Performance of Panel-Estimated GFR Among Hospitalized Older Adults.

RATIONALE & OBJECTIVE: Older adults represent nearly half of all hospitalized patients and are vulnerable to inappropriate dosing of medications eliminated through the kidneys. However, few studies in this population have evaluated the performance of equations for estimating the glomerular filtration rate (GFR)-particularly those that incorporate multiple filtration markers. STUDY DESIGN: Cross-sectional diagnostic test substudy of a randomized clinical trial. SETTING & PARTICIPANTS: Adults≥65 years of age presenting to the emergency department of Copenhagen University Hospital Amager and Hvidovre in Hvidovre, Denmark, between October 2018 and April 2021. TESTS COMPARED: Measured GFR (mGFR) determined using 99mTc-DTPA plasma clearance compared with estimated GFR (eGFR) calculated using 6 different equations based on creatinine; 3 based on creatinine and cystatin C combined; and 2 based on panels of markers including creatinine, cystatin C, ß-trace protein (BTP) and/or ß2-microglobulin (B2M). OUTCOME: The performance of each eGFR equation compared with mGFR with respect to bias, relative bias, inaccuracy (1-P30), and root mean squared error (RMSE). RESULTS: We assessed eGFR performance for 106 patients (58% female, median age 78.3 years, median mGFR 62.9mL/min/1.73m2). Among the creatinine-based equations, the 2009 CKD-EPIcr equation yielded the smallest relative bias (+4.2%). Among the creatinine-cystatin C combination equations, the 2021 CKD-EPIcomb equation yielded the smallest relative bias (-3.4%), inaccuracy (3.8%), and RMSE (0.139). Compared with the 2021 CKD-EPIcomb, the CKD-EPIpanel equation yielded a smaller RMSE (0.136) but larger relative bias (-4.0%) and inaccuracy (5.7%). LIMITATIONS: Only White patients were included; only a subset of patients from the original clinical trial underwent GFR measurement; and filtration marker concentration can be affected by subclinical changes in volume status. CONCLUSIONS: The 2009 CKD-EPIcr, 2021 CKD-EPIcomb, and CKD-EPIpanel equations performed best and notably outperformed their respective full-age spectrum equations. The addition of cystatin C to creatinine-based equations improved performance, while the addition of BTP and/or B2M yielded minimal improvement. FUNDING: Grants from public sector industry (Amgros I/S) and government (Capital Region of Denmark). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with registration number NCT03741283. PLAIN-LANGUAGE SUMMARY: Inaccurate kidney function assessment can lead to medication errors, a common cause of hospitalization and early readmission among older adults. Several novel methods have been developed to estimate kidney function based on a panel of kidney function markers that can be measured from a single blood sample. We evaluated the accuracy of these new methods (relative to a gold standard method) among 106 hospitalized older adults. We found that kidney function estimates combining 2 markers (creatinine and cystatin C) were highly accurate and noticeably more accurate than estimates based on creatinine alone. Estimates incorporating additional markers such as ß-trace protein and ß2-microglobulin did not further improve accuracy.

Overall and inter-individual effect of four different drug classes on soluble urokinase plasminogen activator receptor in type 1 and type 2 diabetes.

AIM: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. METHODS: We conducted post hoc analyses of a randomized, open-label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin-creatinine ratio ≥30 and ≤500 mg/g assigned to 4-week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4-week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR-reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated-measures linear mixed-effects models were employed. RESULTS: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best-performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best-performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best-performing drug and the other three was -19.7% (95% CI -23.1, -16.3; P < 0.001). CONCLUSIONS: We demonstrated no overall effect of 4-week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels.

Estimated glomerular filtration rate based on creatinine, cystatin C, ß-trace protein and ß2 microglobulin in patients undergoing nontraumatic lower extremity amputation.

