Intrinsic capacity and frailty in older adults with end-stage kidney disease undergoing pre-kidney transplant comprehensive geriatric assessment.

OBJECTIVE: Frailty has been extensively studied in end-stage kidney disease (ESKD) and kidney transplant (KT) patients. The identification of frailty is useful to predict adverse outcomes among ESKD and KT patients. The recent concept of intrinsic capacity (IC) appears as a good and easy-to-understand tool to screen for and monitor frailty in older adults with ESKD. This study aims to assess the relationships between frailty and IC in older adults with ESKD awaiting KT. DESIGN: Cross-sectional study SETTING AND PARTICIPANTS: 236 patients from a day-care geriatric unit undergoing pre-KT geriatric assessment between 2017 and 2022 were included in the main sample, and 151 patients in an independent multicentric replication sample. MEASUREMENTS: Frailty was evaluated using the physical frailty phenotype (PFP) and IC measures using the World Health Organization's screening (step 1) and diagnostic (step 2) tools for five IC domains (vitality, locomotion, audition, cognition, psychology). Multivariate regressions were run to assess relationships between PFP and IC domains, adjusted for age, sex, and comorbidities. Analyses were replicated using another independent multicenter cohort including 151 patients with ESKD to confirm the results. RESULTS: Impairments in the locomotion, psychology, and vitality IC domains according to WHO screening tools were associated with frailty (odds ratio 9.62 [95% CI 4.09-24.99], 3.19 [95% CI 1.11-8.88], and 3.11 [95% CI 1.32-7.29], respectively). When IC were measured linearly with z-scores, all IC domains except hearing were inversely associated with frailty. In the replication cohort, results were overall similar, with a greater association between psychology domain and frailty. CONCLUSION: This study highlights the relationship between frailty and IC in ESKD patients. We assume that IC may be assessed and monitored in ESKD patients, to predict and prevent future frailty, and post-KT adverse outcomes.

Mechanisms of systemic low-grade inflammation in HIV patients on long-term suppressive antiretroviral therapy: the inflammasome hypothesis.

OBJECTIVE: We aimed to determine the contribution of inflammasome activation in chronic low-grade systemic inflammation observed in patients with HIV (PWH) on long-term suppressive antiretroviral therapy (ART) and to explore mechanisms of such activation. DESIGN: Forty-two PWH on long-term suppressive ART (HIV-RNA < 40 copies/ml) were compared with 10 HIV-negative healthy controls (HC). METHODS: Inflammasome activation was measured by dosing mature interleukin (IL)-1ß and IL-18 cytokines in patient serum. We explored inflammasome pathways through ex vivo stimulation of PWH primary monocytes with inflammasome activators; expression of inflammasome components by transcriptomic analysis; and metabolomics analysis of patient sera. RESULTS: Median (Q1; Q3) age, ART and viral suppression duration in PWH were 54 (48; 60), 15 (9; 20) and 7.5 (5; 12) years, respectively. Higher serum IL-18 was measured in PWH than in HC (61 (42; 77) vs. 36 (27-48 pg/ml), P = 0.009); IL-1ß was detected in 10/42 PWH (0.5 (0.34; 0.80) pg/ml) but not in HC. Monocytes from PWH did not produce more inflammatory cytokines in vitro , but secretion of IL-1ß in response to NOD like receptor family, pyrin domain containing 3 (NLRP3) inflammasome stimulation was higher than in HC. This was not explained at the transcriptional level. We found an oxidative stress molecular profile in PWH sera. CONCLUSION: HIV infection with long-term effective ART is associated with a serum inflammatory signature, including markers of inflammasome activation, and an increased activation of monocytes upon inflammasome stimulation. Other cells should be investigated as sources of inflammatory cytokines in PWH. Oxidative stress might contribute to this chronic low-grade inflammation.

Does Inflammation Contribute to Cancer Incidence and Mortality during Aging? A Conceptual Review.

Aging is associated with chronic low-grade inflammation, cancer incidence and mortality. As inflammation contributes to cancer initiation and progression, one could hypothesize that age-associated chronic low-grade inflammation contributes to the increase in cancer incidence and/or mortality observed during aging. Here, we review the evidence supporting this hypothesis: (1) epidemiological associations between biomarkers of systemic inflammation and cancer incidence and mortality in older people, (2) therapeutic clues suggesting that targeting inflammation could reduce cancer incidence and mortality and (3) experimental evidence from animal models highlighting inflammation as a link between various mechanisms of aging and cancer initiation and progression. Despite a large body of literature linking aging, inflammation and cancer, convincing evidence for the clear implication of specific inflammatory pathways explaining cancer incidence or mortality during aging is still lacking. Further dedicated research is needed to fill these gaps in evidence and pave the way for the development of applications in clinical care.

