Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways.

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Author Correction: Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Portable hypothermic oxygenated machine perfusion for organ preservation in liver transplantation: A randomized, open-label, clinical trial.

BACKGROUND AND AIMS: In liver transplantation, cold preservation induces ischemia, resulting in significant reperfusion injury. Hypothermic oxygenated machine perfusion (HMP-O 2 ) has shown benefits compared to static cold storage (SCS) by limiting ischemia-reperfusion injury. This study reports outcomes using a novel portable HMP-O 2 device in the first US randomized control trial. APPROACH AND RESULTS: The PILOT trial (NCT03484455) was a multicenter, randomized, open-label, noninferiority trial, with participants randomized to HMP-O 2 or SCS. HMP-O 2 livers were preserved using the Lifeport Liver Transporter and Vasosol perfusion solution. The primary outcome was early allograft dysfunction. Noninferiority margin was 7.5%. From April 3, 2019, to July 12, 2022, 179 patients were randomized to HMP-O 2 (n=90) or SCS (n=89). The per-protocol cohort included 63 HMP-O 2 and 73 SCS. Early allograft dysfunction occurred in 11.1% HMP-O 2 (N=7) and 16.4% SCS (N=12). The risk difference between HMP-O 2 and SCS was -5.33% (one-sided 95% upper confidence limit of 5.81%), establishing noninferiority. The risk of graft failure as predicted by Liver Graft Assessment Following Transplant score at seven days (L-GrAFT 7 ) was lower with HMP-O 2 [median (IQR) 3.4% (2.4-6.5) vs. 4.5% (2.9-9.4), p =0.024]. Primary nonfunction occurred in 2.2% of all SCS (n=3, p =0.10). Biliary strictures occurred in 16.4% SCS (n=12) and 6.3% (n=4) HMP-O 2 ( p =0.18). Nonanastomotic biliary strictures occurred only in SCS (n=4). CONCLUSIONS: HMP-O 2 demonstrates safety and noninferior efficacy for liver graft preservation in comparison to SCS. Early allograft failure by L-GrAFT 7 was lower in HMP-O 2 , suggesting improved early clinical function. Recipients of HMP-O 2 livers also demonstrated a lower incidence of primary nonfunction and biliary strictures, although this difference did not reach significance.

Commercial insurance delays direct-acting antiviral treatment for hepatitis C kidney transplantation into uninfected recipients.

INTRODUCTION: The advent of direct-acting antivirals (DAAs) has created an avenue for transplantation of hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-). The donor transmission of HCV is then countered by DAA administration during the post-operative period. However, initiation of DAA treatment is ultimately dictated by insurance companies. METHODS: A retrospective chart review of 52 D+/R- kidney recipients who underwent DAA treatment post-transplant was performed. Patients were grouped according to their prescription coverage plans, managed by either commercial or government pharmacy benefit managers (PBMs). RESULTS: Thirty-nine patients had government PBMs and 13 had commercial PBMs. Demographics were similar between the two groups. All patients developed HCV viremia, but cleared the virus after treatment with DAA. Patients with government PBMs were treated earlier compared to those with commercial PBMs (11 days vs 26 days, P = .01). Longer time to DAA initiation resulted in higher peak viral loads (ß = 0.39, R2  = .15, P = .01) and longer time to HCV viral load clearance (ß = 0.41, R2  = .17, P = .01). CONCLUSIONS: D+/R- transplantation offers patients an alternative strategy to increase access. However, treatment can be profoundly delayed by a third-party payer authorization process that may be subjecting patients to unnecessary risks and worsened outcomes.

Transplantation of viral-positive hepatitis C-positive kidneys into uninfected recipients offers an opportunity to increase organ access.

The advent of direct-acting antivirals (DAAs) has provided the impetus to transplant kidneys from hepatitis C virus-positive donors into uninfected recipients (D+/R-). Thirty D+/R- patients received DAA treatment. Sustained virologic response (SVR12) was defined as an undetectable viral load in 12 weeks after treatment. An age-matched cohort of uninfected donor and recipient pairs (D-/R-) transplanted during same time period was used for comparison. The median day of viral detection was postoperative day (POD) 2. The detection of viremia in D+/R- patients was 100%. The initial median viral load was 531 copies/µL (range: 10-1 × 108 copies/µL) with a median peak viral load of 3.4 × 105 copies/µL (range: 804-1.0 × 108 copies/µL). DAAs were initiated on median POD 9 (range: 5-41 days). All 30 patients had confirmed SVR12. During a median follow-up of 10 months, patient and graft survival was 100%, and acute rejection was 6.6% with no major adverse events related to DAA treatment. Delayed graft function was significantly decreased in D+/R- patients as compared to the age-matched cohort (27% vs 60%; P = .01). D+/R- transplantation offers patients an alternative strategy to increase access.

