Pretransplant malignancy in pediatrics is not a risk factor for renal graft failure.

BACKGROUND: In adults, pretransplant malignancy (PTM) negatively impacts patient survival due to immunosuppression regimens influencing post-transplantation tumor growth. Few reports investigate the outcomes of pediatric kidney transplantation with PTM. We compare transplant outcomes for pediatric patients with PTM to matched controls, including cancer types extending beyond Wilms tumor. METHODS: The United Network of Organ Sharing Database was queried to identify pediatric transplant recipients with histories of PTM. All PTM patients were matched to non-PTM patients, at a 1:1 ratio, with 0.001 match tolerance. Matching variables included transplant year, recipient age, recipient gender, recipient race, donor type, and prior transplant. Death-censored graft and patient survival were analyzed. All statistics were reported with 95% confidence intervals (CI). RESULTS: After propensity matching, 285 PTM and 285 non-PTM patients were identified, with transplant dates from 1990 to 2020. Median Kidney Donor Profile Index values were comparable between cohorts, 17% and 12%, respectively (p = .065). Kaplan-Meier analysis revealed that PTM patients did not have a significantly different rate of death-censored graft failure, compared to the non-PTM group [HR 0.76; 95% CI (0.54-1.1)]. There was also no difference in the overall survival between the two groups of patients [HR 1.1; 95% CI (0.66-2.0)]. CONCLUSION: A history of pediatric malignancy has minimal independent effect on their post-transplant survival. Additionally, pediatric patients with PTM demonstrated equivalent rates of graft survival. Thus, in contrast to adults, renal failure in children with history of pediatric malignancies should not be considered a complicating factor for renal transplantation.

Unrecognized opportunities: The landscape of pediatric kidney-paired donation in the United States.

BACKGROUND: Pediatric (age < 18 years) kidney transplant (KT) candidates face increasingly complex choices. The 2014 kidney allocation system nearly doubled wait times for pediatric recipients. Given longer wait times and new ways to optimize compatibility, more pediatric candidates may consider kidney-paired donation (KPD). Motivated by this shift and the potential impact of innovations in KPD practice, we studied pediatric KPD procedures in the US from 2008 to 2021. METHODS: We describe the characteristics and outcomes of pediatric KPD recipients with comparison to pediatric non-KPD living donor kidney transplants (LDKT), pediatric LDKT recipients, and pediatric deceased donor (DDKT) recipients. RESULTS: Our study cohort includes 4987 pediatric DDKTs, 3447 pediatric non-KPD LDKTs, and 258 pediatric KPD transplants. Fewer centers conducted at least one pediatric KPD procedure compared to those that conducted at least one pediatric LDKT or DDKT procedure (67, 136, and 155 centers, respectively). Five centers performed 31% of the pediatric KPD transplants. After adjustment, there were no differences in graft failure or mortality comparing KPD recipients to non-KPD LDKT, LDKT, or DDKT recipients. DISCUSSION: We did not observe differences in transplant outcomes comparing pediatric KPD recipients to controls. Considering these results, KPD may be underutilized for pediatric recipients. Pediatric KT centers should consider including KPD in KT candidate education. Further research will be necessary to develop tools that could aid clinicians and families considering the time horizon for future KT procedures, candidate disease and histocompatibility characteristics, and other factors including logistics and donor protections.

Missed Opportunities to Diagnose and Treat Tertiary Hyperparathyroidism After Transplant.

