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Key words: diabetic nephropathy; nodular glomerulosclerosis; non-diabetic patient; renal allograft [ABSTRACT FROM PUBLISHER]

Abstract Background The molecular mechanisms that regulate the entry of dietary sterols into the body and their removal via hepatobiliary secretion are now beginning to be defined. These processes are specifically disrupted in the rare autosomal recessive disease, Sitosterolemia (MIM 210250). Mutations in either, but not both, of two genes ABCG5 or ABCG8, comprising the STSL locus, are now known to cause this disease and their protein products are proposed to function as heterodimers. Under normal circumstances cholesterol, but not non-cholesterol sterols, is preferentially absorbed from the diet. Additionally, any small amounts of non-cholesterol sterols that are absorbed are rapidly taken up by the liver and preferentially excreted into bile. Based upon the defects in sitosterolemia, ABCG5 and ABCG8 serve specifically to exclude non-cholesterol sterol entry at the intestinal level and are involved in sterol excretion at the hepatobiliary level. Methods Here we report the biochemical and immuno-localization of ABCG5 and ABCG8 in human liver, gallbladder and intestine using cell fractionation and immunohistochemical analyses. Results We raised peptide antibodies against ABCG5 and ABCG8 proteins. Using human liver samples, cell fractionation studies showed both proteins are found in membrane fractions, but they did not co-localize with caveolin-rafts, ER, Golgi or mitochondrial markers. Although their distribution in the sub-fractions was similar, they were not completely contiguous. Immunohistochemical analyses showed that while both proteins were readily detectable in the liver, ABCG5 was found predominately lining canalicular membranes, whereas ABCG8 was found in association with bile duct epithelia. At the cellular level, ABCG5 appeared to be apically expressed, whereas ABCG8 had a more diffuse expression pattern. Both ABCG5 and ABCG8 appeared to localize apically as shown by co-localization with MRP2. The distribution patterns of ABCG5 and ABCG8 in the gallbladder were very similar to each other. In the small intestine both ABCG5 and ABCG8 appear to line the brush border. However, at the level of the enterocyte, the cellular distribution patterns of ABCG5 and ABCG8 differed, such that ABCG5 was more diffuse, but ABCG8 was principally apical. Using standard deglycosylation methods, ABCG5 and ABCG8 do not appear to be glycosylated, suggesting a difference between human and mouse proteins. Conclusion We report the distribution patterns of ABCG5 and ABCG8 in human tissues. Cell fractionation studies showed that both proteins co-fractionated in general, but could also be found independent of each other. As predicted, they are expressed apically in both intestine and liver, although their intracellular expression patterns are not completely congruent. These studies support the concept of heterodimerization of ABCG5 and ABCG8, but also support the notion that these proteins may have an independent function.

Introduction: While superb outcomes have been observed in the HIV-positive (HIV+) population, graft failure and subsequent need for kidney retransplantation (re-KT) remain a concern. This study aims to investigate the difference in success rates of re-KT allograft survival in the HIV+ versus HIV-negative (HIV-) population in the current era of transplantation (2014-2022)., Methods: Data was collected from the Organ Procurement and Transplantation Network on all kidney transplant donors and recipients who had their first re-KT between 2014 and 2022. Allograft survival was assessed using Kaplan-Meier analysis with a log-rank test, while risk factors for graft loss were assessed using Cox proportional hazards with statistical significance set to P = 0.05., Results: HIV+ recipients were significantly more likely to be Black (P < 0.001), have an HLA mismatch >3 (P = 0.018), delayed graft function (P = 0.023), and graft loss from primary nonfunction (P < 0.001). Their HIV- counterparts were more likely to be White (P < 0.001) and Hispanic (<0.001), lose their graft from acute rejection (P = 0.044), and have a living donor (P = 0.001). Being HIV+ was associated with a 1.68-fold increased risk of graft loss, an HLA mismatch >3 held a 1.18-fold increase, experiencing delayed graft function held a 1.89-fold increase, and having diabetes was associated with a 1.16-fold increased risk. Living donor kidneys were associated with a 15.8% decrease in risk for graft failure. Kaplan-Meier curves showed a significantly lower duration of kidney allograft survival in the HIV+ community (P = 0.02)., Conclusions: Disproportional graft failure and inadequate HLA mismatching persist within the HIV+ Re-KT community. Stronger organ matching and new approaches for desensitizing retransplant candidates are vital., (Published by Elsevier Inc.)

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level., Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation., Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022., Main Outcomes and Measures: Center volume, changes in cost., Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems., Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Hypogonadism is understudied in men requiring solid organ transplants, particularly among lung transplant recipients. Improvement in serum testosterone levels has been reported in kidney and liver transplantation. Using the TriNetX Research Network, we performed a retrospective cohort study to evaluate the incidence of peri-transplant hypogonadism and the natural course of serum testosterone following successful lung transplantation. Men aged ≥ 18 with a lung transplant and total testosterone drawn within one year pre- and post-transplant were included. Men with receipt of testosterone therapy were excluded. A low testosterone (<300 ng/dL) and normal testosterone (≥300 ng/dL) cohort was created before employing descriptive and analytic statistics to investigate the incidence of peri-transplant hypogonadism and the change in serum testosterone levels following lung transplantation. In our entire cohort, lung transplantation was not associated with a significant increase in post-transplant serum testosterone (329.86 ± 162.56 ng/dL pre-transplant and 355.13 ± 216.11 ng/dL post-transplant, p = 0.483). The number of men with low testosterone decreased by 9.8% following lung transplantation but was not significant, p = 0.404. In this pilot study, no significant change in the number of hypogonadal men nor serum testosterone levels was observed among men undergoing lung transplantation., (© 2024. The Author(s).)