The Abdominal Transplant Surgery Workforce: Current state and future trends.

Transplant surgical workforce concerns have arisen in the last 5 years as reflected in challenges securing job opportunities for new fellows. The present survey was designed by the ASTS Membership and Workforce Committee to describe the current practice characteristics of transplant centers in order to estimate changes in the workforce. The survey questionnaire requested information about the transplant programs, the transplant surgeons involved in the program, and the estimated changes in the staffing of the program over the next 3 years. Seventy-one transplant centers responded from a total of 235 identified and queried (30.2% response rate), with median responding centers per UNOS region of 7 (IQR 4.5-8.5). The recruitment outlook for the next 3 years forecasts a positive inflow of surgeons at a 2:1 rate (incoming:leaving). The new female transplant workforce within the responding cohort has increased from 3.7% in 1980 to 18.4% in 2010. Currently, 13.1% of practicing US transplant surgeons in this survey are female which is higher than many other surgical specialties. This report represents the most up-to-date view into the abdominal transplant surgical workforce. The positive job recruitment outlook for transplant surgeons and the narrowing gender gap are new findings from this study.

Improving pancreas graft utilization through importation.

BACKGROUND: We analyze our outcomes utilizing imported allografts as a strategy to shorten wait list time for pancreas transplantation. METHODS: This is an observational retrospective cohort of 26 recipients who received either a locally procured (n = 16) or an imported pancreas graft (n = 10) at our center between January 2014 and May 2017. Wait list times of this cohort were compared to UNOS Region 9 (New York State and Western Vermont). Hospital financial data were also reviewed to analyze the cost-effectiveness of this strategy. RESULTS: Imported pancreas grafts had significantly increased cold ischemia times (CIT) and peak lipase (PL) levels compared to locally procured grafts (CIT 827 vs 497 minutes; P = .001, PL 563 vs 157 u/L; P = .023, respectively). There were no differences in graft or patient survival. The median wait time was significantly lower for simultaneous kidney-pancreas transplants at our center (518 days, n = 21) compared to Region 9 (1001 days, n = 65) P = .038. Despite financial concerns, the cost of transport for imported grafts was offset by lower standard acquisition costs. CONCLUSIONS: Imported pancreas grafts may be a cost-effective strategy to increase organ utilization and shorten wait times in regions with longer waiting times.

Segment 4 and the left lateral segment regeneration pattern after resection of the middle hepatic vein in a living donor right hepatectomy.

BACKGROUND: Inclusion of the middle hepatic vein (MHV) with a right hepatectomy (RH) in live donor liver transplantation improves venous drainage of the anterior sector of the graft. Its long-term effects on donor left liver (LL) regeneration are not well described. METHODS: Donors who underwent RH with MHV (MHV+, n = 12) were compared with donors who underwent RH with preservation of the MHV (MHV-, n = 24). Peri-operative complications and volume of the entire liver and individual segments were evaluated at 1 year post-donation. RESULTS: There was a trend towards a higher complication rate in the MHV+ group (41% versus 25%), without reaching statistical significance (P = 0.3). Males, high body mass index (BMI) and a smaller residual liver volume (RLV) were predictors for greater LL regeneration. MHV+ donors had impaired regeneration of segment 4 (S4) at 1 year, and compensatory greater left lateral segment regeneration. The absence of venous drainage of S4 (V4) to left hepatic vein (LHV) was a predictor of impaired S4 regeneration. CONCLUSIONS: Regeneration of S4 is impaired in MHV+ donors. Caution should be taken when considering MHV removal on donors with dominant S4, especially on those with potential increased demand for liver regeneration, such as males, higher BMI and a smaller RLV.

WITHDRAWN: Recurrence prediction of hepatocellular carcinoma after liver transplantation by ischemia time and tumor characteristics.

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Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed ("inside-out" (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

High terminal creatinine donors should not preclude simultaneous kidney and pancreas transplantation.

