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BackgroundCytokines, chemokines, adipocytokines, soluble cell receptors, and immune activation markers play an important role in immune responsiveness and can provide prognostic value since they reflect underlying conditions and disease states. This study was undertaken to investigate the components of biological variation for various laboratory tests of blood immunological biomarkers.ResultsEstimates of intra-individual coefficient of variation (CVI) and inter-individual coefficient of variation (CVG) were examined for blood immunological biomarkers. Biomarkers with CVI  40% were adiponectin, IL-1ra, leptin, MIP-1β, sCD163, and sIL-2Rα.ConclusionThe biological variations of biomarkers have important monitoring value for longitudinal investigation and are essential for quality specification of tests that are performed in the laboratory. The CVI was relatively small while CVG was comparatively large and mean values of each biomarker vary between subjects. The individuality of biomarkers significantly influences reference interval values. A majority of the biomarkers in this study had strong individuality and the result of each biomarker should be cautiously interpreted if using established reference interval values. Comparison of a patient's test result with previous ones may be more useful than the usage of conventional reference values.

Subclinical kidney disease is associated with developing hypertension in the general population, but data are lacking among HIV-infected people. We examined associations of kidney function and injury with incident hypertension in 823 HIV-infected and 267 HIV-uninfected women in the Women's Interagency HIV Study, a multicenter, prospective cohort of HIV-infected and uninfected women in the United States. Baseline kidney biomarkers included estimated glomerular filtration rate using cystatin C, urine albumin-to-creatinine ratio, and 7 urine biomarkers of tubular injury: α-1-microglobulin, interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, N-acetyl-β-d-glucosaminidase, and α1-acid-glycoprotein. We used multivariable Poisson regression to evaluate associations of kidney biomarkers with incident hypertension, defined as 2 consecutive visits of antihypertensive medication use. During a median follow-up of 9.6 years, 288 HIV-infected women (35%) developed hypertension. Among the HIV-infected women, higher urine albumin-to-creatinine ratio was independently associated with incident hypertension (relative risk =1.13 per urine albumin-to-creatinine ratio doubling, 95% confidence interval, 1.07-1.20), as was lower estimated glomerular filtration rate (relative risk =1.10 per 10 mL/min/1.73 m2 lower estimated glomerular filtration rate; 95% confidence interval, 1.04-1.17). No tubular injury and dysfunction biomarkers were independently associated with incident hypertension in HIV-infected women. In contrast, among the HIV-uninfected women, urine albumin-to-creatinine ratio was not associated with incident hypertension, whereas higher urine interleukin-18, α1-acid-glycoprotein, and N-acetyl-β-d-glucosaminidase levels were significantly associated with incident hypertension. These findings suggest that early glomerular injury and kidney dysfunction may be involved in the pathogenesis of hypertension in HIV-infected people. The associations of tubular markers with hypertension in HIV-uninfected women should be validated in other studies.

BackgroundBiomarkers such as cytokines, chemokines, and soluble activation markers can be unstable when processing of blood is delayed. The stability of various biomarkers in serum and plasma was investigated when unprocessed blood samples were stored for up to 24h at room and refrigerator temperature.MethodsBlood was collected from 16 healthy volunteers. Unprocessed serum, EDTA and heparinized blood was stored at room (20-25°C) and refrigerator temperature (4-8°C) for 0.5, 2, 4, 6, 8, and 24h after collection before centrifugation and separation of serum and plasma. Samples were batch tested for various biomarkers using commercially available immunoassays. Statistically significant changes were determined using the generalized estimating equation.ResultsIFN-γ, sIL-2Rα, sTNF-RII and β2-microglobulin were stable in unprocessed serum, EDTA and heparinized blood samples stored at either room or refrigerator temperature for up to 24h. IL-6, TNF-α, MIP-1β and RANTES were unstable in heparinized blood at room temperature; TNF-α, and MIP-1β were unstable in unprocessed serum at room temperature; IL-12 was unstable in unprocessed serum at refrigerator temperature; and neopterin was unstable in unprocessed EDTA blood at room temperature. IL-1ra was stable only in unprocessed serum at room temperature.ConclusionAll the biomarkers studied, with the exception of IL-1ra, were stable in unprocessed EDTA blood stored at refrigerator temperature for 24h. This indicates that blood for these biomarkers should be collected in EDTA and if delays in processing are anticipated the unseparated blood should be stored at refrigerator temperature until processing.

