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For assessing human leukocyte antigen compatibility in deceased donor kidney transplantation, virtual crossmatch is used as an alternative to physical crossmatch and has potential to reduce cold ischemia time. The 2014 United States kidney allocation system prioritized highly sensitized candidates but led to increased shipping of kidneys. Using data from the Scientific Registry of Transplant Recipients, we evaluated changes in virtual crossmatch use with the new allocation policy and the impact of virtual crossmatch use on cold ischemia time and transplant outcomes. This was a retrospective cohort study of adult deceased donor kidney recipients in the United States (2011-2018) transplanted with either 9,632 virtual or 71,839 physical crossmatches. Before allocation change, only 9% of transplants were performed relying on a virtual crossmatch. After the 2014 allocation change, this increased by 2.4%/year so that 18% transplants in 2018 were performed with just a virtual crossmatch. There was significant variation in virtual crossmatch use among transplant regions (range 0.7-36%) and higher use was noted among large volume centers. Compared to physical crossmatches, virtual crossmatches were significantly associated with shorter cold ischemia times (mean 15.0 vs 16.5 hours) and similar death-censored graft loss and mortality (both hazard ratios HR 0.99) at a median follow-up of 2.9 years. Thus, our results show that virtual crossmatch is an attractive strategy for shortening cold ischemia time without negatively impacting transplant outcomes. Hence, strategies to optimize use and reduce practice variation may allow for maximizing benefits from virtual crossmatch.

Anti-HLA Donor Specific Antibody (DSA) detection post kidney transplant has been associated with adverse outcomes, though the impact of early DSA screening on stable patients remain unclear. We analyzed impact of DSA detection through screening in 1st year stable patients (

Background Historically, adults with ultra short bowel syndrome (USBS) have been considered candidates for lifetime parenteral nutrition (PN) or are referred for visceral transplantation. We examined the surgical and nutritional outcomes of adult patients with USBS managed at a single intestinal rehabilitation center. Methods We retrospectively reviewed data on 588 adult patients referred to our center between January 2013 and December 2018. USBS was defined as residual small bowel (SB) length ≤ 50 cm. Results Forty-five patients (7.6%) with a mean age of 46.7 years (range 17-78) were identified. Indications for enterectomy included mesenteric ischemia (n=17) and internal hernias (n=6), followed by large intraabdominal fibroids, trauma, and allograft enterectomies, with five cases each. Median SB length was 18.0 cm; 20 patients (44.4%) had their entire SB resected. Thirteen patients had an intact colon, of which nine had preservation of the ileocecal valve. Patients who underwent autologous reconstruction of their gastrointestinal (GI) tract required a lower total PN volume (29.0 ± 7.6 vs. 40.8 ± 13.2 ml/Kg/day, p=0.002) and presented better short- and long- term survival (p=0.005). Patients with no gut had higher mortality (p=0.036). Hormonal therapy with the glucagon-like peptide-2 analog teduglutide was used in nine patients (20%) five of whom were weaned off TPN. Excluding patients with no gut (n=20), discontinuation of total PN rate for patients with an end ostomy or tube decompression (n= 6), jejunocolostomy (n= 10), and jejunoileostomy (n=9) were 0%, 40%, and 77.7%, respectively. Eleven patients (44%) with some residual small intestine achieved nutritional autonomy in an average of 20 months after GI reconstruction. Fifteen patients were listed for transplantation (33.3%). Seven patients underwent isolated SB transplantation and achieved nutritional autonomy in an average of three months after transplantation. One-year patient and graft survival were 100%. After a 37-month median follow-up period, 36 of 42 patients followed by our center were still alive (85.7%). Conclusion Nutritional autonomy can be achieved in a significant number of patients with USBS in specialized centers with surgical and/or hormonal therapy. The presence of an intact colon and ileocecal valve can significantly increase the adaptation rate. Moreover, restoration of GI tract continuity has a positive impact on medical management and survival.

BACKGROUND. The liver transplant risk score (LTRS) was developed to stratify 90-day mortality of patients referred for liver transplantation (LT). We aimed to validate the LTRS using a new cohort of patients. METHODS. The LTRS stratifies the risk of 90-day mortality of LT recipients based on their age, body mass index, diabetes, model for end-stage liver disease (MELD) score, and need for dialysis. We assessed the performance of the LTRS using a new cohort of patients transplanted in the United States between July 2013 and June 2017. Exclusion criteria were age

This study aimed to investigate whether magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) can be a viable noninvasive alternative to liver biopsy for the quantification of living liver donor steatosis. Hepatic steatosis for 143 donors was graded by MRI-PDFF. Study endpoints included liver volume regeneration in donors, recipient outcomes including length of hospital stay, deaths, primary non-function (PNF), early allograft dysfunction (EAD), and small for size syndrome (SFSS). Correlation between MRI-PDFF determined donor steatosis and endpoints were analyzed. Donors had lower steatosis grade than non-donors. Donor remnant liver regenerated to an average of 82% of pre-donation volume by 101 ± 24 days with no complications. There was no correlation between percent liver regeneration and steatosis severity. Among recipients, 4 underwent redo-transplantation and 6 died, with no association with degree of steatosis. 52 recipients (36%) fulfilled criteria for EAD (driven by INR), with no difference in hepatic steatosis between groups. MRI-PDFF reliably predicted donor outcomes. Living donors with no or mild steatosis based on MRI-PDFF (ie