INTRODUCTION: Tertiary hyperparathyroidism (3HPT) is common after renal transplant. However, guidelines for diagnosis are not clear and few patients are treated surgically. This study aims to determine rates of diagnosis and treatment of 3HPT in renal transplant patients with hypercalcemia. MATERIALS AND METHODS: This retrospective chart review identified all renal transplant recipients at a single tertiary care institution between 2011 and 2021. Patients with post-transplant hypercalcemia (> 10.2 mg/dL) were identified. The time in months of index hypercalcemia was noted. Measurement of parathyroid hormone (PTH) levels after index hypercalcemia was determined and noted as elevated if > 64 pg/mL at least 6 mo after transplant. Documentation of symptoms of hyperparathyroidism, a diagnosis of hyperparathyroidism in the electronic medical record, and medical or surgical management of patients with classic 3HPT (elevated calcium and PTH) were determined. RESULTS: Of 383 renal transplant recipients, hypercalcemia was identified in 132 patients. The majority of hypercalcemic patients had PTH levels measured (127, 96.2%). PTH was elevated in 109 (82.6%). Among the 109 patients with classic 3HPT, 54 (49.5%) had a documented diagnosis of hyperparathyroidism in the electronic medical record (P = 0.01). Kidney stones or abnormal DEXA scan were present in 16 (14.7%) and 18 (16.5%), respectively. Most patients were managed non-surgically (101, 92.6%); calcimimetics were prescribed for 42 (38.5%, P = 0.01). Eight (7.3%) patients with classic 3HPT were referred to a surgeon (P = 0.35); all were initially prescribed calcimimetics (P = 0.001). CONCLUSIONS: 3HPT is underdiagnosed in patients with elevated calcium and PTH levels post-transplant. A significant percentage of these patients go without surgical referral and curative treatment.

Benefit of Kidney Transplantation for Post Lung Transplantation Renal Failure.

INTRODUCTION: Nephrotoxicity is a significant side effect of thoracic transplantation. Many lung transplant patients will require subsequent renal transplantation (KAL). Recently, simultaneous lung/kidney transplants (SLuK) have become an attractive option for patients with end-stage renal disease at the time of lung transplantation. This article explores SLuK outcomes compared to conventional KAL, as well as outcomes among KAL patients against those were KAL listed but never transplanted. MATERIALS AND METHODS: The United Network for Organ Sharing/the Organ Procurement and Transportation Network database was used to identify SLuK patients (n = 74), KAL transplants (n = 456), and patients who were listed for KAL but were never transplanted (n = 626). Significance was determined by chi2, Wilcoxon rank sum test, or independent t-tests. Death-censored graft survival for subgroups was estimated using Kaplan-Meier with log-rank for significance. Analyses were completed using SPSS Statistics 28. RESULTS: The SLuK cohort was older (P = 0.04), more likely diabetic (P < 0.001), and had shorter life expectancies (P < 0.001) than KAL patients. Of those SLuK transplants within 5 y, 84% of patients were alive 1 y post transplant and 82% were alive 3 y post-transplant (compared to 74.6% and 60.3% of overall SLuK). Patients who did undergo KAL were younger and had a lower body mass index (both P < 0.001) compared to those who did not. Those who received a kidney had increased survival times compared to WL patients (P < 0.001). CONCLUSIONS: Conventional KAL transplants are still favorable for average lung recipients. However, recent improvements have made SLuK an option for patients with renal dysfunction. Those patients who were able to receive KAL transplants were better surgical candidates than those who remained on the waitlist.

Characterization of Kidney Retransplantation Following Graft Failure Due to BK Virus Nephropathy.

INTRODUCTION: Immunosuppression following kidney transplantation increases risk of BK polyomavirus reactivation, a common cause of graft dysfunction and failure. Subsequent retransplantation is a viable option that has not been extensively studied. This study further characterizes BK Virus Nephropathy (BKVN) and retransplantation in the most expansive population to date, geographically, temporally, and in magnitude. MATERIALS AND METHODS: The OPTN/UNOS database was used to identify patients who received kidney or kidney-pancreas transplantation between 1987 and 2018 that resulted in BKVN-attributed failure (n = 1587). This population was divided into those who underwent retransplantation (n = 495) and those who did not (n = 1092). RESULTS: The retransplanted cohort was younger (45 vs. 53 yr; P<0.0001) and had fewer prior kidney transplants (P<0.003), lower expected post-transplant survival (P<0.001), lower rates of delayed graft function (DGF) (14.1% vs. 22.2%; P=0.0008), a greater proportion of white patients (55.4% vs. 43.2%; P=0.0002), a greater proportion of living donors (35.8% vs. 23.0%; P<0.0001), and longer allograft lifespan (2.95 vs. 2.41 yr; P<0.0001), compared to those not retransplanted. Among retransplants, DGF and high kidney donor profile index (KDPI) were associated with decreased allograft lifespan (P=0.001, P=0.0005, respectively). Steroid induction had no effect on allograft lifespan when compared to steroid-free regimens (P=0.915). Retransplanted allografts lasted longer than previous BKVN-failed grafts (10.44 and 3.70 years, respectively; P<0.0001). CONCLUSIONS: Retransplantation following BKVN-associated graft failure has been associated with favorable outcomes. To maximize allograft lifespan in retransplantation, clinicians may consider selection of low KDPI donors, prevention of delayed graft function, and tailored immunosuppressive regimens that minimize steroids.