Kidney Function and Cognitive Decline in Older Adults: Examining the Role of Neurodegeneration.

BACKGROUND/OBJECTIVES: Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function and cognitive decline in older adults and to assess the involvement of cortical beta-amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association. DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT). SETTINGS: Thirteen memory centers (France and Monaco, 2008-2016). PARTICIPANTS: A total of 1,334 community-dwellers >70 years old without dementia at baseline. MEASUREMENTS: We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD-Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z-score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z-score using mixed-effect models and (2) progression on CDR using Cox models and mixed-effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta-amyloid (measured with positron emission tomography). RESULTS: Median (IQR) eGFR was 73(60-84) mL/min/1.73 m2 . Two hundred sixty-nine participants experienced progression on CDR score during follow-up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01-1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z-score (adjusted ß-coefficient -0.004, 95% CI -0.014; 0.006). Associations were not modified after further adjustment for beta-amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270). CONCLUSIONS: We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.

New insights on IgA vasculitis with underlying solid tumor: a nationwide French study of 30 patients.

OBJECTIVE: IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the baseline characteristics and/or outcome of vasculitis. We aimed to describe the presentation of IgAV in patients with cancer (IgAV ca+) compared to patients without cancer. METHODS: We conducted a nationwide retrospective study of adult patients in France who presented with both IgAV and cancer. Baseline characteristics were described and compared with those of the 260 patients included in a nationwide French IgAV study. RESULTS: Thirty patients were included. The mean age was 69 ± 12 years; 80% were men. Compared to patients without underlying cancer, IgAV ca+ patients were older (69 ± 12 vs. 50 ± 18 years; p < 0.0001) and they presented more frequently with necrotic purpura (53 vs. 26%; p < 0.002) and intra-alveolar hemorrhage (10 vs. 0.5%; p < 0.0001). IgAV ca+ patients frequently had elevated serum IgA levels (79 vs. 53%; p < 0.034); most (n = 22, 73%) had adenocarcinoma or urothelial carcinoma involving the large intestines (n = 6), bladder (n = 5), and lung (n = 5). Most IgAV ca+ patients had progressive cancer (n = 21); a minority had metastatic disease (n = 2) at IgAV diagnosis. After a median follow-up of 3 months, 8 deaths were observed but none was related to IgAV. CONCLUSION: Compared to their noncancer counterpart, patients with IgAV related to cancer were older and more frequently presented with necrotizing purpura, intra-alveolar hemorrhage, and elevated serum IgA levels. Adult patients with IgAV and these latter characteristics should be carefully screened for cancer. Key Points • Clinical and biological characteristics of patients presenting with IgAV are distinct depending on the underlying cause of vasculitis related to cancer. • Patients with IgAV related to cancer are older, and compared to their counterparts without IgAV, they present more frequently with necrotic purpura, alveolar hemorrhage, and elevated serum IgA levels. • All adult patients with IgAV should be screened for cancer, and there should be a focus on elderly male patients presenting with necrotic purpura and/or alveolar hemorrhage.

[Contributions of a geriatric outpatient consultation in a dialysis facility]. / Apports d'une consultation gériatrique dans une association d'antennes d'auto-dialyse.

CONTEXT: The role of comprehensive geriatric assessment for older patients with advanced chronic kidney disease still needs to be defined. In this population, data is lacking on the care proposals made by geriatricians during comprehensive geriatric assessment and on the follow-up of these proposals. OBJECTIVES: To describe a population of older outpatients with advanced renal disease seen at a geriatric consultation, and geriatric syndromes identified. To study care suggestions made by the geriatrician, and the follow-up of these suggestions. METHODS: Retrospective monocentric study, including all outpatients treated with hemodialysis and seen at the geriatric consultation implemented in a dialysis facilities network in Aquitaine region, France, from 2014 to 2017. Six domains were analysed: functional independence, cognition, gait/balance, mood, nutrition and drug prescription. RESULTS: Among 49 patients, mean age 79 years, 50% had a loss of independence, 32% cognitive impairment, 24% mood disturbance, 55% gait or balance disturbance, and 65% potentially inappropriate medications. The most frequent care suggestions of the geriatrician were drugs optimisation, intervention of a psychologist, a dietetician or a speech and language therapist, home support service implementation, and the exploration of cognitive impairment. Suggestions of intervention of other healthcare professionals, drug optimisation and biological/imaging tests were followed in respectively 46, 33 and 18% of cases. CONCLUSION: A geriatric outpatient consultation in a nephrology facility allows identification of frequent and multiples geriatric syndromes, requiring coordinated interventions. Collaboration between healthcare professionals, including a geriatrician, should be reinforced to improve design and follow-up of the individualised care plan for older patients with advanced chronic kidney disease.