The use of kidneys donated after circulatory death (DCD) provides an invaluable expansion of the organ supply for transplantation. Here we investigated the effect of DCD on fibrotic changes on 1-year post-transplant surveillance kidney allograft biopsy. Recipients of a deceased donor kidney transplant between 2013 and 2017 at a single institution, who survived 1 year and underwent surveillance biopsy, were included in the analysis (n = 333: 87 DCD kidneys, 246 kidneys donated after brain death [DBD]). Banff scores for interstitial fibrosis and tubular atrophy were summed as IFTA and compared between the groups. DCD and DBD groups were comparable for baseline characteristics. Delayed graft function was 39% in DCD vs. 19% in DBD, p = 0.0002. Patient and graft survival were comparable for DCD and DBD cohorts. IFTA scores were higher in DCD compared to DBD (2.43±0.13 vs. 2.01±0.08, p = 0.0054). On multivariate analysis, the odds of IFTA>2 in the DCD group was 2.5x higher (95%CI: 1.35-4.63) than in the DBD group. Within the DCD group, kidneys with IFTA>2 had inferior 5-year graft survival (p = 0.037). In conclusion, compared DBD kidneys, DCD kidneys developed a greater degree of fibrotic changes on 1-year post-transplant surveillance biopsy, which affected graft longevity within the DCD cohort. This article is protected by copyright. All rights reserved.

BACKGROUND: We assessed if the risk of post-liver transplant mortality within 24 h could be stratified at the time of listing using the liver transplant risk score (LTRS). Secondary aims were to assess if the LTRS could stratify the risk of 30-day, 1-year mortality, and survival beyond the first year. METHODS: MELD, BMI, age, diabetes, and the need for dialysis were the five variables used to calculate the LTRS during patients’ evaluation for liver transplantation. Mortality rates at 24 h, 30 days, and 1-year were compared among groups of patients with different LTRS. Patients with ABO-incompatibility, redo, multivisceral, partial graft and malignancies except for hepatocellular carcinoma were excluded. Data of 48,616 adult liver transplant recipients were extracted from the Scientific Registry of Transplant Recipients between 2002 and 2017. RESULTS: 24-h mortality was 0.9%, 1.0%, 1.1%, 1.7%, 2.3%, 2.0% and 3.5% for patients with LTRS of 0,1,2,3,4, 5 and ≥ 6, respectively (P < 0.001). 30-day mortality was 3.5%, 4.2%, 4.9%, 6.2%, 7.6%, 7.2% and 10.1% respectively (P < 0.001). 1-year mortality was 8.6%, 10.8%, 12.9%, 13.9%, 18.5%, 20.3% and 28.6% respectively (P < 0.001). 10-year survival was 61%, 56%, 57%, 54%, 47%, and 31% for patients with 0, 1, 2, 3, 4, 5 and ≥ 6 points respectively (P < 0.001). CONCLUSION: Perioperative mortality and long-term survival of patients undergoing LT can be accurately estimated at the time of listing by the LTRS.

Background and aims Liver transplantation is the most effective treatment for end-stage liver disease (ESLD). Whether moderately macrosteatotic livers (30%-60%) represent a risk for worsened graft function is controversial. The uncertainty, in large part, is owing to the heterogeneous steatosis grading. Our aim was to determine the short- and long-term outcomes of moderately macrosteatotic allografts that were graded according to a standardized institutional protocol. Methods We performed a retrospective analysis of transplants performed between 1994 and 2014. All patients with allografts biopsied pretransplantation were included. Relevant donor and recipient variable were recorded. Moderately macrosteatotic livers were compared with mildly macrosteatotic and nonsteatotic livers. Primary outcomes of interest were patient survival at 90 days, 1 year, and 5 years. Cox regression analyses were carried out to compare survival between the 2 groups. Results We compared 65 allografts with moderate macrosteatosis and 810 with no or mild macrosteatosis. Patients with moderately macrosteatotic allografts were 2.69 times as likely to die within the first 90 days after transplant (75.1% vs 91.6% survival) after adjusting for donor age, donor race, recipient age, recipient race, recipient body mass index, recipient diabetes, presence of hepatocellular carcinoma, days on waitlist, Model for End-Stage Liver Disease (MELD) score at transplantation, cold ischemia time. However, for recipients who survive 90 days, moderately macrosteatotic allografts had comparable long-term survival. Conclusion Our study shows that moderate macrosteatosis is a strong predictor of early but not late mortality. Further studies are needed to distinguish the specific cohort of patients for whom moderately macrosteatotic allografts will lead to acceptable outcomes.