AIMS: The study's aim is to compare current and new equations for estimating glomerular filtration rate (GFR) based on creatinine, cystatin C, ß-trace protein (BTP) and ß2 microglobulin (B2M) among patients undergoing major amputation. METHODS: This is a secondary analysis of data from a prospective cohort study investigating patients undergoing nontraumatic lower extremity amputation. Estimated GFR (eGFR) was calculated using equations based on creatinine (eGFRcre[2009] and eGFRcre[2021]), cystatin C (eGFRcys), the combination of creatinine and cystatin C (eGFRcomb[2012] and eGFRcomb[2021]) or a panel of all 4 filtration markers (eGFRpanel). Primary outcome was changed in eGFR across amputation according to each equation. Two case studies of prior amputation with GFR measured by 99mTc-DTPA clearance are described to illustrate the relative accuracies of each eGFR equation. RESULTS: Analysis of the primary outcome included 29 patients (median age 75 years, 31% female). Amputation was associated with a significant decrease in creatinine concentration (-0.09 mg/dL, P = 0.004), corresponding to a significant increase in eGFRcre[2009] (+6.1 mL/min, P = 0.006) and eGFRcre[2021] (+6.3 mL/min, P = 0.006). Change across amputation was not significant for cystatin C, BTP, B2M or equations incorporating these markers (all P > 0.05). In both case studies, eGFRcre[2021] yielded the largest positive bias, eGFRcys yielded the largest negative bias and eGFRcomb[2012] and eGFRcomb[2021] yielded the smallest absolute bias. CONCLUSION: Creatinine-based estimates were substantially higher than cystatin C-based estimates before amputation and significantly increased across amputation. Estimates combining creatinine and cystatin were stable across amputation, while the addition of BTP and B2M is unlikely to be clinically relevant.

Interseason waning of vaccine-induced hemagglutination inhibition antibody titers and contributing factors to pre-existing humoral immunity against influenza in community-dwelling older adults 75 years and older.

BACKGROUND: Seasonal influenza causes significant morbidity and mortality with a disproportionately high disease burden in older adults. Strain-specific hemagglutination-inhibition (HAI) antibody titer is a well-established measure of humoral immunity against influenza and pre-vaccination HAI titer is a valuable indicator of pre-existing humoral immunity at the beginning of each influenza season in highly vaccinated older adults. While vaccine-induced HAI antibody titers are known to wane over time, accurate assessment of their interseason waning has been challenging. This is because pre-vaccination HAI titers are routinely measured using current season vaccine strain antigens instead of the prior season vaccines with which individuals were immunized; as such, they do not accurately represent residual antibody titers from prior season vaccination. This study took advantage of available pre-vaccination HAI titers measured using both current and prior season vaccine strain antigens in a longitudinal influenza immunization study with participants enrolled for multiple consecutive influenza seasons from 2014 through 2017. Influenza A virus (IAV) H3N2 and influenza B virus (IBV) strains in the vaccine formula changed in 2015 and again in 2016 season. IAV H1N1 vaccine strain remained the same from 2014 through 2016 seasons, but changed in 2017. We also investigated factors contributing to pre-existing humoral immunity. RESULTS: Interseason waning of HAI titers was evident, but rates of waning varied among vaccine strains and study seasons, from 18% (p = .43) to 61% (p < .01). Rates of waning were noticeably greater when pre-vaccination HAI titers were measured by the routine approach, i.e., using current season vaccine strain antigens, from 33% (p = .12) to 83% (p < .01), adjusting for age at prior study season, sex, race, and education. This was largely because the routinely measured pre-vaccination HAI titers underrepresented residual HAI titers from prior season vaccinations. Moreover, interseason antibody waning and prior season post-vaccination HAI titers had significant and independent associations with pre-vaccination HAI titers. CONCLUSIONS: The routinely measured pre-vaccination HAI titer overestimates interseason HAI antibody waning as it underestimates residual antibody titers from prior season vaccination when virus strains in the vaccine formula change. Moreover, interseason antibody waning and prior season post-vaccination HAI titers independently contribute to pre-existing humoral immunity in this highly vaccinated, community-dwelling older adult population.