Uncontrolled HIV infection progresses to the depletion of systemic and mucosal CD4 and AIDS. Early HIV infection may be associated with increases in the concentration of MIP-3α in the blood and gut fluids. MIP-3α/CCL20 is the only chemokine known to interact with CCR6 receptors which are expressed on immature dendritic cells and both effector and memory CD8+ and CD4+ T cells. The role and prognostic value of blood levels of MIP-3α in HIV-infected individuals has yet to be described. We determined the serum levels of MIP-3α, and IFN-γ, in 167 HIV-1-infected and 27 HIV-1-uninfected men participating in the Multicenter AIDS Cohort Study (MACS). The blood biomarkers were measured using enzyme-linked immunosorbent assays (ELISA) and the cell phenotypes using flow cytometry. Median serum levels of MIP-3α in HIV-1-infected and uninfected men was significantly different (p

BackgroundSerum albumin concentrations are a strong predictor of mortality and cardiovascular disease in human immunodeficiency virus (HIV)-infected individuals. We studied the longitudinal associations between serum albumin levels and kidney function decline in a population of HIV-infected women.Study designRetrospective cohort analysis.Setting & participantsStudy participants were recruited from the Women's Interagency HIV Study (WIHS), a large observational study designed to understand risk factors for the progression of HIV infection in women living in urban communities. 908 participants had baseline assessment of kidney function and 2 follow-up measurements over an average of 8 years.PredictorThe primary predictor was serum albumin concentration.OutcomesWe examined annual change in kidney function. Secondary outcomes included rapid kidney function decline and incident reduced estimated glomerular filtration rate (eGFR).MeasurementsKidney function decline was determined by cystatin C-based (eGFR(cys)) and creatinine-based eGFR (eGFR(cr)) at baseline and follow-up. Each model was adjusted for kidney disease and HIV-related risk factors using linear and relative risk regression.ResultsAfter multivariate adjustment, each 0.5-g/dL decrement in baseline serum albumin concentration was associated with a 0.56-mL/min faster annual decline in eGFR(cys) (P < 0.001), which was attenuated only slightly to 0.55 mL/min/1.73 m(2) after adjustment for albuminuria. Results were similar whether using eGFR(cys) or eGFR(cr). In adjusted analyses, each 0.5-g/dL lower baseline serum albumin level was associated with a 1.71-fold greater risk of rapid kidney function decline (P < 0.001) and a 1.72-fold greater risk of incident reduced eGFR (P < 0.001).LimitationsThe cohort is composed of only female participants from urban communities within the United States.ConclusionsLower serum albumin levels were associated strongly with kidney function decline and incident reduced eGFRs in HIV-infected women independent of HIV disease status, body mass index, and albuminuria.

ObjectiveTo evaluate the association of bone turnover biomarkers with blood levels of alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BAP), osteocalcin (OC), tartrate-resistant acid phosphatase (TRAP), parathyroid hormone (PTH), and other blood markers in HIV-1 infected men receiving anti-retroviral therapy (ART). Advances in the treatment of HIV-1 infection have extended the life span of HIV-1 infected individuals. However, these advances may come at the price of metabolic side effects and bone disorders, including premature osteopenia, osteoporosis and osteonecrosis.MethodsAnalyses of Ostase BAP, osteocalcin, and TRAP in blood were measured in three groups of MACS participants: 35 HIV-1 infected men on ART (A); 35 HIV-1- infected men not on ART (B); and 34 HIV-1 uninfected men (C).ResultsThe mean and standard deviation results for groups A, B, and C were 19.7 ± 6.56, 17.2 ± 3.96, and 16.9 ± 5.78 for ostase BAP; 7.9 ± 9.53, 8.5 ± 8.30, and 5.5 ± 1.65 for osteocalcin; and 3.9 ± 1.04, 3.1 ± 0.81, and 2.5 ± 0.59 for TRAP, respectively. Simple and multivariate analyses showed significant differences in mean TRAP and BAP concentrations between the three groups. In addition strong correlations between blood levels of Ostase BAP and TRAP (r=0.570, p=0.0004), and between blood levels of Ostase BAP and PTH (r=0.436, P=0.0098) for HIV-1 infected men on ART were observed.ConclusionNew strategies for measurement of blood and urine biochemical markers of bone formation and resorption during bone turnover can be useful for clinical monitoring of treatment of HIV-1 infected patients. Recently developed methods for measuring serum levels of TRAP and Ostase BAP represent superior laboratory tools for assessing the hyperactivity of osteoclasts, osteoblasts and bone loss in HIV-1 infected individuals receiving ART. Measurements of TRAP and BAP as bone turnover biomarkers are economical and are important for monitoring bone metabolism during ART and the need for osteoporosis treatment.