Transplantation of kidneys from deceased donors with acute kidney injury (AKI) can expand the donor pool. We investigated the effect of donor AKI on renal function and chronic changes on protocol biopsies at 1-year post-transplant. Donor AKI was defined according to Acute Kidney Injury Network (AKIN) criteria. Between 2013 and 2017, 333 kidneys were transplanted and subsequently biopsied after 1 year. Fifty-three kidneys from AKI donors (AKIN stage I n = 42, stage II n = 8, stage III n = 3) were compared to 280 kidneys from non-AKI donors. At 1-year follow-up, patient and graft survival were comparable. Donor AKI was not predictive of IFTA (Banff interstitial fibrosis plus tubular atrophy scores) at 1-year post-transplant biopsy (2.10 ± 1.28 in AKI, 2.09 ± 1.22 in non-AKI, P = .95). Donor AKI was also not associated with progression of IFTA from 3 to 12 months (P = .69), or inferior glomerular filtration rate (eGFR, P = .94). In a multivariate analysis, the odds of IFTA >2 were comparable between AKI and non-AKI groups. In conclusion, the transplantation of kidneys from donors with predominantly stage I AKI results in comparable function and degree of fibrosis on protocol biopsies 1-year post-transplant. Selected grafts from donors with AKI are a valuable tool for expanding the donor pool for kidney transplantation.

Aging in later life engenders numerous changes to the cerebral microvasculature. Such changes can remain clinically silent but are associated with greater risk for negative health outcomes over time. Knowledge is limited about the pathogenesis, prevention, and treatment of potentially detrimental changes in the cerebral microvasculature that occur with advancing age. In this review, we summarize literature on aging of the cerebral microvasculature, and we propose a conceptual framework to fill existing research gaps and advance future work on this heterogeneous phenomenon. We propose that the major gaps in this area are attributable to an incomplete characterization of cerebrovascular pathology, the populations being studied, and the temporality of exposure to risk factors. Specifically, currently available measures of age-related cerebral microvasculature changes are indirect, primarily related to parenchymal damage rather than direct quantification of small vessel damage, limiting the understanding of cerebral small vessel disease (cSVD) itself. Moreover, studies seldom account for variability in the health-related conditions or interactions with risk factors, which are likely determinants of cSVD pathogenesis. Finally, study designs are predominantly cross-sectional and/or have relied on single time point measures, leaving no clear evidence of time trajectories of risk factors or of change in cerebral microvasculature. We argue that more resources should be invested in 1) developing methodological approaches and basic science models to better understand the pathogenic and etiological nature of age-related brain microvascular diseases and 2) implementing state-of-the-science population study designs that account for the temporal evolution of cerebral microvascular changes in diverse populations across the lifespan.

Cardiovascular disease (CVD) may increase depression risk. Risk for future CVD, which can be estimated by the Framingham Risk Score (FRS), and depression risk are both linked to systemic inflammation. Dietary consumption of proinflammatory food can be measured using the Dietary Inflammatory Index (DII) score. We examined the potential impact of DII on depression and whether this effect is independent of FRS. We hypothesized that (1) both FRS and DII would be associated with depression (Patient Health Questionnaire-9 ≥ 10) and (2) associations between DII and depressive symptoms (continuous) would be mediated by FRS. Data were included from adults without CVD who were participants of the 2007-2012 National Health and Nutrition Examination Survey (n = 11 624). Using logistic regression, we tested cross-sectional associations of FRS, DII (adjusting for FRS), and joint effects of FRS and DII with depression. Finally, using the Sobel method, we tested whether FRS mediates the relationship between DII and depressive symptoms. Individuals with FRS or DII scores in the top 2 quartiles had higher odds of depressive symptoms than those in the bottom quartile. The association of DII with depressive symptoms remained after FRS adjustment. The joint effects of elevated DII and FRS were additive. There was no evidence for mediation by FRS between DII and depressive symptoms. Thus, higher DII remained associated with increased odds of depressive symptoms net CVD risk. Collectively, the joint effects of CVD risk and DII indicate that a proinflammatory diet could add to risk for depressive symptoms even in those with a high FRS.

Due to shortage of donor, kidney transplants (KTs) from donors with acute kidney injury (AKI) are expanding. Although previous studies comparing clinical outcomes between AKI and non-AKI donors in KTs have shown comparable results, data on high-volume analysis of KTs outcomes with AKI donors are limited. This study aimed to analyze the selection trends of AKI donors and investigate the impact of AKI on graft failure using the United states cohort data. We analyzed a total 52,757 KTs collected in the Scientific Registry of Transplant Recipient (SRTR) from 2010 to 2015. The sample included 4,962 (9.4%) cases of KTs with AKI donors (creatinine ≥ 2 mg/dL). Clinical characteristics of AKI and non-AKI donors were analyzed and outcomes of both groups were compared. We also analyzed risk factors for graft failure in AKI donor KTs. Although the incidence of delayed graft function was higher in recipients of AKI donors compared to non-AKI donors, graft and patient survival were not significantly different between the two groups. We found donor hypertension, cold ischemic time, the proportion of African American donors, and high KDPI were risk factors for graft failure in AKI donor KTs. KTs from deceased donor with AKI showed comparable outcomes. Thus, donors with AKI need to be considered more actively to expand donor pool. Caution is still needed when donors have additional risk factors of graft failure.