Alterations of monocyte NF-κB p65/RelA signaling in a cohort of older medical patients, age-matched controls, and healthy young adults.

BACKGROUND: Altered monocyte NF-κB signaling is a possible cause of inflammaging and driver of aging, however, evidence from human aging studies is sparse. We assessed monocyte NF-κB signaling across different aging trajectories by comparing healthy older adults to older adults with a recent emergency department (ED) admission and to young adults. METHODS: We used data from: 52 older (≥65 years) Patients collected upon ED admission and at follow-up 30-days after discharge; 52 age- and sex-matched Older Controls without recent hospitalization; and 60 healthy Young Controls (20-35 years). Using flow cytometry, we assessed basal NF-κB phosphorylation (pNF-κB p65/RelA; Ser529) and induction of pNF-κB following stimulation with LPS or TNF-α in monocytes. We assessed frailty (FI-OutRef), physical and cognitive function, and plasma levels of IL-6, IL-18, TNF-α, and soluble urokinase plasminogen activator receptor. RESULTS: Patients at follow-up were frailer, had higher levels of inflammatory markers and decreased physical and cognitive function than Older Controls. Patients at follow-up had higher basal pNF-κB levels than Older Controls (median fluorescence intensity (MFI): 125, IQR: 105-153 vs. MFI: 80, IQR: 71-90, p < 0.0001), and reduced pNF-κB induction in response to LPS (mean pNF-κB MFI fold change calculated as the log10 ratio of LPS-stimulation to the PBS-control: 0.10, 95% CI: 0.08 to 0.12 vs. 0.13, 95% CI: 0.10 to 0.15, p = 0.05) and TNF-α stimulation (0.02, 95% CI: - 0.00 to 0.05 vs. 0.10, 95% CI: 0.08 to 0.12, p < 0.0001). Older Controls had higher levels of inflammatory markers than Young Controls, but basal pNF-κB MFI did not differ between Older and Young Controls (MFI: 81, IQR: 70-86; p = 0.72). Older Controls had reduced pNF-κB induction in response to LPS and TNF-α compared to Young Controls (LPS: 0.40, 95% CI: 0.35 to 0.44, p < 0.0001; and TNF-α: 0.33, 95% CI: 0.27 to 0.40, p < 0.0001). In Older Controls, basal pNF-κB MFI was associated with FI-OutRef (p = 0.02). CONCLUSIONS: Increased basal pNF-κB activity in monocytes could be involved in the processes of frailty and accelerated aging. Furthermore, we show that monocyte NF-κB activation upon stimulation was impaired in frail older adults, which could result in reduced immune responses and vaccine effectiveness.

T-cell immunity against cytomegalovirus in HIV infection and aging: relationships with inflammation, immune activation, and frailty.

Both aging and treated human immunodeficiency virus (HIV) infection are characterized by low-level chronic inflammation and immune activation which contribute to the development of age-related diseases, frailty, and early mortality. Chronic cytomegalovirus (CMV) infection is highly prevalent in older adults and HIV-infected populations. A number of studies have shown that CMV induces broad and strong T-cell responses in CMV-seropositive older adults and HIV-infected individuals. CMV infection rarely develops into clinical disease in immunocompetent individuals. However, a large body of literature has shown adverse effects of chronic CMV infection on the health and longevity of these populations. It has been hypothesized that chronic CMV infection may be a driver of chronic inflammation and immune activation, and may further contribute to the development of frailty. Thus, there is a need to better understand the extent of the impact of chronic CMV infection on T-cell immunity and health in aging and HIV infection. In this review, we will address important considerations and challenges in the assessment of chronic CMV infection and CMV-specific T-cell responses. We will then review recent data on relationships between T-cell responses to CMV and levels of inflammatory markers and immune activation, as well as the onset of frailty.

Histological and Molecular Adipose Tissue Changes Are Related to Metabolic Syndrome Rather Than Lipodystrophy in Human Immunodeficiency Virus-Infected Patients: A Cross-Sectional Study.

Background: In human immunodeficiency virus (HIV)-infected patients on combination antiretroviral therapy (cART), lipodystrophy shares many similarities with metabolic syndrome, but only metabolic syndrome has objective classification criteria. We examined adipose tissue changes related to lipodystrophy and metabolic syndrome to clarify whether it may be acceptable to focus diagnosis on metabolic syndrome rather than lipodystrophy. Methods: This is a cross-sectional study of 60 HIV-infected men on cART and 15 healthy men. We evaluated lipodystrophy (clinical assessment) and metabolic syndrome (JIS-2009). We compared adipocyte size, leukocyte infiltration, and gene expression in abdominal subcutaneous adipose tissue biopsies of patients with and without lipodystrophy and with and without metabolic syndrome. Results: Lipodystrophy was only associated with increased macrophage infiltration (P = .04) and adiponectin messenger ribonucleic acid ([mRNA] P = .008), whereas metabolic syndrome was associated with larger adipocytes (P < .0001), decreased expression of genes related to adipogenesis and adipocyte function (P values between <.0001 and .08), increased leptin mRNA (P = .04), and a trend towards increased expression of inflammatory genes (P values between .08 and .6). Conclusions: Metabolic syndrome rather than lipodystrophy was associated with major unfavorable abdominal subcutaneous adipose tissue changes. In a clinical setting, it may be more relevant to focus on metabolic syndrome diagnosis in HIV-infected patients on cART with regards to adipose tissue dysfunction and risk of cardiometabolic complications.

Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial.

BACKGROUND AND AIM: Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. METHODS: Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end-stage liver disease score 12 (± 3.9). Patients received rifaximin 550-mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing. RESULTS: Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-α, transforming growth factor ß-1, and high sensitivity C-reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin. CONCLUSION: Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).

Association between routine laboratory tests and long-term mortality among acutely admitted older medical patients: a cohort study.

BACKGROUND: Older people have the highest incidence of acute medical admissions. Old age and acute hospital admissions are associated with a high risk of adverse health outcomes after discharge, such as reduced physical performance, readmissions and mortality. Hospitalisations in this population are often by acute admission and through the emergency department. This, along with the rapidly increasing proportion of older people, warrants the need for clinically feasible tools that can systematically assess vulnerability in older medical patients upon acute hospital admission. These are essential for prioritising treatment during hospitalisation and after discharge. Here we explore whether an abbreviated form of the FI-Lab frailty index, calculated as the number of admission laboratory test results outside of the reference interval (FI-OutRef) was associated with long term mortality among acutely admitted older medical patients. Secondly, we investigate other markers of aging (age, total number of chronic diagnoses, new chronic diagnoses, and new acute admissions) and their associations with long-term mortality. METHODS: A cohort study of acutely admitted medical patients aged 65 or older. Survival time within a 3 years post-discharge follow up period was used as the outcome. The associations between the markers and survival time were investigated by Cox regression analyses. For analyses, all markers were grouped by quartiles. RESULTS: A total of 4,005 patients were included. Among the 3,172 patients without a cancer diagnosis, mortality within 3 years was 39.9%. Univariate and multiple regression analyses for each marker showed that all were significantly associated with post-discharge survival. The changes between the estimates for the FI-OutRef quartiles in the univariate- and the multiple analyses were negligible. Among all the markers investigated, FI-OutRef had the highest hazard ratio of the fourth quartile versus the first quartile: 3.45 (95% CI: 2.83-s4.22, P < 0.001). CONCLUSION: Among acutely admitted older medical patients, FI-OutRef was strongly associated with long-term mortality. This association was independent of age, sex, and number of chronic diagnoses, new chronic diagnoses, and new acute admissions. Hence FI-OutRef could be a biomarker of advancement of aging within the acute care setting.

Immunosenescence of the CD8(+) T cell compartment is associated with HIV-infection, but only weakly reflects age-related processes of adipose tissue, metabolism, and muscle in antiretroviral therapy-treated HIV-infected patients and controls.

BACKGROUND: Despite effective antiretroviral therapy (ART), HIV-infected patients exhibit systemic inflammation, early onset of age-related diseases, and features of immunosenescence. The role of inflammation in the development of age-related diseases is widely recognized. However, the role of immunosenescence is not well established. Studying immunosenescence in HIV-infection could give insight into its role in ageing processes. In this cross-sectional study, we aimed to investigate whether ART-treated HIV-infected patients exhibit immunosenescence; and whether immunosenescence is associated with age-related processes of inflammation, metabolism, adipose tissue, and muscle. T cell immunosenescence and exhaustion were assessed by flow cytometry analysis of CD8 (+) cells from 43 ART-treated HIV-infected patients (HIV(+)) and ten Controls using markers of differentiation: CD27/CD28; maturation: CD27/CD45RA; senescence: killer cell lectin-like receptor G1 (KLRG1); and exhaustion: programmed death-1 (PD-1). Relationships between CD8 (+) T cell immunosenescence, exhaustion, and age-related processes were assessed using linear regressions. RESULTS: HIV-infection was strongly associated with more highly differentiated and mature CD8 (+) T cell phenotypes. PD-1 and KLRG1 expression did not differ between HIV(+) and Controls, but depended on differentiation and maturation stages of the cells. CD8 (+) T cell maturation was associated with age. KLRG1 expression was associated with age, metabolic syndrome, visceral adipose tissue, and high muscle mass. PD-1 expression was not associated with age-related parameters. CONCLUSIONS: HIV-infection strongly affected CD8 (+) T cell differentiation and maturation, whereas age-related processes were only weakly associated with immune parameters. Our findings suggest that, in contrast to inflammation, immunosenescence appears to be highly dependent on HIV-infection and is only to a small extent associated with age-related parameters in well-treated HIV-infection.

Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases.

Fisetin, a flavonoid naturally occurring in plants, fruits, and vegetables, has recently gained attention for its potential role as a senotherapeutic agent for the treatment of age-related chronic diseases. Senotherapeutics target senescent cells, which accumulate with age and disease, in both circulating immune cell populations and solid organs and tissues. Senescent cells contribute to development of many chronic diseases, primarily by eliciting systemic chronic inflammation through their senescence-associated secretory phenotype. Here, we explore whether fisetin as a senotherapeutic can eliminate senescent cells, and thereby alleviate chronic diseases, by examining current evidence from in vitro studies and animal models that investigate fisetin's impact on age-related diseases, as well as from phase I/II trials in various patient populations. We discuss the application of fisetin in humans, including challenges and future directions. Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases, potentially transforming future healthcare for older and multimorbid patients. However, further studies are needed to establish the safety, pharmacokinetics, and efficacy of fisetin as a senotherapeutic, identify relevant and reliable outcome measures in human trials, optimize dosing, and better understand the possible limitations of fisetin as a senotherapeutic agent.

Growth differentiation factor 15 (GDF15) levels are associated with malnutrition in acutely admitted older adults.

BACKGROUND AND AIMS: The aging process is often accompanied by high risk of malnutrition and elevated levels of growth differentiation factor 15 (GDF15). GDF15 is an increasingly recognized biomarker for regulation of metabolism, but few studies have investigated the connection between GDF15 and malnutrition in older age and how it relates to other features of aging such as decreased appetite and physical function. Therefore, we investigated the associations between GDF15 levels and nutritional status, appetite, and physical function in acutely admitted older adults. METHODS: Plasma GDF15 levels were measured using immunoassays in 302 older adults (≥65 years) admitted to the emergency department (ED). Nutritional status was evaluated with the Mini Nutritional Assessment Short-Form (MNA®-SF), appetite was evaluated with the Simplified Nutritional Appetite Questionnaire (SNAQ), and physical function was evaluated with handgrip strength (HGS), 30-s chair stand test (30s-RSS), and gait speed (GS). Associations between GDF15 and each outcome was determined by logistic regression adjusted for age, sex, and C-reactive protein (CRP). RESULTS: Each doubling in plasma GDF15 level was associated with an adjusted odds ratio (OR) (95% confidence interval) of 1.59 (1.10-2.29, P = 0.01) for risk of malnutrition compared to normal nutrition and 1.19 (0.85-1.69, P = 0.3)) for malnutrition compared to risk of malnutrition. Each doubling in GDF15 was associated with an adjusted OR of 1.63 (1.21-2.23)) for having poor appetite, 1.46 (1.07-1.99) for having low HGS, 1.74 (1.23-2.51) for having low 30s-RSS, and 1.99 (1.39-2.94) for having low GS. CONCLUSION: Among older adults admitted to the ED, higher GDF15 levels were significantly associated with malnutrition, poor appetite, and low physical function independent of age, sex, and CRP.

Self-rated health and chronic inflammation are related and independently associated with hospitalization and long-term mortality in the general population.

The subjective indicator of health self-rated health (SRH) and the chronic inflammation biomarker soluble urokinase plasminogen activator receptor (suPAR) are both robust predictors of healthcare use and mortality. However, the possible relationship between SRH and suPAR in the assessment of hospitalization and mortality risk is unknown. We used data from the Danish population-based Inter99 cohort to examine the association between SRH and suPAR and test their individual and combined associations with 2-year risk of acute hospitalization and 5- and 15-year mortality. SRH and serum suPAR levels were measured in 5490 participants (median age 45.1 years, 48.7% men). Poorer SRH was associated with elevated suPAR. In unadjusted analyses, SRH and suPAR were individually associated with higher risks of acute hospitalization and mortality, and both measures remained independently associated with higher risks of hospitalization and 15-year mortality after mutual adjustments. The association of suPAR with mortality was stronger in poorer SRH categories, and when combined, SRH and suPAR could identify different groups of individuals with increased risk of acute hospitalization and mortality. Both SRH and suPAR were independently associated with risk of acute hospitalization and mortality, and different combinations of the two measures could identify different groups of individuals at increased risk.

Mild Cognitive Impairment Is Associated with Poorer Nutritional Status on Hospital Admission and after Discharge in Acutely Hospitalized Older Patients.

In acutely hospitalized older patients (≥65 years), the association between mild cognitive impairment (MCI) and malnutrition is poorly described. We hypothesized that (1) MCI is associated with nutritional status on admission and after discharge; (2) MCI is associated with a change in nutritional status; and (3) a potential association is partly explained by frailty, comorbidity, medication use, and age. We combined data from a randomized controlled trial (control group data) and a prospective cohort study (ClinicalTrials.gov: NCT01964482 and NCT03052192). Nutritional status was assessed on admission and follow-up using the Mini Nutritional Assessment-Short Form. MCI or intact cognition (noMCI) was classified by three cognitive performance tests at follow-up. Data on frailty, comorbidity, medication use, and age were drawn from patient journals. MCI (n = 42) compared to noMCI (n = 47) was associated with poorer nutritional status with an average difference of -1.29 points (CI: -2.30; -0.28) on admission and -1.64 points (CI: -2.57; -0.70) at 4-week follow-up. Only age influenced the estimates of -0.85 (CI: -1.86; 0.17) and -1.29 (CI: -2.25; -0.34), respectively. In acutely hospitalized older patients, there is an association between MCI and poorer nutritional status upon admission and four weeks after discharge. The association is partly explained by higher age.

Soluble urokinase plasminogen activator receptor and decline in kidney function among patients without kidney disease.

Background: Hospitalized patients are at an increased risk of developing kidney disease after discharge, often despite the absence of any clinical indicators during hospitalization. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of systemic chronic inflammation that can be measured from routine blood samples. We determined whether elevated suPAR during hospitalization is associated with a decline in estimated glomerular filtration rate (eGFR) after discharge. Methods: This was a retrospective longitudinal cohort study of patients without detectable kidney disease presenting to the emergency department on two separate occasions during a 3-year period. The association between suPAR and a decline in eGFR was assessed by linear mixed models for repeated measures adjusting for age, sex, C-reactive protein, sodium, diabetes, hypertension and cardiovascular disease. Results: In total, 5124 patients (median age 65.9 years, 51.0% female) were included. The median suPAR was 2.9 ng/mL, the median time to readmission was 144 days and the expected rate of eGFR decline over this period was 5.1 mL/min/1.73 m2/year. Adjusting for other risk factors, patients with suPAR <3, 3-6 or ≥6 ng/mL had an expected eGFR decline of 4.3, 5.2 or 9.0 mL/min/1.73 m2/year, respectively. Similarly, patients with suPAR in the lowest (<2.4 ng/mL), middle (2.4-3.6 ng/mL) or highest (≥3.6 ng/mL) tertile had an expected eGFR decline of 4.2, 4.6 or 6.5 mL/min/1.73 m2/year, respectively. In both cases, a higher suPAR level was significantly and independently associated with a higher rate of eGFR decline (P < .001). Conclusions: A higher suPAR level was associated with accelerated eGFR decline among patients presenting to the emergency department, suggesting that routine suPAR measurements may have utility for the early detection of kidney disease.

Longitudinal course of GDF15 levels before acute hospitalization and death in the general population.

Growth differentiation 15 (GDF15) is a potential novel biomarker of biological aging. To separate the effects of chronological age and birth cohort from biological age, longitudinal studies investigating the associations of GDF15 levels with adverse health outcomes are needed. We investigated changes in GDF15 levels over 10 years in an age-stratified sample of the general population and their relation to the risk of acute hospitalization and death. Serum levels of GDF15 were measured three times in 5-year intervals in 2176 participants aged 30, 40, 50, or 60 years from the Danish population-based DAN-MONICA cohort. We assessed the association of single and repeated GDF15 measurements with the risk of non-traumatic acute hospitalizations. We tested whether changes in GDF15 levels over 10 years differed according to the frequency of hospitalizations within 2 years or survival within 20 years, after the last GDF15 measurement. The change in GDF15 levels over time was dependent on age and sex. Higher GDF15 levels and a greater increase in GDF15 levels were associated with an increased risk of acute hospitalization in adjusted Cox regression analyses. Participants with more frequent admissions within 2 years, and those who died within 20 years, after the last GDF15 measurement already had elevated GDF15 levels at baseline and experienced greater increases in GDF15 levels during the study. The change in GDF15 levels was associated with changes in C-reactive protein and biomarkers of kidney, liver, and cardiac function. Monitoring of GDF15 starting in middle-aged could be valuable for the prediction of adverse health outcomes.

The Psychometric Hepatic Encephalopathy Syndrome score does not correlate with blood ammonia, endotoxins or markers of inflammation in patients with cirrhosis.