Understanding human γδ T cell biology toward a better management of cytomegalovirus infection.

Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti-CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV-specific response are αß and non-Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV-induced non-Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non-Vγ9Vδ2 T cells can be activated either by stress-induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co-stimulatory signals such as the ICAM-1-LFA-1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at-risk patients. In particular, non-Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non-Vγ9Vδ2 T cell therapy in immunocompromised patients.

Quality of Life: Psychological Symptoms-Effects of a 2-Month Healthy Diet and Nutraceutical Intervention; A Randomized, Open-Label Intervention Trial (RISTOMED).

Depression symptoms and lower health-related quality of life (HRQoL) are associated with inflammation. This multicenter dietary intervention was shown to reduce inflammation in older people. This was the main outcome. Here, we describe the effects on HRQoL, anxiety, and depressive symptoms according to inflammation status. Overall, 125 healthy older subjects (65-80 year) were recruited (Italy, France, and Germany) and randomized into four arms (A, Healthy diet (HD); B, HD plus De Simone Formulation probiotic blend; C, HD plus AISA d-Limonene; D, HD plus Argan oil). The HD was weight maintaining, rich in antioxidant vitamins, polyphenols, polyunsaturated fatty acids (n6: n3 ratio = 3:1), and fiber. Data on inflammatory parameters, mental (MCS) and physical (PCS) component summaries of HRQoL (SF-36), anxiety symptoms (STAI state), and depressive symptoms (CES-D) were collected before and after 56 days of intervention. Body fat mass proportion (BFM) was considered a co-variable. A decrease of CES-D score was seen in the four arms (A: -40.0%, p = 0.001; B: -32.5%, p = 0.023; C: -42.8%, p = 0.004; and D: -33.3%, p = 0.21). Within the subgroups of subjects with medium/high inflammation a similar decrease in CES-D score occurred in all groups (A: -44.8%, p = 0.021; B, -46.7%, p = 0.024; C, -52.2%, p = 0.039; D, -43.8%, p = 0.037). The effect of interventions on CES-D was not related to baseline inflammation. MCS-HRQoL improved in A and C. There was no change in anxiety or PCS-HRQoL. In this trial with no control group, a decrease in depressive symptoms in healthy older volunteers was observed after a 2-month healthy diet intervention, independently of inflammation but with possible limitations due to participation.

Is the subcutaneous route an alternative for administering ertapenem to older patients? PHACINERTA study.

BACKGROUND: Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria. OBJECTIVES: To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons. METHODS: Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0-24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386. RESULTS: Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted. CONCLUSIONS: SC administration of ertapenem is an alternative to IV administration in older patients.

Estimated Glomerular Filtration Rate Decline and Incident Frailty in Older Adults.

BACKGROUND AND OBJECTIVES: Low eGFR is known to be associated with frailty, but the association between the longitudinal decline of eGFR and incident frailty in older persons remains to be determined. The objective of this study was to investigate whether a fast decline on eGFR would be associated with incident frailty. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Community dwellers, aged ≥70, were included in this secondary analysis of the 5-year Multidomain Alzheimer Preventive Trial (MAPT). eGFR was calculated using CKD-Epidemiology Collaboration equation at baseline and at 6, 12, and 24 months. The lowest quartile of eGFR slope (-4.1 ml/min per 1.73 m2 per yr) defined a fast decline. The frailty phenotype (unintentional weight loss, exhaustion, low physical activity, slow gait, low handgrip strength assessed with a 0-5 score, where higher is worse; a score ≥3 defines frailty) was assessed at baseline, 6, 12, 24, 36, 48, and 60 months. Cox models were used to test the association between fast eGFR decline and incident frailty. RESULTS: A total of 833 participants were frail neither at baseline nor at 2 years and had appropriate follow-up data. Median (IQR) baseline eGFR was 73 (61-84) ml/min per 1.73 m2. Frailty occurred in 95 (11%) participants between 24 and 60 months. Among them, 31/207 (15%) had fast eGFR decline between baseline and 24 months, and 64/626 (10%) did not. In a Cox model adjusted for demographic variables, cardiovascular comorbidity, C-reactive protein, and baseline eGFR, a fast eGFR decline was associated with incident frailty (HR 1.67, 95% CI 1.03 to 2.71). Sensitivity analyses provided consistent findings. CONCLUSIONS: In community-dwelling older adults with relatively preserved baseline eGFR, a fast eGFR decline is associated with incident frailty.