Background. Early acute kidney rejection remains an important clinical issue. Methods. The current study included 552 recipients who had 1–2 surveillance or indication biopsy within the 1 y posttransplant. We evaluated the impact of type of allograft inflammation on allograft outcome. They were divided into 5 groups: no inflammation (NI: 95), subclinical inflammation (SCI: 244), subclinical T cell–mediated rejection (TCMR) (SC-TCMR: 110), clinical TCMR (C-TCMR: 83), and antibody-mediated rejection (AMR: 20). Estimated glomerular filtration rate (eGFR) over time using linear mixed model, cumulative chronic allograft scores/interstitial fibrosis and tubular atrophy (IFTA) ≥2 at 12 mo, and survival estimates were compared between groups. Results. The common types of rejections were C-TCMR (15%), SC-TCMR (19.9%), and AMR (3.6%) of patients. Eighteen of 20 patients with AMR had mixed rejection with TCMR. Key findings were as follows: (i) posttransplant renal function: eGFR was lower for patients with C-TCMR and AMR (P

Psychomotor slowing is common in children with sickle cell disease (SCD), but little is known about its severity in adults. We conducted a cross-sectional study to quantify psychomotor speed, measured with the digit symbol substitution test (DSST), in relationship with disease severity in adults with SCD attending an outpatient clinic (n = 88, age 36.3 years). Genotype was used to group patients in “severe” (homozygous for hemoglobin S or compound heterozygous with β0 thalassemia) or “moderate” groups (compound heterozygous for HbS, with either HbC or β+ thalassemia). Analyses were repeated after exclusion of patients with a history of stroke (n = 11). Mild impairment in processing speed was detectable in both the “severe” and the “moderate” group (30% and 9%, respectively; age-adjusted P = .14). Compared with the “moderate” group, those in the “severe” group had significantly lower standardized DSST scores (P = .004), independent of adjustment for factors that differed between the groups: hemoglobin, ferritin, hydroxyurea use, blood pressure parameters, and stroke history. Results were similar after excluding patients with stroke. Psychomotor slowing in SCD differs in relationship to genotype; this difference appears unrelated to history of stroke or severity of anemia and other risk factors examined cross-sectionally. Although less prevalent, mild cognitive impairment was also detectable in patients with a less severe genotype. Longitudinal studies of SCD should include all diseases genotypes and examine factors that would reduce the risk of slow processing speed and perhaps more general cognitive impairment in each subgroup.

This prospective observational cohort study compared the impact of subclinical tubulitis with or without interstitial inflammation to interstitial inflammation alone and to no inflammation in early post kidney transplant biopsies. A study cohort of 415 patients (living and deceased donor recipients) was divided into three groups on the basis of their three-month biopsy: 149 patients with No Inflammation (NI), 83 patients with Isolated Interstitial Inflammation (IIF), and 183 patients with Tubulitis [(with or without interstitial inflammation) (TIF) but not meeting criteria for Banff IA]. TIF was further divided into 56 patients with tubulitis without interstitial inflammation (TIF0) and 127 patients with tubulitis alongside interstitial inflammation (TIF1). TIF was significantly associated with higher incidence of subsequent T-cell mediated rejection (clinical or subclinical) at one year compared to IIF (31% vs 15%) and NI (31% vs 17%). Chronicity on one-year biopsy was significantly higher in TIF compared to IIF (22% vs 11%) and NI (22% vs 7%). De novo donor-specific antibody development was significantly higher in TIF compared to NI (6% vs 0.7%). Tubulitis subgroups (TIF0 and TIF1) revealed comparable effects on de novo donor-specific antibody and interstitial fibrosis/tubular atrophy development. However, tubulitis with interstitial inflammation had a significantly higher incidence of subsequent rejection and posed an increased hazard for the composite end point (subsequent acute rejection and death censored graft loss) compared to other groups [adjusted hazard 2.1 (95% confidence interval 1.2-3.5)]. Thus, subclinical tubulitis is a marker of adverse immunological events, but tubulitis with interstitial inflammation has a worse prognosis. Hence, the Banff 1997 (TIF1) and Banff 2005 classifications (TIF) for borderline change may have different implications.

