Racial and Neighborhood-Level Disparities in COVID-19 Incidence among Patients on Hemodialysis in New York City.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected socially disadvantaged populations. Whether disparities in COVID-19 incidence related to race/ethnicity and socioeconomic factors exist in the hemodialysis population is unknown. METHODS: Our study involved patients receiving in-center hemodialysis in New York City. We used a validated index of neighborhood social vulnerability, the Social Vulnerability Index (SVI), which comprises 15 census tract-level indicators organized into four themes: socioeconomic status, household composition and disability, minority status and language, and housing type and transportation. We examined the association of race/ethnicity and the SVI with symptomatic COVID-19 between March 1, 2020 and August 3, 2020. COVID-19 cases were ascertained using PCR testing. We performed multivariable logistic regression to adjust for demographics, individual-level social factors, dialysis-related medical history, and dialysis facility factors. RESULTS: Of the 1378 patients on hemodialysis in the study, 247 (17.9%) developed symptomatic COVID-19. In adjusted analyses, non-Hispanic Black and Hispanic patients had significantly increased odds of COVID-19 compared with non-Hispanic White patients. Census tract-level overall SVI, modeled continuously or in quintiles, was not associated with COVID-19 in unadjusted or adjusted analyses. Among non-Hispanic White patients, the socioeconomic status SVI theme, the minority status and language SVI theme, and housing crowding were significantly associated with COVID-19 in unadjusted analyses. CONCLUSIONS: Among patients on hemodialysis in New York City, there were substantial racial/ethnic disparities in COVID-19 incidence not explained by neighborhood-level social vulnerability. Neighborhood-level socioeconomic status, minority status and language, and housing crowding were positively associated with acquiring COVID-19 among non-Hispanic Whites. Our findings suggest that socially vulnerable patients on dialysis face disparate COVID-19-related exposures, requiring targeted risk-mitigation strategies.

Young, healthy South Asians have enhanced lipogenic sensitivity to dietary sugar.

OBJECTIVE: South Asians have higher rates of type 2 diabetes and cardiovascular disease compared to most other racial/ethnic groups. Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar may accelerate the development of these chronic diseases in this population. STUDY DESIGN: Hepatic DNL in response to a calorically sweetened beverage was measured in an outpatient setting in 15 South Asians and 15 Caucasians with similar and normal body mass indexes, waist circumferences, glucose tolerance and lipid profiles. Blood was sampled before and hourly for 4 h after the ingestion of a single beverage made with glucose (1·5 g/kg) and fructose (1·5 g/kg). The main outcome, DNL, was measured as the increase in %palmitate (16:0) in very low-density lipoprotein (VLDL) triglyceride (TG) over 4 h. RESULTS: After the sugar dose, the increase in %16:0 in VLDL TG was significantly greater in South Asians vs Caucasians (P = 0·01). VLDL and total TG also increased to a significantly greater extent in South Asians (P = 0·04 and <0·001, respectively). Although the fasting and postsugar levels of insulin and glucose did not differ between groups, the DNL response significantly correlated with the insulin response to sugar in South Asians (r = 0·56, P = 0·03). CONCLUSIONS: Hepatic DNL in response to a sugar challenge was greater in healthy, young South Asians compared to Caucasians despite normal indices of insulin sensitivity, and it correlated with the insulin response. These findings suggest an early, insulin-related, gene-nutrient interaction contributing to the high prevalence of diabetes and coronary disease in this population.

Retention of gene expression in porcine islets after agarose encapsulation and long-term culture.

Agarose encapsulation of porcine islets allows extended in vitro culture, providing ample time to determine the functional capacity of the islets and conduct comprehensive microbiological safety testing prior to implantation as a treatment for type 1 diabetes mellitus. However, the effect that agarose encapsulation and long-term culture may have on porcine islet gene expression is unknown. The aim of the present study was to compare the transcriptome of encapsulated porcine islets following long-term in vitro culture against free islets cultured overnight. Global gene expression analysis revealed no significant change in the expression of 98.47% of genes. This indicates that the gene expression profile of free islets is highly conserved following encapsulation and long-term culture. Importantly, the expression levels of genes that code for critical hormones secreted by islets (insulin, glucagon, and somatostatin) as well as transcripts encoding proteins involved in their packaging and secretion are unchanged. While a small number of genes known to play roles in the insulin secretion and insulin signaling pathways are differentially expressed, our results show that overall gene expression is retained following islet isolation, agarose encapsulation, and long-term culture.

