Pedro Leão Neves

Gla-Rich Protein Is a Novel Vitamin K-Dependent Protein Present in Serum That Accumulates at Sites of Pathological Calcifications

Mineralization of soft tissues is an abnormal process that occurs in any body tissue and can greatly increase morbidity and mortality. Vitamin K-dependent (VKD) proteins play a crucial role in these processes; matrix Gla protein is considered one of the most relevant physiological inhibitors of soft tissue calcification know to date. Several studies have suggested that other, still unknown, VKD proteins might also be involved in soft tissue calcification pathologies. We have recently identified in sturgeon a new VKD protein, Gla-rich protein (GRP), which contains the highest ratio between number of Gla residues and size of the mature protein so far identified. Although mainly expressed in cartilaginous tissues of sturgeon, in rat GRP is present in both cartilage and bone. We now show that GRP is a circulating protein that is also expressed and accumulated in soft tissues of rats and humans, including the skin and vascular system in which, when affected by pathological calcifications, GRP accumulates at high levels at sites of mineral deposition, indicating an association with calcification processes. The high number of Gla residues and consequent mineral binding affinity properties strongly suggest that GRP may directly influence mineral formation, thereby playing a role in processes involving connective tissue mineralization.

Use of ambulatory blood pressure monitoring to compare antihypertensive efficacy and safety of two angiotensin II receptor antagonists, losartan and valsartan

The efficacy and safety of Iosartan and valsartan were evaluated in a multicenter, double-blind, randomized trial in patients with mild to moderate essential hypertension. Blood pressure responses to once-daily treatment with either losartan 50 mg (n = 93) or valsartan 80 mg (n = 94) for 6 weeks were assessed through measurements taken in the clinic and by 24-hour ambulatory blood pressure monitoring (ABPM). Both drugs significantly reduced clinic sitting systolic (SiSBP) and diastolic blood pressure (SiDBP) at 2, 4, and 6 weeks. Maximum reductions from baseline in SiSBP and SiDBP on 24hour ABPM were also significant with the two treatments. The reduction in blood pressure was more consistent across patients in the losartan group, as indicated by a numerically smaller variability in change from baseline on all ABPM measures, which achieved significance at peak (P = .017) and during the day (P = .002). In addition, the numerically larger smoothness index with losartan suggested a more homogeneous antihypertensive effect throughout the 24-hour dosing interval. The anti hypertensive response rate was 54% with losartan and 46% with valsartan. Three days after discontinuation of therapy, SiDBP remained below baseline in 73% of losartan and 63% of valsartan patients. Both agents were generally well tolerated. Losartan, but not valsartan, significantly decreased serum uric acid an average 0.4 mg/dL at week 6. In conclusion, once-daily losartan 50 mg and valsartan 80 mg had similar anti hypertensive effects in patients with mild to moderate essential hypertension. Losartan produced a more consistent blood pressure-lowering response and significantly lowered uric acid, suggesting potentially meaningful differences between these two A II receptor antagonists.

Elderly Patients in Chronic Hemodialysis: Risk Factors for Left Ventricular Hypertrophy

In the past few years in Western countries, there has been an increasing proportion of elderly patients beginning renal replacement therapy. Left ventricular hypertrophy (LVH) is associated with an increased mortality rate due to cardiovascular disease, the main cause of death in patients on chronic hemodialysis. In this study, we evaluated 67 chronic hemodialysis patients older than 65 years (33 women and 34 men; mean age, 72.6 years; mean time on chronic hemodialysis, 51.3 months). Several biological and laboratory data were analyzed. The left ventricular mass was calculated using the Penn convention criteria. LVH was observed in 49 patients (73%). These 49 patients were divided into two groups (group 1, concentric hypertrophy, n = 22; and group 2, eccentric hypertrophy, n = 27) and compared with a control group (patients without LVH, n = 18). Group 1 (P = 0.06) and group 2 (P = 0.055) showed higher systolic blood pressures and group 2 showed a lower hematocrit (P = 0.024). The echocardiographic parameters were expectedly different: group 1 had higher posterior left ventricular wall thickness (P = 0.0001), interventricular septum thickness (P = 0.0001), and left ventricular wall relative thickness (P = 0.002), and group 2 had higher left ventricular end-diastolic diameter (P = 0.0001), interventricular septum thickness (P = 0.01), and posterior left ventricular wall thickness (P = 0.023). Using the left ventricular mass index as the dependent variable and the evaluated biological and laboratory data as the independent variables, we found in a stepwise multiple regression model that only systolic blood pressure (t = 3.430; P = 0.0011), age (t = 2.059; P = 0.044), interdialytic weight gain (t = 2.236; P = 0.029), and hematocrit (t = -1.961; P = 0.054) independently influenced the left ventricular mass index (R2 = 0.313; P = 0.0001). Further studies are needed to determine whether reduction of the left ventricular mass index, through control of blood pressure and correction of anemia, will decrease the cardiovascular events in this particular population.

Magnesium and FGF-23 are independent predictors of pulse pressure in pre-dialysis diabetic chronic kidney disease patients

Background The aim of our study was to evaluate the relevance of magnesium and FGF-23 in terms of cardiovascular disease in a population of type 2 diabetic patients with nephropathy. Methods In a cross-sectional study, we included 80 type 2 diabetic patients with chronic kidney disease (CKD) stages 2, 3 and 4. We analysed mineral metabolism, inflammation, oxidative stress and insulin resistance. Our population was divided into two groups according to their pulse pressure (PP) as follows: G-1 with PP < 50 mmHg (n = 34) and G-2 with PP ≥ 50 mmHg (n = 46). Results We found that G-2 patients showed lower calcium (P = 0.004), eGFR (P = 0.001), magnesium (P = 0.0001), osteocalcin (P = 0.0001) and 25(OH)D3 (P = 0.001), and higher iPTH (P = 0.001), FGF-23 (P = 0.0001), malonaldehyde (P = 0.0001), interleukin 6 (P = 0.001) and HOMA-IR (P = 0.033). No differences were found between the two groups regarding age, duration of disease, haemoglobin, HgA1c and phosphorus. In a multivariate analysis, we found that FGF-23 and magnesium independently influenced the PP [OR = 1.239 (1.001–2.082), P = 0.039 and OR = 0.550 (0.305–0.727), P = 0.016, respectively]. Conclusions In our diabetic population with early stages of CKD, FGF-23 as well as lower magnesium levels were significantly and independently associated with higher PP levels, an established marker of cardiovascular morbidity and mortality.

Low Magnesium Levels and FGF-23 Dysregulation Predict Mitral Valve Calcification as well as Intima Media Thickness in Predialysis Diabetic Patients

Background. Mitral valve calcification and intima media thickness (IMT) are common complications of chronic kidney disease (CKD) implicated with high cardiovascular mortality. Objective. To investigate the implication of magnesium and fibroblast growth factor-23 (FGF-23) levels with mitral valve calcification and IMT in CKD diabetic patients. Methods. Observational, prospective study involving 150 diabetic patients with mild to moderate CKD, divided according to Wilkins Score. Carotid-echodoppler and transthoracic echocardiography were used to assess calcification. Statistical tests used to establish comparisons between groups, to identify risk factors, and to establish cut-off points for prediction of mitral valve calcification. Results. FGF-23 values continually increased with higher values for both IMT and calcification whereas the opposite trend was observed for magnesium. FGF-23 and magnesium were found to independently predict mitral valve calcification and IMT (P < 0.05). Using Kaplan-Meier analysis, the number of deaths was higher in patients with lower magnesium levels and poorer Wilkins score. The mean cut-off value for FGF-23 was 117 RU/mL and for magnesium 1.7 mg/dL. Conclusions. Hypomagnesemia and high FGF-23 levels are independent predictors of mitral valve calcification and IMT and are risk factors for cardiovascular mortality in this population. They might be used as diagnostic/therapeutic targets in order to better manage the high cardiovascular risk in CKD patients.

Insulin resistance as a predictor of cardiovascular morbidity and end-stage renal disease

BACKGROUND Cardiovascular disease (CVD) is the main risk factor of morbidity and mortality in chronic kidney disease (CKD) patients. Insulin resistance (IR) has been reported to be a strong risk factor for CVD. The purpose of this study was to examine the usefulness of IR as a predictor of cardiovascular morbidity and end-stage renal disease (ESRD). METHODS We followed during a period of 56months 119 type 2 diabetic CKD patients (stages 2 to 4) without history of CVD at the beginning of the study. Several laboratory parameters and left ventricular mass index (LVMI) were analyzed. The degree of IR was estimated by the Homeostasis Model Assessment (HOMA-IR). Cardiovascular morbidity was assessed according to the presence of cardiovascular hospital admission during the study period, defined by admissions caused by coronary heart disease, congestive heart failure, peripheral vascular disease and cerebrovascular disease. The population was divided in two groups: G-1 with cardiovascular admission (n=48) and G-2: without admission (n=71). The multiple logistic regression was used to assess predictors of cardiovascular morbidity and ESRD. The renal survival was evaluated by the Kaplan-Meier and long-rank test. RESULTS We found that G-1 patients showed significantly higher HOMA-IR (3.8 vs 0.77, p=0.0001) and that HOMA-IR upper tercile showed significantly higher age, eGFR, LVMI, phosphorus, iPTH and IL-6. In a multivariate logistic regression model HOMA-IR and IL-6 were independent risk factors of cardiovascular morbidity (OR=2.847 [95% CI 1.048-7.735, p=0.012] and OR=2.483 [95% CI 1.221-5.049, p=0.04], respectively). In a univariate logistic regression model patients in the upper tercile presented significantly more cardiovascular admissions that in the lower tercile. CKD progression to ESRD was observed in 24 patients and those in the upper HOMA-IR tercile showed a higher CKD progression to ESRD than the rest of study patients. A multivariate logistic regression model showed that HOMA-IR (OR=1.034, 95% CI (1.005-1.650) p=0.040) was an independent predictor of ESRD. Kaplan-Meier analysis showed a difference in renal survival in the HOMA-IR terciles (log rank=8.093; p=0.017). CONCLUSION In our study IR is an important risk factor for cardiovascular morbidity and ESRD in a diabetic CKD population.

Magnesium and Mortality in Patients with Diabetes and Early Chronic Kidney Disease

Objective: Cardiovascular disease is extensively described as being associated with chronic kidney disease, representing the most important cause of morbidity and mortality in these patients. Recent studies have suggested that hypomagnesaemia may be involved in the pathogenesis of cardiovascular disease in chronic kidney disease patients. Methods: An observational, prospective study involving 191 diabetic patients at chronic kidney disease stages 1-3 divided into groups according to baseline levels of magnesium; 1: < 1.2 mg/dL, 2: 1.2-2.3 mg/dL and 3: ≥ 2.3 mg/dL. Different serum parameters were analyzed and compared between Mg levels. Carotid eco-Doppler and transthoracic echocardiography were also used to assess calcification features Statistical tests were used to find predictors of cardiovascular mortality, hospitalizations and disease progression. Results: Patients’ survival at 54 months in group 1, 2 and 3 was 27.8%, 73.8% and 80.2%, respectively (p<0.001). Magnesium was found to be an independent predictor of both mortality and hospitalizations, with a statistically significant decrease in mortality and hospitalizations observed at higher levels of magnesium. Magnesium levels were also negatively correlated with known cardiovascular risk factors and with serum creatinine. Patients with lower magnesium level were more likely to start a renal replacement therapy. Conclusions: Lower magnesium levels result in a greater risk of cardiovascular mortality and hospitalization as well as an accelerated progression of renal disease to renal replacement therapy.

Homocysteine Is a Risk Factor in Predialysis Patients When Associated with Malnutrition and Inflammation

The increased level of plasma total homocysteine (tHcy) in chronic kidney disease patients has been reported as a new and independent risk factor for cardiovascular disease. However, after the description of reverse epidemiology in the renal population, the association of tHcy and nutrition became less clear. We evaluated the association between homocysteine, nutritional status, and inflammation, and their impact on mortality in 95 predialysis patients. High sensitivity C-Reactive Protein (hs-CRP), interleukin 6 (IL-6), Tumor Necrosis Factor α (TNF-α)], and tHcy were evaluated, as was the nutritional status by the modified Subjective Global Nutritional Assessment (mSGA). We divided our population in four groups according to their tHcy and mSGA values being above or below the mean level and found the lowest survival in the group with tHcy and mSGA above the mean level, as well as higher levels of IL-6 (P = .03) and TNF-α (P = .045). Higher levels of homocysteine can be associated with higher mortality in predialysis patients, as long as they are associated with malnutrition and inflammation.

Hypertension and Chronic Kidney Disease: Cause and Consequence – Therapeutic Considerations

There is a strong relationship between hypertension and Chronic Kidney Disease (CKD). Hypertension is an important cause of End-Stage Renal Disease (ESRD), contributing to the disease itself or, most commonly, contributing to its progression. On the other hand, hypertension is highly prevalent in CKD patients, playing a role in the high cardiovascular morbidity and mortality of this particular population. This chapter will focus on the pathogenesis of hypertension-related CKD and its role on the progression of renal disease itself. The pathogenesis and treatment of hypertension resulting from CKD will also be addressed.

Severe Relapsing Goodpasture's Disease Successfully Treated with Mycophenolate Mofetil.

Goodpastures disease is a rare autoimmune disorder characterised by the development of antiglomerular basement membrane autoantibodies, which typically presents with rapidly progressive crescentic glomerulonephritis and pulmonary haemorrhage. Even with aggressive nonspecific immunosuppression and plasma exchange, mortality remains high. We report a case of life-threatening Goodpastures disease with relapsing pulmonary haemorrhage refractory to conventional therapy. Second line treatment was based on mycophenolate mofetil 1 g every 12 hours and prednisolone 60 mg/day. In this case, the use of a low-dose mycophenolate mofetil regimen turned out to be insufficient. However, in our opinion higher mycophenolate mofetil doses should be considered an alternative treatment, mainly in relapsing disease, due to its mechanism of action and current insufficient therapeutic weapons.