The cerebral microvasculature is exceptionally vulnerable to changes due to aging. Both the radiological and clinical manifestations of cerebral small vessel disease (cSVD) in older age are highly heterogeneous, ranging from no symptomatology to devastating neurocognitive complications, including stroke, dementia, and depression. To date, the exact pathogenesis of cSVD is unknown; neither prevention nor treatments are currently available for this potentially very disabling condition. This chapter reviews recent advances in neuroimaging methodologies that have improved our understanding of the appearance of cSVD and the underlying mechanisms. We will discuss new venues for future research focusing on: (a) methodologies to measure early stages of cSVD, examining damage primarily in small vessels and secondarily in parenchyma; and (b) lifespan study designs to capture the onset and evolution of cSVD over time, as well as the temporality of exposure to risk factors.

Identifying promoters of cerebral small vein integrity is important to counter vascular contributions to cognitive impairment and dementia. Purpose In this preliminary investigation, the effects of a randomized 24-month physical activity (PA) intervention on changes in cerebral small vein integrity were compared to those of a health education (HE) control. Methods Cerebral small vein integrity was measured in 24 older adults (n = 8, PA; n = 16, HE) using ultra-high field MRI before and at the end of the 24-month intervention. Deep medullary veins were defined as straight or tortuous; percent change in straight length, tortuous length, and tortuosity ratio were computed. Microbleed count and white matter hyperintensities were also rated. Results Accelerometry-based values of PA increased by 17.2% in the PA group but declined by 28.0% in the HE group. The PA group, but not the HE group, had a significant increase in straight vein length from baseline to 24-month follow-up (P = 0.02 and P = 0.21, respectively); the between-group difference in percent change in straight length was significant (increase: median, 93.6%; interquartile range, 112.9 for PA; median, 28.4%; interquartile range, 90.6 for HE; P = 0.07). Between group differences in other markers were nonsignificant. Conclusions Increasing PA in late-life may promote cerebral small vein integrity. This should be confirmed in larger studies.

The aim of this study was to compare outcomes between living donor liver transplant (LDLT) and deceased donor liver transplant (DDLT) at a single center to demonstrate the advantages of LDLT and provide justification for the increased utilization and application of this procedure.LDLT comprises a very small percentage of all liver transplants performed in the United States, this despite its advantages and a shortage of the availability of deceased donor organs.A retrospective review of all adult LDLT (n = 245) and DDLT (n = 592) performed at a single center over 10 years (2009-2019), comparing survival outcomes by Kaplan-Meier analysis and comparing other measures of outcome such as recovery times, complications, costs, and resource utilization.Patient survival outcomes were superior in LDLT recipients (3-year 86% vs 80%, P = 0.03). Other outcomes demonstrated shorter length of hospital stay (11 vs 13 days, P = 0.03), less likelihood of intraoperative blood transfusion (52% vs 78%, P0.01), and less likelihood of need for posttransplant dialysis (1.6% vs 7.4%, P0.01). Early reoperation and biliary/vascular complication rates were similar. Hospital costs related to the transplant were 29.5% lower for LDLT. Complications in living donors were acceptable with no early or late deaths, 3-month reoperation rate of 3.1%, and overall complication rate of 19.5%. Given its advantages, we have expanded LDLT-in 2018, LDLT comprised 53.6% of our transplants (national average 4.8%), and our transplant rate increased from 44.8 (rate per 100-person years) in 2015 to 87.5 in 2018.LDLT offers advantages over DDLT including superior outcomes and less resource utilization. The time has come to change the paradigm of how LDLT is utilized in this country.

Supplemental Digital Content is available in the text., Background. There are no instruments that can identify patients at an increased risk of poor outcomes after liver transplantation (LT) based only on their preoperative characteristics. The primary aim of this study was to develop such a scoring system. Secondary outcomes were to assess the discriminative performance of the predictive model for 90-day mortality, 1-year mortality, and 5-year patient survival. Methods. The study population was represented by 30 458 adults who underwent LT in the United States between January 2002 and June 2013. Machine learning techniques identified recipient age, Model for End-Stage Liver Disease score, body mass index, diabetes, and dialysis before LT as the strongest predictors for 90-day postoperative mortality. A weighted scoring system (minimum of 0 to a maximum of 6 points) was subsequently developed. Results. Recipients with 0, 1, 2, 3, 4, 5, and 6 points had an observed 90-day mortality of 6.0%, 8.7%, 10.4%, 11.9%, 15.7%, 16.0%, and 19.7%, respectively (P ≤ 0.001). One-year mortality was 9.8%, 13.4%, 15.8%, 17.2%, 23.0%, 25.2%, and 35.8% (P ≤ 0.001) and five-year survival was 78%, 73%, 72%, 71%, 65%, 59%, and 48%, respectively (P = 0.001). The mean 90-day mortality for the cohort was 9%. The area under the curve of the model was 0.952 for the discrimination of patients with 90-day mortality risk ≥10%. Conclusions. Short- and long-term outcomes of patients undergoing cadaveric LT can be predicted using a scoring system based on recipients’ preoperative characteristics. This tool could assist clinicians and researchers in identifying patients at increased risks of postoperative death.