Transplant patient classification and tacrolimus assays: more evidence of the need for assay standardization.

BACKGROUND: A global tacrolimus proficiency study recently showed clinically significant variability between laboratories, the inability of a common calibrator to harmonize methods, and differences in patient classification depending on the test method. The authors evaluated (1) the effect of a change in methodology on patient classification based on tacrolimus blood concentration and (2) the ability of 2 methods to position the concentration in a given specimen within the correct range. METHODS: A total of 839 consecutive samples were analyzed at The Rogosin Institute and New York Presbyterian Hospital for routine tacrolimus monitoring over 30 days. Concordance analysis between the methods was performed covering dosage target ranges of 8-10, 6-8, 4-6 ng/mL currently used at our center. Six Sigma Metrics were applied to statistically evaluate the discordance rate. RESULTS: Deming regression comparing liquid chromatography-tandem mass spectrometry and immunoassay yielded y = 0.927x - 0.24; 95% confidence interval, 0.903-0.951; R = 0.875; n = 839. There were 310 pairs (37%) discordant by 1, 21 (2.5%) discordant by 2, and 4 (0.5%) discordant by 3 therapeutic ranges. Surprisingly, 40% of patient samples were discordant when therapeutic ranges were 2 ng/mL wide. This discordant rate is equivalent to 1.7 Sigma and falls far below the minimum acceptable threshold of 3 Sigma. CONCLUSIONS: Both methods are capable of measuring tacrolimus in the clinically relevant range between 1 and 10 ng/mL, yet 40% of the samples were discordant with an unacceptable Sigma level. Standardization of tacrolimus assays will mitigate this issue.

The need for standardization of tacrolimus assays.

BACKGROUND: Owing to the lack of an internationally recognized tacrolimus reference material and reference method, current LC-MS and immunoassay test methods used to monitor tacrolimus concentrations in whole blood are not standardized. The aim of this study was to assess the need for tacrolimus assay standardization. METHODS: We sent a blinded 40-member whole-blood tacrolimus proficiency panel (0-30 µg/L) to 22 clinical laboratories in 14 countries to be tested by the following assays: Abbott ARCHITECT (n = 17), LC-MS (n = 9), and Siemens Dade Dimension (n = 5). Selected LC-MS laboratories (n = 4) also received a common calibrator set. We compared test results to a validated LC-MS method. Four samples from the proficiency panel were assigned reference values by using exact-matching isotope-dilution mass spectrometr at LGC. RESULTS: The range of CVs observed with the tacrolimus proficiency panel was as follows: LC-MS 11.4%-18.7%, ARCHITECT 3.9%-9.5%, and Siemens Dade 5.0%-48.1%. The range of historical within-site QC CVs obtained with the use of 3 control concentrations were as follows: LC-MS low 3.8%-10.7%, medium 2.0%-9.3%, high 2.3%-9.0%; ARCHITECT low 2.5%-9.5%, medium 2.5%-8.6%, high 2.9%-18.6%; and Siemens/Dade Dimension low 8.7%-23.0%, medium 7.6%-13.2%, high 4.4%-10.4%. Assay bias observed between the 4 LC-MS sites was not corrected by implementation of a common calibrator set. CONCLUSIONS: Tacrolimus assay standardization will be necessary to compare patient results between clinical laboratories. Improved assay accuracy is required to provide optimized drug dosing and consistent care across transplant centers globally.

Report of a pilot, double-blind, placebo-controlled study of megestrol acetate in elderly dialysis patients with cachexia.