Background: Tacrolimus extended-release tablets have been Food and Drug Administration-approved for use in the de novo kidney transplant population. Dosing requi rements often vary for tacrolimus based on several factors including variation in metabolism based on CYP3A5 expression. Patients who express CYP3A5 often require higher dosing of immediate-release tacrolimus, but this has not been established for tacrolimus extended-release tablets in the de novo setting., Aim: To obtain target trough concentrations of extended-release tacrolimus in de novo kidney transplant recipients according to CYP3A5 genotype., Methods: Single-arm, prospective, single-center, open-label, observational study (ClinicalTrials.gov: NCT037 13645). Life cycle pharma tacrolimus (LCPT) orally once daily at a starting dose of 0.13 mg/kg/day based on actual body weight. If weight is more than 120% of ideal body weight, an adjusted body weight was used. LCPT dose was adjusted to maintain tacrolimus trough concentrations of 8-10 ng/mL. Pharmacogenetic analysis of CYP3A5 genotype was performed at study conclusion., Results: Mean time to therapeutic tacrolimus trough concentration was longer in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (6 d vs 13.5 d vs 4.5 d; P = 0.025). Mean tacrolimus doses and weight-based doses to achieve therapeutic concentration were higher in CYP3A5 intermediate and extensive metabolizers vs CYP3A5 non-expressers (16 mg vs 16 mg vs 12 mg; P = 0.010) (0.20 mg/kg vs 0.19 mg/kg vs 0.13 mg/kg; P = 0.018). CYP3A5 extensive metabolizers experienced lower mean tacrolimus trough concentrations throughout the study period compared to CYP3A5 intermediate metabolizers and non-expressers (7.98 ng/mL vs 9.18 ng/mL vs 10.78 ng/mL; P = 0 0.008). No differences were identified with regards to kidney graft function at 30-d post-transplant. Serious adverse events were reported for 13 (36%) patients., Conclusion: Expression of CYP3A5 leads to higher starting doses and incremental dosage titration of extended-release tacro limus to achieve target trough concentrations. We suggest a higher starting dose of 0.2 mg/kg/d for CYP3A5 expressers., Competing Interests: Conflict-of-interest statement: Adam Diamond serves as an active member of the Veloxis Pharmaceuticals Speaker’s Bureau (honoraria provided)., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited., Methods: We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19., Results: We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31-462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19-2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62-2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01-2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26-2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06-2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine., Conclusions: Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of the American Association for the Study of Liver Diseases.)