The aim of the study is to provide a comprehensive overview of identical twin kidney transplantation in the modern era. We provide epidemiologic trends in the US twin population from 1959 to 2000, current methods to identify zygosity, outcomes for identical twin transplants, and a comprehensive management strategy for identical twin kidney transplantation. By 2019, we project that 433 010 dizygotic and monozygotic twins will be alive and at risk for developing ESRF. Monozygosity between a donor-recipient pair can be confirmed by concordance in sex, blood type, and HLA antigen match with precision testing using 13/17 Short Tandem Repeat sequencing to a likelihood of nearly 100%. Among identical twin transplants from 2001 to 2017, excellent patient and kidney graft survival rates were noted. Approximately 50% of kidney transplant recipients of identical twins transplant did not receive maintenance immunosuppression, and no differences in graft survival were noted among patients with and without immunosuppression at 6 and 12 months (P = .8 and .7). Patients with glomerulonephritis as the cause of ESRF had lower graft survival (P = .06) suggesting that recurrent glomerulonephritis as a likely cause of graft loss among these recipients.

We investigated the effect of clinical and subclinical T cell-mediated rejection (C-TCMR and SC-TCMR) on allograft histology, function, and progression.Adult kidney recipients with 2 protocol biopsies were divided into No-TCMR on biopsies (n = 104), SC-TCMR (n = 56), and C-TCMR (n = 32) in at least 1 biopsy. Chronicity (ci + ct + cg + cv) scores, renal function, and the burden of renal disease measured by area under the curve (serum creatinine, mg mo/dL) were compared.Baseline characteristics were similar except for mean donor age and Kidney Donor Profile index scores. Patients with C-TCMR had higher mean serum creatinine, lower mean estimated glomerular filtration rate, and higher area under the curve with 95% confidence interval (75.2 [67.7-82.7]) as opposed to patients with SC-TCMR and No-TCMR (58.3 [53.6-62.9], 65.1 [58.8-71.5]), P = 0.0004. Chronicity scores were higher at 3 months in C-TCMR (2.30 ± 1.58) compared with SC-TCMR (2.02 ± 1.42) and No-TCMR (1.31 ± 1.18), P = 0.0001 and also at 12 months. At last follow-up, 18.8% patients with C-TCMR had ≥50% decline in estimated glomerular filtration rate from 3 months compared with 7% and 1% among No-TCMR and SC-TCMR groups (P = 0.038). Multivariate analyses revealed higher odds of Δ-creatinine ≥ 0.5 mg/dL from 3 months to last follow-up for C-TCMR (3.39 [95% confidence interval, 1.25-9.20]) versus No-TCMR (P = 0.016).Kidney transplant recipients with C-/SC-TCMR have heightened early allograft chronicity and worse renal function compared with those with No-TCMR. Progressive renal dysfunction was noted among patients with C-TCMR as opposed to SC-TCMR and No-TCMR.

The cerebral microvasculature is exceptionally vulnerable to changes due to aging. Both the radiological and clinical manifestations of cerebral small vessel disease (cSVD) in older age are highly heterogeneous, ranging from no symptomatology to devastating neurocognitive complications, including stroke, dementia, and depression. To date, the exact pathogenesis of cSVD is unknown; neither prevention nor treatments are currently available for this potentially very disabling condition. This chapter reviews recent advances in neuroimaging methodologies that have improved our understanding of the appearance of cSVD and the underlying mechanisms. We will discuss new venues for future research focusing on: (a) methodologies to measure early stages of cSVD, examining damage primarily in small vessels and secondarily in parenchyma; and (b) lifespan study designs to capture the onset and evolution of cSVD over time, as well as the temporality of exposure to risk factors.

Introduction: Blacks are at a higher risk for adverse brain-related outcomes, including stroke and dementia. Due to associations of vascular risk factors with brain health, differences in brain health may result from a greater burden of vascular risk factors in blacks, especially in midlife. However, the role of vascular risk factors in midlife racial disparities in brain health have been underexplored. We thus examined racial differences in midlife brain health and tested whether vascular and metabolic risk factors partly explain cross-sectional racial differences. Hypothesis: A composite cardiometabolic risk (CMR) score statistically mediates cross-sectional relationships between race and brain health measures. Methods: 747 adults (20.6% black) aged 30–54, underwent MRI to assess cerebral blood flow (CBF) and morphology. Components of composite CMR were: body mass index, waist circumference, high-density lipoproteins, triglycerides, glucose, insulin, SBP, and DBP. Mediation was tested using the PROCESS v2.14 macro. All models were adjusted for age, sex, income, education, and intracranial volume. Results: Blacks exhibited lower gray matter volume, smaller hippocampi, less cortical surface area, and a thinner cerebral cortex than whites (all p’s Conclusions: Race differences in some indicators of brain health are evident in midlife. Cardiovascular and metabolic risk factors may partly explain some of these differences. These results have implications for understanding vascular contributions to disparities in brain health prior to the onset of stroke and other clinical outcomes.

