Role of endothelial function determined by asymmetric dimethylarginine in the prediction of resistant hypertension: A subanalysis of ReHOT trial.

The authors conducted a subanalysis of the ReHOT (Resistant Hypertension Optimal Treatment) study to evaluate the association between endothelial dysfunction and resistant hypertension in a population of patients treated in a staged fashion for hypertension. One hundred and three hypertensive patients were followed for 6 months and participated in seven visits (V0-V6) 28 days apart. There was a first phase (V0-V3) of antihypertensive adjustment with three drugs and determination of resistant hypertension and a second randomized phase (V3-V6) of treatment with a fourth drug (clonidine or spironolactone) in the hypertensive patients characterized as resistant. Of the 103 patients included, 86 (83.5%) underwent the randomization visit (V3), 71 were characterized as non-resistant hypertensives (82.5%), and 15 as resistant hypertensives (17.5%). Serum asymmetric dimethylarginine (ADMA) was shown to be an independent predictor of resistant hypertension after adjustment for multiple variables (OR: 11.42, 95% CI: 1.02-127.71, P = .048), and in addition, there was a reduction in blood pressure levels and ADMA values during follow-up with a positive correlation in both groups and a greater reduction in the group of resistant hypertensives. We demonstrated that ADMA was an independent predictor of resistant hypertension, and we observed that the improvement in blood pressure levels obtained with the treatment was proportional to the reduction in ADMA values, suggesting a complementary role of ADMA not only as a stratification tool for the occurrence of resistant hypertension, but also as a possible therapeutic target in this population.

Cocaine-Induced Renal Artery Dissection as a Cause of Secondary Hypertension: A Rare Presentation.

BACKGROUND Cocaine abuse is a globally recognized problem with great socioeconomic and health impacts on society. We report a case of dissection of vertebral arteries and right renal artery after cocaine abuse that clinically presented as atypical headache and hypertension. CASE REPORT A 36-year-old male sought emergency care due to cervical pain after cocaine abuse. The pain was located to the right cervical side with irradiation to the homolateral temporal region. He had no previous comorbidities, except for cocaine abuse on a weekly basis. Angiotomography showed alterations compatible with recent arterial dissection of the right vertebral artery, confirmed on angioresonance. The patient received double anti-aggregation and antihypertensive drugs and was discharged. He was readmitted 5 days later due to hypertensive crisis and mild abdominal pain. Abdominal ultrasound with a Doppler of renal arteries showed signs right renal artery stenosis. Magnetic resonance angiography confirmed dissection of the same vessel. The patient underwent arteriography with stent implantation in the right renal artery. During outpatient follow-up, he progressed with gradual reduction of antihypertensive drugs. CONCLUSIONS There is only 1 case report correlating renal artery dissection with cocaine use and none with concomitant presentation of dissection in the vertebral and renal arterial beds. The scarcity of reports is a consequence of many problems. Therefore, young patients presenting with new-onset hypertension or abdominal pain and cocaine abuse history should raise suspicion for renal artery dissection.

Clinical Applications of Point-of-Care Testing in Different Conditions.

BACKGROUND: The use of point-of-care testing (POCT) in different clinical applications is justified by the fact that the time to release the result is shortened, allowing the physician to define the diagnosis and most appropriate therapy in a shorter time. However, the negative aspects must also be highlighted and studied so that we can move forward with the use of these devices. These negative aspects include greater analytical imprecision compared to laboratory automation, the variability between different equipment from different manufacturers, the risk of inappropriate use, a low level of global regulation, higher costs compared with laboratory testing and cost ineffectiveness in terms of health care. Methods and. RESULTS: This review presents some clinical applications of POCT in different scenarios, such as for diabetes mellitus, infectious diseases, pediatrics, and chronic kidney disease, among others. CONCLUSIONS: We hope to see a global consensus on an acceptable quality standard for performing POCT that is adaptable, practical, and cost effective in primary care settings, ensuring patient safety, and minimizing the risk of harm.

