Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected ...donors may be a neglected public health resource.
To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation).
Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649).
Single center.
10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors.
Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy.
The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis.
Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment.
Nonrandomized study design and a small number of patients.
Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection.
Merck Sharp & Dohme.
BACKGROUNDFrailty increases early hospital readmission and mortality risk among kidney transplantation (KT) recipients. Although frailty represents a high-risk state for this population, the ...correlates of frailty, the patterns of the 5 frailty components, and the risk associated with these patterns are unclear.
METHODSSix hundred sixty-three KT recipients were enrolled in a cohort study of frailty in transplantation (12/2008-8/2015). Frailty, activities of daily living (ADL)/instrumental ADL (IADL) disability, Centers for Epidemiologic Studies Depression Scale depression, education, and health-related quality of life (HRQOL) were measured. We used multinomial regression to identify frailty correlates. We identified which patterns of the 5 components were associated with mortality using adjusted Cox proportional hazards models.
RESULTSFrailty prevalence was 19.5%. Older recipients (adjusted prevalence ratio PR, 2.22; 95% confidence interval CI, 1.21-4.07) were more likely to be frail. The only other factors that were independently associated with frailty were IADL disability (PR, 3.22; 95% CI, 1.72-6.06), depressive symptoms (PR, 11.31; 95% CI, 4.02-31.82), less than a high school education (PR, 3.10; 95% CI, 1.30-7.36), and low HRQOL (fair/poorPR, 3.71; 95% CI, 1.48-9.31). The most common pattern was poor grip strength, low physical activity, and slowed walk speed (19.4%). Only 2 patterns of the 5 components emerged as having an association with post-KT mortality. KT recipients with exhaustion and slowed walking speed (hazards ratio = 2.43; 95% CI, 1.17-5.03) and poor grip strength, exhaustion, and slowed walking speed (hazard ratio, 2.61; 95% CI, 1.14-5.97) were at increased mortality risk.
CONCLUSIONSAge was the only conventional factor associated with frailty among KT recipients; however, factors rarely measured as part of clinical practice, namely, HRQOL, IADL disability, and depressive symptoms, were significant correlates of frailty. Redefining the frailty phenotype may be needed to improve risk stratification for KT recipients.
The epidemic of drug overdose deaths in the United States has led to an increase in organ donors.
To characterize donors who died of overdose and to analyze outcomes among transplant recipients.
...Prospective observational cohort study.
Scientific Registry of Transplant Recipients, 1 January 2000 to 1 September 2017.
138 565 deceased donors; 337 934 transplant recipients at 297 transplant centers.
The primary exposure was donor mechanism of death (overdose-death donor ODD, trauma-death donor TDD, or medical-death donor MDD). Patient and graft survival and organ discard (organ recovered but not transplanted) were compared using propensity score-weighted standardized risk differences (sRDs).
A total of 7313 ODDs and 19 897 ODD transplants (10 347 kidneys, 5707 livers, 2471 hearts, and 1372 lungs) were identified. Overdose-death donors accounted for 1.1% of donors in 2000 and 13.4% in 2017. They were more likely to be white (85.1%), aged 21 to 40 years (66.3%), infected with hepatitis C virus (HCV) (18.3%), and increased-infectious risk donors (IRDs) (56.4%). Standardized 5-year patient survival was similar for ODD organ recipients compared with TDD organ recipients (sRDs ranged from 3.1% lower to 3.9% higher survival) and MDD organ recipients (sRDs ranged from 2.1% to 5.2% higher survival). Standardized 5-year graft survival was similar between ODD and TDD grafts (minimal difference for kidneys and lungs, marginally lower sRD, -3.2% for livers, and marginally higher sRD, 1.9% for hearts). Kidney discard was higher for ODDs than TDDs (sRD, 5.2%) or MDDs (sRD, 1.5%); standardization for HCV and IRD status attenuated this difference.
Inability to distinguish between opioid and nonopioid overdoses.
In the United States, transplantation with ODD organs has increased dramatically, with noninferior outcomes in transplant recipients. Concerns about IRD behaviors and hepatitis C among donors lead to excess discard that should be minimized given the current organ shortage.