OBJECTIVE: We examined the effects of megestrol acetate versus placebo and progressive resistance physical exercise on weight, lean muscle mass, quality of life, ability to exercise, proinflammatory cytokines, and anti-inflammatory cytokines, and their correlations with one another. DESIGN: We organized a prospective 20-week, randomized, double-blind, placebo-controlled pilot trial of hemodialysis patients. SETTING: This study took place at the Outpatient Unit of the Northport Veteran Affairs Medical Center. SUBJECTS: We studied nine male hemodialysis patients who had two or more of the following: albumin level <4.0 g/dL, total cholesterol <150 mg/dL, protein catabolic rate <0.8 g/kg/day, and predialysis serum urea nitrogen <60 mg/dL. Their ages were 50 to 83 years. Two were diabetic, and seven were nondiabetic. INTERVENTIONS: Interventions included megestrol acetate (MA) or placebo 800 mg oral daily for 20 weeks, along with weight resistance physical therapy with weights twice a week before dialysis. Patients were followed prospectively for an additional 4 weeks. MAIN OUTCOME MEASUREMENTS: Weight, body composition, activities of daily living, ability to exercise, and plasma cytokine levels were measured. RESULTS: At 24 weeks, the MA group had a statistically significant weight gain (11.1-pound increase vs. 1.5-pound decrease for the placebo group, P = .018), body fat gain (6.2-pound increase vs. a 0.4-pound decrease for the placebo group, P = .044) and fat-free mass gain (5-pound increase vs. a 1.2-pound decrease in the placebo group). The MA group also had a greater tendency toward increased appetite and sense of well-being. The MA group showed a greater improvement in ability to exercise (mean change in rate of perceived exertion (RPE), 4.7) vs. the placebo group (mean change in RPE vs. 0.5, P = .02). Elevated cytokine levels were evident at baseline in both groups. In all patients, increases in weight, fat-free mass, sense of well-being, appetite, and ability to exercise were negatively correlated with tumor necrosis factor receptor subunit p75 (P < .05). There was a trend toward all of these parameters to be negatively correlated with tumor necrosis factor receptor subunit p55, although only sense of well-being was statistically significant (P < .05). CONCLUSION: In a pilot trial in dialysis patients, MA showed significant benefits in improving weight and ability to exercise. Cytokine changes were correlated with weight gains and increases in fat-free mass.

Atherosclerosis in survivors of Kawasaki disease.

OBJECTIVES: To test the hypothesis that long-term survivors of low-risk Kawasaki disease (KD) have ongoing vascular inflammation and dysfunction and a higher risk of accelerated atherosclerosis than healthy control subjects. STUDY DESIGN: Twenty-eight patients with KD (7-20 years after acute illness) and 27 age-matched healthy control subjects were examined for medical and dietary history, serum markers of atherosclerotic risk and inflammation, carotid intimal-medial thickness (CIMT) with vascular ultrasound scanning and arterial stiffness with applanation tonometry. RESULTS: Patients and control subjects were similar in age, sex, body mass index, waist-to-hip ratio, blood pressure, cigarette smoking, family history, diet, high-density lipoprotein cholesterol level, lipoprotein (a) level, homocysteine level, glucose level, insulin level, CIMT, arterial stiffness, C-reactive protein level, and inflammatory cytokine level. Levels of total cholesterol and apolipoprotein B were significantly higher in patients with KD than in control subjects. CONCLUSIONS: There was no evidence of increased atherosclerosis. Small but significant differences in cholesterol and apolipoprotein B levels could suggest increased future risk for atherosclerosis and warrant further study.

Evaluation of 2 immunoassays for monitoring low blood levels of tacrolimus.

The objective of this study was to evaluate the analytical performance of 2 new tacrolimus immunoassays (Dade Dimension Xpand and Abbott ARCHITECT) for therapeutic drug monitoring as possible replacements for the current method in our laboratory, the Abbott IMx tacrolimus assay. Attending physicians at our institute desire to minimize calcineurin inhibitor therapy in kidney allograft recipients to prolong graft survival and improve the quality of life of their patients. Proposed future target trough levels of tacrolimus in whole blood are in the range of 2-4 ng/mL, which requires an assay with a limit of quantification (LOQ) below this range, ideally around 1 ng/mL (European Consensus Recommendation from the Committee on Tacrolimus Optimization). Method comparison analysis of the Dade and ARCHITECT assays showed good correlation to the IMx assay, with correlation coefficients of 0.94 and 0.96, respectively. Both assays reported tacrolimus concentrations lower on average than IMx as demonstrated by slopes of 0.83 (Dade) and 0.93 (ARCHITECT). LOQ for both Dade instruments tested was >4 ng/mL, whereas the LOQ for the ARCHITECT i2000 and i1000 instruments was 0.8 and 0.5 ng/mL, respectively (upper 95% confidence limit). Values reported from both Dade instruments were observed to shift over time, whereas the values on the IMx and ARCHITECT instruments were stable. The Abbott ARCHITECT Tacrolimus assay is a sensitive and precise assay that meets the new LOQ recommendation, 1 ng/mL, for monitoring tacrolimus in whole blood.