Objective: To determine if addition of the S-nitrosylating agent ethyl nitrite (ENO) to the preservation solution can improve perfusion parameters in pumped human kidneys., Background: A significant percentage of actively stored kidneys experience elevations in resistance and decreases in flow rate during the ex vivo storage period. Preclinical work indicates that renal status after brain death is negatively impacted by inflammation and reduced perfusion-processes regulated by protein S-nitrosylation. To translate these findings, we added ENO to the preservation solution in an attempt to reverse the perfusion deficits observed in nontransplanted pumped human kidneys., Methods: After obtaining positive proof-of-concept results with swine kidneys, we studied donated human kidneys undergoing hypothermic pulsatile perfusion deemed unsuitable for transplantation. Control kidneys continued to be pumped a 4°C (ie, standard of care). In the experimental group, the preservation solution was aerated with 50 ppm ENO in nitrogen. Flow rate and perfusion were recorded for 10 hours followed by biochemical analysis of the kidney tissue., Results: In controls, perfusion was constant during the monitoring period (ie, flow rate remained low and resistance stayed high). In contrast, the addition of ENO produced significant and sustained reductions in resistance and increases in flow rate. ENO-treated kidneys had higher levels of cyclic guanosine monophosphate, potentially explaining the perfusion benefits, and increased levels of interleukin-10, suggestive of an anti-inflammatory effect., Conclusions: S-Nitrosylation therapy restored the microcirculation and thus improved overall organ perfusion. Inclusion of ENO in the renal preservation solution holds promise to increase the number and quality of kidneys available for transplant., Competing Interests: Conflicts of interest: Drs Reynolds and Stamler hold patents related to renitrosylation some of which have been licensed for commercial development. Their institution is aware of these conflicts and appropriate management plans are in place. None of the other authors have relevant conflicts to disclose., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There are many potential treatment options for patients with early stage hepatocellular carcinoma (HCC) and practice patterns vary widely. This project aimed to use a Delphi conference to generate consensus regarding the management of small resectable HCC., Methods: A base case was established with review by members of AHPBA Research Committee. The Delphi panel of experts reviewed the literature and scored clinical case statements to identify areas of agreement and disagreement. Following initial scoring, discussion was undertaken, questions were amended, and scoring was repeated. This cycle was repeated until no further likelihood of reaching consensus existed., Results: The panel achieved agreement or disagreement consensus regarding 27 statements. The overarching themes included that resection, ablation, transplantation, or any locoregional therapy as a bridge to transplant were all appropriate modalities for early or recurrent HCC. For larger lesions, consensus was reached that radiofrequency ablation and microwave ablation were not appropriate treatments., Conclusion: Using a validated system for identifying consensus, an expert panel agreed that multiple treatment modalities are appropriate for early stage HCC. These consensus guidelines are intended to help guide physicians through treatment modalities for early HCC; however, clinical decisions should continue to be made on a patient-specific basis., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Hepatectomy is a complex procedure with high morbidity and mortality. Early prediction/prevention of major complications is highly valuable for patient care. Surgical APGAR score (SAS) has been validated to predict post-surgical complications (PCs). We aimed to define a simple complications classification following hepatectomy based on a therapy-oriented severity Clavien-Dindo classification (CDC). 119 patients undergoing liver resection were included. PCs were determined at follow-up based on CDC. Clinicopathological factors were used to calculate SAS. A receiver-operator characteristic (ROC) curve analysis estimated the predictive value of SAS for PCs. Circulating markers levels of liver injury were analyzed as critical elements on PCs. SAS (P=0.008), estimated blood-loss (P=0.018) and operation time (P=0.0008) were associated with PCs. SAS was reduced in patients with (+) compared to those without (-) complications (6.64±1.84 vs 5.70±1.79, P=0.0079). The area-under-the-curve was 0.646 by ROC, indicating an acceptable discrimination with 65% possibility to distinguish (-) and (+) groups (P=0.004). Best cutoff value for SAS was ≤6/≥7, at which sensitivity and specificity were maximal. ALT/ASL levels were significantly different within the group with 9-10 SAS points (P=0.01 and 0.02). In conclusion, SAS provides accurate risk stratification for major PCs after hepatectomy, and might help improving the overall patient outcome., Competing Interests: Disclosure statement The authors declare no conflicts of interest

Noninvasive biomarker profiles of acute rejection (AR) could affect the management of liver transplant (LT) recipients. Peripheral blood was collected following LT for discovery (Northwestern University [NU]) and validation (National Institute of Allergy and Infectious Diseases Clinical Trials in Organ Transplantation [CTOT]-14 study). Blood gene profiling was paired with biopsies showing AR or ADNR (acute dysfunction no rejection) as well as stable graft function samples (Transplant eXcellent-TX). CTOT-14 subjects had serial collections prior to AR, ADNR, TX, and after AR treatment. NU cohort gene expression (46 AR, 45 TX) was analyzed using random forest models to generate a classifier training set (36 gene probe) distinguishing AR vs TX (area under the curve 0.92). The algorithm and threshold were locked and tested on the CTOT-14 validation cohort (14 AR, 50 TX), yielding an accuracy of 0.77, sensitivity 0.57, specificity 0.82, positive predictive value (PPV) 0.47, and negative predictive value (NPV) 0.87 for AR vs TX. The probability score line slopes were positive preceding AR, and negative preceding TX and non-AR (TX + ADNR) (P ≤ .001) and following AR treatment. In conclusion, we have developed a blood biomarker diagnostic for AR that can be detected prior to AR-associated graft injury as well a normal graft function (non-AR). Further studies are needed to evaluate its utility in precision-guided immunosuppression optimization following LT., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Aims: A high proportion of patients develop chronic kidney disease (CKD) after liver transplantation (LT). We aimed to develop clinical/protein models to predict future glomerular filtration rate (GFR) deterioration in this population., Approach and Results: In independent multicenter discovery (CTOT14) and single-center validation (BUMC) cohorts, we analyzed kidney injury proteins in serum/plasma samples at month 3 after LT in recipients with preserved GFR who demonstrated subsequent GFR deterioration versus preservation by year 1 and year 5 in the BUMC cohort. In CTOT14, we also examined correlations between serial protein levels and GFR over the first year. A month 3 predictive model was constructed from clinical and protein level variables using the CTOT14 cohort (n = 60). Levels of β-2 microglobulin and CD40 antigen and presence of hepatitis C virus (HCV) infection predicted early (year 1) GFR deterioration (area under the curve [AUC], 0.814). We observed excellent validation of this model (AUC, 0.801) in the BUMC cohort (n = 50) who had both early and late (year 5) GFR deterioration. At an optimal threshold, the model had the following performance characteristics in CTOT14 and BUMC, respectively: accuracy (0.75, 0.8), sensitivity (0.71, 0.67), specificity (0.78, 0.88), positive predictive value (0.74, 0.75), and negative predictive value (0.76, 0.82). In the serial CTOT14 analysis, several proteins, including β-2 microglobulin and CD40, correlated with GFR changes over the first year., Conclusions: We have validated a clinical/protein model (PRESERVE) that early after LT can predict future renal deterioration versus preservation with high accuracy. This model may help select recipients at higher risk for subsequent CKD for early, proactive renal sparing strategies., (© 2019 by the American Association for the Study of Liver Diseases.)

Objectives: Pancreas transplant improves quality of life and survival of patients irrespective of pretransplant C-peptide levels. Our objectives were to examine complications and outcomes in patients without measureable C-peptide (insulin-dependent type 1 diabetes mellitus) and carefully selected patients with measurable C-peptide (insulin-dependent type 2 diabetes mellitus) after pancreas transplant., Materials and Methods: We conducted a retrospective analysis to examine the demographic, transplant factors, complications, and outcomes in patients with nondetectable pretransplant C-peptide (insulin-dependent type 1 diabetes mellitus) and patients with detectable pretransplant C-peptide (insulin-dependent type 2 diabetes mellitus)., Results: Of 214 consecutive pancreas transplant procedures over a 12-year period, 112 had pretransplant C-peptide level testing (63 patients with type 1 and 49 with type 2 diabetes mellitus). Patients with type 1 disease were more likely to be female (P = .048), and patients with type 2 disease were more likely to be African American (P < .001) and have undergone previous pancreas transplant (P = .042). We observed no differences in donor factors or posttransplant factors (C-peptide after year 2, glucose, and hemoglobin A1C, except that patients with type 2 disease had more pancreatitis) (P = .036). There were no differences in posttransplant complications; however, patients with type 2 disease had significantly higher BK virus nephropathy (P = .006). There were no differences in outcomes between cohorts (rejection, graft loss, or death; P = not significant)., Conclusions: Pancreas transplant can be performed with excellent and equivalent outcomes in patients with type 1 and carefully selected type 2 diabetes mellitus. Patients with type 2 disease are more likely to have posttransplant pancreatitis and BK virus nephropathy, affecting the net benefit for transplant.

Background: Kidney transplantation improves survival and quality of life for patients with end-stage kidney disease (ESKD). However, there is a shortage of donated organs, resulting in long wait times and the potential for death before a donor is found. Non-directed (also called altruistic) living kidney donation is a growing type of donation; however, few studies have examined the values and motivation of individuals evaluated to be a non-directed donor., Objectives: This qualitative study explores the motivations and values of individuals evaluated for non-directed donation., Design: Focus groups were conducted with individuals who had been evaluated for non-directed living kidney donation. Grounded theory method guided the data analysis., Participants: Participants (N = 11) were individuals who completed the evaluation for a non-directed living kidney donation., Findings: Qualitative analyses revealed eight major themes participants considered in making their decision to donate to a non-related person: (i) motivation to donate; (ii) minimise perceived risk; (iii) ideal selected recipient; (iv) change in lifestyle; (v) source of donation knowledge; (vi) history of altruistic acts; (vii) donation chain and (viii) others' response., Conclusions: Results suggest that non-directed living kidney donors think deeply about their decision and have a resolve to help others that is aligned with their values. As organ availability remains at a critical shortage, unwillingness to consider non-directed living donors (NDD) due to beliefs of ill motivations appears unsupported. Future directions call for the need of standard practice of care in kidney donation evaluations across transplant centers., (© 2019 European Dialysis and Transplant Nurses Association/European Renal Care Association.)

Background: Management of asymptomatic small well-differentiated (panNET) <2 cm remains controversial. A consensus conference was held on this topic. The impact of attending the conference and participating in the audience response survey on surgeon's clinical approach to pancreatic neuroendocrine tumors was assessed., Methods: Audience members were surveyed using a smartphone real-time response system at the beginning and end of the conference., Results: The majority of 75 attendees underwent fellowship training, and 30% had >10 years experience as attending surgeons. Previously published consensus statements on the topic were considered insufficient to guide surgical practice by 82% of attendees, and over 96% desired additional data. After review of the data, consensus statements, and decision-making process, a significant number of participants changed their opinions regarding indications for tissue biopsy (p = 0.001), size thresholds for excision (p = 0.002), and regional lymph node dissection (p = 0.002) independent of whether a consensus was reached by the content-expert panel., Conclusions: This represented the first Delphi process consensus on the topic, and the survey confirmed the topic as well-chosen and timely. Attendees changed opinions on management of panNET regardless of whether formal consensus was reached. Therefore, statements of consensus combined with presentation of literature and live discussion served to impact attendees' approach to this disease., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. All rights reserved.)

Background: Variation in the management of PNETs exist due to the limited high-level evidence to guide clinical practice. The aim of this work is to generate consensus guidelines with a Delphi process for managing PNETs., Methods: A panel of experts reviewed the surgical literature and scored a set of clinical case statements using a web-based survey to identify areas of agreement and disagreement. Results of the survey were discussed after each round of review. This cycle was repeated until no further likelihood of reaching consensus existed., Results: Twenty-two case statements related to surgical indications, preoperative biopsy, extent of resection, type of surgery, and tumor location were scored. Using a pre-defined definition of consensus, the panel achieved consensus on the following: i) resection is not recommended for <1 cm lesions; ii) resection is recommended for lesions greater than 2 cm; iii) lymph node dissection is recommended for radiographically-suspicious nodes with splenectomy for distal lesions; iv) tumor enucleation and central pancreatectomy are acceptable when technically feasible. No consensus was reached regarding issues of preoperative biopsy or 1-2 cm tumors., Conclusions: Using a structured, validated system for identifying consensus, an expert panel identified areas of agreement regarding critical management decisions for patients with PNET. Issues without consensus warrant additional clinical investigation., (Copyright © 2018. Published by Elsevier Ltd.)