An unusual case of acute primary HIV-1 infection in a man with a high plasma viral load, a 51-fold increase in C-reactive protein, and antibodies against only gp160 is described. Numerous serum cytokine concentrations were elevated during HIV-1 seroconversion.

BackgroundCystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine.DesignRetrospective cohort analysis.MethodsCystatin C and creatinine were measured from specimens taken and stored during the 1999-2000 examination among 908 HIV-infected participants in the Women's Interagency HIV study (WIHS). Mean follow-up was 10.2 years. Predictors of differential glomerular filtration rate (GFR) estimates were evaluated with multivariable linear regression. The associations of baseline categories (90 ml/min per 1.73 m) of creatinine estimated GFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging.ResultsCKD risk factors were associated with lower eGFRcys and eGFRcr-cys values compared with eGFRcr. Relative to eGFR more than 90, the eGFR less than 60 category by eGFRcys (Adjusted hazard ratio: 2.56; 95% confidence interval: 1.63-4.02), eGFRcr-cys (3.11; 1.94-5.00), and eGFRcr (2.34; 1.44-3.79) was associated with increased mortality risk. However, the eGFR 60-90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28-2.53) and eGFRcr-cys (1.91; 1.38-2.66) but not eGFRcr (1.20; 0.85-1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (P

ObjectiveHIV-infected persons have substantially higher risk of kidney failure than persons without HIV, but serum creatinine levels are insensitive for detecting declining kidney function. We hypothesized that urine markers of kidney injury would be associated with declining kidney function among HIV-infected women.MethodsIn the Women's Interagency HIV Study, we measured concentrations of albumin-to-creatinine ratio, interleukin-18 (IL-18), kidney injury marker-1 (KIM-1), and neutrophil gelatinase-associated lipocalin from stored urine among 908 HIV-infected and 289 HIV-uninfected participants. Primary analyses used cystatin C-based estimated glomerular filtration rate (CKD-EPI eGFRcys) as the outcome, measured at baseline and 2 follow-up visits over 8 years; secondary analyses used creatinine (CKD-EPI eGFRcr). Each urine biomarker was categorized into tertiles, and kidney decline was modeled with both continuous and dichotomized outcomes.ResultsCompared with the lowest tertiles, the highest tertiles of albumin-to-creatinine ratio (-0.15 mL/min per 1.73 m, P < 0.0001), IL-18 (-0.09 mL/min per 1.73 m, P < 0.0001) and KIM-1 (-0.06 mL/min per 1.73 m, P < 0.001) were independently associated with faster eGFRcys decline after multivariate adjustment including all 3 biomarkers among HIV-infected women. Among these biomarkers, only IL-18 was associated with each dichotomized eGFRcys outcome: ≥3% (relative risk = 1.40; 95% confidence interval: 1.04 to 1.89); ≥5% (1.88; 1.30 to 2.71); and ≥10% (2.16; 1.20 to 3.88) for the highest versus lowest tertile. In alternative models using eGFRcr, the high tertile of KIM-1 had independent associations with 5% (1.71; 1.25 to 2.33) and 10% (1.78; 1.07 to 2.96) decline, and the high IL-18 tertile with 10% decline (1.97; 1.00 to 3.87).ConclusionsAmong HIV-infected women in the Women's Interagency HIV Study cohort, novel urine markers of kidney injury detect risk for subsequent declines in kidney function.

Pseudohyponatremia is a clinical condition characterized by an increased fraction of protein or lipid in plasma, thereby resulting in an artificially low plasma sodium concentration ([[[Na.sup.+]].sub.p]). Since the automated method of measuring [[[Na.sup.+]].sub.p] in most laboratories involves the use of an indirect ion-selective electrode (I-ISE), this method does not correct for elevated protein or lipid concentrations. In I-ISE, the plasma sample is diluted before the actual measurement is obtained, and the [[[Na.sup.+]].sub.p] is determined based on the assumption that plasma is normally composed of 93% plasma water. Therefore, the [[[Na.sup.+]].sub.p] as determined by I-ISE will be artificially low in clinical conditions when the plasma water content (PWC) is hyponatremia; ion-selective electrode; hyperproteinemia doi: 10.1152/ajprenal.00493.2006.