High and Low Frequency Domino Liver Transplantation Centers Demonstrate Similar Performance Outcomes.

INTRODUCTION: A Domino Liver Transplant (DLT) is a successfully validated surgical option for a subset of patients awaiting liver transplant. Increased utilization of DLTs could increase the donor organ pool. However, DLTs occur primarily at a small number of high volume centers, and are rarely performed at lower volume transplant centers. This study compares DLT recipient performance outcomes between high frequency DLT centers and low frequency DLT centers. METHODS: The UNOS/OPTN STAR database was queried for DLTs performed at transplant centers between 1996-2018. 193 patients were identified and categorized into high (>5 DLTs) or low (≤5 DLTs) frequency centers. Our primary endpoint was allograft survival. Our secondary endpoints were graft status at last follow up and mortality secondary to cardiac, renal, or respiratory failure. RESULTS: Overall median allograft survival between high and low volume DLT centers was similar (48.2 months versus 42.7 months, P >0.314). The one-year (82% versus 76%), three-year (57% versus 56%), and five-year (45% versus 43%) survival percentages were also similar between the high and low volume DLT centers respectively. Overall mortality from cardiac (high 4% versus low 1.7%), renal (high 0.8% versus low 1.7%), or respiratory failure (high 0.8% versus low 1.7%) was similarly low in both groups. CONCLUSION: Low volume and high volume DLT centers are associated with similar outcomes of allograft survival and mortality. DLTs should be utilized more frequently, when the criteria are met, including in centers with limited experience, to expand the donor pool, decrease time on the waitlist, and improve overall survival.

Myocardial GRK2 Reduces Fatty Acid Metabolism and ß-Adrenergic Receptor-Mediated Mitochondrial Responses.

G-protein coupled receptor (GPCR) kinase 2 (GRK2) is upregulated in heart failure (HF) patients and mouse models of cardiac disease. GRK2 is a regulator of ß-adrenergic receptors (ßARs), a GPCR involved in ionotropic and chronotropic responses. We and others have recently reported GRK2 to be localized in the mitochondria, although its function in the mitochondria and/or metabolism remain not clearly defined. We hypothesized that upregulation of GRK2 reduced mitochondrial respiratory function and responses to ßAR activation. Utilizing isolated mouse primary adult cardiomyocytes (ACMs), we investigated the role of glucose, palmitate, ketone bodies, and BCAAs in mediating cell survival. Our results showed that myocyte upregulation of GRK2 promotes palmitate-induced cell death. Isotopologue labeling and mass spectrometry showed that the upregulation of GRK2 reduces ß-hydroxybutyryl CoA generation. Next, using isoproterenol (ISO), a non-selective ßAR-agonist, we determined mitochondrial function in mouse and human primary ACMs. Upregulation of GRK2 impaired ISO-mediated mitochondrial functional responses, which we propose is important for metabolic adaptations in pathological conditions. Increased cardiac levels of GRK2 reduced fatty acid-specific catabolic pathways and impaired ISO-stimulated mitochondrial function. Our data support the notion that GRK2 participates in bioenergetic remodeling and may be an important avenue for the development of novel pharmacological strategies in HF.

Challenges with non-descriptive compliance labeling of end-stage renal disease patients in accessibility for renal transplantation.

Non-descriptive and convenient labels are uninformative and unfairly project blame onto patients. The language clinicians use in the Electronic Medical Record, research, and clinical settings shapes biases and subsequent behaviors of all providers involved in the enterprise of transplantation. Terminology such as noncompliant and nonadherent serve as a reason for waitlist inactivation and limit access to life-saving transplantation. These labels fail to capture all the circumstances surrounding a patient's inability to follow their care regimen, trivialize social determinants of health variables, and bring unsubstantiated subjectivity into decisions regarding organ allocation. Furthermore, insufficient Medicare coverage has forced patients to ration or stop taking medication, leading to allograft failure and their subsequent diagnosis of noncompliant. We argue that perpetuating non-descriptive language adds little substantive information, increases subjectivity to the organ allocation process, and plays a major role in reduced access to transplantation. For patients with existing barriers to care, such as racial/ethnic minorities, these effects may be even more drastic. Transplant committees must ensure thorough documentation to correctly encapsulate the entirety of a patient's position and give voice to an already vulnerable population.

