UNASSIGNED: Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage.
UNASSIGNED: We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia.
UNASSIGNED: At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m2 and 90% of participants had a urinary albumin excretion rate (AER) <30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF: -13.5% (-16.7 to -10.1), EGF-MCP1 ratio: -26.9% (-32.2 to -21.3), and tubular secretion score -0.9% (-1.8 to 0.0), versus -12.0% (CI: -12.9 to -11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14]).
UNASSIGNED: Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally.

The present study aimed to inspect the serum levels of the soluble receptors, sTNFR1 and sTNFR2, in patients with COVID-19. The large production of inflammatory cytokines is an essential process in the pathogenesis of COVID-19. TNF is a multifaceted proinflammatory cytokine which has soluble and membrane receptors. Thus, knowing the role of these receptors will help better understand this disease\'s immunopathogenesis. We included 131 patients confirmed for SARS-CoV-2, separated into three groups: ward patients without O2 support, group A (n = 14); ward patients with O2 support, group B (n = 85), and patients in an intensive care unit (ICU), group C (n = 32), making up the receptors dosed by flow cytometry. The results showed that sTNFR1 and sTNFR2 are associated with disease severity, being higher in group C when compared to group A. As for the levels of receptors and their relationship with the degree of lung involvement, we found higher values of sTNFR1 in patients in group 1 (pulmonary involvement < 25%), suggesting that inflammatory processes related to TNF are not necessarily associated with the primary site of infection. When we analysed the patients who passed away compared to those who recovered, both receptors significantly increased the mortality numbers. These findings suggest a relevant influence of soluble receptors in the inflammatory processes involved in the pathogenesis of COVID-19. Wherefore, we suggest using these receptors as biomarkers of severity and mortality of the disease.

BACKGROUND: Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk.
RESULTS: Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels.
CONCLUSIONS: In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.

OBJECTIVE: In-vivo studies of the bioavailability of major components of the tumor necrosis factor alpha (TNFα) biosystem inside the gestational sac during embryogenesis have not been reported. We sought to determine the concentration of TNFα, soluble (s) TNFα receptors (sTNFR1, sTNFR2), and RANTES in the primate extraembryonic celomic fluid (ECF).
METHODS: A validated timed-pregnant baboon animal model (N: 10) for experimental research in pregnancy was used to collect paired maternal blood and ECF samples in ongoing pregnancies. The concentrations (pg/dL) of TNFα, sTNFR1, sTNFR2, and RANTES were then determined by ELISA immunoassays.
RESULTS: All animals delivered at term healthy newborns. The differential concentration of TNFα, sTNFR1, sTNFR2, and RANTES between the maternal plasma and the ECF could be determined with ratios for TNFα (5.4), sTNFR2 (1.85) and RANTES (3.59) that contrasted with that of sTNFR1 (0.07), which favored the gestational sac compartment. No significant correlations were noted between maternal plasma and ECF TNFR1, sTNFR2 and RANTES. There was a trend for a correlation between TNFα in maternal plasma and ECF (R=0.74; p=0.07).
CONCLUSIONS: We report the physiological concentrations of TNFα, sTNFR1, sTNFR2, and RANTES in extraembryonic celomic fluid during embryogenesis in primates.

Currently there are no biomarkers that are predictive of when patients with type-2 diabetes (T2D) will progress to more serious kidney disease i.e., diabetic nephropathy (DN). Biomarkers that could identify patients at risk of progression would allow earlier, more aggressive treatment intervention and management, reducing patient morbidity and mortality.
Study participants (N=88; control n=26; T2D n=32; DN n=30) were recruited from the renal unit at Antrim Area Hospital, Antrim, UK; Whiteabbey Hospital Diabetic Clinic, Newtownabbey, UK; Ulster University (UU), Belfast, UK; and the University of the Third Age (U3A), Belfast, UK; between 2019 and 2020. Venous blood and urine were collected with a detailed clinical history for each study participant.
In total, 13/25 (52.0%) biomarkers measured in urine and 25/34 (73.5%) biomarkers measured in serum were identified as significantly different between control, T2D and DN participants. DN patients, were older, smoked more, had higher systolic blood pressure and higher serum creatinine levels and lower eGFR function. Serum biomarkers significantly inversely correlated with eGFR.
This pilot-study identified several serum biomarkers that could be used to predict progression of T2D to more serious kidney disease: namely, midkine, sTNFR1 and 2, H-FABP and Cystatin C. Our results warrant confirmation in a longitudinal study using a larger patient cohort.

The immune response is hypothesized as an important factor in the disease outcome of leptospirosis. Exaggerated immune response may promote tissue damage that lead to severe disease outcome. In this study TNF, IL-10, sTNFR1 levels were measured among sixty-two hospitalized leptospirosis confirmed patients in Sri Lanka. Thirty-one serum samples from healthy individuals were obtained as controls. PCR-RFLP method was used to identify TNF gene polymorphisms and to determine their association with TNF expression and disease severity in leptospirosis. TNF (p = 0.0022) and IL-10 (p < 0.0001) were found to be significantly elevated in leptospirosis patients, while sTNFR1 (p < 0.0001) was significantly suppressed. TNF was not significantly elevated in patients with complications while the anti-inflammatory cytokine IL-10 was significantly elevated among patients with complications (p = 0.0011) and with mortality (p = 0.0088). The ratio of IL-10 to TNF was higher among patients with complications (p = 0.0008) and in fatal cases (p = 0.0179). No association between TNF gene polymorphisms and TNF expression was detected due to the low frequency of heterozygous and mutated genes present in this study population. Thus the findings of the study show that elevated levels of IL-10 in the acute phase of disease could lead to severe outcomes and a high IL-10/TNF ratio is observed in patients with complications due to leptospirosis.