National Institutes of Health.
Frailty and Access to Kidney Transplantation Haugen, Christine E; Chu, Nadia M; Ying, Hao ...
Clinical journal of the American Society of Nephrology,
04/2019, Letnik:
14, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Frailty, a syndrome distinct from comorbidity and disability, is clinically manifested as a decreased resistance to stressors and is present in up to 35% of patient with ESKD. It is associated with ...falls, hospitalizations, poor cognitive function, and mortality. Also, frailty is associated with poor outcomes after kidney transplant, including delirium and mortality. Frailty is likely also associated with decreased access to kidney transplantation, given its association with poor outcomes on dialysis and post-transplant. Yet, clinicians have difficulty identifying which patients are frail; therefore, we sought to quantify if frail kidney transplant candidates had similar access to kidney transplantation as nonfrail candidates.
We studied 7078 kidney transplant candidates (2009-2018) in a three-center prospective cohort study of frailty. Fried frailty (unintentional weight loss, grip strength, walking speed, exhaustion, and activity level) was measured at outpatient kidney transplant evaluation. We estimated time to listing and transplant rate by frailty status using Cox proportional hazards and Poisson regression, adjusting for demographic and health factors.
The mean age was 54 years (SD 13; range, 18-89), 40% were women, 34% were black, and 21% were frail. Frail participants were almost half as likely to be listed for kidney transplantation (hazard ratio, 0.62; 95% confidence interval, 0.56 to 0.69;
<0.001) compared with nonfrail participants, independent of age and other demographic factors. Furthermore, frail candidates were transplanted 32% less frequently than nonfrail candidates (incidence rate ratio, 0.68; 95% confidence interval, 0.58 to 0.81;
<0.001).
Frailty is associated with lower chance of listing and lower rate of transplant, and is a potentially modifiable risk factor.
BACKGROUNDHealth-related quality of life (HRQOL) reflects a patient’s disease burden, treatment effectiveness, and health status and is summarized by physical, mental, and kidney disease-specific ...scales among end-stage renal disease patients. Although on average HRQOL improves postkidney transplant (KT), the degree of change depends on the ability of the patient to withstand the stressor of dialysis versus the ability to tolerate the intense physiologic changes of KT. Frail KT recipients may be extra vulnerable to either of these stressors, thus affecting change in HRQOL after KT.
METHODSWe ascertained frailty, as well as physical, mental, and kidney disease-specific HRQOL in a multicenter prospective cohort of 443 KT recipients (May 2014 to May 2017) using Kidney Disease Quality of Life Instrument Short Form. We quantified the short-term (3 months) rate of post-KT HRQOL change by frailty status using adjusted mixed-effects linear regression models.
RESULTSMean HRQOL scores at KT were 43.3 (SD, 9.6) for physical, 52.8 (SD, 8.9) for mental, and 72.6 (SD, 12.8) for kidney disease-specific HRQOL; frail recipients had worse physical (P < 0.001) and kidney disease-specific HRQOL (P = 0.001), but similar mental HRQOL (P = 0.43). Frail recipients experienced significantly greater rates of improvement in physical HRQOL (frail, 1.35 points/month; 95% confidence interval CI, 0.65-2.05; nonfrail, 0.34 points/month; 95% CI, −0.17-0.85; P = 0.02) and kidney disease-specific HRQOL (frail, 3.75 points/month; 95% CI, 2.89-4.60; nonfrail, 2.41 points/month; 95% CI, 1.78-3.04; P = 0.01), but no difference in mental HRQOL (frail, 0.54 points/month; 95% CI, −0.17-1.25; nonfrail, 0.46 points/month; 95% CI, −0.06-0.98; P = 0.85) post-KT.
CONCLUSIONSDespite decreased physiologic reserve, frail recipients experience improvement in post-KT physical and kidney disease-specific HRQOL better than nonfrail recipients.
OBJECTIVE:To test whether frailty, a novel measure of physiologic reserve, is associated with longer kidney transplant (KT) length of stay (LOS), and modifies the association between LOS and ...mortality.
BACKGROUND:Better understanding of LOS is necessary for informed consent and discharge planning. Mortality resulting from longer LOS has important regulatory implications for hospital and transplant programs. Which recipients are at risk of prolonged LOS and its effect on mortality are unclear. Frailty is a novel preoperative predictor of poor KT outcomes including delayed graft function, early hospital readmission, immunosuppression intolerance, and mortality.
METHODS:We used registry-augmented hybrid methods, a novel approach to risk adjustment, to adjust for LOS risk factors from the Scientific Registry of Transplant Recipients (n = 74,859) and tested whether (1) frailty, measured immediately before KT in a novel cohort (n = 589), was associated with LOS (LOSnegative binomial regression; LOS ≥2 weekslogistic regression) and (2) whether frailty modified the association between LOS and mortality (interaction term analysis).
RESULTS:Frailty was independently associated with longer LOS relative risk = 1.15, 95% confidence interval (CI)1.03–1.29; P = 0.01 and LOS ≥2 weeks (odds ratio = 1.57, 95% CI1.06–2.33; P = 0.03) after accounting for registry-based risk factors, including delayed graft function. Frailty also attenuated the association between LOS and mortality (nonfrail hazard rate = 1.55 95% CI1.30–1.86; P < 0.001; frail hazard rate = 0.97, 95% CI0.79–1.19, P = 0.80; P for interaction = 0.001).
CONCLUSIONS:Frail KT recipients are more likely to experience a longer LOS. Longer LOS among nonfrail recipients may be a marker of increased mortality risk. Frailty is a measure of physiologic reserve that may be an important clinical marker of longer surgical LOS.
To better understand the function of cholinergic projection neurons in the ventral pallidum (VP), we examined behavioral responses to appetitive (APP) and aversive (AV) odors that elicited approach ...or avoidance, respectively. Exposure to each odor increased cFos expression and calcium signaling in VP cholinergic neurons. Activity and Cre-dependent viral vectors selectively labeled VP cholinergic neurons that were activated and reactivated in response to either APP or AV odors, but not both, identifying two non-overlapping populations of VP cholinergic neurons differentially activated by the valence of olfactory stimuli. These two subpopulations showed differences in electrophysiological properties, morphology, and projections to the basolateral amygdala. Although VP neurons are engaged in both approach and avoidance behavioral responses, cholinergic signaling is only required for approach behavior. Thus, two distinct subpopulations of VP cholinergic neurons differentially encode valence of olfactory stimuli and play distinct roles in approach and avoidance behaviors.
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•VP cholinergic projection neurons are engaged in approach and avoidance behaviors•Opposing valence odors activate distinct subpopulations of VP cholinergic neurons•These two subpopulations differentially integrate into VP circuits•VP cholinergic signaling is required for approach behavior
Kim et al. identify two distinct subpopulations of VP cholinergic projection neurons activated by an appetitive vs. aversive odor. These two subpopulations display different properties, which indicate differential integration of each subpopulation into neural circuits. These results demonstrate functional heterogeneity of VP cholinergic neurons.
BACKGROUNDAmong community-dwelling older adults, frailty is associated with heightened markers of inflammation and subsequent mortality. Although frailty is common among ESRD patients, the role of ...frailty and markers of inflammation in this population remains unclear. We quantified these associations in patients on the kidney transplant (KT) waitlist and tested whether frailty and/or markers of inflammation improve waitlist mortality risk prediction.
METHODSWe studied 1,975 ESRD patients on the KT waitlist (11/1/09-2/28/17) in a multi-center cohort study of frailty. Serum inflammatory markers (interleukin-6 IL-6, soluble tumor necrosis factor-α receptor-1 sTNFR1, and C-reactive protein CRP) were analyzed in 605 of these participants; we calculated the inflammatory index score using IL-6 and sTNFR1. We compared the C-statistic of an established registry-based prediction model for waitlist mortality adding frailty and/or inflammatory markers (1SD change in log IL-6, sTNFR1, CRP, or inflammatory index).
