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- Gla-rich protein (GRP) as an early and novel marker of vascular calcification and kidney dysfunction in diabetic patients with CKD: a pilot cross-sectional studyPublication . Silva, Ana P.; Viegas, Carla; Mendes, Filipa; Macedo, Ana; Guilherme, Patrícia; Tavares, Nelson; Dias, Carolina; Rato, Fátima; Santos, Nélio; Faísca, Marília; Almeida, Edgar de; Neves, Pedro Leão; Simes, DinaVascular calcification (VC) is one of the strongest predictors of cardiovascular risk in chronic kidney disease (CKD) patients. New diagnostic/prognostic tools are required for early detection of VC allowing interventional strategies. Gla-rich protein (GRP) is a cardiovascular calcification inhibitor, whose clinical utility is here highlighted. The present study explores, for the first time, correlations between levels of GRP in serum with CKD developmental stage, mineral metabolism markers, VC and pulse pressure (PP), in a cohort of 80 diabetic patients with mild to moderate CKD (stages 2-4). Spearman's correlation analysis revealed a positive association of GRP serum levels with estimated glomerular filtration rate (eGFR) and α-Klotho, while a negative correlation with phosphate (P), fibroblast growth factor 23 (FGF-23), vascular calcification score (VCS), PP, calcium (x) phosphate (CaxP) and interleukin 6 (IL-6). Serum GRP levels were found to progressively decrease from stage 2 to stage 4 CKD. Multivariate analysis identified low levels of eGFR and GRP, and high levels of FGF-23 associated with both the VCS and PP. These results indicate an association between GRP, renal dysfunction and CKD-mineral and bone disorder. The relationship between low levels of GRP and vascular calcifications suggests a future, potential utility for GRP as an early marker of vascular damage in CKD.
- Klotho levels: association with insulin resistance and albumin-to-creatinine ratio in type 2 diabetic patientsPublication . Silva, Ana Paula; Mendes, Filipa; Pereira, Luisa; Fragoso, André; Baptista Gonçalves, Rui; Santos, Nelio; Rato, Fátima; Neves, Pedro LeãoThe present study aimed at evaluating the relationship between Klotho levels and insulin resistance and albumin-to-creatinine ratio (ACR) in type 2 diabetic patients with CKD. We conducted an observational, cross-sectional study in our outpatient diabetic nephropathy clinic from 2014 to 2016, enrolling a total of 107 type 2 diabetic patients with stage 2-3 CKD, with a mean age of 59 years. Several clinical and laboratorial parameters were evaluated, including those related to mineral and carbohydrate metabolism. The mean eGFR at baseline was 53.2 mL/min, and the mean levels of ACR and Klotho were 181.9 A mu g/mg and 331.1 pg/m, respectively. In the simple linear regression model, Klotho levels were correlated with age, phosphorus, PTH, ACR, HOMA, IL-6, FGF-23, OxLDL, eGFR and vitamin D levels. Applying a multivariate linear regression model, only the ACR, HOMA-IR, FGF-23 and vitamin D independently influenced the Klotho levels. In the generalized linear model, only the Klotho groups were statistically significant as independent variable (p = 0.007). The results show that the group 1 (< 268) compared with group 3 (> 440) had higher odds in the higher ACR (ae181), ORa = 3.429, p = 0.014. There were no statistically significant differences between Klotho groups 2 and 3, and the HOMA-IR obtained showed that group 1 (< 268) had greater odds of HOMA-IR ae2 when compared with group 3 (> 440), ORa = 21.59, p = 0.017. Our results showed that Klotho levels are influenced by FGF23, vitamin D and insulin resistance. This suggests that Klotho levels might be affected by renal function as well as having a relevant role on insulin metabolism and ACR homeostasis.
