Distinct subpopulations of ventral pallidal cholinergic projection neurons encode valence of olfactory stimuli.

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.

Patient Perspectives on Solid Organ Transplantation From Donors With Hepatitis C Viremia to Recipients Without Hepatitis C Viremia.

Background: Organ transplantation from donors with hepatitis C viremia (HCV) to recipients without HCV (HCV D+/R-) has excellent medical outcomes. Less is known about the psychosocial impact and experiences of HCV D+/R- recipients, particularly outside of clinical trials. Methods: We conducted in-depth, semistructured interviews with 24 HCV D+/R- recipients (kidney, n = 8; lung, n = 7; liver, n = 5; heart, n = 3; simultaneous heart and kidney, n = 1) who received transplants outside of clinical trials and were treated for HCV after transplant to assess their experiences and perspectives. We used thematic analysis to analyze the interviews. Results: Interviewees' reasons for accepting an HCV D + organ were based on perceived benefits and confidence in the effectiveness of HCV treatment. The majority (62%) received HCV treatment within 1 month after transplant (range, 1 day-2 months). Most interviewees reported positive transplant outcomes, including reduced wait times and improved survival, health, physical activity, and quality of life. Overall, themes and experiences did not differ significantly between different organ transplant types. Generally, interviewees did not perceive stigma from those aware of the HCV D+ transplant; yet, disclosure was selective and a few recipients reported concerns from family members about posttransplant HCV transmission risk. Other common concerns included treatment costs and delays, which were not always anticipated by recipients. Conclusions: Our findings suggest that HCV D+/R- kidney, liver, and heart and lung transplant recipients outside of clinical trials had overall positive experiences. However, HCV transmission risk, treatments costs, and treatment delays were a source of concern that might be mitigated with targeted pretransplant education.

Functionally refined encoding of threat memory by distinct populations of basal forebrain cholinergic projection neurons.

Neurons of the basal forebrain nucleus basalis and posterior substantia innominata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA). Using a genetically encoded acetylcholine (ACh) sensor in mice, we demonstrate that BLA-projecting cholinergic neurons can 'learn' the association between a naive tone and a foot shock (training) and release ACh in the BLA in response to the conditioned tone 24 hr later (recall). In the NBM/SIp cholinergic neurons express the immediate early gene, Fos following both training and memory recall. Cholinergic neurons that express Fos following memory recall display increased intrinsic excitability. Chemogenetic silencing of these learning-activated cholinergic neurons prevents expression of the defensive behavior to the tone. In contrast, we show that NBM/SIp cholinergic neurons are not activated by an innately threatening stimulus (predator odor). Instead, VP/SIa cholinergic neurons are activated and contribute to defensive behaviors in response to predator odor, an innately threatening stimulus. Taken together, we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli, demonstrating functionally refined organization of specific types of memory within the cholinergic basal forebrain of mice.

Functionally refined encoding of threat memory by distinct populations of basal forebrain cholinergic projection neurons.

Neurons of the basal forebrain nucleus basalis and posterior substantia innominata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA). Using a genetically-encoded acetylcholine (ACh) sensor in mice, we demonstrate that BLA-projecting cholinergic neurons can "learn" the association between a naïve tone and a foot shock (training) and release ACh in the BLA in response to the conditioned tone 24h later (recall). In the NBM/SIp cholinergic neurons express the immediate early gene, Fos following both training and memory recall. Cholinergic neurons that express Fos following memory recall display increased intrinsic excitability. Chemogenetic silencing of these learning-activated cholinergic neurons prevents expression of the defensive behavior to the tone. In contrast, we show that NBM/SIp cholinergic neurons are not activated by an innately threatening stimulus (predator odor). Instead, VP/SIa cholinergic neurons are activated and contribute to defensive behaviors in response to predator odor, an innately threatening stimulus. Taken together, we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli, demonstrating functionally refined organization of specific types of memory within the cholinergic basal forebrain of mice.

Twenty years in the making: tolerance in a living-related kidney transplant recipient.

Kidney transplant recipients require lifelong immunosuppression to prevent graft rejection. However, immunosuppression is associated with adverse effects. A minority of kidney transplant recipients can be weaned off immunosuppression and maintain their graft function, a situation referred to as "functional or operational tolerance". We describe a case of a 70-year-old man who received a haploidentical hematopoietic cell transplant for lymphoma 22 years before receiving a kidney transplant from the same donor and was weaned off all immunosuppression by four months post-transplant. Tolerance was present, and there has been no graft rejection or graft vs. host disease. This case demonstrates successful long-term hematopoietic chimerism and functional tolerance after receiving a kidney transplant from the same donor.