Normothermic machine perfusion (NMP) is an emerging technology to preserve liver allografts more effectively than cold storage (CS). However, little is known about the effect of NMP on steatosis and the markers indicative of hepatic quality during NMP. To address these points, we perfused 10 discarded human livers with oxygenated NMP for 24 hours after 4-6 hours of CS. All livers had a variable degree of steatosis at baseline. The perfusate consisted of packed red blood cells and fresh frozen plasma. Perfusate analysis showed an increase in triglyceride levels from the 1st hour (median, 127 mg/dL; interquartile range [IQR], 95-149 mg/dL) to 24th hour of perfusion (median, 203 mg/dL; IQR, 171-304 mg/dL; P = 0.004), but tissue steatosis did not decrease. Five livers produced a significant amount of bile (≥5 mL/hour) consistently throughout 24 hours of NMP. Lactate in the perfusate cleared to <3 mmol/L in most livers within 4-8 hours of NMP, which was independent of bile production rate. This is the first study to characterize the lipid profile and functional assessment of discarded human livers at 24 hours of NMP. Liver Transplantation 24 233-245 2018 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Context: There is evidence that depression after liver transplant (LTX) is associated with increased morbidity and mortality; however, the effect of depression treatment on LTX outcomes has not been well established., Objective/setting/design: This single-center, longitudinal cohort study aimed to determine whether depression treatment influences outcomes after LTX. Depression diagnosis was based on medical history and documentation from psychosocial providers., Patients/intervention/main Outcome Measures: Patients were studied from October 2010 to June 2013 and separated into 3 groups for analysis: no depression, adequately treated depression, and inadequately treated depression. Adequacy of depression treatment was determined using the Antidepressant Treatment History Form., Results: Of the 161 patients included in the analysis, 103 did not have depression, 24 had adequately treated depression, and 34 had inadequately treated depression. Baseline demographics were similar between the groups. Patients with inadequately treated depression had significantly more encounters with a health-care provider (P = .03). Graft loss tended to be higher in these patients (27% in the inadequately treated group, 17% in the adequately treated, and 14% in the no depression group, P = .25). The adequately treated group was more likely than the inadequately treated group to be on antidepressants at 30 days post-LTX (P = .001). The inadequately treated group was more likely to be on a sleep aid 30 days post-LTX (P = .01)., Conclusion: Inadequately treated depression led to increased health-care resource utilization. Patients with adequately treated depression had similar outcomes as those with no depression. Use of sleep aids early post-LTX may be a surrogate indicator of inadequately treated depression., (© 2016, NATCO.)

Kidney disease is a costly and prevalent condition that affects African Americans more than any other group. The purpose of this study was to determine the knowledge of kidney disease African American patients have about their disease. Four qualitative focus groups were conducted with kidney disease patients in which the patients gave thoughts and opinions on kidney disease and various components and factors of the condition. The data were independently reviewed and analyzed using Qualrus coding software. Dominant themes discussed in the focus groups included: causes of kidney disease, patient thoughts on dialysis as a treatment for kidney disease, information source for disease knowledge, thoughts on God and faith, reaction to kidney disease, and types of treatment available. The study found that the majority of patients were unaware of specific causes and risk factors of kidney disease, were unsure of available treatments, and had a severe lack of knowledge and support system in dealing with the condition. Early prevention and education programs aimed at high-risk populations would be very beneficial in decreasing the incidence and increase of kidney disease., (© The Author(s) 2014.)

Context: Kidney disease is a common disease that is best treated through kidney transplant. The kidney transplant process is complex and can be difficult to navigate and most likely requires an adequate amount of health literacy., Objective: To assess the relationship between health literacy and transplant outcomes, including whether a patient was listed for or received a transplant., Design: A cross-sectional study measuring patients' health literacy and transplant outcomes., Setting and Participants: Participants from a single transplant center were invited to participate if they were referred to the center for transplant and spoke English. Of the 92 patients, 30 (33%) were in the vascular access clinic, 31 (34%) were posttransplant, and 31 (34%) were pretransplant., Intervention: Health literacy was measured by using 3 tools: Rapid Estimate of Adult Literacy of Medicine-Transplant (REALM-T), Newest Vital Sign (NVS), and Decision-Making Capacity Assessment Tool (DMCAT)., Main Outcome Measure: Two dichotomous variables: whether the patient was listed for transplant and/or received a transplant. Descriptive and univariate statistics were calculated. Six logistic regression models were used to test for a correlation between each of the tools and patients' likelihood to be listed for and/or receive a transplant., Results: Fifty-three patients (58%) were formally listed for a transplant, and 36 (39%) received a transplant. The REALM-T, NVS, and DMCAT each significantly predicted whether or not a patient was listed for transplant (odds ratios, 1.044, 1.672, and 1.408). The NVS and DMCAT significantly predicted whether a patient received a transplant (odds ratios, 1.667 and 1.256). Health literacy is a positive and significant predictor of transplant outcomes. Clinicians should take assessments of health literacy into account when speaking to patients about kidney transplant.