Context.--Monoclonal proteins can interfere with the conjugated bilirubin assay on the Beckman Coulter AU5400 and AU2700 instruments and produce spurious results. Protein depletion eliminates the interference, suggesting that monoclonal proteins cause the problem. Objectives.--To determine the interference rate with the Beckman Coulter AU5400 and AU2700 conjugated bilirubin assay and to identify the interfering substance. Design.--Beckman Coulter bilirubin results from 33 720 samples analyzed during 6 months were evaluated for interference. On a subset of samples, protein G columns were used to specifically remove immunoglobulin G (IgG) to determine the cause of the interference. Another 117 samples containing a (known) monoclonal protein were selected to determine the interference rate. Results.--From 26 different patients, 103 samples had conjugated bilirubin results greater than the total bilirubin for a false-positive rate of 0.3%. Removal of IgG from a subset of those samples with IgG monoclonal protein and increased polyclonal IgG eliminated the conjugated bilirubin interference. In separate, selected samples containing monoclonal proteins, the false-positive interference rate was 7.7% (9 of 117) and was greatest when the monoclonal protein concentration was greater than 4 g/dL. Another 11 of the 117 samples (9.4%) with monoclonal proteins exhibited assay interference by producing false-negative results. The overall interference rate, therefore, was 17.1%. Conclusion.--The false-positive interference rate for the Beckman Coulter conjugated bilirubin assay was 0.3% for routinely analyzed serum/plasma samples. In addition to monoclonal proteins, we found that polyclonal immunoglobulins can also interfere with the conjugated bilirubin assay. The overall interference rate was 17.1% for samples with a monoclonal protein. (Arch Pathol Lab Med. 2014; 138:950-954; doi: 10.5858/arpa.2013-0042-0A), Serum and plasma samples containing monoclonal proteins (also called paraproteins and monoclonal immunoglobulins) have been shown to interfere with several chemistry assays on a variety of automated chemistry analyzers and [...]

Abstract: Human chorionic gonadotropin (hCG) stimulates testosterone production by the testicles and can normalize suppressed testosterone concentrations in males following prolonged anabolic steroid use. Because of the potential for abuse by males, hCG is on the World Anti‐Doping Agency (WADA) list of prohibited substances. The majority of WADA‐accredited laboratories measure urinary hCG using an automated immunoassay. Only immunoassays that recognize the intact alpha and beta heterodimer of hCG (intact hCG) should be used to measure urinary hCG for doping control purposes since intact hCG is the only biologically active molecule. WADA further requires that confirmation testing is performed using an intact hCG immunoassay that is different from the one used in the initial testing procedure or by liquid chromatography–tandem mass spectrometry (LC–MS/MS). In this study we measured the concentration of intact hCG, free β‐subunit (hCGβ) and β‐subunit core fragment (hCGβcf) in 570, 275, and 256 male urine samples, respectively, by an immunoextraction LC–MS/MS method. Mean concentrations of intact hCG, hCGβ and hCGβcf were 0.04 IU/L, 0.47 pmol/L and 0.16 pmol/L, respectively. The upper reference limits (97.5th percentile) for intact hCG, hCGβ and hCGβcf were 0.21 IU/L, 0.40 pmol/L, and 1.86 pmol/L, respectively. Based on these data, we recommend a threshold of 1.0 IU/L for intact hCG (false positive rate of <1 in 10 000) for detecting male athletes that dope with hCG. [ABSTRACT FROM AUTHOR]

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Endogenous steroid use can increase urinary testosterone/epitestosterone (T/E) values. In addition, ethanol in amounts >0.5 g per kg of body weight (g/kg) can also increase T/E values. However, the effect of smaller doses of ethanol on T/E values is unknown. The influence of 0.2 and 0.4 g/kg of ethanol on baseline T/E values in 20 men and 20 women with low and high baseline T/E values was investigated and correlated with ethyl glucuronide (EtG) and ethyl sulfate (EtS) concentrations. T/E values for 7 of the women were excluded from the study because of undetectable T concentrations or for other reasons. One man and 1 woman with a high T/E baseline value had a significant increase in their T/E value after ingestion of 0.2 g/kg of ethanol. One man and 2 women with a high T/E baseline, and 1 woman with a low T/E baseline had significantly increased T/E values after ingestion of 0.4 g/kg of ethanol. There was wide variability in peak EtG concentrations and a lack of correlation between ethanol dose and EtG concentrations. Interestingly, 1 man and 2 women with increased T/E values following ethanol ingestion had EtG concentrations below the World Anti‐Doping Agency (WADA) cut‐off of 5000 ng/mL. These findings demonstrate that small amounts of ethanol can elevate T/E values, with women being more susceptible. In addition, consideration should be given to the lowering of the WADA EtG cut‐off to detect samples with elevated T/E values from ingestion of low doses of ethanol. [ABSTRACT FROM AUTHOR]