Kidney Donation After Circulatory Death Using Thoracoabdominal Normothermic Regional Perfusion: The Largest Report of the United States Experience.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has been increasingly used for donation after circulatory death (DCD) procurements in the United States. We present the largest report of outcomes of kidney transplants performed using DCD donor grafts perfused with TA-NRP. METHODS: Adult DCD kidney transplants between 2020 and 2022 in the United Network for Organ Sharing database were included. Donors with ≥50 min between asystole and aortic cross-clamp time in which the heart was also transplanted were considered TA-NRP donors. All other donors were considered direct recovery donors. Multivariable regressions were used to assess delayed graft function, as well as posttransplant survival and all-cause graft failure at 30, 90, and 180 d. A propensity-matched analysis of cohorts matched on donor Kidney Donor Profile Index was performed. RESULTS: Of the 16 140 total DCD kidney transplants performed during the study period, 306 (1.9%) used TA-NRP. TA-NRP donors were younger ( P < 0.001) and had lower Kidney Donor Profile Index ( P < 0.001) compared with direct recovery donors. Recipients receiving grafts recovered using TA-NRP were younger ( P < 0.001) and more likely to be blood group O ( P < 0.001). Transplants using TA-NRP had lower likelihood of delayed graft function (adjusted odds ratio 0.22 [95% confidence interval, 0.15-0.31], P < 0.001) but similar 180-d survival ( P = 0.8) and all-cause graft failure ( P = 0.3) as transplants using direct recovery grafts. These inferences were unchanged on propensity-matched analysis. CONCLUSIONS: Our results demonstrate that kidney transplants using TA-NRP DCD allografts have positive short-term mortality and graft survival outcomes, with significantly decreased rates of delayed graft function compared with direct recovery DCD grafts.

Wait Time Advantage for Transplant Candidates With HIV Who Accept Kidneys From Donors With HIV Under the HOPE Act.

BACKGROUND: Kidney transplant (KT) candidates with HIV face higher mortality on the waitlist compared with candidates without HIV. Because the HIV Organ Policy Equity (HOPE) Act has expanded the donor pool to allow donors with HIV (D + ), it is crucial to understand whether this has impacted transplant rates for this population. METHODS: Using a linkage between the HOPE in Action trial (NCT03500315) and Scientific Registry of Transplant Recipients, we identified 324 candidates listed for D + kidneys (HOPE) compared with 46 025 candidates not listed for D + kidneys (non-HOPE) at the same centers between April 26, 2018, and May 24, 2022. We characterized KT rate, KT type (D + , false-positive [FP; donor with false-positive HIV testing], D - [donor without HIV], living donor [LD]) and quantified the association between HOPE enrollment and KT rate using multivariable Cox regression with center-level clustering; HOPE was a time-varying exposure. RESULTS: HOPE candidates were more likely male individuals (79% versus 62%), Black (73% versus 35%), and publicly insured (71% versus 52%; P < 0.001). Within 4.5 y, 70% of HOPE candidates received a KT (41% D + , 34% D - , 20% FP, 4% LD) versus 43% of non-HOPE candidates (74% D - , 26% LD). Conversely, 22% of HOPE candidates versus 39% of non-HOPE candidates died or were removed from the waitlist. Median KT wait time was 10.3 mo for HOPE versus 60.8 mo for non-HOPE candidates ( P < 0.001). After adjustment, HOPE candidates had a 3.30-fold higher KT rate (adjusted hazard ratio = 3.30, 95% confidence interval, 2.14-5.10; P < 0.001). CONCLUSIONS: Listing for D + kidneys within HOPE trials was associated with a higher KT rate and shorter wait time, supporting the expansion of this practice for candidates with HIV.

A2/A2B to B deceased donor kidney transplantation in the Kidney Allocation System era.