BACKGROUND: Simultaneous pancreas and kidney transplantation (SPK) in the setting of end-stage renal disease offers unmatched outcomes in insulin dependent diabetic patients. Donor pool expansion through the transplantation of kidneys with acute kidney injury (AKI) is controversial. METHODS: 59 SPK transplants were classified by presence of donor AKI, defined as donor terminal creatinine ≥ 1.5x the initial creatinine or donor terminal creatinine > 4.0 mg/dL. Endpoints included graft and patient survival, delayed graft function (DGF), serum creatinine, glomerular filtration rate (GFR), Hemoglobin A1c (HbA1c) and acute rejection. RESULTS: The donor AKI group (n = 35) had significantly higher rates of DGF (38 v. 9%, p = 0.01). There was no difference in creatinine or GFR at 1, 3, 6 and 12 months. HbA1c was comparable at 3, 6 and 12 months. There was no significant difference in the percentage of patients that required anti-diabetic agents after transplant (14 v. 4%, p = 0.56). CONCLUSIONS: We observed increased rates of DGF in SPK recipients with donor AKI. However, equivalent outcomes of pancreas and kidney function in both groups were observed.

The use of LCP-Tacrolimus (Envarsus XR) in simultaneous pancreas and kidney (SPK) transplant recipients.

BACKGROUND: Extended release LCP-tacrolimus (LCPT) allows once-daily dosing in transplant recipients. The improved bioavailability may be beneficial for simultaneous pancreas-kidney recipients (SPK). METHODS: This is a study of 39 SPK recipients on standard immediate-release tacrolimus (IR-TAC, n = 21) or LCPT (n = 18). Coefficient of variability (CV = 100∗standard deviation/mean) was calculated to assess drug levels. Hemoglobin A1c (HbA1c), tacrolimus and creatinine levels were measured postoperatively. RESULTS: There was no difference in tacrolimus CV in the IR-TAC and LCPT groups at 1 month or 3 months postoperatively; however, a greater difference was observed at 1 year (41.0 vs. 33.1%; p = 0.19). There were six episodes of acute rejection in the IR-TAC group compared to zero episodes in the LCPT group (p = 0.01). HbA1c was significantly higher in the IR-TAC group compared to LCPT at 3 (5.5 vs. 4.9%, p = 0.01), 6 (5.6 vs. 4.9%, p = 0.01) and 12 months (5.8 vs. 5.1%, p = 0.07). CONCLUSIONS: Significantly lower rates of rejection were observed in patients receiving LCPT. The once daily dosing may facilitate medication adherence and result in improved long-term outcomes.

Preoperative C-Peptide Predicts Weight Gain After Pancreas Transplantation.

BACKGROUND: Transplant recipients are susceptible to cardiovascular complications, obesity, and increased insulin resistance after transplant. Here we assess weight gain in diabetic recipients after pancreas transplantation. METHODS: This is a single-center study of 32 simultaneous pancreas and kidney and 5 pancreas after kidney transplant recipients from 2014 to 2018. Starting C-peptide levels ≤ 0.1 ng/mL were used to denote insulin nondetectability (n = 25) and C-peptide levels > 0.1 ng/mL as insulin detectability (n = 12). Hemoglobin A1c, body mass index (BMI), and weight following transplantation were assessed. RESULTS: Hemoglobin A1c at 1 year was 5.9% in the insulin nondetectable recipients and 5.6% in the insulin detectable group (P = .56). Average BMI after transplant was higher in the insulin detectable group 28.6 versus 24.4 kg/m2 (P = .03) despite no difference in starting BMIs (24.9 versus 24.0 kg/m2, P = .42). The insulin detectable group also had a larger percentage weight change from their starting weight 13.1% versus 0.9 % at 1 year (P = .02). Linear regression demonstrated that starting C-peptide was a significant predictor of weight gain posttransplant. CONCLUSIONS: Patients with elevated C-peptides at time of transplant are susceptible to rapid weight gain postoperatively. These patients may benefit from aggressive nutritional management.

Transplant surgery enters a new era: Increasing immunosuppressive medication adherence through mobile apps and smart watches.