Context: Health literacy affects a patient's ability to navigate through the system of care for late-stage kidney disease, including evaluation, waiting, and recovering from kidney transplant., Objectives: To develop and provide a preliminary evaluation of a knowledge and decision-making capacity tool, which is a component of health literacy., Design: Cross-sectional design with purposive sampling., Setting: Vascular access, dialysis, and outpatient transplant clinics., Methods: A Decision-Making Capacity Assessment Tool (DMCAT) was developed and administered to 127 adults at different stages in the kidney care process., Results: The DMCAT tool is positively and significantly correlated to the other 2 previously validated instruments and accounts for more variance than the other 2 tools in the regression models. We found significant differences in patients' health literacy and decision-making capacity related to their stage of care. Decision-making capacity appeared to be an important component of health literacy and should be considered as health care providers tailor care to meet patients' needs.

Hepatic ischemia/reperfusion (l/R) injury continues to be a critical problem. The role of nitric oxide in liver I/R injury is still controversial. This study examines the effect of endothelial nitric oxide synthase (eNOS) over-expression on hepatic function following I/R. Adenovirus expressing human eNOS (Ad-eNOS) was administered by tail vein injection into C57BL/6 mice. Control mice received either adenovirus expressing LacZ or vehicle only. Sixty minutes of total hepatic ischemia was performed 3 days after adenovirus treatment, and mice were sacrificed after 6 or 24 hrs of reperfusion to assess hepatic injury. eNOS over expression caused increased liver injury as evidenced by elevated AST and ALT levels and decreased hepatic ATP content. While necrosis was not pervasive in any group, TUNEL demonstrated significantly increased apoptosis in Ad-eNOS infected livers. Western blotting demonstrated increased levels of protein nitration and upregulation of the pro-apoptotic proteins bax and p53. Our data suggest that over-expression of eNOS is detrimental in the setting of hepatic I/R.

Background: There is limited data analyzing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of everolimus (EVR) between African Americans and Caucasians. The purpose of this study was to determine and compare the EVR PKs and concentration-associated efficacy and toxicity in African American and Caucasian adult kidney transplant recipients., Methods: This was a retrospective PK and PD analysis of all patients who received EVR at the Medical University of South Carolina Transplant Center between 2006 and 2012., Results: Forty-three patients received EVR (22 African Americans, 21 Caucasians). Baseline demographics, immunosuppression, and immunologic risk were similar between races, except for preexisting hypertension, deceased donor type, and cold ischemic time, which were higher in African American patients. PK analysis revealed that African American patients received higher initial EVR doses (2.1 ± 0.8 versus 1.6 ± 0.6 mg/d, P = 0.036), leading to higher early EVR concentrations (EVR >6 ng/mL during the first 60 days: 36% versus 10%, P = 0.037). Efficacy analysis demonstrated similar EVR effects on acute rejection rates (9% versus 10%, P = 0.961), chronic allograft changes (18% versus 14%, P = 0.729), and renal function, with both groups having improved creatinine clearance with EVR therapy (ΔeGFR: 27 versus 12 mL·min·1.73 m). Toxicity analysis demonstrated that African American patients had a trend toward higher rates of EVR discontinuation (46% versus 19%, P = 0.065) and significantly more diarrhea/gastrointestinal intolerance (73% versus 38%, P = 0.022)., Conclusions: These results demonstrate EVR therapy is effective at preventing rejection and improving graft function in both African American and Caucasian adult renal transplant patients. Conflicting with previous mammalian target of rapamycin PK/PD analyses in African American patients, this study cohort demonstrated higher early EVR levels in the African American patients.

We evaluated the efficacy and safety of immunosuppressive regimens containing a mammalian target of rapamycin (mTOR) inhibitor with tacrolimus (TAC) minimization therapy in solid organ transplant recipients. A PubMed search was conducted using the terms (mTOR OR sirolimus OR everolimus) AND tacrolimus AND renal AND (low OR reduced OR reduction OR minimization) AND transplant*; limited to title/abstract and English-language articles published from January 1, 2003, through January 28, 2013. Twenty-one relevant studies of TAC minimization therapy were identified and evaluated in the context of known concerns associated with immunosuppressive therapy. Review of these studies suggests that immunosuppressive regimens including an mTOR inhibitor and TAC minimization therapy better preserve renal function versus standard-dose TAC, without significant changes in patient survival or graft rejection rates. Among patients treated with an mTOR inhibitor plus TAC minimization therapy in 12 randomized controlled trials (n=856 kidney, n=190 heart, n=108 lung, n=719 liver patients), reported rates of infection (BK, cytomegalovirus, or Epstein-Barr virus) and malignancy were low (0% to 7%). Other adverse events were more commonly reported including dyslipidemia/hyperlipidemia in up to two thirds of patients, new-onset diabetes mellitus in up to 38%, wound complications in up to 22%, and hypertension in up to 17%., (© 2013.)

