantation had persistent obstruction following ureteroplasty (p = 0.06). CONCLUSION: Percutaneous antegrade ureteroplasty can be considered a viable minimally invasive treatment option for pediatric patients who develop early ureteral obstruction (<6 months) following kidney transplantation. In patients who are successfully treated with ureteroplasty, 67% can develop vesicoureteral reflux into the transplant kidney. Patients who fail early percutaneous ureteroplasty or develop obstruction >1 year after transplantation are best managed with surgical intervention.

Trends in Survival for Pediatric Transplantation.

OBJECTIVES: Progress in pediatric transplantation measured in the context of waitlist and posttransplant survival is well documented but falls short of providing a complete perspective for children and their families. An intent-to-treat analysis, in which we measure survival from listing to death regardless of whether a transplant is received, provides a more comprehensive perspective through which progress can be examined. METHODS: Univariable and multivariable Cox regression was used to analyze factors impacting intent-to-treat survival in 12 984 children listed for heart transplant, 17 519 children listed for liver transplant, and 16 699 children listed for kidney transplant. The Kaplan-Meier method and log-rank test were used to assess change in waitlist, posttransplant, and intent-to-treat survival. Wait times and transplant rates were compared by using χ2 tests. RESULTS: Intent-to-treat survival steadily improved from 1987 to 2017 in children listed for heart (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.96-0.97), liver (HR 0.95, 95% CI 0.94-0.97), and kidney (HR 0.97, 95% CI 0.95-0.99) transplant. Waitlist and posttransplant survival also improved steadily for all 3 organs. For heart transplant, the percentage of patients transplanted within 1 year significantly increased from 1987 to 2017 (60.8% vs 68.7%); however, no significant increase was observed in liver (68.9% vs 72.5%) or kidney (59.2% vs 62.7%) transplant. CONCLUSIONS: Intent-to-treat survival, which is more representative of the patient perspective than individual metrics alone, steadily improved for heart, liver, and kidney transplant over the study period. Further efforts to maximize the donor pool, improve posttransplant outcomes, and optimize patient care while on the waitlist may contribute to future progress.

Three decades' analysis of pediatric liver transplantation outcomes reveals limited long-term improvements.

BACKGROUND: The aim of this study was to assess improvements in long-term survival of pediatric patients after liver transplantation by analyzing outcomes in transplant recipients who survived beyond 1 year after transplantation. There has been a marked increase in the 1-year survival of pediatric patients, from 78% in transplant recipients between 1987 and 1990 to 95% in transplant recipients between 2011 and 2017. The long-term outcomes have not seen a similar trend, creating a disparity that warrants analysis. METHODS: We analyzed 13 753 pediatric patients who survived for 1 year after receiving orthotopic liver transplantation between 1987 and 2017. The study period was divided into six eras. Outcomes were analyzed using the Kaplan-Meier method for time-to-event analysis, and multivariable Cox regression. RESULTS: There were no significant gains in long-term outcomes among 1-year survivors over the past three decades. Log-rank tests for equality of survivor functions between each era and 1987-1990 were not statistically significant. Cause of death analysis revealed that although infections caused 20.6% of deaths in patients transplanted between 1987 and 1990, this number dropped to 5.6% in those transplanted between 2011 and 2017 (p = .01). Malignancy caused 10.6% of deaths in 1987-1990 but caused 22.2% of the deaths in 2011-2017 (p = .04). CONCLUSION: Despite the gratifying gains in short-term survival of pediatric patients, 1-year survivors have no significant improvements in long-term survival after undergoing a liver transplantation. Long-term sequelae of immunosuppression, such as malignancy and infection, continue to be the most common causes of death. This study highlights the necessity for better long-term management of immunosuppression.

Systematic review: hepatitis C viraemic allografts to hepatitis C-negative recipients in solid organ transplantation.