Definition of reference ranges for ß-isomerized carboxy-terminal telopeptide collagen type I for children and adolescents.

BACKGROUND: Bone metabolism involves many complex pathways that are disturbed by several bone diseases. The literature shows some limitations concerning pediatric reference intervals to bone markers, mainly because of the low number of patients included in the studies, the heterogeneity of methods, beyond the fact that it is time-consuming and expensive. The aim of this study was to determine reference values for ß-isomerized carboxy-terminal telopeptides collagen type I (ß-CTX), a marker of bone resorption, for children and adolescents. METHODS: Blood samples from 246 patients were collected and ß-CTX was measured using an electrochemiluminescence immunoassay (ECLI). RESULTS AND CONCLUSIONS: We propose reference ranges for ß-CTX concentration from the 2.5 percentile and 97.5 percentile for each age group. The reference values obtained, concerning children and adolescents, might be useful in the evaluation of diseases such as osteosarcoma and anorexia in both childhood as adolescence.

Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment).

The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01643434.

Chronic kidney disease induces inflammation by increasing Toll-like receptor-4, cytokine and cathelicidin expression in neutrophils and monocytes.

TLR expression in neutrophils and monocytes is associated with increased cytokine synthesis, resulting in increased inflammation. However, the inflammatory pathway related to TLR and cathelicidin expression in these cells from CKD patients is unclear. To evaluate TLR4, cathelicidin, TNF-α, IL-6, IL-10 and MCP-1 expression in neutrophils and monocytes from HD and CKD patients. Blood samples were drawn from 47 CKD and 43 HD patients and 71 age and gender-matched healthy volunteers (CONT). TLR4 was analyzed using flow cytometry. Cathelicidin, TNF-α, IL-6, IL-10 and MCP-1 were analyzed via ELISA.TLR4 expression in neutrophils was higher in HD patients than in stage 3 and 4 CKD patients. In these cells, we observed a positive correlation between TLR4 and cathelicidin, TNF-α, IL-6, IL-10 and MCP-1 levels. In monocytes, TLR4 expression was significantly higher in CKD 3 and 4 groups than in the control and HD groups and positively and negatively correlated with IL-6 and MCP-1 and cathelicidin, respectively. TNF-α, IL-6 and MCP-1 serum levels were higher in HD and CKD patients than in control. Cathelicidin and IL-10 levels were only higher in HD patients. IL-6 serum levels were positively correlated with all cytokines, and cathelicidin was negatively correlated with MCP-1 (r = - 0.35; p < 0.01) and positively correlated with IL-10 (r = 0.37; p = 0.001). These results suggest that a uremic environment induces high TLR4, cathelicidin and cytokine expression and may increase inflammation. Thus, future studies should be conducted to evaluate whether TLR4 and cathelicidin should be targets for anti-inflammatory therapeutic strategies.

Point-of-Care Testing: General Aspects.

Point-of-Care Testing (POCT) has been highlighted in the health care sector in recent decades. On the other hand, due to its low demand, POCT is at a disadvantage compared to conventional equipment, since its cost is inversely proportional to the volume of use. In addition, for the implementation of POCT to succeed, it is essential to rely on the work of a multidisciplinary team. The awareness of health professionals of the importance of each step is perhaps the critical success factor. The trend towards the continuous advancement of the use of POCT and the great potential of its contributions reinforce the need to implement quality management tools, including performance indicators, to ensure their results. This review presents some advantages and disadvantages concerning POCT and the real need to use it. A worldwide call for the availability of easy-to-use health technologies that are increasingly closer to the final user is one of the main reasons for this focus.