Associations of C-reactive protein and homocysteine concentrations with the impairment of intrinsic capacity domains over a 5-year follow-up among community-dwelling older adults at risk of cognitive decline (MAPT Study).

BACKGROUND: The World Health Organization (WHO) recently proposed an innovative model of care focusing on functional rather than disease-based perspectives, based on a construct of intrinsic capacity (IC). OBJECTIVE: This study aimed to analyze if low-grade inflammation (LGI) (chronically raised C-reactive protein - CRP) and hyperhomocysteinemia (HHcy) were associated with variation in IC domains (mobility, cognition, psychological and vitality) and in a combined IC Z-score over a 5-year follow-up among non-demented, community-dwelling older adults at risk of cognitive decline. DESIGN: This observational study included 1516 subjects ≥70 years (64.5% female, mean age 75.4 years, SD = 4.5), volunteers from the interventional study Multidomain Alzheimer Preventive Trial (MAPT). Plasma CRP (at baseline, 6 and 12 months) and homocysteine (at baseline) concentrations were measured. LGI was defined as having ≥2 consecutively CRP readings >3 to 10 mg/L between baseline and 12 months, and HHcy was defined as homocysteine >15 µM/L. IC domains were operationalized as follows: Psychological. Depressive symptoms evaluated by the Geriatric Depression Scale (GDS); Mobility. Assessed by the Short Physical Performance Battery (SPPB); Cognitive function. Examined by a Z-score combining four tests; Vitality. Based on hand grip strength. Outcomes were combined into a composite IC Z-score. RESULTS: IC Z-score decreased among groups with no inflammation and LGI after 5 years, but this decrease was more pronounced among the LGI group (unadjusted mean group difference: 0.09, 95%CI: 0.01 to 0.16; p = 0.032). Participants with HHcy also presented IC Z-score decreases over time. Combined conditions provided more pronounced declines, even after adjusting for potential confounders. CONCLUSION: LGI and HHcy were both related with impairment on the combined IC levels among older adults after a 5-year follow-up. Identifying biomarkers that strongly associate with IC may help to settle strategies aiming to prevent the incidence and slow down the evolution of age-related functional decline and care dependency.

Association of 3-Year Multidomain Intervention and Omega-3 Supplementation with Frailty Incidence.

OBJECTIVES: To assess the associations of long-term lifestyle multidomain intervention (MI) and omega-3 supplementation with frailty level evolution and frailty incidence in community-dwelling older persons. DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial. SETTING: Thirteen memory centers in France and Monaco between 2008 and 2011. PARTICIPANTS: A total of 1588 community-dwelling persons aged 70 years or older with memory complaints (without dementia), slow gait speed, or limitation in one instrumental activity of daily living. INTERVENTION: A 3-year MI (43 group sessions including cognitive training, physical activity, and nutrition advice and three preventive consultations) plus daily omega-3 fatty acids, MI plus placebo, omega-3 alone, or placebo alone. MEASUREMENTS: The frailty phenotype (unintentional weight loss, exhaustion, low physical activity, slow gait, low handgrip strength: 0 to 5 score, higher is worse; a score of 3 or higher defines frailty) was assessed at baseline, 6, 12, 24, and 36 months. We used mixed-effect models for frailty level (0-5 score as an ordinal variable) and Cox models for frailty incidence. RESULTS: No differences were found between the intervention groups and placebo on the 3-year evolution of frailty level. Among 1394 non-frail participants at baseline, frailty incidence occurred in 134 (9.6%) persons: 26 (7.6%) in the MI plus omega-3 group, 34 (10%) in the omega-3 alone group, 31 (8.5%) in the MI plus placebo group, and 43 (12.3%) in the placebo-alone group). No differences regarding frailty incidence were found between intervention groups and placebo. After exclusion of 53 participants with incident frailty during the first year of follow-up, MI plus omega-3 was associated with a lower frailty incidence compared with placebo (hazard ratio = .43; 95% confidence interval = .22-.81). CONCLUSION: In community-dwelling older persons, the combination of a long-term lifestyle MI and omega-3 supplementation did not reduce frailty level or incidence. The reduction of frailty incidence associated with the combined intervention in a sensitivity analysis needs to be further confirmed. J Am Geriatr Soc 67:1700-1706, 2019.