RESULTSThe registry-based model had moderate predictive ability (c-statistic=0.655). Frailty was associated with increased mortality (2.19, 95%CI:1.26-3.79) but did not improve risk prediction (c-statistic=0.646; P=0.65). Like frailty, IL-6 (2.13, 95%CI:1.41-3.22), sTNFR1 (1.70, 95%CI:1.12-2.59), CRP (1.68, 95%CI:1.06-2.67), and the inflammatory index (2.09, 95%CI:1.38-3.16) were associated with increased mortality risk; unlike frailty, adding IL-6 (c-statistic=0.777; P=0.02), CRP (c-statistic=0.728; P=0.02), or inflammatory index (c-statistic=0.777; P=0.02) substantially improved mortality risk prediction.
CONCLUSIONFrailty and markers of inflammation were associated with increased waitlist mortality risk, but only markers of inflammation significantly improved ESRD risk prediction. These findings help clarify the accelerated aging physiology of ESRD and highlight easy to measure markers of increased waitlist mortality risk.
The Kidney Allocation System (KAS), a major change to deceased donor kidney allocation, was implemented in December 2014. Goals of KAS included directing the highest-quality organs to ...younger/healthier recipients and increasing access to deceased donor kidney transplantation (DDKT) for highly sensitized patients and racial/ethnic minorities. Using national registry data, we compared kidney distribution, DDKT rates for waitlist registrants, and recipient characteristics between January 1, 2013, and December 3, 2014 (pre-KAS) with those between December 4, 2014, and August 31, 2015 (post-KAS). Regional imports increased from 8.8% pre-KAS to 12.5% post-KAS; national imports increased from 12.7% pre-KAS to 19.1% post-KAS (P<0.001). The proportion of recipients >30 years older than their donor decreased from 19.4% to 15.0% (P<0.001). The proportion of recipients with calculated panel-reactive antibody =100 increased from 1.0% to 10.3% (P<0.001). Overall DDKT rate did not change as modeled using exponential regression adjusting for candidate characteristics (P=0.07). However, DDKT rate (incidence rate ratio, 95% confidence interval) increased for black (1.19; 1.13 to 1.25) and Hispanic (1.13; 1.05 to 1.20) candidates and for candidates aged 18-40 (1.47; 1.38 to 1.57), but declined for candidates aged >50 (0.93; 0.87 to 0.98 for aged 51-60 and 0.90; 0.85 to 0.96 for aged >70). Delayed graft function in transplant recipients increased from 24.8% pre-KAS to 29.9% post-KAS (P<0.001). Thus, in the first 9 months under KAS, access to DDKT improved for minorities, younger candidates, and highly sensitized patients, but declined for older candidates. Delayed graft function increased substantially, possibly suggesting poorer long-term outcomes.
Fluorescence imaging of calcium dynamics in neuronal populations is powerful because it offers a way of relating the activity of individual cells to the broader population of nearby cells. The ...method’s growth across neuroscience has particularly been driven by the introduction of sophisticated mathematical techniques related to motion correction, image registration, cell detection, spike estimation, and population characterization. However, for many researchers, making good use of these techniques has been difficult because they have been devised by different workers and impose differing – and sometimes stringent – technical requirements on those who seek to use them.
We have built a simple toolbox of analysis routines that encompass the complete workflow for analyzing calcium imaging data. The workflow begins with preprocessing of data, includes motion correction and longitudinal image registration, detects active cells using constrained non-negative matrix factorization, and offers multiple options for estimating spike times and characterizing population activity. The routines can be navigated through a simple graphical user interface. Although written in MATLAB, a standalone version for researchers who do not have access to MATLAB is included.
We have used the toolbox on two very different preparations: spontaneously active brain slices and microendoscopic imaging from deep structures in awake behaving mice. In both cases, the toolbox offered a seamless flow from raw data all the way through to prepared graphs.
The field of calcium imaging has benefited from the development of numerous innovative mathematical techniques. Here we offer a simple toolbox that allows ordinary researchers to fully exploit these techniques.
•Provides an end-to-end user-friendly workflow for calcium imaging data analysis.•Motion correction and longitudinal registration across imaging sessions.•Cell detection utilizes constrained non-negative matrix factorization.•Spike estimation utilizes a maximum likelihood method.•Spike distance metrics, pairwise correlation analysis, Earth Mover’s Distance.
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