Kidney transplantation from blood type A2/A2B donors to type B recipients (A2→B) has increased dramatically under the current Kidney Allocation System (KAS). Among living donor transplant recipients, A2-incompatible transplants are associated with an increased risk of all-cause and death-censored graft failure. In light of this, we used data from the Scientific Registry of Transplant Recipients from December 2014 until June 2022 to evaluate the association between A2→B listing and time to deceased donor kidney transplantation (DDKT) and post-DDKT outcomes for A2→B recipients. Among 53 409 type B waitlist registrants, only 12.6% were listed as eligible to accept A2→B offers ("A2-eligible"). The rates of DDKT at 1-, 3-, and 5-years were 32.1%, 61.4%, and 72.1% among A2-eligible candidates and 14.1%, 29.9%, and 44.1% among A2-ineligible candidates, with the former experiencing a 133% higher rate of DDKT (Cox weighted hazard ratio (wHR) = 2.192.332.47; P < .001). The 7-year adjusted mortality was comparable between A2→B and B-ABOc (type B/O donors to B recipients) recipients (wHR 0.780.941.13, P = .5). Moreover, there was no difference between A2→B vs B-ABOc DDKT recipients with regards to death-censored graft failure (wHR 0.771.001.29, P > .9) or all-cause graft loss (wHR 0.820.961.12, P = .6). Following its broader adoption since the implementation of the kidney allocation system, A2→B DDKT appears to be a safe and effective transplant modality for eligible candidates. As such, A2→B listing for eligible type B candidates should be expanded.

Distinct subpopulations of ventral pallidal cholinergic projection neurons encode valence of olfactory stimuli.

The ventral pallidum (VP) mediates motivated behaviors largely via the action of VP GABA and glutamatergic neurons. In addition to these neuronal subtypes, there is a population of cholinergic projection neurons in the VP, whose functional significance remains unclear. To understand the functional role of VP cholinergic neurons, we first examined behavioral responses to an appetitive (APP) odor that elicited approach, and an aversive (AV) odor that led to avoidance. To examine how VP cholinergic neurons were engaged in APP vs. AV responses, we used an immediate early gene marker and in-vivo fiber photometry, examining the activation profile of VP cholinergic neurons in response to each odor. Exposure to each odor led to an increase in the number of cFos counts and increased calcium signaling of VP cholinergic neurons. Activity and cre-dependent viral vectors were designed to label engaged VP cholinergic neurons in two distinct contexts: (1) exposure to the APP odor, (2) followed by subsequent exposure to the AV odor, and vice versa. These studies revealed two distinct, non-overlapping subpopulations of VP cholinergic neurons: one activated in response to the APP odor, and a second distinct population activated in response to the AV odor. These two subpopulations of VP cholinergic neurons are spatially intermingled within the VP, but show differences in electrophysiological properties, neuronal morphology, and projections to the basolateral amygdala. Although VP cholinergic neurons are engaged in behavioral responses to each odor, VP cholinergic signaling is only required for approach behavior. Indeed, inhibition of VP cholinergic neurons not only blocks approach to the APP odor, but reverses the behavior, leading to active avoidance. Our results highlight the functional heterogeneity of cholinergic projection neurons within the VP. These two subpopulations of VP cholinergic neurons differentially encode valence of olfactory stimuli and play unique roles in approach and avoidance behaviors.

The effect of induction immunosuppression for kidney transplant on the latent HIV reservoir.

The HIV latent viral reservoir (LVR) remains a major challenge in the effort to find a cure for HIV. There is interest in lymphocyte-depleting agents, used in solid organ and bone marrow transplantation to reduce the LVR. This study evaluated the LVR and T cell receptor repertoire in HIV-infected kidney transplant recipients using intact proviral DNA assay and T cell receptor sequencing in patients receiving lymphocyte-depleting or lymphocyte-nondepleting immunosuppression induction therapy. CD4+ T cells and intact and defective provirus frequencies decreased following lymphocyte-depleting induction therapy but rebounded to near baseline levels within 1 year after induction. In contrast, these biomarkers were relatively stable over time in the lymphocyte-nondepleting group. The lymphocyte-depleting group had early TCRß repertoire turnover and newly detected and expanded clones compared with the lymphocyte-nondepleting group. No differences were observed in TCRß clonality and repertoire richness between groups. These findings suggest that, even with significant decreases in the overall size of the circulating LVR, the reservoir can be reconstituted in a relatively short period of time. These results, while from a relatively unique population, suggest that curative strategies aimed at depleting the HIV LVR will need to achieve specific and durable levels of HIV-infected T cell depletion.

Patient and Graft Survival After A1/A2-incompatible Living Donor Kidney Transplantation.