Systemic lupus erythematosus predicts increased left ventricular mass.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with premature atherosclerosis and vascular stiffening. Whether SLE alters left ventricular (LV) structure and function in the absence of valvular and clinical coronary artery disease is unknown. METHODS AND RESULTS: SLE patients without clinical or echocardiographic evidence of valvular or coronary disease were age and gender matched to a reference group (n=173 in both groups). Subjects underwent echocardiography to quantify LV structure and function and carotid ultrasonography to detect atherosclerosis. Disease characteristics and radial applanation tonometry to measure arterial stiffness were evaluated in SLE patients. The 2 groups were similar in subjects' body size, hypertension and diabetes status, smoking status, and cholesterol levels. LV mass (38.3 versus 32.8 g/m(2.7)), ejection fraction (71% versus 67%), and prevalence of LV hypertrophy (17.9% versus 6.4%) were higher in SLE patients than in referent subjects (all P<0.001). The combination of SLE and hypertension further increased LV mass. In multivariable analysis, LV mass was associated with SLE (P<0.001) in addition to body mass index, diabetes mellitus, and hypertension. Among SLE patients, LV mass was associated with arterial stiffness (P<0.001). Carotid atherosclerosis, SLE duration, damage index, serum creatinine, and homocysteine were significantly related to LV mass in univariate but not multivariable analyses. CONCLUSIONS: SLE predicts increased LV mass, possibly because of inflammation-related arterial stiffening. Excess LV hypertrophy may contribute to the increased cardiac morbidity and mortality observed in SLE patients.

The effect of dietary carbohydrate on genes for fatty acid synthase and inflammatory cytokines in adipose tissues from lean and obese subjects.

BACKGROUND: Hepatic de novo lipogenesis (DNL) is markedly stimulated in humans by low-fat diets enriched in simple sugars. However, the dietary responsiveness of the key enzyme controlling DNL in human adipose tissue, fatty acid synthase (FAS), is uncertain. HYPOTHESIS: Adipose tissue mRNA for FAS is increased in lean and obese subjects when hepatic DNL is elevated by a eucaloric, low-fat, high-sugar diet. DESIGN: Twelve lean and seven obese volunteers were given two eucaloric diets (10% vs. 30% fat; 75% vs. 55% carbohydrate; sugar/starch 60/40) each for 2 weeks by a random-order cross-over design. FAS mRNA in abdominal and gluteal adipose tissues was compared to hepatic DNL measured in serum by isotopic and nonisotopic methods. Adipose tissue mRNA for tumor necrosis factor-alpha and IL-6, which are inflammatory cytokines that modulate DNL, was also assayed. RESULTS: The low-fat high-sugar diet induced a 4-fold increase in maximum hepatic DNL (P<.001) but only a 1.3-fold increase in adipose tissue FAS mRNA (P=.029) and no change in cytokine mRNA. There was a borderline significant positive correlation between changes in FAS mRNA and hepatic DNL (P=.039). Compared to lean subjects, obese subjects had lower levels of FAS mRNA and higher levels of cytokine mRNA (P<.001). CONCLUSIONS: The results suggest that key elements of human adipose tissue DNL are less responsive to dietary carbohydrate than is hepatic DNL and may be regulated by diet-independent factors. Irrespective of diet, there is reduced expression of the FAS gene and increased expression of cytokine genes in adipose tissues of obese subjects.

Preclinical carotid atherosclerosis in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis is associated with increased morbidity and mortality because of cardiovascular disease, independent of traditional risk factors. OBJECTIVE: To determine the prevalence of preclinical atherosclerosis in patients with rheumatoid arthritis and to identify clinical and biological markers for atherosclerotic disease in this patient population. DESIGN: Matched, cross-sectional study. SETTING: Hospital for Special Surgery in New York City. PATIENTS: 98 consecutive outpatients with rheumatoid arthritis who were followed by rheumatologists and 98 controls matched on age, sex, and ethnicity. MEASUREMENTS: Cardiovascular risk factor ascertainment and carotid ultrasonography in all participants; disease severity, disease treatment, and inflammatory markers in patients with rheumatoid arthritis. RESULTS: Despite a more favorable risk factor profile, patients with rheumatoid arthritis had a 3-fold increase in carotid atherosclerotic plaque (44% vs. 15%; P < 0.001). The relationship between rheumatoid arthritis and carotid atherosclerotic plaque remained after accounting for age, serum cholesterol levels, smoking history, and hypertensive status; adjusted predicted prevalence was 7.4% (95% CI, 3.4% to 15.2%) for the control group and 38.5% (CI, 25.4% to 53.5%) for patients with rheumatoid arthritis. Age (P < 0.001) and current cigarette use (P < 0.014) were also significantly associated with carotid atherosclerotic plaque. Among patients with rheumatoid arthritis, atherosclerosis was related to age, hypertension status, and use of tumor necrosis factor-alpha inhibitors (a possible marker of disease severity). LIMITATIONS: The study had a cross-sectional design, and inflammatory markers were determined only once. CONCLUSIONS: Patients with rheumatoid arthritis have a high prevalence of preclinical atherosclerosis independent of traditional risk factors, suggesting that chronic inflammation and, possibly, disease severity are atherogenic in this population.