Atypical Presentation of Bacteremia in Older Patients Is a Risk Factor for Death.

BACKGROUND: The absence of fever in bacteremia in patients who are older is known to delay diagnosis. Our objective was to determine whether atypical presentation was associated to mortality as a result of bacteremia in this patient cohort as well as possible factors associated with this atypical presentation. METHODS: We conducted an observational prospective study in 2 French university hospitals in 2016-2017 including patients ages ≥75 years with bacteremia. Atypical presentation was defined as the absence of a temperature ≥38.3°C or <36°C, chills, or hypotension. Mortality and dependence for activities of daily living (ADL) were recorded at 1 week (D7) and 3 months (D90). RESULTS: Among the 151 patients (mean age 85.4±5.8 years) enrolled, atypical presentation prevalence was 21.2%. D7 and D90 mortality rates were 7.9% and 40.0%, respectively. Atypical presentation was independently associated with D7 (odds ratio (OR) 4.46, 95% confidence interval (CI) 1.04-19.24) and D90 mortality (OR 3.76, 95% CI 1.30-10.92) after controlling for other prognostic factors. Patients with diabetes and those infected with Staphylococcus aureus were more likely to have atypical signs of infection. ADL score decreased from 3.6±2.0 before bacteremia to 2.8±2.1 at D90 (P <0.001). CONCLUSION: Patients who are older with bacteremia have poor vital and functional prognoses in the short and long terms. The absence of typical signs of infection is associated with mortality. Blood culture should be considered for patients who are older, especially with diabetes with acute unexplained clinical manifestations.

Discrepancy Between Equations Estimating Kidney Function in Geriatric Care: A Study of Implications for Drug Prescription.

BACKGROUND: In older patients, the agreement is low between creatinine clearance estimated with the Cockcroft-Gault equation (eCrCl) and glomerular filtration rate estimated with the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI). The implications of these discrepancies for drug prescription have so far been assessed only for a few selected molecules. OBJECTIVE: The aim of this study was to investigate the proportion of geriatric patients receiving drugs with a different recommended dose or indication (i.e. an adjustment discrepancy) depending on eCrCl versus eGFRCKD-EPI estimates of kidney function. METHODS: Patients admitted to acute geriatric care units in our university hospital were eligible for inclusion. All drug classes were studied. We retrospectively determined recommended prescriptions according to eCrCl and eGFRCKD-EPI. RESULTS: Sixty percent of patients received at least one drug requiring dose adjustment and/or received a drug with a relative contraindication based on their estimated kidney function. Thirty-one percent of patients received at least one drug with an adjustment discrepancy: 20% received at least one drug for which the recommended dose differed depending on eCrCl versus eGFRCKD-EPI estimates of kidney function, 4% received a drug with a relative contraindication according to eCrCl but not eGFRCKD-EPI, and 7% received both. Factors independently associated with an adjustment discrepancy were older age and lower weight. Main drug classes involved were benzodiazepines, anticoagulants, and anti-microbial drugs. CONCLUSION: In acute geriatric care units, recommended drug dose adjustments are frequently discordant according to the equations used to estimate kidney function, notably for benzodiazepines, anticoagulants, and anti-microbial drugs. The consequences for treatment efficacy and safety should be investigated.

Non-Complement-Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival.

C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity >6237 and >10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P<0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.

TCR-dependent sensitization of human γδ T cells to non-myeloid IL-18 in cytomegalovirus and tumor stress surveillance.

Human γδ T cells contribute to tissue homeostasis under normal conditions and participate in lymphoid stress surveillance against infection and tumors. However, the molecular mechanisms underlying the recognition of complex cell stress signatures by γδ T cells are still unclear. Tumor cells and human cytomegalovirus (HCMV)-infected cells are known targets of γδ T cells. We show here that many tumor and CMV-infected cells express caspase-1 inflammasomes and release interleukin (IL)-18. Engagement of the T-cell receptor (TCR) on Vδ2neg γδ T cells controlled the direct innate immune sensing of IL-18 that enhanced cytotoxicity and interferon gamma (IFNγ) production. This TCR-dependent sensitization to IL-18 was mediated by the upregulation of the innate IL-18 receptor ß chain (IL-18Rß) expression. These findings shed light on inflammasomes as a unified stress signal of tumor and infected cells to alert γδ T cells. Moreover, uncovering the TCR-mediated sensitization of γδ T cells to inflammatory mediators establishes a molecular link between the innate and adaptive immune functions of γδ T cells that could fine tune the commitment of antigen-experienced γδ T cells to inflammatory responses.