ABO type B and O kidney transplant candidates have increased difficulty identifying a compatible donor for living donor kidney transplantation (LDKT) and are harder to match in kidney paired donation registries. A2-incompatible (A2i) LDKT increases access to LDKT for these patients. To better inform living donor selection, we evaluated the association between A2i LDKT and patient and graft survival. Methods: We used weighted Cox regression to compare mortality, death-censored graft failure, and all-cause graft loss in A2i versus ABO-compatible (ABOc) recipients. Results: Using Scientific Registry of Transplant Recipients data 2000-2019, we identified 345 A2i LDKT recipients. Mortality was comparable among A2i and ABOc recipients; weighted 1-/5-/10-y mortality was 0.9%/6.5%/24.2%, respectively, among A2i LDKT recipients versus 1.4%/7.7%/22.2%, respectively, among ABOc LDKT recipients (weighted hazard ratio [wHR], 0.811.041.33; P = 0.8). However, A2i recipients faced higher risk of death-censored graft failure; weighted 1-/5-/10-y graft failure was 5.7%/11.6%/22.4% for A2i versus 1.7%/7.5%/17.2% for ABOc recipients (wHR in year 1 = 2.243.565.66; through year 5 = 1.251.782.53; through year 10 = 1.151.552.07). By comparison, 1-/5-/10-y wHRs for A1-incompatible recipients were 0.631.966.08/0.390.942.27/0.390.831.74. Conclusions: A2i LDKT is generally safe, but A2i donor/recipient pairs should be counseled about the increased risk of graft failure and be monitored as closely as their A1-incompatible counterparts posttransplant.

One-Year Outcomes of the Multi-Center StudY to Transplant Hepatitis C-InfeCted kidneys (MYTHIC) Trial.

INTRODUCTION: Transplanting kidneys from hepatitis C virus (HCV) viremic donors into HCV-negative patients (HCV D-RNA-positive/R-negative) has evolved from experimental to "standard-of-care" at many centers. Nevertheless, most data derive from single centers and provide only short-term follow-up. METHODS: The Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC) study was a multicenter (7 sites) trial of HCV D-RNA-positive/R-negative kidney transplantation (KT) followed by 8 weeks of glecaprevir/pibrentasvir (G/P) initiated 2 to 5 days post-KT. Prespecified outcomes included probability of KT (vs. matched waitlist comparators) and 1-year safety outcomes, allograft function, and survival. RESULTS: Among 63 enrolled patients, 1-year cumulative incidence of KT was approximately 3.5-fold greater for the MYTHIC cohort versus 2055 matched United Network for Organ Sharing (UNOS) comparators who did not opt-in to receive a kidney from an HCV-viremic donor (68% vs. 19%, P < 0.0001). Of 30 HCV D-RNA-positive/R-negative KT recipients, all achieved HCV cure. None developed clinically significant liver disease or HCV-related kidney injury. Furthermore, 1-year survival was 93% and 1-year graft function was excellent (median creatinine 1.17; interquartile range [IQR]: 1.02-1.38 mg/dl). There were 4 cases of cytomegalovirus (CMV) disease among 10 CMV-negative patients transplanted with a kidney from an HCV-viremic/CMV-positive donor. CONCLUSION: The 1-year findings from this multicenter trial suggest that opting-in for HCV-viremic KT offers can increase probability of KT with excellent 1-year outcomes. Trial Registration: NCT03781726.

National Landscape of Human Immunodeficiency Virus-Positive Deceased Organ Donors in the United States.

BACKGROUND: Organ transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV (HIV D+/R+) presents risks of donor-derived infections. Understanding clinical, immunologic, and virologic characteristics of HIV-positive donors is critical for safety. METHODS: We performed a prospective study of donors with HIV-positive and HIV false-positive (FP) test results within the HIV Organ Policy Equity (HOPE) Act in Action studies of HIV D+/R+ transplantation (ClinicalTrials.gov NCT02602262, NCT03500315, and NCT03734393). We compared clinical characteristics in HIV-positive versus FP donors. We measured CD4 T cells, HIV viral load (VL), drug resistance mutations (DRMs), coreceptor tropism, and serum antiretroviral therapy (ART) detection, using mass spectrometry in HIV-positive donors. RESULTS: Between March 2016 and March 2020, 92 donors (58 HIV positive, 34 FP), representing 98.9% of all US HOPE donors during this period, donated 177 organs (131 kidneys and 46 livers). Each year the number of donors increased. The prevalence of hepatitis B (16% vs 0%), syphilis (16% vs 0%), and cytomegalovirus (CMV; 91% vs 58%) was higher in HIV-positive versus FP donors; the prevalences of hepatitis C viremia were similar (2% vs 6%). Most HIV-positive donors (71%) had a known HIV diagnosis, of whom 90% were prescribed ART and 68% had a VL <400 copies/mL. The median CD4 T-cell count (interquartile range) was 194/µL (77-331/µL), and the median CD4 T-cell percentage was 27.0% (16.8%-36.1%). Major HIV DRMs were detected in 42%, including nonnucleoside reverse-transcriptase inhibitors (33%), integrase strand transfer inhibitors (4%), and multiclass (13%). Serum ART was detected in 46% and matched ART by history. CONCLUSION: The use of HIV-positive donor organs is increasing. HIV DRMs are common, yet resistance that would compromise integrase strand transfer inhibitor-based regimens is rare, which is reassuring regarding safety.