A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism.

OBJECTIVE: Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption. METHODS: We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects. RESULTS: Hepatic expression of ChREBP-ß and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-ß and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls. CONCLUSIONS: In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis.

Decreased neurotrophin TrkB receptor expression reduces lesion size in the apolipoprotein E-null mutant mouse.

BACKGROUND: Accumulation of macrophages and smooth muscle cells in the vascular wall is critical for the development of atherosclerotic lesions. Although much is known about the factors that regulate macrophage recruitment to the vascular wall, the ability of growth factors to regulate smooth muscle cell recruitment in lesion development in vivo is unclear. Our previous studies demonstrated that neurotrophins and their receptors, the Trk receptor tyrosine kinases, are potent chemotactic factors for smooth muscle cells, and the expression of brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, is upregulated in human atherosclerotic lesions. METHODS AND RESULTS: TrkB(+/-) mice on a 129/B6 background were backcrossed to apolipoprotein E (ApoE)-null (ApoE(-/-)) mice on the C57Bl/6 background for 6 to 8 generations. Immunohistochemical analysis demonstrated BDNF immunoreactivity in areas of macrophage and smooth muscle cell infiltration, whereas TrkB immunoreactivity was predominant in areas of neointimal smooth muscle cells. Moreover, haplodeficient expression of TrkB in ApoE(-/-) mice was associated with a 30% to 40% reduction in lesion size compared with ApoE(-/-) mice with normal expression of TrkB and a 45% decrease in smooth muscle cell accumulation in the lesions. Finally, reconstitution with bone marrow from ApoE(-/-) mice with normal TrkB expression did not restore lesion development in TrKB(+/-)/ApoE(-/-) mice. CONCLUSIONS: These results suggest that TrkB expression on smooth muscle cells contributes to lesion development in the cholesterol-fed ApoE-null mutant mouse. These data demonstrate, for the first time, a role for the neurotrophin TrkB receptor in atherosclerotic lesion development.

First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors.

PURPOSE: Agarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective. METHODS: Thirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant. RESULTS: RMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs. CONCLUSION: The data support the safety of RMB therapy in advanced-malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing.

Evaluation of the eZono 4000 with eZGuide for ultrasound-guided procedures.

Ultrasound-guided procedures are increasingly common in a variety of acute care settings, such as the operating room, critical care unit and emergency room. However, accurate judgment of needle tip position using traditional ultrasound technology is frequently difficult, and serious injury can result from inadvertently advancing beyond or through the target. Needle navigation is a recent innovation that allows the clinician to visualize the needle position and trajectory in real time as it approaches the target. A novel ultrasound machine has recently been introduced that is portable and designed for procedural guidance. The eZono 4000™ features an innovative needle navigation technology that is simple to use and permits the use of a wide range of commercially available needles, avoiding the inconvenience and cost of proprietary equipment. This article discusses this new ultrasound machine in the context of other currently available ultrasound machines featuring needle navigation.

Serum Inflammatory and Immune Mediators Are Elevated in Early Stage Diabetic Nephropathy.

