Effect of hemodialysis session on acute changes in inflammatory and cardiovascular risk biomarkers

Background: Inflammation is associated with enhanced cardiovascular risk profile and increased cardiovascular mortality in end-stage kidney disease patients undergoing hemodialysis. Mechanisms of activated acute phase reaction in patients on chronic hemodialysis remain to be identified. As successful treatment of the inflammatory condition in these patients may improve long-term survival, we studied potential changes in different inflammatory biomarkers of cardiovascular risk in end-stage kidney disease patients after a mid-week hemodialysis session. Methods: Inflammatory biomarkers of cardiovascular risk (cystatin-C, homocysteine, C-reactive protein, procalcitonin, pentraxin-3, serum amyloid-A) and atherogenic plasma lipoproteins (Lipoprotein(a), cholesterol low and high density lipoproteins) were studied in 21 end-stage kidney disease patients previously and after a mid-week hemodialysis session. Results: We found a significant reduction in serum levels of low molecular weight molecules: cystatin-C (5.56 to 1.85 mg/L, 66.73%, p < 0.001), homocysteine (22.85 to 13.25 µmol/L, 42.01%, p < 0.001) and procalcitonin (0.788 to 0.457 ng/mL, 42.01%, p < 0.001). Large molecules as C-reactive protein (9.70 to 9.90 mg/L, 2.06%, p = 0.022) and pentraxin-3 (1.67 to 4.28 ng/mL, 156%, p < 0.001) increased, but serum amyloid-A decreased (15.90 to 12.70 mg/L, 20.13%, p < 0.05). There was no change in Lipoprotein (a) levels. Conclusion: Pentraxin-3 was a more specific inflammatory vascular marker than C-reactive protein, and the best inflammatory marker associated with hemodialysis. Homocysteine, procalcitonin and the other small proteins could be released and removed during hemodialysis session. Further studies are needed to understand the behavior and significance of these markers after successive hemodialysis

Modified Serum ALP Values and Timing of Apparition of Knee Epiphyseal Ossification Centers in Preterm Infants with Cholestasis and Risk of Concomitant Metabolic Bone Disease of Prematurity

The usefulness of serum alkaline phosphatase (ALP) and phosphorous in screening and monitoring of metabolic bone disease of prematurity (MBDP) still has some limitations, especially in preterm infants with concomitant conditions such as cholestasis. We aimed to assess a modification of serum ALP (M-ALP) as a biomarker for MBDP in preterm infants, and the use of ultrasound monitoring for the apparition of knee ossification centers as marker of bone mineralization. Biochemical and clinical registers were taken from 94 preterm newborns 1 was demonstrated to be more specific (87.5%) in the diagnosis of MBDP than the cut-off value of serum ALP > 500 IU/L (62.5%). ALP/M-ALP > 1 showed 100% sensitivity and specificity for the diagnosis of MBDP, and a good correlation with specific bone ALP (B-ALP). Patients with the knee nucleus by post-menstrual week 37 had lower B-ALP compared to patients with no nucleus, and no patients with MBDP presented the nucleus by the 40th week. In the absence of reliable specific B-ALP, reinterpreting serum ALP values by M-ALP plus monitoring of knee ossification centers contribute to better management of MBDP in preterm infants with cholestasis

Uncovering genetic causes of hypophosphatemia

Background Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. Methods By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17?55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ?2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). Results We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. Conclusion Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype

New biological-markers and end-stage kidney disease

RESUMEN: Los pacientes con enfermedad renal crónica en fase terminal tienen alto riesgo cardiovascular (RCV). Los factores de RCV clásicos no justifican este exceso de riesgo. Las últimas Guías Europeas (2012) asocian enfermedad renal crónica (ERC) en estadio avanzado con RCV alto o muy alto. Sin embargo, este aumento no lo relacionan con ningún marcador biológico. El objetivo de esta investigación es evaluar el RCV de estos pacientes con los factores de RCV clásicos y emergentes, y definir el estado inflamatorio en la ERC, con diferentes terapias de reemplazo renal (diálisis peritoneal, hemodiálisis), y con trasplante renal. Se estudiaron factores de RCV emergente y nuevos marcadores biológicos relacionados con el sistema inmunológico, como homocisteína, lipoproteína (a), proteína C-reactiva, pentraxina-3, componente sérico amiloide-A, procalcitonina y cistatina-C. Los resultados apoyan la infraestimación del RCV con tablas tradicionales, y aconsejan el análisis de nuevos marcadores en la evaluación clínica y seguimiento del riesgo cardiovascular.ABSTRACT: The end-stage chronic kidney disease patients have high cardiovascular risk. The major risk factors of cardiovascular risk can not justify this excess of risk. The last European Guideline of cardiovascular risk (2012) associates end-stage chronic kidney disease to high or very high cardiovascular risk. However this increase of risk is not related to any particular biological marker. The aim of this research is evaluate the cardiovascular risk of ESKD patients with major and emerging cardiovascular risk factors, and also define the inflammatory state in ESKD patients, with the different renal replacement therapies (peritoneal dialysis, hemodialysis), and with renal transplantation. Emerging risk factors and new biological markers related to immune system, such as homocistein, lipoproteín(a), C-reactive protein, pentraxin-3, serum amyloid-A, procalcitonin and cystatin-C, were studied. Results support cardiovascular risk underestimation with traditional tables, and advise the analysis of new markers in clinical evaluation and monitoring of cardiovascular risk

TNF inhibitors exert a "hidden" beneficial effect in the cardiovascular lipoprotein profile of RA patients

Purpose: A high cardiovascular risk has been described in patients with rheumatoid arthritis (RA); the effects of different biological agents have also been described in these patients. The aim of the present study is to examine the effects of tumor necrosis factor inhibitors (TNFi) in the lipoprotein profile of RA patients using a broad laboratory assessment including a large number of non-routine tests. Patients and Methods: RA patients treated with and without TNFi (70 patients in each group) were cross-sectionally compared regarding a broad spectrum of lipoprotein parameters including serum levels of total and HDL, LDL and VLDL cholesterol triglycerides, lipoprotein A (LpA), apolipoprotein A1 (Apo A), B100 (Apo B) and paroxonase. For each lipoprotein subfraction (HDL, LDL and VLDL), we assess specific concentrations of cholesterol, triglycerides, phospholipids and proteins and total mass of each one. Additionally, HDL Apo A, LDL and VLDL Apo B concentrations and number of particles of LDL and VLDL were also determined. Exploratory univariate and multivariate analyses of the different variables were performed. Results: Seventy patients in each subset were enrolled. Patients on treatment with TNFi showed a trend to be younger and to have a longer disease duration. Regarding the lipoprotein analyses, borderline significant higher levels of serum Apo A were detected and an independent association with lower HDL mass, LDL triglyceride, VLDL cholesterol, VLDL Apo B, VLDL mass, number of VLDL cholesterol molecules and number of particles of VLDL was clearly observed. Conclusion: TNFi treatment was associated with beneficial atherogenic effects at the lipoprotein level especially centered in the VLDL-related parameters consistent with a reduction of the atherogenic risk.Funding: This study was carried out with the support of Instituto de Salud Carlos III (ISCIII) (grant number PI0810119)

Evolution of Mitochondrially Derived Peptides Humanin and MOTSc, and Changes in Insulin Sensitivity during Early Gestation in Women with and without Gestational Diabetes

Our purpose is to study the evolution of mitochondrially derived peptides (MDPs) and their relationship with changes in insulin sensitivity from the early stages of pregnancy in a cohort of pregnant women with and without gestational diabetes (GDM). MDPs (humanin and MOTSc) were assessed in the first and second trimesters of gestation in 28 pregnant women with gestational diabetes mellitus (GDM) and a subgroup of 45 pregnant women without GDM matched by BMI, age, previous gestations, and time of sampling. Insulin resistance (IR) was defined as a HOMA-IR index ≧ 70th percentile. We observed a significant reduction in both humanin and MOTSc levels from the first to the second trimesters of pregnancy. After adjusting for predefined variables, including BMI, statistically nonsignificant associations between lower levels of humanin and the occurrence of a high HOMA-IR index were obtained (adjusted OR = 2.63 and 3.14 for the first and second trimesters, linear p-trend 0.260 and 0.175, respectively). Regarding MOTSc, an association was found only for the second trimester: adjusted OR = 7.68 (95% CI 1.49-39.67), linear p-trend = 0.012. No significant associations were observed in humanin change with insulin resistance throughout pregnancy, but changes in MOTSc levels were significantly associated with HOMA-IR index: adjusted OR 3.73 (95% CI 1.03-13.50). In conclusion, MOTSc levels, especially a strong decrease from the first to second trimester of gestation, may be involved in increasing insulin resistance during early gestatio