Longevity Matching for Living Donor Renal Transplantation.

INTRODUCTION: This study identifies the effect of individual donor and recipient characteristics on graft survival in living-donor kidney transplantation (LDKT) using a recently described novel measure, kidney life years (KLYs). MATERIALS AND METHODS: The Organ Procurement and Transplantation Network/United Network for Organ Sharing database was used to identify first-time kidney-only LDKT recipients between 1987 and 2020 who did not experience death with a functioning graft (DWFG) and were not missing relevant information (n = 87,290). Patient characteristics were evaluated using Cox and multiple regression analyses, with the dependent variable being KLYs. An equation for expected KLYs based on patient characteristics was created using regression coefficients. The equation was validated using bootstrapped Pearson correlations and then applied to the DWFG group for comparison. RESULTS: Based on statistical significance from Cox and multiple linear regression analyses, 9 of the original 18 variables were selected for inclusion in the equation. Variables with notable impact included HLA match points (0.021 KLYs; 95% CI: [0.019,0.024]; P ≤ .001), Donor Age (-0.030 KLYs; 95% CI: [-0.035,-0.025]; P ≤ .001), and Donor African American Ethnicity (-2.356 KLYs; 95% CI: [-2.552,-2.159]; P ≤ .001). Equation validation was supported, given a negative correlation (r = -0.071; P ≤ .001) between expected KLY change and observed graft failure. Expected KLY change was found to be greater in those who eventually DWFG when compared with all other LDKTs (t = -5.735, P ≤ .001). CONCLUSIONS: Increasing HLA match points may be more beneficial for graft longevity than minimizing donor age in comparisons using realistic between-donor differences. Additionally, greater average expected KLYs in those who ultimately DWFG may illustrate an opportunity for improved donor-recipient matching.

Waitlist Outcomes for Exception and Non-exception Liver Transplant Candidates in the United States Following Implementation of the Median MELD at Transplant (MMaT)/250-mile Policy.

BACKGROUND: Since February 2020, exception points have been allocated equivalent to the median model for end-stage liver disease at transplant within 250 nautical miles of the transplant center (MMaT/250). We compared transplant rate and waitlist mortality for hepatocellular carcinoma (HCC) exception, non-HCC exception, and non-exception candidates to determine whether MMaT/250 advantages (or disadvantages) exception candidates. METHODS: Using Scientific Registry of Transplant Recipients data, we identified 23 686 adult, first-time, active, deceased donor liver transplant (DDLT) candidates between February 4, 2020, and February 3, 2022. We compared DDLT rates using Cox regression, and waitlist mortality/dropout using competing risks regression in non-exception versus HCC versus non-HCC candidates. RESULTS: Within 24 mo of study entry, 58.4% of non-exception candidates received DDLT, compared with 57.8% for HCC candidates and 70.5% for non-HCC candidates. After adjustment, HCC candidates had 27% lower DDLT rate (adjusted hazard ratio = 0.680.730.77) compared with non-exception candidates. However, waitlist mortality for HCC was comparable to non-exception candidates (adjusted subhazard ratio [asHR] = 0.931.031.15). Non-HCC candidates with pulmonary complications of cirrhosis or cholangiocarcinoma had substantially higher risk of waitlist mortality compared with non-exception candidates (asHR = 1.271.702.29 for pulmonary complications of cirrhosis, 1.352.043.07 for cholangiocarcinoma). The same was not true of non-HCC candidates with exceptions for other reasons (asHR = 0.540.881.44). CONCLUSIONS: Under MMaT/250, HCC, and non-exception candidates have comparable risks of dying before receiving liver transplant, despite lower transplant rates for HCC. However, non-HCC candidates with pulmonary complications of cirrhosis or cholangiocarcinoma have substantially higher risk of dying before receiving liver transplant; these candidates may merit increased allocation priority.

Does race impact outcomes after parathyroidectomy for secondary and tertiary hyperparathyroidism?