- Mineral metabolism and inflammation: factors related to left ventricular hypertrophy in patients with diabetic nephropathyPublication . Jerónimo, Teresa; Fragoso, Andr?; Mendes, Filipa; Silva, Ana Paula; Pimentel, Ana; Tavares, Nelson; Camacho, Ana; Neves, Pedro LeãoLeft ventricular hypertrophy (LVH) is an important risk factor for cardiovascular disease in patients with diabetic nephropathy (DN) and is an independent predictor of mortality in patients with chronic kidney disease (CKD). The aim of this study was to evaluate the association of LVH with mineral metabolism and inflammation in a population of patients with DN. In an observational study were included 119 type 2 diabetic patients with CKD stages 3 and 4. The population was divided into two groups, according to the presence of LVH: group 1 (G-1) with LVH (left ventricular mass index (LVMI) > 125 g/m2 in male patients and LVMI > 110 g/m2 in female patients) and group 2 (G-2) without LVH (LVMI ? 125 g/m2 in male patients and LVMI ? 110 g/m2 in female patients). The patient characteristics of each group were compared regarding several biological and laboratory parameters. Patients with LVH displayed lower values of estimated glomerular filtration rate (eGFR) (p = 0.0001) and albumin (p = 0.046), and higher levels of phosphorus (p = 0.0001), intact parathyroid hormone (iPTH) (p = 0.0001), insulin resistance (HOMA-IR) (p = 0.0001) and interleukin-6 (IL-6) (p = 0.0001), compared with patients without LVH. In a logistic regression model, phosphorus (odd ratio (OR) = 1.825 (1.075-4.414), p = 0.038), iPTH (OR = 1.991 (1.098-3.000), p = 0.004) and IL-6 (OR = 3.538 (1.863-6.719), p = 0.0001) were independently related to LVH. In a multiple linear regression model, phosphorus (r = 0.602, p = 0.038), iPTH (r = 1.009, p = 0.044) and IL-6 (r = 1.264, p = 0.0001) were positively related to LVMI. Phosphorus, PTH and IL-6 were related to LVH in our diabetic population with CKD stages 3 and 4
- Calcific uraemic arteriolopathy - A mini-reviewPublication . Mendes, Filipa; Rocha, Sofia Couto; Agapii, Rodica; Silva, Ana; Fragoso, Andr?; Jerónimo, Teresa; Pimentel, Ana; Neves, Pedro LCalcific Uraemic Arteriolopathy (CUA) or calciphylaxis, is a thrombotic disorder of skin and subcutaneous tissue which typically presents with painful purpuric nodules that may progress to necrotic ulcers, and is a severe, life-threatening condition. CUA is an uncommon clinical entity that affects mostly haemodialysis (HD) patients. Although the process of vascular calcification was initially thought to be the result of a passive deposition of calcium-phosphate crystals, current knowledge suggests a distinct mechanism, including cellular activity with differentiation of vascular smooth muscle cells (VSMCs) into chondrocyte as well as osteoblast-like cellular phenotypes and deficiencies in calcification inhibitors. Although multiple studies suggest a potential relationship between warfarin and CUA, larger prospective studies are needed in order to better evaluate this association, and randomised controlled trials are needed to assess the benefit of distinct interventions in this setting. In this article the topic of CUA is reviewed based on a clinical case of a 65-year-old man undergoing haemodialysis, who underwent an aortic valve replacement one year earlier, receiving a mechanical heart valve, and who has been under warfarin therapy since then
- Fracturing issue concerning cardiovascular mortality in chronic kidney disease patientsPublication . Mendes, Filipa; Silva, Ana P.; Alonso, Isis; Fragoso, André; Pereira, Luisa Helena; Jerónimo, Teresa; Pimentel, Ana; Neves, Pedro L.With the ageing of population worldwide, the riskof both osteoporosis and chronic kidney disease increased. These two conditions multiply the riskof bone fractures. The higher riskoffractures in CKD is accompanied bya higher mortality rate in hemodialysis patients. According to the Universityof Michigan’s study,the risk mortalityafter hip fracturewas 6.5 times higher in stage 5 CKD patients compared with patient with normal kidney function. In this study we analyzed the role of bone mineral metabolism and of hip fractures on cardiovascular mortality in a population of chronic kidney disease pre-dialysis patients. Methods: In an observational study, we included 300 patients followed in a pre-dialysis clinic during a 8 years period (2005-2013). Descriptive statistics and the Cox proportional hazard regression model were used to find risk factors of cardiovascular mortality.The mean age of these patients was 69.38 years, the mean eGFR (MDRD) was 20.40 ml/min and 60% (180) were female. Results: Using the Cox proportional hazard regression model, adjusted to age, gender, Diabetes Mellitus, Charlson comorbidity index, e-GFR, calcium, phosphorus, PTH, 25 OHD, osteocalcin, albumin and hip fractures, we found that25(OH)2D3 (HR= 0.950, 95% CI, 0.697 to 0.993 p=0.035), eGFR (HR= 0.638, 95% CI, 0.586 to 0.993, p=0.028) and hip fractures (HR= 1.753, 95% CI, 1.294 to 1.893 p=0.036) were independent risk factors of cardiovascular mortality. Conclusions: In our population of chronic kidney pre-dialysis patients, the levels of 25 (OH)2D3 and renal function, as well asthe presence of hip fractures increased the risk of cardiovascular mortality.
- Angels and demons regarding cardiovascular disease in diabetic renal patients: the role of FGF-23 Andklotho on the pulse pressurePublication . Silva, Ana Paula; Mendes, Filipa; Fragoso, André; Santos, Nélio; Rato, Fátima; Faísca, Marilia; Neves, Pedro LeãoThe last decade have shown thatFGF23 and Klotho may have relevant independent actions on the renal and cardiovascular systems. Theyinterfere with vascular functions and may playa role in vascularcalcification, atherosclerosis and arteriolosclerosis. On the other hand, pulse pressureis awell-known risk factorof cardiovascular morbidityand mortality in renal patients. The aim of this study isto investigate the relationship between FGF-23 and Klothowith pulse pressure in type 2 diabetic with chronic kidney disease (CKD) stages 2-3.
- Risk factors for fractures in type 2 diabetic with chronic kidney disease stage: the saints and the sinnersPublication . Gomes, Ana; Mendes, Filipa; Fragoso, André; Santos, Nélio; Rato, Fátima; Faísca, Marília; Neves, Pedro LeãoSince the population in the developed world is aging, the burden offragility fractures is aconstantly increasing problem. Despite the fact that potent bone-specific pharmaceutical agents have become available, the problem of how to identify patients with high fracture risk yet remains an enigma. Some studies mention the role of a normal mineral metabolism is critical for skeletal development and preservation of bone integrity. The aim of this study isto investigate the association of mineralmetabolism with hip fractures in type 2 diabetic with chronic kidney disease (CKD).
- Altered serum levels of FGF-23 and magnesium are independent risk factors for an increased albumin-to-creatinine ratio in type 2 diabetics with chronic kidney diseasePublication . Silva, Ana Paula; Mendes, Filipa; Fragoso, André; Jerónimo, Teresa; Pimentel, Ana; Gundlach, Kristina; Büchel, Janine; Santos, Nélio; Neves, Pedro LeãoAims: To investigate the role of FGF-23 and magnesium in relation to the albumin-to-creatinine ratio in type 2 diabetics with chronic kidney disease (CKD) stages 2-4.Methods: In a cross-sectional study we included all eligible type 2 diabetic patients with CKD stages 2-4, followed in our outpatient Diabetic Kidney clinic. We used descriptive statistics, the Student's t-test, ANOVA and the chi-square tests. Our population was divided according to the UACR (G1 30-300 mg/g and G2 >= 300 mg/g), and compared these groups regarding several biological and laboratorial parameters. We employed a multiple regression model to identify risk factors of increased UACR.Results: The patients in G2 displayed a lower eGFR (p = 0.0001) and, had lower levels of magnesium (p = 0.004) as well as higher levels of FGF-23 (p = 0.043) compared to patients in Gl.FGF-23 (beta = 0.562, P = 0.0001) and the magnesium (beta = - 8.916, p = 0.0001) were associated with increased UACR.Conclusions: A dysregulation of mineral metabolism, reflected by altered levels of magnesium and FGF-23, correlates with an increased UACR in type 2 diabetic patients with CKD stages 2-4. (C) 2016 Elsevier Inc. All rights reserved.
- FGF23-klotho axis as predictive factors of fractures in type 2 diabetics with early chronic kidney diseasePublication . Ribeiro, Ana Luisa; Mendes, Filipa; Carias, Eduarda; Rato, Fátima; Santos, Nélio; Neves, Pedro Leão; Silva, Ana PaulaBackground: The aim of our study was to evaluate the relevance of FGF23-klotho axis in the predisposition for bone fractures in type 2 diabetic patients with early chronic kidney disease. Methods: In a prospective study we included 126 type 2 diabetic patients with CKD stages 2-3 (from 2010 to 2017). We used descriptive statistics, ANOVA and chi-square test. Our population was divided into two groups according to the occurrence of a bone fracture event or not, and the groups were compared considering several biological and laboratorial parameters. We employed a multiple regression model to identify risk factors for bone fracture events and hazard ratios (HR) were calculated using a backward stepwise likelihood ratio (LR) Cox regression. Results: Patients with a fracture event displayed higher levels of FGF-23, Phosphorus, PTH, TNF-alpha, OxLDL, HOMA-IR, calcium x phosphorus product and ACR and lower levels of Osteocalcin, alpha-Klotho, 25(OH)D3 and eGFR compared with patients without a fracture event (p < 0.001). The number of patients with a fracture event was higher than expected within inclining CKD stages (chi 2, p = 0.06). The occurrence of fracture and the levels of TNF-alpha, klotho, 25(OH)D3 and OxLDL were found to predict patient entry into RRT (p < 0.05). Age, osteocalcin, alpha-Klotho and FGF-23 independently influenced the occurrence of bone fracture (p < 0.05). Conclusions: alpha-Klotho and FGF-23 levels may have a good clinical use as biomarkers to predict the occurrence of fracture events. (C) 2019 Elsevier Inc. All rights reserved.
- Risk factors of hip fractures in chronic kidney disease patientsPublication . Mendes, Filipa; Gomes, Ana; Alonso, Isis; Fragoso, André; Pereira, Luisa Helena; Jerónimo, Teresa; Pimentel, Ana; Neves, Pedro L.In the Western World the general population is getting older. This implies a higher prevalence of osteoporosis as well as a greater incidence of patients with chronic kidney disease. These two conditions increase the riskof bone fractures. Metabolic and hormonal disarrangement in end-stage renal disease (ESRD) negativelyaffects bone remodeling as it promotes a decrease in Vitamin D availability, hyperphosphatemia, hypocalcemia, high secretion of parathormone and chronic metabolic acidosis. The NHANES III showed that even moderate-to-severe CKD patients may present with a significant increased riskoffracturewhich is justified by hyperparathyroidism at the earlystages of the disease.