BACKGROUND: The pathogenesis of hepatic encephalopathy (HE) remains unclear but impaired clearance of gut-derived neurotoxins and increased systemic inflammation are thought to play key roles. The diagnosis is based on detection of neurophysiological and neuropsychometric abnormalities. The Psychometric Hepatic Encephalopathy Score (PHES) have been found to correlate with markers of systematic inflammation including interleukin 6, C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α). This study explores the associations between the PHES score and systemic inflammation, endotoxins and disease severity using baseline data from a trial involving patients with cirrhosis and minimal or no HE (NCT01769040). METHODS: Arterial blood was obtained during hepatic vein catheterization, from 54 patients [median age 55 (range, 33-70) years; 83% men] with decompensated but stable cirrhosis. None had clinical evidence of HE but 34 (55.6%) had an abnormal PHES score indicating the presence of minimal HE. Relationships were sought between the PHES score and markers of systemic inflammation, high sensitivity-CRP, cytokines (SDF-1α, TGF-b1, IP-10, IL-6, 10 and 18, and TNF-α; lipopolysaccharide (LPS), the lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14); and the blood ammonia. RESULTS: No significant relationships were found between the PHES score and any of the variables tested with the single exception of the correlation with serum IL-6 (r=-0.29, 95% confidence interval, -0.53 to -0.02, P=0.031). No independent predictors of the PHES score were identified in regression analyses. CONCLUSIONS: No predictive associations were identified between the PHES scores and circulating blood ammonia, endotoxins, or markers of systemic inflammation in this patient population.

Association of GDF15 With Inflammation and Physical Function During Aging and Recovery After Acute Hospitalization: A Longitudinal Study of Older Patients and Age-Matched Controls.

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine. Its plasma levels increase during aging and acute illness. In older Patients and age-matched Controls, we evaluated whether GDF15 levels (i) were associated with recovery after acute illness, and (ii) reflected different trajectories of aging and longitudinal changes in health measures. Fifty-two older Patients (≥65 years) were included upon admission to the emergency department (ED). At 30 days after discharge (time of matching), Patients were matched 1:1 on age and sex with Controls who had not been hospitalized within 2 years of inclusion. Both groups were followed up after 1 year. We assessed plasma levels of GDF15 and inflammatory biomarkers, frailty, nutritional status (mini nutritional assessment short-form), physical and cognitive function, and metabolic biomarkers. In Patients, elevated GDF15 levels at ED admission were associated with poorer resolution of inflammation (soluble urokinase plasminogen activator receptor [suPAR]), slowing of gait speed, and declining nutritional status between admission and 30-day follow-up. At time of matching, Patients were frailer and overall less healthy than age-matched Controls. GDF15 levels were significantly associated with participant group, on average Patients had almost 60% higher GDF15 than age-matched Controls, and this difference was partly mediated by reduced physical function. Increases in GDF15 levels between time of matching and 1-year follow-up were associated with increases in levels of interleukin-6 in Patients, and tumor necrosis factor-α and suPAR in age-matched Controls. In older adults, elevated GDF15 levels were associated with signs of accelerated aging and with poorer recovery after acute illness.

Dysphagia Prevalence, Time Course, and Association with Probable Sarcopenia, Inactivity, Malnutrition, and Disease Status in Older Patients Admitted to an Emergency Department: A Secondary Analysis of Cohort Study Data.

There is evolving evidence for an association between dysphagia and sarcopenia in older adults. For optimizing the acute health care initiative across health care settings, this study investigated prevalence and time-course of dysphagia in older patients admitted to an emergency department (ED) as well as its association with parameters for probable sarcopenia, inactivity, malnutrition, disease status, and systemic inflammation. A secondary analysis of data from the FAM-CPH cohort study on acutely admitted older medical patients (n = 125). Data were collected upon ED admission as well as four and 56 weeks after discharge. Using the Eating Assessment Tool cut-off score ≥ 2, signs of dysphagia were present in 34% of the patients at ED admission and persisted in 25% of the patients 56 weeks after discharge. Signs of dysphagia at 56-week follow-up were significantly (p < 0.05) associated with probable sarcopenia (low handgrip strength (OR = 3.79), low leg muscle strength (OR = 8.14), and low physical performance (OR = 5.68)) and with baseline swallowing inactivity (OR = 5.61), malnutrition (OR = 4.35), and systemic inflammation (OR = 1.33). Signs of dysphagia in older patients admitted to an ED was prevalent, persisted 56 weeks after discharge, and was associated with probable sarcopenia and related conditions; all modifiable targets for management of dysphagia in older patients.