BACKGROUND: Racial disparities in care exist for diseases with heterogeneous treatment guidelines. The impact of these disparities on outcomes after parathyroidectomy for secondary(2HPT) and tertiary hyperparathyroidism(3HPT) was explored. METHODS: The 2015-2019 NSQIP datasets were used. Patients who underwent parathyroidectomy for 2HPT and 3HPT were identified and analyzed separately. Patients were stratified by race (white vs. non-white); demographics, comorbidities, and outcomes were compared. Studied outcomes included 30-day morbidity, mortality, unplanned reoperation, readmission, and postoperative length of stay(LOS). RESULTS: There were 1,150 patients with 2HPT and 262 with 3HPT. For 2HPT, 65.5% were non-white; morbidity, reoperation, and prolonged LOS(>3days) occurred disproportionately more often in non-white patients. Non-white race was independently associated with morbidity; higher ASA class and alkaline phosphatase levels were associated with prolonged LOS. For 3HPT, 53.1% were non-white; a prolonged LOS(>1day) occurred disproportionately more often in non-white patients. Higher alkaline phosphatase levels were independently associated with prolonged LOS. CONCLUSION: Race and markers of advanced disease negatively impact outcomes after parathyroidectomy for 2HPT and 3HPT. Attention to racial disparities and earlier referral may positively impact outcomes.

Deciphering the True Immunologic Risk in Renal Transplantation in Patients With HIV.

Since 1995, rates of end-stage renal disease have risen dramatically in patients living with HIV infection. However, given the concern for higher rates of acute rejection in this patient population, the immunologic threat posed by HIV infection is a specter clinicians must continually confront. Living donor transplantation may negate this risk; this study aims to assess the benefit of living donor transplantation in this population and to ascertain the immunologic risk faced by patients who are HIV-infected. The 2021 UNOS database was queried, and all HIV-infected kidney transplant recipients since 1987 were identified. Recipients were stratified based on deceased (DDKT) vs living (LDKT) donor status. Overall survival, allograft survival, acute rejection, panel reactive antibody (PRA) percentage, and crossmatch positivity were compared between groups. One thousand two hundred twenty-six patients underwent DDKT, and 304 patients underwent LDKT. Living donor kidney transplantation demonstrated greater overall survival (P = .045) and graft survival (P < .001). However, no difference in acute rejection was noted between the cohorts, and no difference in overall or graft survival was evident based on PRA percentage. Crossmatch positive status did not negatively affect graft survival. Patients with HIV undergoing LDKT fared better than those undergoing DDKT. Nevertheless, patients at higher immunologic risk-elevated PRA% and crossmatch positivity-did not experience graft loss at a higher rate than patients at lower immunologic risk. These results were valid in both DDKT and LDKT cohorts. These findings suggest that infection with HIV does not overtly increase patients' immunologic risk, and concerns surrounding transplantation in this population may be overestimated.

Renal Cell Carcinoma in End-Stage Kidney Disease and the Role of Transplantation.

Kidney transplant patients have a higher risk of renal cell carcinoma (RCC) compared to non-transplanted end-stage kidney disease (ESKD) patients. This increased risk has largely been associated with the use of immunosuppression; however, recent genetic research highlights the significance of tissue specificity in cancer driver genes. The implication of tissue specificity becomes more obscure when addressing transplant patients, as two distinct metabolic environments are present within one individual. The oncogenic potential of donor renal tissue is largely unknown but assumed to pose minimal risk to the kidney transplant recipient (KTR). Our review challenges this notion by examining how donor and recipient microenvironments impact a transplant recipient's associated risk of renal cell carcinoma. In doing so, we attempt to encapsulate how ESKD-RCC and KTR-RCC differ in their incidence, pathogenesis, outcome, and approach to management.

Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype.

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.

Simple Prediction Score for Developing Surgical Site Infection after Clean Neck Operation.