Consensus - reference ranges of vitamin D [25(OH)D] from the Brazilian medical societies. Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC/ML) and Brazilian Society of Endocrinology and Metabolism (SBEM) / Posicionamento oficial da Sociedade Brasileira de Patologia Clínica/Medicina Laboratorial (SBPC/ML) e da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) sobre intervalos de referência da vitamina D [25(OH)D]

ABSTRACT Introduction: Vitamin D is considered a pre-hormone and plays a crucial role in calcium homeostasis and, consequently, in bone health. The best source of vitamin D is the skin in response to sunlight. Only small amounts of this vitamin are found in some foods (especially fatty fish), which makes availability of vitamin D in the diet limited. Brazilian population studies show that the prevalence of hypovitaminosis D in our country is high. Objective: To define the reference intervals for vitamin D [25(OH)D]. Discussion: Consensus of specialists - literature review. Conclusion: The standardization of reference intervals is fundamental for the correct diagnosis and treatment of hypovitaminosis D.

RESUMO Introdução: A vitamina D é considerada um pré-hormônio e apresenta papel crucial na homeostase do cálcio e, consequentemente, na saúde óssea. A maior fonte de vitamina D é a pele, em resposta à luz solar. Apenas pequenas quantidades dessa vitamina são encontradas em alguns alimentos (especialmente peixes gordurosos), o que faz com que a disponibilidade da vitamina D na dieta seja limitada. Estudos populacionais brasileiros demonstram que a prevalência da hipovitaminose D no nosso país é elevada. Objetivo: Definição dos intervalos de referência para vitamina D [25(OH)D]. Discussão: Consenso de especialistas - revisão da literatura. Conclusão: A padronização dos intervalos de referência é fundamental para o correto diagnóstico e tratamento da hipovitaminose D.

Impact of metabolic syndrome on resting energy expenditure in patients with chronic kidney disease.

BACKGROUND & AIMS: Resting energy expenditure (REE) changes in patients with chronic kidney disease (CKD) may contribute to mortality increase. The obesity and inflammation is associated with high REE and when not compensated by adequate intake, may determine an unfavorable clinical outcome in this population. We aimed to evaluate the influence of metabolic syndrome (MetS) on REE in CKD patients. METHODS: One hundred eighty-three patients were stratified according to glomerular filtration rate (GFR) and divided in groups: without CKD (GFR > 60 ml/min/1.73 m2) and CKD (GFR < 60 ml/min/1.73 m2) and according to the presence or absence of MetS. REE was measured by indirect calorimetry; body composition was assessed by bioelectrical impedance analysis and blood and urine were collected for biochemical tests. RESULTS: REE was lower in the group with CKD compared with those without CKD (1293 ± 364 vs 1430 ± 370 kcal/d, P = 0.01). The group with CKD without MetS showed decrease in REE compared to the groups without CKD, regardless the presence of Mets, and those with CKD and MetS (1173 ± 315 vs 1392 ± 324 vs 1460 ± 410 vs 1424 ± 376 kcal/d, P < 0.05, respectively). Multivariate analysis showed an independent association of CKD in determining REE when adjusted for lean body mass. The inclusion of MetS as an independent variable in the same analysis model neutralized the impact of CKD on the REE (P = 0.19). Patients without MetS, REE correlated with estimated GFR and the protein equivalent (r = 0.33, P < 0.01, r = 0.21, P = 0.04, respectively), whereas in MetS patients, these correlations were not observed. CONCLUSION: The presence of CKD is independently associated with reduced REE. The observed decrease in REE is reversed in patients with MetS independent of renal function.

TNF-α depuration is a predictor of mortality in critically ill patients under continuous veno-venous hemodiafiltration treatment.

INTRODUCTION: Critically ill patients with acute kidney injury (AKI) present high mortality rates. The magnitude of inflammatory response could determine the prognosis of such patients. Continuous renal replacement therapy (CRRT) may play an important role in removing inflammatory mediators in patients with AKI. AIM: To investigate whether the magnitude of inflammatory mediator's removal is associated with mortality among critically ill patients on CVVHDF, a CRRT modality. METHODS: This study consisted of 64 critically ill patients requiring CVVHDF. Plasma levels of C3a, TNF-α, IL-10, IL-6, IL-1ß, sTNFRI and sTNFRII were determined by enzyme-linked immunosorbent assay (ELISA) at the beginning of CVVHDF and after 24h (outlet). Clearance of cytokines during the first 24h of CVVHDF was calculated. Clinical and laboratory data were acquired from patient's records data. RESULTS: Mean age of patients requiring CVVHDF was 63years, 67.2% were men and 87.3% were Caucasian. Thirty-five (35) patients (54.7%) died. Comparing non-survivors with the group of survivors we observed higher incidence of sepsis (68.6 versus 37.9%, p<0.05), higher APACHE II score (34.8±7.6 versus 29.2±7.1, p<0.05) and higher lactate levels (23.2±17.6 versus 16.4±6.6, p<0.05). According to the inter-tertile range of TNF-α clearance (ITR1 (<0.54); ITR2 (0.54-2.93); ITR3 (>2.93)) we found that those patients with higher TNF-α removal by RRT (ITR3) had a better survival. Multivariable analysis showed that lower clearance of TNF-α remained independently associated with high mortality after adjustment for sex, age, use of vasoactive drugs, APACHE II score sepsis, creatinine and lactate before CVVHDF (HR: 0.179, 95% IC: 0.049-0.661, p<0.01). CONCLUSION: The attenuation of inflammatory response may be related to the lower mortality observed on those patients with higher TNF-α removal by CVVHDF.

Low estimated glomerular filtration rate and chronic kidney failure following liver transplant: a retrospective cohort study.

BACKGROUND: Patients undergoing orthotropic liver transplant (LTx) often present with chronic kidney disease (CKD). Identification of patients who will progress to end-stage renal disease (ESRD) might allow not only the implementation of kidney protective measures but also simultaneous kidney transplant. STUDY DESIGN: Retrospective cohort study in adults who underwent LTx at a single center. ESRD, death, and composite of ESRD or death were studied outcomes. RESULTS: 331 patients, who underwent LTx, were followed up for 2.6 ± 1.4 years; 31 (10%) developed ESRD, 6 (2%) underwent kidney transplant after LTx and 25 (8%) remained on chronic hemodialysis. Patients with preoperative eGFR lesser than 60 ml/min per 1.73 m2 had a 4-fold increased risk of developing ESRD after adjustment for sex, diabetes mellitus, APACHE II score, use of nephrotoxic drugs, and severe liver graft failure (HR = 3.95, 95% CI 1.73, 9.01; p = 0.001). Other independent risk factors for ESRD were preoperative diabetes mellitus and post-operative severe liver graft dysfunction. CONCLUSION: These findings emphasize low eGFR prior to LTx as a predictor for ESRD or death. The consideration for kidney after liver transplant as a treatment modality should be taken into account for those who develop chronic kidney failure after LTx.

Effects of spermidine and p-cresol on polymorphonuclear cell apoptosis and function.

Polymorphonuclear leukocytes (PMNs) from chronic kidney disease (CKD) patients display accelerated apoptosis and dysfunction, which may predispose CKD patients to infections. In this study, we investigated the effect of spermidine and p-cresol on apoptosis and function on PMN from healthy subjects. We measured the effect of spermidine and p-cresol on apoptosis, ROS production unstimulated and stimulated (S. aureus and PMA) and expression of CD95, caspase 3, and CD11b on PMN. After incubation with p-cresol and spermidine, we did not observe any changes in apoptosis, viability or expression of caspase 3 and CD95 in PMN from healthy subjects. PMN incubated for 10 minutes with spermidine demonstrated a significant reduction in spontaneous, S. aureus and PMA-stimulated ROS production. p-cresol induced a decrease in PMA-stimulated ROS production. Spermidine and p-cresol also induced a decrease in the expression of CD11b on PMN. Spermidine and p-cresol decreased the expression of CD11b and oxidative burst of PMN from healthy subjects and had no effect on PMN apoptosis and viability.