Patients treated in intensive care units (ICUs) are at high risk of malnutrition and the resulting homeostasis, metabolic, histological and immunological disorders, especially leading to organ failure and increased susceptibility to infection. In 163 patients with malnutrition [mild in 33 (19.6%), moderate in 69 (42.9%), severe in 61 (37.4%)] treated in the ICU, changes in the concentration of selected proteins [interleukin (IL)-1Ra, tumor necrosis factor α (TNF-α), soluble tumour necrosis factor receptor-1 (sTNFR1), IL-6, IL-10, sTLR4, MyD88, A20, HSP70, HMGB1] were examined. In the whole group of malnourished patients, median values of sTNFR1, TNF-α, IL-6, TLR4, IL-1Ra were significantly increased, while the levels of MyD88 and A20 proteins were significantly reduced (in comparison to the well-nourished healthy group). Only the sTNFR1 protein showed a significant difference between mild, moderate and severe malnutrition, and increased concentrations as the severity of malnutrition increased (the correlation study found that as the degree of malnutrition increased, the sTNFR1 concentrations increased; p = 0.0000, R = 0.5442). It was observed that death was significantly more frequent in the group of patients who on the first day of hospitalization in the ICU scored 5 or more points on the NRS 2002 scale (p = 0.0004). In the patients who died significantly higher concentrations of sTNFR1, IL-6, IL-10, HSP70 were observed in comparison to the patients who survived. The present results are encouraging and indicate the desirability of undertaking multicentre clinical trials including monitoring of sTNFR1 in assessing the severity of malnutrition and immune disorders in the first hours after admission to the ICU, because it can be assumed that without early diagnosis of innate immunity disorders any attempts at their modulation may be ineffective.

BACKGROUND: Chronic inflammation (CI) is a common trait of aging associated with adverse outcomes including mortality. We hypothesized that recombinant human Lactoferrin (rhLf) would reduce chronic inflammation of aging.
METHODS: Thirty-six community dwelling older adults were randomly assigned to rhLf or placebo treatment in 1:1 ratio for 3 months. IL-6, sTNFR1, Comprehensive Metabolic Panel (CMP), and Complete Blood Count (CBC) were measured at baseline, 1 month, 3 months, and 6 months. Physical and cognitive measures were completed at same timepoints, including 4-m walking speed (m/s), grip strength (kg), 6-min walking distance (m), home activity measured by accelerometer, trail making test - Part A (s) and - Part B (s), and Digit symbol substitution test (number correctly coded). Primary outcomes were differences in IL-6 and sTNFR1 concentrations evaluated by generalized linear model with log-link and gamma family distribution, controlling for baseline cytokine concentrations.
RESULTS: rhLF was well-tolerated. There were a significant number of abdominal complaints and increased drop-out rate in placebo group. Participants in rhLf arm had non-significant lower mean percent increase in IL6 at 3 months (rhLf mean IL-6 6% lower than control, P = 0.843), and sTNFaR1 (rhLf mean 2% lower than control, P = 0.36). No significant changes were observed for the cognitive or physical measures.
CONCLUSIONS: Treatment with rhLf did not significantly alter serum IL6 or sTNFR1 concentrations of older adults. This study may have been underpowered to detect difference, but provided evidence that a larger sample-size could more definitively determine the effect of rhLF on age-associated CI.

UNASSIGNED: Substantial causes of high mortality (30-50%) of people with severe infections treated in intensive care units (ICUs) are still inadequately known in terms of mechanisms and insufficient diagnostic tools for immune responses in sepsis.
UNASSIGNED: The aim of this study was to establish a practical value of determining the concentration of chosen proteins (by ELISA) in peripheral blood as potential in early diagnostics of severe infections, paying special attention to their prognostic values.
UNASSIGNED: In 163 patients treated in ICUs, changes were assessed in the concentration of chosen proteins relating to the TLR4 receptor signalling pathway, including its effectors of pro- and anti-inflammatory cytokines (IL-1Ra, TNF-α, sTNFR1, IL-6, IL-10, sTLR4, MyD88, TNFAIP3/A20, HSP70, and HMGB1). In the analysis of changes in the process of immune response in severely ill patients with and without infections, a significantly higher concentration of sTNFR1 was observed in patients with infections than those who deceased. In the ROC curves tests, it was noted that an assessment of the concentration of sTNFR1 proteins (AUC = 0.686 and cut-off point = 24.841 pg/ml) was a particularly efficient tool, with prognostic significance in patients with infections.
UNASSIGNED: In other patients treated in an ICU, the efficiency of determining IL-6 (AUC = 0.736) was confirmed and at the same time, the effectiveness of this cytokine in predicting death in cases with infections was excluded. The results of the present study are encouraging, suggesting the benefits of undertaking multi-center clinical trials, which consider monitoring sTNFR1 in different groups of patients with infections treated in intensive care units.

Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear.
Prospective cohort.
African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement.
Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ).
Incident KFRT, all-cause mortality.
Cox proportional hazards models.
Among 500 participants with available samples, mean glomerular filtration rate was 44.7mL/min/1.73m2, and median urinary protein-creatinine ratio was 0.09g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P>0.05 for interaction).
Limited generalizability to other ethnic groups or causes of CKD.
Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.