Background: Clean neck operations (thyroidectomies, parathyroidectomies, and lymph node resection) are among the most common procedures performed in the United States. Surgical site infections (SSIs) after clean neck operations are rare, but the consequences are devastating and often life-threatening. The aim of this study was to develop a score that will identify patients at high risk for developing a SSI after a clean neck procedure. Materials and Methods: Patients with either thyroidectomies, parathyroidectomies, or lymph node resection of the neck were identified from the 2016 and 2017 databases of the American College of Surgeons National Surgical Quality Improvement Program and were used for this analysis. Our primary goal was to build a scoring system with which we will be able to identify patients at high risk for SSI after a clean neck operation. Results: Of a total of 99,877 patients, 72,719 patients had a thyroidectomy, 22,043 patients had parathyroidectomy, and 5,115 patients had lymph node resection of the neck. Multivariable logistic regression identified the following independent risk factors associated with post-operative SSI: male gender (adjusted odds ratio [aOR], 1.25; 95% confidence interval [CI], 1.03-1.51), diabetes mellitus (aOR, 1.34; 95% CI, 1.07-1.67), smoking (aOR, 1.66; 95% CI, 1.36-2.04), pre-operative steroid use (aOR, 1.75; 95% CI, 1.21-2.53), cancer diagnosis (aOR, 1.44; 95% CI, 1.17-1.77), radical lymphadenectomies (aOR, 2.94; 95% CI, 2.16-4), and total operative time ≥198 minutes (aOR, 2.25; 95% CI, 1.82-2.78). Afterward, we developed a prognostic score for calculating the odds of having post-operative SSI. One point was allotted for each of the aforementioned factors, except lymphadenectomies where two points were allotted, and operative time was excluded. Our score was associated with a stepwise higher risk of post-operative SSI after a clean neck operation. Conclusions: Pre-operative and intra-operative factors can predict which patients undergoing a clean neck surgery may develop SSI. Our prognostic score may help guide surgeons identify patients at high-risk for SSI after clean neck surgery and these patients might benefit from prophylactic use of antibiotic agents.

Outcomes of Older Patients in the Recent Era of Heart Kidney Transplantation.

BACKGROUND AND OBJECTIVE: Variable age thresholds are often used at transplant centers for simultaneous heart and kidney transplantation (HKT). We hypothesize that selected older recipients enjoy comparable outcome to younger recipients in the current era of HKT. METHODS: We performed a retrospective analysis of HKT outcomes in the United Network for Organ Sharing (UNOS) registry from 2006 to 2018, classifying patients by age at transplant as ≥ 65 or < 65 years. The primary outcome was patient death. Secondary outcomes included all-cause kidney graft failure and death-censored kidney allograft failure. RESULTS: Of 973 patients, 774 (80%) were younger than 65 years (mean 52 ± 10 years) and 199 (20%) were 65 years or older (mean 67 ± 2 years). The older HKT cohort had fewer blacks (22% vs 35%, P = .01) and women (12 vs 18%, P = .04). Fewer older patients received dialysis (30% vs 54%, P < .001) and mechanical support (36% vs 45%, P = .03) before HKT. Older recipients received organs from slightly older donors. The median follow-up time was shorter for patients 65 years or older than for the younger group (2.3 vs 3.3 years, P < .001). Patient survival was similar between the groups (mean 8.8 vs 9.8 years, P = .3), with the most common causes of death being cardiovascular (29%) and infectious complications (28%). There was no difference in all-cause kidney graft survival (mean 8.7 vs 9.3 years, P = .8). Most commonly, recipients died with a functional renal allograft (59.8%), and this occurred more commonly in older patients (81.4% vs 54.8%, P = .001). Cox proportional hazard modeling showed that higher donor age (hazard ratio [HR] 1.015, P = .01; HR 1.022, P = .02) and use of pre-transplant dialysis (HR 1.5, P = .004; HR 1.8, P = .006) increased the risk for both all-cause and death-censored kidney allograft failure, respectively. CONCLUSIONS: Our study showed that carefully selected older patients have outcomes similar to those of a younger cohort and argues for comprehensive evaluation of the recipients with age as part of comorbidity assessment rather than use of an arbitrary age threshold for candidacy.

Fatty liver: The metabolic syndrome increases major hepatectomy mortality.