Background: Studies suggest that cardiovascular disease (CVD) is a risk factor for depression. Both heart disease and stroke increase the risk of developing depressive symptoms and CVD increases vulnerability to late-life depression. Comorbid depression has serious health consequences, including decreased compliance with treatment and rehabilitation. Reducing the rate of comorbid depression may improve adherence and outcomes, while reducing disability and cost. Development of CVD and depression are also linked to increased systemic inflammation. It is thought that inflammatory processes occurring in CVD may increase susceptibility to depression. One potentially modifiable source of systemic inflammation is diet. We thus examined the association of inflammatory diet and CVD risk score on depression. Methods: Using 2007-2012 National Health and Nutrition Examination Survey data, we calculated a Dietary Inflammatory Index score (DII), which represents the role of diet in systemic inflammation using the 24-hour dietary recall interview. Sex-specific CVD risk scores were calculated using a modified Framingham Risk equation. Current depression was determined using the Patient Health Questionnaire. Only participants with complete information and without prevalent CVD were included ( n = 11,624). Pearson χ 2 test and t-test were used for group comparisons. Using multivariable logistic regression, adjusted for age, sex, race, education, household income, supplement use, cholesterol-lowering medication, history of cancer, BMI and physical activity, we examined associations between: 1) CVD risk and current depression, 2) DII and current depression, adjusting for CVD risk, and 3) the joint effects of both CVD risk and DII on depression. Results: Individuals with current depression were: younger, more likely to be female, non-white, have a high school degree or less, household income Q3 :1.61, 95% confidence interval [CI]:1.24-2.10; OR Q4 :1.47, CI:1.08-2.00). Individuals with the highest two quartiles of DII compared to those with the lowest quartile, while controlling for CVD risk, had increased odds of current depression (OR Q3 :1.41, CI: 1.07-1.84; OR Q4 :1.46, CI: 1.16-1.84). Individuals with both CVD and DII scores in the 4 th quartile had a higher risk of depression than those with low DII and CVD risk (OR:2.21, CI: 1.57-3.13). Conclusions: A pro-inflammatory diet is associated with increased odds of depression independently of CVD risk status. These results suggest that modifying the intake of pro-inflammatory foods may reduce the prevalence of depression with possible consequential benefits for those at high CVD risk.

BACKGROUND AND PURPOSE: Traditional neuroimaging markers of small-vessel disease focus on late-stage changes. We aimed to adapt a method of venular assessment at 7T for use in older adults. We hypothesized that poorer venular morphologic characteristics would be related to other small-vessel disease neuroimaging markers and a higher prevalence of small-vessel disease–Alzheimer disease risk factors. MATERIALS AND METHODS: Venules were identified in periventricular ROIs on SWI and defined as tortuous or straight. The tortuosity ratio was defined as total tortuous venular length divided by total straight venular length. White matter hyperintensity burden (visually rated from 0 to 3) and the number of microbleeds (0, 1, >1) were determined. Differences in tortuous and straight venular lengths were evaluated. Relationships with demographic variables, allele producing the e4 type of apolipoprotein E (APOE4), growth factors, pulse pressure, physical activity, and Modified Mini-Mental State Examination were assessed via Spearman correlations. RESULTS: Participants had 42% more tortuous venular tissue than straight (median, 1.42; 95% CI, 1.13–1.62). APOE4 presence was associated with a greater tortuosity ratio (ρ = 0.454, P = .001), and these results were robust to adjustment for confounders and multiple comparisons. Associations of the tortuosity ratio with sex and vascular endothelial growth factor did not survive adjustment. Associations of the tortuosity ratio with other variables of interest were not significant. CONCLUSIONS: Morphologic measures of venules at 7T could be useful biomarkers of the early stages of small-vessel disease and Alzheimer disease. Longitudinal studies should examine the impact of apolipoprotein E and vascular endothelial growth factor on the risk of venular damage.

Adults with homozygous sickle cell anemia have, on average, lower cognitive function than unaffected controls. The mechanisms underlying cognitive deterioration in this population are poorly understood, but cerebral small vessel disease (CSVD) is likely to be implicated. We conducted a systematic review using the Prisma Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of articles that included both measures of cognitive function and magnetic resonance imaging (MRI) neuroimaging markers of small vessel disease. While all five studies we identified reported small vessel disease by MRI, only two of them found a significant relationship between structural changes and cognitive performance. Differences in methodologies and small sample sizes likely accounted for the discrepancies between the studies. We conclude that while MRI is a valuable tool to identify markers of CSVD in this population, larger studies are needed to definitely establish a link between MRI-detectable abnormalities and cognitive function in sickle cell anemia.