The high rate of immunosuppressive medication non-adherence in transplant recipients demands the search for a solution that targets modifiable risk factors and incorporates mobile health technology to better engage and educate patients. Kidney transplant recipients (kidneys alone or multi-organ) were randomized to receive a mobile app known as Transplant Hero, both the app and a smart watch, or neither. The coefficient of variability (CV) of tacrolimus levels was measured at one and three months. No statistically significant differences in CV levels were observed between the three groups at either one or three months. Although mobile health apps are a promising strategy for increasing medication adherence, further research is required to determine how to best use this technology.

Young donors with severe acute kidney injury offer an opportunity to expand the donor pool.

BACKGROUND: This study assessed our experience transplanting kidneys from young donors with severe acute kidney injury. METHODS: We performed a single center retrospective analysis of 315 kidney transplants between 1/1/2014-12/31/2016. Donor kidneys were classified according to the Acute Kidney Injury Network (AKIN) criteria. A case-matched cohort was created using recipient age, history of diabetes, donor specific antibody, donor age and donor after cardiac death. Primary endpoints were graft function measured by eGFR at 90 days and at 1-year. RESULTS: Stage 3 AKIN recipients had significantly greater eGFR at one year (63.9 ml/min v. 51.2 ml/min, p < 0.001) compared to those with Stage 0 AKIN. This difference was abrogated when compared to a case matched cohort (eGFR at 90 days or 1 year; p > 0.05). Donor and recipient characteristics on eGFR at 1 year were analyzed using linear and logistic regression. Only donor age had a significant impact on recipient eGFR. CONCLUSIONS: Donor kidneys with severe acute injury can achieve optimal 1-year outcomes. Donor age is the most significant predictor of eGFR >45 ml/min after transplant.

Surgical treatment of hepatocellular carcinoma beyond Milan criteria. Results of liver resection, salvage transplantation, and primary liver transplantation.

BACKGROUND: There is no clear consensus regarding the best treatment strategy for patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with cirrhosis and HCC beyond Milan who had undergone liver resection (LR) or primary orthotopic liver transplantation (OLT) between November 1995 and December 2005 were included in this study. Pathological tumor staging was based on the American Liver Tumor Study Group modified Tumor-Node-Metastasis classification. RESULTS: A total of 23 HCC patients were primarily treated by means of LR, 5 of whom eventually underwent salvage OLT. An additional 32 patients underwent primary OLT. The overall actuarial survival rates at 3 and 5 years were 35% after LR, and 69% and 60%, respectively, after primary OLT. Recurrence-free survival at 5 years was significantly higher after OLT (65%) than after LR (26%). Of the patients who underwent LR, 11 (48%) experienced HCC recurrence only in the liver; 6 of these 11 presented with advanced HCC recurrence, poor medical status, or short disease-free intervals and were not considered for transplantation. Salvage OLT was performed in 5 patients with early stage recurrence (45% of patients with hepatic recurrence after LR and 22% of all patients who underwent LR). At a median of 18 months after salvage OLT, all 5 patients are alive, 4 are free of disease, and 1 developed HCC recurrence 16 months after salvage OLT. CONCLUSION: For patients with HCC beyond Milan criteria, multimodality treatment-including LR, salvage OLT, and primary OLT-results in long-term survival in half of the patients. When indicated, LR can optimize the use of scarce donor organs by leaving OLT as a reserve option for early stage HCC recurrence.

Exploring the usage of a mobile phone application in transplanted patients to encourage medication compliance and education.

BACKGROUND: Medication non-adherence in transplant patients is a grave problem that results in increased rejection episodes, graft loss and significant morbidity. METHODS: The efficacy of users and non-users of a mobile phone application (mobile app) in promoting medication adherence was investigated. The Beliefs about Medicine Questionnaire (BMQ) and Morisky Medication Adherence Scale (MMAS-8) were used in these cohorts to assess the predilection for poor adherence. Serum tacrolimus, creatinine levels, and rejection episodes were also recorded. Lastly, the patients were tested on their recall of their immunosuppression. RESULTS: Overall, patients had extremely negative beliefs about medication reflected in their tendency toward higher predicted rates of non-adherence. Interestingly, though not significant, app users had higher rates of medication recollection. CONCLUSIONS: The high-risk nature of this population demands efforts to abrogate non-adherence. Caregivers are charged with the responsibility to offer patients a feasible option to safeguard treatment compliance. Mobile apps are a potentially powerful tool, which can be used to decrease non-adherence.