BACKGROUND: As the obesity epidemic worsens, the prevalence of fatty liver disease has increased. However, minimal data exist on the impact of combined fatty liver and metabolic syndrome on hepatectomy outcomes. Therefore, the aim of this analysis is to measure the outcomes of patients who do and do not have a fatty liver undergoing hepatectomy in the presence and absence of the metabolic syndrome. METHODS: Patients with fatty and normal livers undergoing major hepatectomy (≥3 segments) were identified in the 2014 to 2018 American College of Surgeon National Surgical Quality Improvement Program database. Patients undergoing partial hepatectomy and those with missing liver texture data were excluded. Propensity matching was used and adjusted for multiple variables. A subgroup analysis stratified by the metabolic syndrome (body mass index ≥30 kg/m2, hypertension and diabetes) was performed. Demographics and outcomes were compared by χ2 and Mann-Whitney tests. RESULTS: Of 2,927 hepatectomies, 30% of patients (N = 863) had a fatty liver. The median body mass index was 28.6, and the metabolic syndrome was present in 6.3% of patients (N = 184). After propensity matching, 863 patients with fatty and 863 with normal livers were compared. Multiple outcomes were significantly worse in patients with fatty livers (P <.05), including serious morbidity (32% vs 24%), postoperative invasive biliary procedures (15% vs 10%), organ space infections (11% vs 7.8%), and pulmonary complications. Patients with fatty livers and the metabolic syndrome had significantly increased postoperative cardiac arrests, pulmonary embolisms, and mortality (P < .05). CONCLUSION: Fatty liver disease is associated with significantly worse outcomes after major hepatectomy. The metabolic syndrome confers an increased risk of postoperative mortality.

Frailty Predicts Morbidity and Mortality After Laparoscopic Cholecystectomy for Acute Cholecystitis: An ACS-NSQIP Cohort Analysis.

BACKGROUND: Current guidelines recommend laparoscopic cholecystectomy be offered for patients with acute cholecystitis except those deemed as high risk. Few studies have examined the impact of frailty on outcomes for patients undergoing laparoscopic cholecystectomy. Therefore, the aim of this study was to determine the association of frailty with postoperative morbidity and mortality in patients undergoing laparoscopic cholecystectomy for acute cholecystitis. METHODS: Patients undergoing laparoscopic cholecystectomy for acute cholecystectomy were identified from 2005 to 2010 in the American College of Surgeons National Surgical Quality Improvement Project (NSQIP). The Modified Frailty Index (mFI) was used a surrogate for frailty, and patients were stratified as non-frail (mFI 0), low frailty (mFI 1-2), intermediate frailty (mFI 3-4) and high frailty (mFI ≥ 5). Univariable and multivariable analyses were performed. Receiver operator curves (ROC) and an area under the curve (AUC) were generated to determine accuracy of mFI in predicting postoperative morbidity and mortality. RESULTS: Of the 6898 patients undergoing laparoscopic cholecystectomy, 3245 (47%) patients were non-frail. There were 2913 (42%) patients with low-frailty, 649 (9%) patients with intermediate frailty, and 91 (2%) with high frailty. Clavien IV complications were higher for intermediate frail patients (OR 1.81, 95% CI 1.00-3.28, p = 0.050) and high-frail patients (OR 4.59, 95% CI 1.98-10.7, p < 0.001). Additionally, mortality was higher for patients with intermediate frailty (OR 4.69, 95% CI 1.37-16.0, p = 0.014) and high frailty (OR 12.2, 95% CI 2.67-55.5, p = 0.001). The mFI had excellent accuracy for mortality (AUC = 0.83) and Clavien IV complications (AUC = 0.73). CONCLUSION: Frailty is associated with postoperative morbidity and mortality in patients undergoing laparoscopic cholecystectomy for acute cholecystitis.

Tissue repair and stem cell renewal in carcinogenesis.

Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem-cell-like properties and in its possible derivation from normal tissue stem cells. But stem cell activity is tightly controlled, raising the question of how normal regulation might be subverted in carcinogenesis. The long-known association between cancer and chronic tissue injury, and the more recently appreciated roles of Hedgehog and Wnt signalling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal.

Hedgehog signalling in prostate regeneration, neoplasia and metastasis.

Metastatic cancers adopt certain properties of normal cells in developing or regenerating organs, such as the ability to proliferate and alter tissue organization. We find here that activity of the Hedgehog (Hh) signalling pathway, which has essential roles in developmental patterning, is required for regeneration of prostate epithelium, and that continuous pathway activation transforms prostate progenitor cells and renders them tumorigenic. Elevated pathway activity furthermore distinguishes metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis. Pathway activity is triggered in response to endogenous expression of Hh ligands, and is dependent upon the expression of Smoothened, an essential Hh response component that is not expressed in benign prostate epithelial cells. Monitoring and manipulating Hh pathway activity may thus offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential.