Optimized meropenem dosage regimens using a pharmacokinetic/pharmacodynamic population approach in patients undergoing continuous venovenous haemodiafiltration with high-adsorbent membrane.

BACKGROUND: The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane. OBJECTIVES: To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA. METHODS: A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC). RESULTS: The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required. CONCLUSIONS: We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.

Data on genotypic distribution and linkage disequilibrium of several ANRIL polymorphisms in hemodialysis patients.

A long non-coding RNA called ANRIL located on chromosome 9p21.3 has been identified as a novel genetic factor associated with cardiovascular disease. Investigation of several single nucleotide polymorphisms (SNPs) of Noncoding Antisense RNA in the INK4 Locus (ANRIL) gene are of particular interest. This article reports data related to the research article entitled: "Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients" (Arbiol-Roca et al. [1]). Data presented show the genotypic distribution of four selected ANRIL SNPs: rs10757278, rs4977574, rs10757274 and rs6475606 in a cohort constituted by 284 hemodialysis patients. This article analyzes the Hardy-Weinberg disequilibrium of each studied SNP, and the linkage disequilibrium between them.

Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Single nucleotide polymorphisms (SNPs) in ANRIL gene have been associated with higher cardiovascular morbidity and mortality in general population. The main objective was to ascertain whether ANRIL polymorphisms could identify risk of major adverse cardiovascular event (MACE) in patients starting on hemodialysis (HD). METHODS: This was a prospective observational cohort study. 284 CKD patients starting on HD were included in the study and followed until achievement of the primary end-point (MACE) or end of the study. All patients were genotyped for four ANRIL SNPs (rs10757278, rs4977574, rs10757274 and rs6475606). Kaplan-Meier curves and multivariate Cox survival analyses, together with multiple logistic regression were used to analyze the association between ANRIL SNPs and MACE. RESULTS: We found that ANRIL SNP rs10757278 was a representative SNP of a strong linkage disequilibrium block and showed significant genotypic associations with MACE in hemodialysis patients. Homozygous patients for the risk allele (GG) showed 2.17 (1.05-4.49) fold increased risk of MACE during hemodialysis than carriers of the protective allele (AA or AG). Diabetes mellitus was a strong enhancer of this effect. CONCLUSIONS: Our results indicate that ANRIL polymorphisms may confer risk to development of MACE in incident patients on hemodialysis.

Rapid detection of HLA-B*51 by real-time polymerase chain reaction and high-resolution melting analysis.

HLA-B*51, a class I human leukocyte antigen (HLA) molecule, is the strongest known genetic risk factor for Behçet disease. However, there are only few articles reporting methods to determine the presence or absence of HLA-B51. For this reason, we designed and developed an easy, fast, and inexpensive real-time high-resolution melting (HRM) assay to detect HLA-B*51. We genotyped 61 samples by our HRM assay and by conventional polymerase chain reaction, and no discrepancies were found between results. Besides, a subgroup of 25 samples was also genotyped in a different laboratory, and another subgroup of 16 samples was obtained from the International Histocompatibility Working Group DNA Bank, and a full concordance of results was observed with those obtained by HRM. Regarding the identifying system evaluated, we obtained 100% of specificity, sensibility, and repeatability, and 0% of false positive and false negative rates. Therefore, this HRM analysis is easily applicable to the rapid detection of HLA-B*51, exhibits a high speed, and requires a very low budget.

Metabolismo óseo. Vitamina D Y PTH / Bone metabolism. Vitamin D and parathyroid hormone

La vitamina D es una hormona involucrada en un complejo sistema endocrino que regula la homeostasis mineral, protege la integridad del esqueleto y modula el crecimiento y la diferenciación celular en una amplia variedad de tejidos. El hígado y el riñón son los órganos donde se producen el calcidiol o 25-hidroxivitamina D3 (forma circulante de vitamina D más abundante) y el calcitriol o 1-*,25-dihidroxivitamina D3 (la forma biológicamente más activa), respectivamente. La concentración de calcidiol es el índice más fiable para definir las situaciones de déficit, insuficiencia, hipovitaminosis, suficiencia y toxicidad de vitamina D. Su cuantificación se realiza mayoritariamente por métodos de RIA, aunque se están introduciendo con fuerza en el mercado los de ELISA y quimioluminiscencia; por su parte, los métodos para cuantificar calcitriol son de RIA con inmunoextracción. Hay que destacar que para establecer una correcta definición del umbral exacto de la situación de vitamina D, en una comunidad, se necesita tener un método de cuantificación bien estandarizado y con valores de referencia propios. La paratirina (PTH) es el regulador más importante en la homeostasis del calcio, ya que potencia su reabsorción en el túbulo renal, haciendo que se incremente su concentración sanguínea. En la circulación existen formas moleculares diferentes y de procedencia tisular, vida media, destino y afección en la enfermedad variadas; precisamente el conocimiento de esta heterogeneidad es el que ha permitido poder interpretar resultados procedentes de métodos que cuantifican diferentes regiones de la molécula. Actualmente se usan métodos inmunométricos (sándwich) de segunda generación para cuantificarla, por lo que se puede obviar la presencia de péptidos de cadena larga de la región aminoterminal que se metabolizan en algunos estadios de la insuficiencia renal. La concentración de paratirina tiene un marcado ritmo circadiano, por lo que se aconseja la toma de muestra no antes de las 7 de la mañana y, en sentido académico, una extracción después de las 10 h de la mañana podría discriminar entre población normal e hiperparatiroidismo primario leve. La PTH se ha introducido como prueba protocolizada en campo operatorio abierto en paratiroidectomía y tiroidectomía. En el primer caso, descensos de un 50% respecto a su valor basal representan éxito quirúrgico; en el segundo caso, se pueden seleccionar pacientes con riesgo de hipocalcemia

Vitamin D is a hormone involved in a complex endocrine system that regulates mineral homeostasis, protects the integrity of the skeleton, and modulates growth and cellular differentiation in a wide variety of tissues. Calcidiol, or 25-hydroxivitamin D3 (the more abundant circulating form of vitamin D), is synthesized in the liver, and calcitriol, or 1-*,25-dihydroxivitamin D3 (the biologically more active form), is synthesized in the kidney. The concentration of calcidiol is the most reliable index for defining vitamin D deficiency, insufficiency, hypovitaminosis, sufficiency and toxicity. It is mainly quantified by radioimmunoassay (RIA) methods, although ELISA and chemoluminescence are being strongly introduced in the market. Calcitriol quantification methods usually consist of RIA with immunoextraction. It is important to highlight that to accurately define vitamin D levels in a community, a standardized method of quantification and specific reference values are required. Parathyrin (PTH) is the most important regulator in calcium homeostasis, since it promotes calcium reabsorption in the renal tubules, increasing calcium concentrations in blood. There are several different molecular forms in the circulation with distinct tissular origin, half life, purpose, and involvement in disease. Indeed, knowledge of this heterogeneity is what has enabled results from methods that quantify different regions of the molecule to be interpreted. Currently, second generation immunometric (sandwich) methods are used to quantify PTH, so that the presence of long chain N-terminal peptides appearing in some stages of renal insufficiency can be obviated. PTH concentrations have a marked circadian rhythm and consequently sample extraction after 7 am is advisable, and, theoretically, extraction after 10 am could discriminate between the normal population and that with mild primary hyperparathyroidism. PTH determination has been introduced as a standardized test in open parathyroidectomy and thyroidectomy. In the first case, reductions of 50% with respect to the basal value represent surgical success; in the second case, patients at risk for hypocalcemia can be selected