BACKGROUND: Given the success of direct-acting antivirals (DAAs) in treating hepatitis C (HCV), interest is growing in utilizing solid organs from allografts with active HCV to expand donor availability. AIM: To review post-transplant outcomes and patient survival in HCV-negative recipients receiving solid organ transplants (SOT) from viraemic, that is, HCV+/NAT+ (nucleic acid testing) allografts. METHODS: A literature search was conducted on PubMed and EMBASE from 01/01/2007 to 4/17/2021 for articles matching eligibility criteria. Two authors independently screened titles and abstracts. Disagreements were solved by a third independent reviewer. Methodological quality assessment was done using a modified Newcastle-Ottawa scale (NOS). Data synthesis was done qualitatively using median, ranges and percentages. RESULTS: Thirty-five studies were included (or 852 SOTs): 343 kidney, 233 heart, 204 liver, and 72 lung transplants from viraemic allografts. Of the recipients eligible for sustained virological response at 12 weeks (SVR12) calculation, 100% achieved cure from HCV. No deaths/graft failures were reported to be related to HCV transmission. Seven SOT recipients had viral relapse, with all seven patients treated successfully. Four patients developed fibrosing cholestatic hepatitis with complete resolution post-treatment. CONCLUSIONS: Transplanting viraemic organs into uninfected individuals can become the standard of care for patients who do not have contraindications to DAAs.

Donor Gamma-Glutamyl Transferase Is Associated With Liver Allograft Discard and Failure.

INTRODUCTION: The disparity between the number of individuals on the wait list and available liver allografts creates the need for a system that maximizes donor liver utilization and predicts graft failure. RESEARCH QUESTION: This study aimed to determine the relationship between donor Gamma-Glutamyl Transferase (GGT), liver discard, and graft failure. DESIGN: Through multivariate analysis from 53 966 deceased liver donors, we adjusted for donor clinical and demographic characteristics and compared donor GGT with allograft discard. We compared donor GGT ranges with graft failure and analyzed data from 47 269 liver recipients. RESULTS: After adjusting for other factors, donor GGT was significantly associated with liver discard, with GGT over 200 U/L being most significant (OR 2.74, CI 2.51-2.99). Donor GGT under 20 U/L was also found to be a protective factor for post-transplant graft failure (HR 0.91, CI 0.83 - 1.00). CONCLUSION: Going forward, GGT should be included among other characteristics associated with allograft discard considered during the procurement process.

Splenic Artery Transposition for Liver Transplantation: An Underutilized Technique?

BACKGROUND: Successful liver transplantation is dependent on restoration of hepatic arterial (HA) flow. Although uncommon, some native recipient HAs are not suitable or inadequate for anastomosis, thereby necessitating extra-anatomic HA reconstruction. Splenic artery transposition (SAT) is 1 method of HA reconstruction, in which the recipient splenic artery is transposed to reestablish perfusion of the donor liver. Due to the rarity of the technique, literature describing outcomes is limited. In the current report, we describe 3 patients (2 adults, 1 pediatric) who underwent complex upper abdominal surgery before whole-organ deceased donor liver transplantation with SAT. METHODS: The demographic and patient care information was collected prospectively and subsequently reviewed retrospectively. Given the de-identified nature of the data included, this study was exempt from approval from an ethics board. RESULTS: Recipient splenic arteries were dissected from their origin at the celiac trunk, for approximately 3-5 cm to ensure a gentle anterior-cranial curve toward the right upper quadrant, allowing anastomosis to the donor celiac trunk in an end-to-end fashion. Postoperatively, all 3 patients had rapid normalization of liver function tests and brisk HA flow demonstrated by Doppler ultrasound. Longer-term follow-up, ranging from 1 to 3 years, reveals continued patency of the reconstructed HAs and liver function tests within normal limits. CONCLUSIONS: Our experience points to SAT as a safe and effective technique for extra-anatomic HA reconstruction.

Prediction of Kidney Allograft Discard Before Procurement: The Kidney Discard Risk Index.

OBJECTIVES: There is an 18.9% discard rate among kidney allografts. Here, we aimed to determine predictors of kidney discard and construct an index to identify high-probability discard kidney allografts prior to procurement. MATERIALS AND METHODS: A total of 102 246 potential kidney allograft donors from the Organ Procurement and Transplantation Network database were used in this analysis. The cohort was randomized into 2 groups. The training set included 67% of the cohort and was used to derive a predictive index for discard that comprised 21 factors identified by univariate and multivariate logistic regression analysis. The validation set included 33% and was used to internally validate the kidney discard risk index. RESULTS: In 77.3% of donors, at least 1 kidney was used for transplant, whereas in 22.7% of donors, both kidneys were discarded. The kidney discard risk index was highly predictive of discard with a C statistic of 0.89 (0.88-0.89). The bottom 10th percentile had a discard rate of 0.73%, whereas the top 10th percentile had a discard rate of 83.65%. The 3 most predictive factors for discard were age, creatinine level, and hepatitis C antibody status. CONCLUSIONS: We identified 21 factors predictive of discard prior to donor procurement and used these to develop a kidney discard risk index with a C statistic of 0.89.

Pediatric discard risk index for predicting pediatric liver allograft discard.

BACKGROUND: Of the 600 pediatric candidates added to the liver waiting list annually, 100 will remain waiting while over 100 liver allografts are discarded, often for subjective reasons. METHODS: We created a risk index to predict discard to better optimize donor supply. We used the UNOS database to retrospectively analyze 17 367 deceased donors (≤18 years old) through univariate and multivariate logistic regression models. Deceased donor clinical characteristics and laboratory values were independent variables with discard being the dependent variable in the analysis. Significant univariate factors (P-value < .05) comprised the multivariate analysis. Significant variables from the multivariate analysis were incorporated into the pDSRI, producing a risk score for discard. RESULTS: From 17 potential factors, 11 were identified as significant predictors (P < .05) of pediatric liver allograft discard. The most significant risk factors were as follows: DCD; total bilirubin >10 mg/dL, and alanine transaminase (ALT) ≥500 IU/L. The pDSRI has a C-statistic of 0.846 for the training set and 0.840 for the validation set. CONCLUSION: The pDSRI uses 11 significant risk factors, including elevated liver function tests, donor demographics, and donor risk/type to accurately predict risk of pediatric liver allograft discard and serve as a tool that may maximize donor yield.

Liver transplant in a recently COVID-19 positive child with hepatoblastoma.

We describe the successful pediatric liver transplant for unresectable hepatoblastoma in a 4-year-old male with COVID-19 prior to transplant. The first negative NP swab was documented 1 month after initial diagnosis, when SARS-CoV-2 antibodies were also detected. The patient was actively listed for liver transplant after completing four blocks of a SIOPEL-4 based regimen due to his PRETEXT IV disease which remained unresectable. Following three additional negative NP swabs and resolution of symptoms for 4 weeks, he underwent a whole-organ pediatric liver transplant. COVID-19 positivity determined via NP swab SARS-CoV-2 real-time RT-PCR (Hologic Aptima SARS-CoV-2 RT-PCR assay). IgG and IgM total SARS- CoV-2 antibodies detected by Ortho Clinical Diagnostics VITROS® Immunodiagnostics Products Anti-SARS-CoV-2 Test. Patient received standard prednisone and tacrolimus-based immunosuppression without induction therapy following transplant. Post-transplant course was remarkable for neutropenia and thrombocytopenia, with discharge home on post-transplant day #11. Surveillance tests have remained negative with persistent SARS-CoV-2 IgG antibodies at 6 weeks after transplant. We describe one of the earliest, if not the first case of liver transplant following recent recovery from COVID-19 in a pediatric patient with a lethal malignant liver tumor. A better understanding of how to balance the risk profile of transplant in the setting of COVID-19 with disease progression if transplant is not performed is needed. We followed existing ASTS guidelines to document clearance of the viral infection and resolution of symptoms before transplant. This case highlights that pediatric liver transplantation can be safely performed upon clearance of COVID-19.

The pediatric solid organ transplant experience with COVID-19: An initial multi-center, multi-organ case series.

The clinical course of COVID-19 in pediatric solid organ transplant recipients remains ambiguous. Though preliminary experiences with adult transplant recipients have been published, literature centered on the pediatric population is limited. We herein report a multi-center, multi-organ cohort analysis of COVID-19-positive transplant recipients ≤ 18 years at time of transplant. Data were collected via institutions' respective electronic medical record systems. Local review boards approved this cross-institutional study. Among 5 transplant centers, 26 patients (62% male) were reviewed with a median age of 8 years. Six were heart recipients, 8 kidney, 10 liver, and 2 lung. Presenting symptoms included cough (n = 12 (46%)), fever (n = 9 (35%)), dry/sore throat (n = 3 (12%)), rhinorrhea (n = 3 (12%)), anosmia (n = 2 (8%)), chest pain (n = 2 (8%)), diarrhea (n = 2 (8%)), dyspnea (n = 1 (4%)), and headache (n = 1 (4%)). Six patients (23%) were asymptomatic. No patient required supplemental oxygen, intubation, or ECMO. Eight patients (31%) were hospitalized at time of diagnosis, 3 of whom were already admitted for unrelated problems. Post-transplant immunosuppression was reduced for only 2 patients (8%). All symptomatic patients recovered within 7 days. Our multi-institutional experience suggests the prognoses of pediatric transplant recipients infected with COVID-19 may mirror those of immunocompetent children, with infrequent hospitalization and minimal treatment, if any, required.

Pediatric length-of-stay index following liver transplantation.

BACKGROUND: PELD scores are used to reduce waitlist mortality, but they do not accurately predict likelihood of prolonged length-of-stay or higher costs associated with it. This study aims to create a pediatric length-of-stay (LOS) index to predict increased risk of prolonged stay following liver transplantation. METHODS: The scoring system generated predicts length-of-stay following pediatric liver transplantation. With univariate and multivariate analyses on data from 5669 pediatric liver transplant recipients, independent recipient/donor risk factors for prolonged stay (>30 days) were identified. Multiple imputations accounted for missing variables. RESULTS: The most significant factors were ICU admission (OR 2.92, CI 2.27-3.75), recipient bilirubin >32 (OR 2.35, CI 1.70-3.25), and hemodialysis 1 week before transplantation (OR 2.27, CI 1.57-3.27). The LOS index assigns weighted scoring points to factors to predict prolonged stay (C-statistic of .72). The index demonstrated discrimination across the population after dividing it into quartiles for prolonged stay. CONCLUSIONS: The pediatric LOS index, utilizing 13 donor/recipient factors, can assess the risk for pediatric liver transplantation prolonged stay. Important predictive factors are hemodialysis, ICU admission, recipient weight and bilirubin, and recipient life support status.

Combined Lung-Liver and Delayed Kidney Transplantation for Cystic Fibrosis Clinical Approach and Outcome: A Case Report.

Reports on the long-term outcomes and immunosuppressive regimens of multiorgan transplant patients are limited. Here, we describe a patient with cystic fibrosis complicated by multiorgan failure who was successfully treated with combined liver lung transplant and delayed kidney transplant, resulting in excellent outcomes. Delayed kidney transplant was done to reduce the operative stress of a single procedure, giving time for adequate resuscitation and weaning from vasopressors. Our patient's postoperative course was complicated by post-transplant lymphoproliferative disease, which was successfully treated with rituximab and reduced dosages of immunosuppression.

Cell type composition and circuit organization of clonally related excitatory neurons in the juvenile mouse neocortex.

Clones of excitatory neurons derived from a common progenitor have been proposed to serve as elementary information processing modules in the neocortex. To characterize the cell types and circuit diagram of clonally related excitatory neurons, we performed multi-cell patch clamp recordings and Patch-seq on neurons derived from Nestin-positive progenitors labeled by tamoxifen induction at embryonic day 10.5. The resulting clones are derived from two radial glia on average, span cortical layers 2-6, and are composed of a random sampling of transcriptomic cell types. We find an interaction between shared lineage and connection type: related neurons are more likely to be connected vertically across cortical layers, but not laterally within the same layer. These findings challenge the view that related neurons show uniformly increased connectivity and suggest that integration of vertical intra-clonal input with lateral inter-clonal input may represent a developmentally programmed connectivity motif supporting the emergence of functional circuits.