BACKGROUND: Diabetes is the leading cause of end stage renal disease (ESRD) in the United States, representing 44% of incident cases [1]. In this study, serum and peripheral blood collected from diabetic patients in five stages of chronic kidney disease (CKD), as defined by glomerular filtration rate (GFR), were compared to healthy (non-CKD) subjects. METHODS: Serum samples were analyzed for 39 inflammatory or immune mediator protein levels and peripheral blood samples were analyzed for expression of 35 gene transcripts. RESULTS: In serum, MCP-1, FGF-2, VEGF, and EGF levels were elevated above controls at all stages of DN. Five mediator levels, GM-CSF, IL-1α, IL-1RA, IL-6, and MIP1ß increased with disease progression until stage 4-5, at which point a decrease was observed paralleling a loss of functional renal mass that occurs in late stage CKD. Five mediator levels: GRO, IFNγ, MDC, Eotaxin, and G-CSF significantly differed from controls at one or more stages without apparent correlation with disease stage. Only a single mediator, sIL2RA, exhibited a linear increase with disease severity consistent with declining GFR. In peripheral blood, the transcript level of seven mediators, ICAM1, TNF-α, TGF-ß, IL-8, IL17RA, IFNγ, and MYD88 were significantly elevated at all disease stages as compared to control. CONCLUSION: Statistically significant differences in protein and transcripts levels between diseased and control can be detected in serum and peripheral blood utilizing high content profiling. These changes occur as early as stage 1-2 before a significant decline in renal function.

Elevated soluble tumor necrosis factor receptor levels in non-obese adults with the atherogenic dyslipoproteinemia.

Adipose tissue expression of tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of obesity-linked insulin resistance and the dyslipoproteinemia of insulin resistance. This study has two aims: (1) to compare select inflammatory mediators in non-smoking, normoglycemic male subjects with and without the atherogenic dyslipoproteinemia (ADL), and (2) to determine the effects of statin therapy on select inflammatory mediators. ADL subjects had higher levels of insulin (16.7 +/- 7.5 versus 11.6 +/- 5.9 microIU/mL, P=0.008), soluble TNF receptor superfamily 1B (sTNFRSF1B) (3.3 +/- 0.7 versus 2.7 +/- 0.5 ng/mL, P=0.005), and interleukin-6 (IL-6) (2.6 +/- 2.2 versus 1.3 +/- 1.8 pg/mL, P=0.006) as compared to those of the non-ADL subjects. After adjustment for age, sTNFRSF1B (P=0.003) was more predictive of ADL than high-sensitivity C-reactive protein (hs-CRP) (P=0.047). Statin therapy did not change sTNFRSF1B, TNF-alpha, IL-6, hs-CRP, whereas soluble TNF receptor superfamily 1A (sTNFRSF1A) increased slightly (P=0.048). A high level of sTNFRSF1B is a strong marker of the pro-inflammatory state in this sample of male ADL subjects.

Risk factors relating blood markers of inflammation and nutritional status to survival in cachectic geriatric patients in a randomized clinical trial.

OBJECTIVES: To evaluate the effect of proinflammatory cytokines, their receptors, and nutritional indicators (at baseline and after 12 weeks of megestrol acetate (MA) treatment) upon long-term survival in geriatric cachectic patients without active acute infections, inflammation, or cancer. DESIGN: Randomized clinical trial with placebo or MA treatment for 12 weeks and then follow-up for more than 4 years. SETTING: Veterans Affairs nursing home in Northport, New York. PARTICIPANTS: Nursing home patients with weight loss of 5% of usual body weight over the previous 3 months or body weight 20% below ideal body weight. INTERVENTION: Random assignment of placebo or MA oral suspension 800 mg/d to the eligible patients for 12 weeks. MEASUREMENTS: White blood cell counts, prealbumin, plasma cytokine levels (or their receptors), including tumor necrosis factor receptor (TNFR), soluble subunits (TNFR-p55 and TNFR-p75), interleukin (IL)-6, soluble IL-2 receptor, and C-reactive protein at baseline and 12 weeks after treatment. RESULTS: There was no difference in survival between the MA and placebo groups. Considering possible confounders, initial IL-6, initial TNFR-p75 levels, and final neutrophil percentage were associated with elevated mortality, whereas higher initial prealbumin, initial albumin, final prealbumin, final albumin, and final weight gain were associated with decreased death. CONCLUSION: In geriatric weight-loss patients with cachexia, certain cytokines and nutritional indicators were effective in predicting long-term mortality, regardless of treatment with MA. Interventions to modify levels of these cytokines or their receptors and improvement in nutritional status by weight gain might be helpful in ameliorating undetected chronic inflammation and thus might prolong the survival of these nursing home residents.