Plasmatic Klotho and FGF23 Levels as Biomarkers of CKD-Associated Cardiac Disease in Type 2 Diabetic Patients.

BACKGROUND: Research over the past decade has focused on the role of Klotho as a cardio protective agent that prevents the effects of aging on the heart and reduces the burden of cardiovascular disease CVD. The role of the interaction between fibroblast growth factor 23-(FGF-23)/Klotho in Klotho-mediated actions is still under debate. The main objective was to ascertain the potential use of plasmatic Klotho and FGF23 as markers for CKD-associated cardiac disease and mortality. METHODS: This was a prospective analysis conducted in an outpatient diabetic nephropathy clinic, enrolling 107 diabetic patients with stage 2⁻3 CKD. Patients were divided into three groups according to their left ventricular mass index and relative wall thickness. RESULTS: Multinomial regression analysis demonstrated that low Klotho and higher FGF-23 levels were linked to a greater risk of concentric hypertrophy. In the generalized linear model (GLM), Klotho, FGF-23 and cardiac geometry groups were statistically significant as independent variables of cardiovascular hospitalization (p = 0.007). According to the Cox regression model, fatal cardiovascular events were associated with the following cardiac geometric classifications; eccentric hypertrophy (p = 0.050); concentric hypertrophy (p = 0.041), and serum phosphate ≥ 3.6 mg/dL (p = 0.025), FGF-23 ≥ 168 (p = 0.0149), α-klotho < 313 (p = 0.044). CONCLUSIONS: In our population, Klotho and FGF23 are associated with cardiovascular risk in the early stages of CKD.

Klotho levels: association with insulin resistance and albumin-to-creatinine ratio in type 2 diabetic patients.

PURPOSE: The 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. METHODS: 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. RESULTS: The mean eGFR at baseline was 53.2 mL/min, and the mean levels of ACR and Klotho were 181.9 µg/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 (≥181), 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 ≥2 when compared with group 3 (>440), ORa = 21.59, p = 0.017. CONCLUSIONS: 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.

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 disease.

AIMS: 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'st-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 G1. FGF-23 (ß=0.562, P=0.0001) and the magnesium (ß=- 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.

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 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.

What is the role of apelin regarding cardiovascular risk and progression of renal disease in type 2 diabetic patients with diabetic nephropathy?

AIMS: To evaluate the association of different apelin levels with cardiovascular mortality, hospitalization, renal function, and cardiovascular risk factors in type 2 diabetic patients with mild to moderate CKD. METHODS: An observational, prospective study involving 150 patients divided into groups according to baseline apelin levels: 1 ≤ 98 pg/mL, 2 = 98-328 pg/mL, and 3 ≥ 329 pg/mL. Baseline characteristics were analyzed and compared. Multivariate Cox regression was used to find out predictors of cardiovascular mortality, and multivariate logistic regression was used to find out predictors of hospitalization and disease progression. Simple linear regressions and Pearson correlations were used to investigate correlations between apelin and renal disease and cardiovascular risk factors. RESULTS: Patients' survival at 83 months in groups 1, 2, and 3 was 39%, 40%, and 71.2%, respectively (P = 0.046). Apelin, age, and eGFR were independent predictors of mortality, and apelin, creatinine, eGFR, resistin, and visfatin were independent predictors of hospitalization. Apelin levels were negatively correlated with cardiovascular risk factors and positively correlated with eGFR. Patients with lower apelin levels were more likely to start a depurative technique. CONCLUSIONS: Apelin levels might have a significant clinical use as a marker/predictor of cardiovascular mortality and hospitalization or even as a therapeutic agent for CKD patients with cardiovascular disease.

Phosphorus as an early marker of morbidity and mortality in type 2 chronic kidney disease diabetic patients.

AIMS: To evaluate the association of different phosphorus levels with cardiovascular mortality and hospitalizations risk in type-2 diabetic patients in phase 3/4 of CKD. METHODS: An observational, prospective study involving 119 patients divided into groups according to baseline phosphorus levels: 1, ≤3.60 mg/dL; 2, 3.60-4.60 mg/dL; and 3, >4.60 mg/dL. Baseline characteristics were analyzed and compared. Multivariate Cox regression and Multivariate Logistic regression were used to find out the predictors of cardiovascular mortality and hospitalizations, respectively. T-test was used to investigate the association of phosphorus and start of hemodialysis. RESULTS: Patients of group 3 presented lower clearance and Hb and increased PTH, Ca×P, LVMI, HOMA, uric acid, IL-6 and more hospitalization days. Patients' mean survival on groups 1, 2 and 3 was 62.5 ± 1.95, 60.1 ± 2.85 and 52.6 ± 2.84 months, respectively (p = 0.001). Phosphorus and creatinine levels were independent predictors of mortality, and phosphorus, creatinine, PTH and age were independent predictors of hospitalizations in this population. Patients who entered hemodialysis presented greater phosphorus levels than those who did not (5.04 ± 1.31 vs. 4.14 ± 1.09; p = 0.001). CONCLUSIONS: Phosphorus was a predictor of cardiovascular mortality and hospitalizations. Phosphorus levels might have a significant clinical use, possibly translated as an early marker of mortality and hospitalizations in this population.

Long-term risk of mortality for acute kidney injury in HIV-infected patients: a cohort analysis.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized human immunodeficiency virus (HIV)-infected patients and is associated with hospital mortality. We aimed to evaluate the impact of AKI on long-term mortality of hospitalized HIV-infected patients. METHODS: Retrospective analysis of a cohort of 433 hospitalized HIV-infected patients who were discharged alive from the hospital. AKI was defined according to 'Risk Injury Failure Loss of kidney function End-stage kidney disease' creatinine criteria, as an increase of baseline serum creatinine (SCr) X 1.5 or in patients with baseline SCr > 4 mg/dL if there was an acute rise in SCr of at least 0.5 mg/dL. Cumulative mortality curves were determined by the Kaplan-Meier method, and log-rank test was employed to analyze statistically significant differences between curves. Cox regression method was used to determine independent predictors of mortality. Risk factors were assessed with univariate analysis, and variables that were statistically significant (P < 0.05) in the univariate analysis were included in the multivariate analysis. RESULTS: Sixty-four patients (14.8%) had AKI. Median follow-up was 37 months. At follow-up 81 patients (18.7%) died. At 1, 2 and 5 years of follow-up, the cumulative probability of death of patients with AKI was 21.2, 25 and 31.3%, respectively, as compared with 10, 13.3 and 16.5% in patients without AKI (log-rank, P = 0.011). In multivariate analysis AKI was associated with increased mortality (adjusted HR 1.7, 95% CI 1.1-3; P = 0.049). CONCLUSIONS: AKI was independently associated with long-term mortality of hospitalized HIV-infected patients.