A learning curve in using orphan liver allografts for transplantation.

Given the critical shortage of donor livers, marginal liver allografts have potential to increase donor supply. We investigate trends and long-term outcomes of liver transplant using national share allografts transplanted after rejection at the local and regional levels. We studied a cohort of 75 050 candidates listed in the Organ Procurement and Transplantation Network for liver transplantation between 2002 and 2016. We compared patients receiving national share and regional/local share allografts from 2002-2006, 2007-2011, and 2012-2016, performing multivariate Cox regression for graft survival. Recipient and center-level covariates that were not significant (P < .05) were removed. Graft survival of national share allografts improved over time. National share allografts had a 26% increased risk for graft failure in 2002-2006 but no impact on graft survival in 2007-2011 and 2012-2016. The cold ischemia time (CIT) of national share allografts decreased from 10.4 to 8.0 hours. We demonstrate that CIT had significant impact on graft survival using national share allografts (CIT <6 hours: hazard ratio 0.75 and CIT >12 hours: hazard ratio 1.25). Despite a trend toward sicker recipients and poorer quality allografts, graft survival outcomes using national share allografts have improved to benchmark levels. Reduction in cold ischemia time is a possible explanation.

Most pediatric transplant centers are low volume, adult-focused, and in proximity to higher volume pediatric centers.

BACKGROUND: Independent studies provide evidence that low volume pediatric solid organ transplant centers have inferior outcomes compared to high volume pediatric centers. The study assessed whether patients treated at low volume pediatric centers have access to higher volume pediatric centers, which offer potentially better outcomes. METHODS: We analyzed center specific data on 467 pediatric solid organ transplant centers in the U.S using the Organ Procurement and Transplantation Network database from 2002 to 2014. The proximities of low volume pediatric centers to high volume pediatric centers were determined using Maptive, a tool based on Google Maps. RESULTS: Most low volume pediatric transplant centers focused on transplantation of adults (84% heart, 83% liver, and 93% kidney programs). A majority of low volume pediatric centers (77% for heart, 53% for lung, 68% for liver and 90% for kidney) were within 150 miles of high volume centers. Among all children listed for transplantation, 30.7% were listed in low volume pediatric centers. Most low volume pediatric centers are adult focused and near high volume pediatric centers. CONCLUSION: We need greater scrutiny of outcomes, particularly waitlist outcomes, of low volume pediatric solid organ transplant centers located close to high volume pediatric solid organ transplant centers. TYPE OF STUDY AND LEVEL OF EVIDENCE: Retrospective Comparative Study, Level III.

The decreasing predictive power of MELD in an era of changing etiology of liver disease.

The field of liver transplantation has shifted considerably in the MELD era, including changing allocation, immunosuppression, and liver failure etiologies, as well as better supportive therapies. Our aim was to evaluate the predictive accuracy of the MELD score over time. The United Network for Organ Sharing provided de-identified data on 120 156 patients listed for liver transplant from 2002-2016. The ability of the MELD score to predict 90-day mortality was evaluated by a concordance (C-) statistic and corroborated with competing risk analysis. The MELD score's concordance with 90-day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015. While lab MELD scores at listing and transplant climbed in that interval, score at waitlist death remained steady near 35. Listing age increased from 50 to 54 years. HCV-positive status at listing dropped from 33 to 17%. The concordance of MELD and mortality does not differ with age (>60 = 0.73, <60 = 0.74), but is lower in diseases that are increasing most rapidly-alcoholic liver disease and non-alcoholic fatty liver disease-and higher in those that are declining, particularly in HCV-positive patients (HCV positive = 0.77; negative = 0.73). While MELD still predicts mortality, its accuracy has decreased; changing etiology of disease may contribute.