Outcomes of SOT Recipients With COVID-19 in Different Eras of COVID-19 Therapeutics.

BACKGROUND: Few reports have focused on newer coronavirus disease 2019 (COVID-19) therapies (remdesivir, dexamethasone, and convalescent plasma) in solid organ transplant recipients; concerns had been raised regarding possible adverse impact on allograft function or secondary infections. METHODS: We studied 77 solid organ transplant inpatients with COVID-19 during 2 therapeutic eras (Era 1: March-May 2020, 21 patients; and Era 2: June-November 2020, 56 patients) and 52 solid organ transplant outpatients. RESULTS: In Era 1, no patients received remdesivir or dexamethasone, and 4 of 21 (19.4%) received convalescent plasma, whereas in Era 2, remdesivir (24/56, 42.9%), dexamethasone (24/56, 42.9%), and convalescent plasma (40/56, 71.4%) were commonly used. Mortality was low across both eras, 4 of 77 (5.6%), and rejection occurred in only 2 of 77 (2.8%) inpatients; infections were similar in hypoxemic patients with or without dexamethasone. Preexisting graft dysfunction was associated with greater need for hospitalization, higher severity score, and lower survival. Acute kidney injury was present in 37.3% of inpatients; renal function improved more rapidly in patients who received remdesivir and convalescent plasma. Post-COVID-19 renal and liver function were comparable between eras, out to 90 d. CONCLUSIONS: Newer COVID-19 therapies did not appear to have a deleterious effect on allograft function, and infectious complications were comparable.

Discontinuation of Proton Pump Inhibitors in Patients With Chronic Kidney Disease.

Purpose: Proton pump inhibitors (PPIs) are commonly used medications and are historically well tolerated. Recent studies have linked PPI use to the development of chronic kidney disease (CKD) and end-stage renal disease. This study investigated the impact of discontinuing PPIs on renal function in patients with CKD. Methods: We conducted a retrospective chart review of patients with established CKD, defined as 2 eGFR (estimated glomerular filtration rate) measurements of less than 60 mL/min/1.73 m2 at least 90 days apart, who were on a PPI from January 1, 2014 to December 31, 2014, with a medication possession ratio greater than or equal to 70%. We compared baseline eGFR to a final eGFR after at least 6 months of discontinuation or continuation of a PPI. After power analysis, we targeted an enrollment of 200 patients (100 in each group) to achieve a power of 0.80 and an alpha of 0.05. Summary: A total of 97 patients in the PPI discontinuation group and 100 patients in the PPI continuation group met the study inclusion criteria. Baseline eGFR in the PPI continuation group was 47.9 mL/min/1.73 m2 and 50.7 mL/min/1.73 m2 in the discontinuation group. Final eGFR in the PPI continuation group was significantly higher than baseline at 51.1 mL/min/1.73 m2 (+3.25 ± 12.8, P = .01). Final eGFR in the PPI discontinuation group was 51.8 mL/min/1.73 m2 (+1.09 ± 12.8, P = .3). The average time between baseline and final eGFRs was 270 days in the PPI continuation group and 301 days in the discontinuation group. There was no statistically significant difference in the change in eGFRs between groups (95% confidence interval [CI] = -5.48-2.03, P = .37). Conclusions: Proton pump inhibitor discontinuation after prolonged continuous use in patients with CKD was not associated with a significant change in renal function after 1 year.

Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients.

Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m2 vs 61 ml/min/1.73 m2 , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation. Clinical Trial: ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.

Optimal Early Diagnosis and Monitoring of Diabetic Kidney Disease in Type 2 Diabetes Mellitus: Addressing the Barriers to Albuminuria Testing.

Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is associated with increased risk of end-stage renal disease (ESRD) and cardiovascular disease (CVD). Urine albumin-to-creatinine ratio (UACR) is a sensitive and early indicator of kidney damage, which should be used routinely to accurately assess CKD stage and monitor kidney health. However, this test currently is performed in only a minority of patients with T2D. Here, we review the importance of albuminuria testing and current barriers that hinder patient access to UACR testing and describe solutions to such testing in a community clinical setting.