Cortisol and adrenal androgens as independent predictors of mortality in septic patients

ObjectiveTo determine the prognostic value of cortisol, Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone-sulfate (DHEAS), together with their ratios (cortisol/DHEA and cortisol/DHEAS), as independent predictors of mortality in septic patients.MethodsProspective cohort study of 139 consecutive patients with a diagnosis of severe sepsis or septic shock. Adrenal hormones were determined within the first 24 hours of the septic process. To determine and compare the predictive ability of each marker for the risk of unfavorable evolution (in-hospital, 28-day and 90-day mortality), ROC (Receiver Operating Characteristic) curves were constructed and the area under the curve (AUC) was determined. As measures of association, adjusted odds ratios (OR) with their 95% confidence intervals (95%CI) were estimated by unconditional logistic regression. Cortisol, DHEA and DHEAS results were compared to lactate, CRP, SOFA and APACHE II Scores.ResultsCortisol showed the best predictive ability, with AUCs of 0.758, 0.759 and 0.705 for in-hospital mortality, and 28-day and 90-day mortality, respectively; whereas AUCs for 28 days mortality for SOFA and APACHE II scores, and other biomarkers studied, such as Lactate or CRP, were 0.644, 0.618, 0.643 and 0.647, respectively. Associations between high cortisol levels (>17.5 μg/dL) and mortality were strong and statistically significant for in-hospital and 28-day mortality: adjusted ORs 10.13 and 9.45 respectively, and lower for long term mortality (90 days): adjusted OR 4.26 (95% CI 1.34-13.56), p trend 0.014. Regarding adrenal androgens, only positive associations were obtained for DHEAS and most of these positive associations did not yield statistical significance. Regarding Cortisol/DHEA and cortisol/DHEAS ratios, they did not improve the predictive ability of cortisol. The only exception was the cortisol/DHEAS ratio, which was the best predictor of mortality at 90 days (AUC 0.737), adjusted OR for highest cortisol/DHEAS ratio values 6.33 (95%CI 1.77-22.60), p trend 0.002.ConclusionBasal cortisol measured within the first 24 hours of the septic process was the best prognostic factor for in-hospital and 28-day mortality, even superior to the Sequential Organ Failure Assessment (SOFA) or Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. The cortisol/DHEAS ratio was an independent predictor of long-term mortality

Circulating levels of mitochondrial oxidative stress-related peptides MOTS-c and Romo1 in stable COPD: a cross-sectional study

Background: MOTS-c and Romo1 are mitochondrial peptides that are modulated by oxidative stress. No previous studies have explored circulating levels of MOTS-c in patients with chronic obstructive pulmonary disease (COPD). Methods: We enrolled 142 patients with stable COPD and 47 smokers with normal lung function in an observational cross-sectional study. We assessed serum levels of both MOTS-c and Romo1 and associated these findings with clinical characteristics of COPD. Results: Compared with smokers with normal lung function, patients with COPD had lower levels of MOTS-c (p = 0.02) and higher levels of Romo1 (p = 0.01). A multivariate logistic regression analysis revealed that above-median MOTS-c levels were positively associated with Romo1 levels (OR 1.075, 95% CI 1.005–1.150, p = 0.036), but no association was found with other COPD characteristics. Below-median levels of circulating MOTS-c were associated with oxygen desaturation (OR 3.25 95% CI 1.456–8.522, p = 0.005) and walking <350 meters (OR 3.246 95% CI 1.229–8.577, p = 0.018) in six-minute walk test. Above-median levels of Romo1 were positively associated with current smoking (OR 2.756, 95% CI 1.133–6.704, p = 0.025) and negatively associated with baseline oxygen saturation (OR 0.776 95% CI 0.641–0.939, p = 0.009). Conclusions: Reduced levels of circulating MOTS-c and increased levels of Romo1 were detected in patients diagnosed with COPD. Low levels of MOTS-c were associated with oxygen desaturation and poorer exercise capacity using 6 min walk test. Romo1 was associated with current smoking and baseline oxygen saturationFunding: This study was funded by Instituto de Investigación Sanitaria of Cantabria (IDIVAL): NextVAL grant: NVAL19/01. This study received funding from GSK (NCT04449419). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decisión to submit it for publication. GSK was provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation. Acknowledgments: We want to particularly acknowledge the patients and the Biobank Valdecilla (PT17/0015/0019) integrated in the Spanish Biobank Network for its collaboration