Performance of two metabolic syndrome definitions in the estimation of cardiovascular disease among hypertensive patients.

The authors evaluated the significance of metabolic syndrome (MetS) diagnosis, as defined by the National Cholesterol Education Program (NCEP) and by the International Diabetes Federation (IDF), in the evaluation of cardiovascular risk in hypertensive patients. Among 638 patients, the prevalence of MetS was 54.7% when the IDF criteria were used, compared with 45.5% when the NCEP criteria were used. MetS correlated significantly with the presence of cardiovascular disease (CVD). In patients without type 2 diabetes mellitus (T2DM), only MetS diagnosed using the IDF criteria was associated with the presence of CVD. In those with T2DM, MetS was not associated with CVD, regardless of the criteria used. The diagnosis of MetS, using either set of criteria, was associated with the development of T2DM. We conclude that, in hypertensive patients without diabetes, a diagnosis of MetS according to IDF criteria, but not the NCEP criteria, is useful in identifying individuals with a higher probability of incident CVD. In patients with diabetes, a population already considered at high risk for CVD, a diagnosis of MetS, regardless of the criteria used, has no further impact on prognosis.

Synergistic effect of simvastatin and ezetimibe on lipid and pro-inflammatory profiles in pre-diabetic subjects.

BACKGROUND: Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol and plant sterols. Synergism of ezetimibe-statin therapy on LDL-cholesterol has been demonstrated, but data concerning the pleiotropic effects of this combination are controversial. OBJECTIVE: This open-label trial evaluated whether the combination of simvastatin and ezetimibe also results in a synergistic effect that reduces the pro-inflammatory status of pre-diabetic subjects. METHODS: Fifty pre-diabetic subjects were randomly assigned to one of 2 groups, one receiving ezetimibe (10 mg/day), the other, simvastatin (20 mg/d) for 12 weeks, followed by an additional 12-week period of combined therapy. Blood samples were collected at baseline, 12 and 24 weeks. RESULTS: Total cholesterol, LDL-cholesterol and apolipoprotein B levels decreased in all the periods analyzed (p < 0.01), but triglycerides declined significantly only after combined therapy. Both drugs induced reductions in C-reactive protein, reaching statistical significance after combining ezetimibe with the simvastatin therapy (baseline 0.59 +/- 0.14, simvastatin monotherapy 0.48 +/- 0.12 mg/dL and 0.35 +/- 0.12 mg/dL, p < 0.023). Such a reduction was independent of LDL-cholesterol change. However, mean levels of TNF-alpha and interleukin-6 and leukocyte count did not vary during the whole study. CONCLUSION: Expected synergistic lowering effects of a simvastatin and ezetimibe combination on LDL-cholesterol, apolipoprotein B and triglycerides levels were confirmed in subjects with early disturbances of glucose metabolism. We suggest an additive effect of this combination also on inflammatory status based on the reduction of C-reactive protein. Attenuation of pro-inflammatory conditions may be relevant in reducing cardiometabolic risk. TITLE/ID OF TRIAL REGISTRATION: Effect of simvastatin and ezetimibe on lipid and inflammation/NCT01103648.

Is cystatin C a useful marker in the detection of diabetic kidney disease?