Mechanisms by which Salmonella establish chronic infections are not well understood. Microbes respond to stress by importing or producing compatible solutes, small molecules that stabilize proteins and lipids. The Salmonella locus opuABCD (also called OpuC) encodes a predicted importer of the compatible solute glycine betaine. Under stress conditions, if glycine betaine cannot be imported, Salmonella enterica produce the disaccharide trehalose, a highly effective compatible solute. We demonstrate that strains lacking opuABCD accumulate more trehalose under stress conditions than wild-type strains. ΔopuABCD mutant strains are more resistant to high-salt, low-pH and -hydrogen peroxide, conditions that mimic aspects of innate immunity, in a trehalose-dependent manner. In addition, ΔopuABCD mutant strains require the trehalose production genes to out-compete wild-type strains in mice and macrophages. These data suggest that in the absence of opuABCD, trehalose accumulation increases bacterial resistance to stress in broth and mice. Thus, opuABCD reduces bacterial colonization via a mechanism that limits trehalose production. Mechanisms by which microbes limit disease may reveal novel pathways as therapeutic targets.

Mechanisms by which Salmonella establish chronic infections are not well understood. Microbes respond to stress by importing or producing compatible solutes, small molecules that stabilize proteins and lipids. The Salmonella locus opuABCD (also called OpuC) encodes a predicted importer of the compatible solute glycine betaine. Under stress conditions, if glycine betaine cannot be imported, Salmonella enterica produce the disaccharide trehalose, a highly effective compatible solute. We demonstrate that strains lacking opuABCD accumulate more trehalose under stress conditions than wild-type strains. ΔopuABCD mutant strains are more resistant to high-salt, low-pH and -hydrogen peroxide, conditions that mimic aspects of innate immunity, in a trehalose-dependent manner. In addition, ΔopuABCD mutant strains require the trehalose production genes to out-compete wild-type strains in mice and macrophages. These data suggest that in the absence of opuABCD, trehalose accumulation increases bacterial resistance to stress in broth and mice. Thus, opuABCD reduces bacterial colonization via a mechanism that limits trehalose production. Mechanisms by which microbes limit disease may reveal novel pathways as therapeutic targets.

Introduction Cognitive impairment (CI) is a serious complication of sickle cell disease (SCD) with a prevalence of more than 40% (Vichinsky, JAMA 2010). It is responsible for functional limitations in schooling in children and in occupation and compliance with therapy in adults, and is therefore recognized as both a medical and social devastation of SCD. While the pathophysiology of SCD-related cognitive impairment is not fully elucidated, SCD patients are exposed to high levels of chronic inflammation and oxidative stress, which are responsible for cognitive impairment in other vascular diseases, suggesting that these factors may also play a role in SCD. Thrombospondin-1 (TSP1) is a secreted protein that stands at the crossroads of multiple inflammatory and oxidative pathways crucial to the SCD pathology (Isenberg, PNAS 2005, JBC 2006, Blood 2008, Csanyi, ATVB 2012; Yao, JASN 2014). Importantly, TSP1 levels are elevated in patients with SCD and correlate with an increased risk of vaso-occlusive complications in adults (Novelli, AJH 2012) and a higher burden of silent cerebral infarcts in children (Faulcon, BJH 2013). Herein, we explored the association between TSP1, oxidative stress and cognitive function in a cohort of patients with SCD. Methods Thirty-four SCD patients (HbSS, HbSC and HbS/β-thalassemia) >18 years and in steady state were recruited from the UPMC Adult Sickle Cell Program outpatient clinic (Pittsburgh, PA). Upon obtaining informed consent, patients underwent a blood draw and the Hopkins Verbal Learning Test - Revised (HVLT-R), a test of episodic memory whose scores are associated with cerebral small vessel disease in SCD patients (Novelli, PRN 2015). Platelet-poor plasma was collected and stored for analysis by ELISA of TSP1 and the oxidized derivative of deoxyguanosine, 8-hydroxy-2-deoxy guanosine (8-OH2dG), a marker of oxidative stress. Statistical analyses were completed using SAS 9.3. Results SCD patients had a mean age of 35 (22-65), were 65% female, 66% had greater than high school education, and 65% had HbSS disease, 30% had HbSC disease, and 5% had S/β-thalassemia. Elevated plasma TSP1 levels correlated inversely with HVLT-R retention score (standardized b=-0.457, p=0.007). Conversely, elevated plasma TSP1 levels positively correlated with increased levels of plasma 8-OH2dG (standardized b=0.361, p Discussion Elevated plasma TSP1 levels are associated with poorer episodic memory in SCD patients. This is the first evidence of a link between a plasma protein associated with vascular disease and cognitive function in adults with SCD. TSP1 levels were also positively correlated with 8-OH2dG, and adding 8-OH2dG to the model of TSP1 and HVTL-R retention appeared to increase the detrimental effect of TSP1. These results suggest that the effect of 8-OH2dG on cognitive function becomes evident only in the presence of higher TSP1 levels and implicate oxidative stress as intermediary to the effect of TSP1 on cognitive function in SCD. Figure 1. Figure 1. Disclosures Isenberg: RCTI, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313; Vasculox, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313.