Background and Objectives: BK virus is an infection in kidney transplantation patients jeopardizing graft survival. Unfortunately, there is no consensus on treatment of BK viremia and nephropathy. Leflunomide has been studied for the treatment of BK viremia and nephropathy, but there are limited data on the utility of leflunomide therapeutic drug monitoring. This study aimed to determine if a pharmacodynamic relationship exists between BK viral load reduction and leflunomide metabolite, A77 1726, serum concentrations., Design, Setting, Participants, & Measurements: This study was a retrospective, single-center, longitudinal analysis of patients identified with BK viremia with or without nephropathy. Patients were grouped according to whether they received leflunomide. All BK viral PCR and A77 1726 concentrations were analyzed to determine pharmacodynamics, and were correlated with clinical outcomes., Results: Of 76 patients identified, 52 received leflunomide therapy and 24 did not. Patients who received leflunomide were further analyzed according to A77 1726 concentrations and BK clearance; there was no difference in BK clearance. There was a lack of correlation between A77 1726 concentrations and log change in BK viral PCR concentration. Multivariate analysis demonstrated that mycophenolate mofetil discontinuation, BK viremia without nephropathy, and mean BK viral load were significantly associated with BK viral clearance; leflunomide use lacked this association., Conclusions: Pharmacodynamic analysis revealed no association between A77 1726 concentrations and BK viral PCR reductions. Multivariate analysis demonstrated that leflunomide therapy was not associated with BK viral clearance. Randomized studies are needed to determine the utility of leflunomide for BK viremia and nephropathy.

Background: There has been increased interest in recent years in reducing or eliminating steroids from the immunosuppression regimen of transplant recipients to reduce adverse effects associated with their use. The purpose of this study was to compare clinical outcomes between early versus late steroid withdrawal after liver transplant to determine the optimal duration of steroid use in this population., Methods: This large-scale, retrospective analysis of liver transplants occurred at our institution between 2000 and 2009. Patients were excluded if they were <18 years old, received a multiorgan transplant, or remained on steroids for >1 year. The early steroid withdrawal group had steroids eliminated by 3 months posttransplant; late steroid withdrawal patients had steroids withdrawn between 3 and 12 months posttransplant., Results: A total of 586 liver transplants occurred during the study period; 330 patients were included in the analysis. Graft survival was significantly lower in the early steroid withdrawal group. There was no difference in patient survival or overall acute rejection. However, the late steroid withdrawal group had a significantly higher rate of early acute rejection episodes. There was no difference with regard to new-onset diabetes after transplant, hyperlipidemia, or cardiovascular events between groups., Conclusion: The results of this study suggest that late corticosteroid withdrawal is associated with better long-term graft survival without increasing the rates of diabetes, hyperlipidemia, or cardiovascular events in liver transplant recipients. A prospective study is warranted to confirm these findings., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose of Review: High prevalence of comorbidities such as diabetes, hypertension, obesity, hepatitis B and C, in minority groups, results in racial minorities being disproportionally represented on transplant waiting lists. Organ transplantation positively impacts patient survival but greater access is limited by a severe donor shortage., Recent Findings: Unfortunately, minority groups also suffer from disparities in deceased and living donation. African-Americans comprise 12.9% of the population and 34% of the kidney transplant waiting list but only 13.8% of deceased donors. Barriers to minority deceased donation include: decreased awareness of transplantation, religious or cultural distrust of the medical community, fear of medical abandonment and fear of racism. Furthermore, African-Americans comprise only 11.8% of living donors. Barriers to minority living donation include: unwillingness to donate, medical comorbid conditions, trust or fear of medical community, loss to follow-up, poor coping mechanisms, financial concerns, reluctance to ask family members and friends, fear of surgery, and lack of awareness about living donor kidney transplantation., Summary: Transplant center-based education classes significantly and positively impact African-American concerns and beliefs surrounding living donation. Community and national strategies utilizing culturally sensitive communication and interventions can ameliorate disparities and improve access to transplantation.

Objective: The aim of this study was to determine whether ethnicity impacts graft outcomes in kidney transplant patients converted to sirolimus (SRL) and maintained on either calcineurin inhibitors (CI) or mycophenolate mofetil (MMF) with steroids., Methods: This study analyzed kidney transplants converted to SRL and transplanted between July 1991 and April 2007. Patients were divided into 4 groups: group 1: African-Americans converted to SRL + CI; group 2: non-African-Americans converted to SRL + CI; group 3: African-Americans converted to SRL + MMF; group 4: non-African-Americans converted to SRL + MMF., Results: A total of 242 patients was included. Demographics, baseline immunosuppression, and reason for SRL conversion were similar among groups. Patients converted to SRL + CI regimens had significantly higher rates of acute rejection before SRL conversion, but equal rates after conversion. Development of proteinuria was similar across groups. African-American patients converted to SRL + MMF tended to have poorer outcomes compared with African-American patients converted to SRL + CI. Non-African-American patients converted to SRL + MMF tended to have better graft outcomes compared with non-African-American patients converted to SRL + CI., Conclusions: African-Americans converted to SRL may benefit from continued CI, whereas non-African-Americans converted to SRL seem to have better outcomes with MMF. Further prospective studies are warranted to confirm these findings.

Background: Although the utility of antibody induction therapy has been demonstrated in clinical trials, the ideal regimen to use based on patient risk factors has not been fully elucidated. The objectives of this study were to determine the impact of either anti-interleukin-2 receptor antibodies (IL-2RA) or thymoglobulin induction therapies versus no induction therapy on acute rejection rates and on 3-year graft survival rates., Methods: This retrospective analysis compared 3 patient groups-those who did not receive induction, those who received IL-2RA induction, and those who received thymoglobulin induction., Results: Three hundred eleven patients were included in this study. Patients were well matched for demographic and immunologic characteristics in the noninduced and IL-2RA induction therapy groups; the thymoglobulin induction group included significantly higher risk patients. The acute rejection rates were significantly lower in the IL-2RA and thymoglobulin groups when compared with the no induction therapy group (28% vs 15% vs 41%, respectively; P = .001), which was confirmed with multivariate analysis. The 3-year graft loss rates (no induction 21% vs IL2-RA induction 19% vs thymoglobulin induction 25%; P > .50) and creatinine concentrations (no induction 1.8 +/- 0.7, IL-2RA induction 2.0 +/- 1.0, and thymoglobulin induction 1.9 +/- 1.2; P = .47) were similar between all groups., Conclusion: The use of induction therapy significantly reduces the incidence of acute rejection. The use of thymoglobulin induction equalizes 3-year graft survival rates in high-risk patients to those seen in low-risk patients receiving either no induction or IL-2RA induction.

In this article, we present an overview of renal transplantation with its complications and discuss the abilities and limitations of ultrasound in evaluating these complications. We included renal transplants performed at our institution between 1993 and 2006 and gathered data on more than 1,000 patients who developed graft dysfunction. We analyzed the ultrasound findings in different posttransplant complications and compared our findings with those in published literature. We present this review article that elaborates and categorizes various transplant complications from an ultrasound perspective. Based on imaging evaluation, the complications of renal transplantation can be divided into four major categories: peri-renal, renal parenchymal, renal collecting system, and renal vascular complications. Common complications included acute tubular necrosis, graft rejection, drug nephrotoxicity, hematoma, lymphocele, urinoma, hydronephrosis, and vascular complications. Ultrasound has a key role in identification and management of most of these complications. However, some parenchymal complications may only be diagnosed on renal biopsy. Ultrasound is a very powerful screening tool to assess renal transplant dysfunction and has a primary role in early diagnosis and management of structural and vascular complications, which may need surgical intervention to save the graft.

Background: Living donation is a safe, effective treatment for patients with end-stage renal disease (ESRD), yet rates of live kidney donation remain low. Potential transplant recipients may be more inclined to ask a family member for a living donation if they feel familial closeness., Methods: The FACES II and the Living Organ Donor Survey were administered to patients attending pretransplant education to assess individual perceptions of family structure and willingness to request a living kidney donation from a family member., Results: A total of 328 potential transplant recipients were included in the study: 200 (61%) African American and 128 (39%) Caucasian. Approximately half were willing to ask for a living donation. Individual's perception of family cohesion, adaptability, and type as measured by FACES II showed most families were mid-range with optimal cohesion and adaptability. Family cohesion and adaptability showed no association with being willing to request a live donation, but those single/never married were only half as likely to ask for donation (odds Ratio [OR] 0.51; 95% confidence interval [CI] 0.31-0.86, P = .01). Lower education (beta = -0.49) and unmarried status (beta = -0.31) predicted a lower cohesion score., Conclusion: Family type, cohesion, and adaptability showed no differences across race and was not related to the potential recipient's willingness to ask for a live donation. Although responses by race did not differ, an important finding showed that only half of ESRD patients are willing to ask for a live organ donation, and those patients that were single/never married were less likely to ask for a living donation. Research surrounding this reluctance is warranted.

Background: This study examined the potential therapeutic effects of a combination therapy consisting of 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) and N-acetyl cysteine (NAC) to attenuate ischemia-reperfusion (I/R) injury in a canine model of autologous renal transplantation., Methods: Male mongrel dogs (15-20 kg) underwent left nephrectomy followed by flushing and static preservation of the kidney in University of Wisconsin (UW) solution for 48 hr. The treatment group received AICAR (50 mg/kg) plus NAC (100 mg/kg) intravenously before the left nephrectomy. The compounds were added to the UW solution as well. All dogs underwent right nephrectomy 48 hr later followed by autotransplantation of the preserved left kidney. Treated dogs received a second dose of AICAR and NAC before implantation of the renal autograft., Results: The treated dogs had excellent urine output posttransplant, with peak serum creatinine of 7.26 mg/dL on postoperative day (POD) 3 that normalized after 14 days. The control group were anuric and developed clinical symptoms of uremia on POD 1. Morphologic evaluation supported the protective effects of combination therapy. Immunohistochemical analysis revealed decrease of tumor necrosis factor-alpha, interferon-gamma, and inducible nitric oxide synthase; and TUNEL assay showed decreased apoptosis in the treated group., Conclusions: Combination therapy with AICAR and NAC attenuates renal I/R injury and improves the outcome of the transplanted kidney after prolonged cold preservation.