BACKGROUND/AIMS: To evaluate cystatin C as a marker of diabetic kidney disease in normoalbuminuric diabetic patients without chronic kidney disease (CKD). METHODS: A cross- sectional study was carried out comprising 243 hypertensive patients, 61 of them with type 2 diabetes, presenting normoalbuminuria and an estimated glomerular filtration rate (eGFR) >or=60 ml/min/1.73 m(2). Renal function assessment included determinations of serum creatinine and cystatin C levels, microalbuminuria, as well as eGFR through Cockcroft-Gault and Modification of Diet in Renal Disease equations. RESULTS: Diabetic patients presented higher cystatin C levels than nondiabetic patients (0.95 +/- 0.19 vs. 0.89 +/- 0.17 mg/l; p < 0.05). In the binary logistic regression, the presence of diabetes and metabolic syndrome was significantly associated with elevated cystatin C levels. Diabetic patients also presented a slightly greater albuminuria (6.72 +/- 4.43 vs. 5.07 +/- 3.59 microg/min; p < 0.05). CONCLUSIONS: Our results suggest that elevated cystatin C levels in diabetic patients may identify a certain degree of renal dysfunction even when albuminuria and eGFR do not mirror CKD. Longitudinal studies with direct GFR measures need to be done in order to confirm the value of cystatin C as an indicative of worse renal outcomes in the diabetic population.

Effect of phosphate binders on oxidative stress and inflammation markers in hemodialysis patients.

It has been suggested that phosphate binders may reduce the inflammatory state of hemodialysis (HD) patients. However, it is not clear whether it has any effect on oxidative stress. The objective of this study was to evaluate the effect of sevelamer hydrochloride (SH) and calcium acetate (CA) on oxidative stress and inflammation markers in HD patients. Hemodialysis patients were randomly assigned to therapy with SH (n=17) or CA (n=14) for 1 year. Before the initiation of therapy (baseline) and at 12 months, we measured in vitro reactive oxygen species (ROS) production by stimulated and unstimulated polymorphonuclear neutrophils and serum levels of tumor necrosis factor alpha, interleukin-10, C-reactive protein, and albumin. There was a significant reduction of spontaneous ROS production in both groups after 12 months of therapy. There was a significant decrease of Staphylococcus aureus stimulated ROS production in the SH group. There was a significant increase in albumin serum levels only in the SH group. In the SH group, there was also a decrease in the serum levels of tumor necrosis factor alpha and C-reactive protein. Our results suggest that compared with CA treatment, SH may lead to a reduction in oxidative stress and inflammation. Therefore, it is possible that phosphate binders exert pleiotropic effects on oxidative stress and inflammation, which could contribute toward decreasing endothelial injury in patients in HD.

Uric acid as a marker for renal dysfunction in hypertensive women on diuretic and nondiuretic therapy.

Hyperuricemia is a common finding in hypertensive patients, especially among those who are on diuretic therapy. However, its clinical relevance regarding cardiovascular and chronic kidney disease (CKD) has not clearly been established. The authors assessed whether, in a population of 385 hypertensive women categorized according to diuretic therapy, the stratification in quartiles by uric acid levels would identify a gradient of changes in renal function and in risk factors for cardiovascular disease. The following were evaluated: serum uric acid, glycemia, total and fractional cholesterol, triglycerides, apolipoprotein (Apo) B, Apo A-I, and C-reactive protein. Renal function was assessed by serum creatinine, albuminuria, and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation, whereas cardiovascular risk was estimated through the Framingham score. A total of 246 women were on diuretic therapy; 139 were taking other antihypertensive medications. There was a reduction in eGFR parallel to the increase in uric acid levels, regardless of diuretic use and without a concomitant increase in albuminuria. In both groups, higher uric acid levels translated into an increase in metabolic syndrome components, in markers of insulin resistance, triglyceride / high-density lipoprotein levels, and Apo B/Apo A-I ratios, as well as in Framingham scores. Hyperuricemia was associated with an increase in inflammatory markers only in patients on diuretic therapy. In a binary logistic regression, hyperuricemia (uric acid >6.0 mg/ dL) was independently associated with CKD (eGFR <60 mL/ min / 1.73 m(2)) (odds ratio, 2.63; 95% confidence interval, 1.61-4.3; P<.001). In hypertensive women, the presence of hyperuricemia indicated a substantial degree of kidney dysfunction as well as a greater cardiovascular risk profile.