Peritoneal Protein Loss, Inflammation, and Nutrition: Refuting Myths.

Peritoneal protein loss (PPL) has been correlated with mortality, malnutrition and inflammation. More recently overhydration was brought to the equation. This study aims to review classic and recent factors associated with PPL. Prevalent and incident peritoneal dialysis (PD) patients were included. Dialysate and serum IL-6 was obtained during PET. Hydration and nutritional status were assessed by bio-impedance. Linear regression and Cox regression were performed. The 78 included patients presented median values of PPL 4.8 g/24 h, serum IL-6: 5.1 pg/mL, and IL-6 appearance rate 153.5 pg/min. Mean extracellular water excess (EWexc) was 0.88 ± 0.94 L, and lean body mass index (LBMI) 17.3 ± 2.4 kg/m2. After mean follow-up of 33.9 ± 29.3 months, 12 patients died. Linear univariable analysis showed positive associations between PPL and small solute transport, body composition (LBMI and EWexc), comorbidities and performing CAPD (vs. cycler). PPL correlated positively with dialysate appearance rate of IL-6, but not with serum IL-6. Linear multivariable analysis confirmed positive association between PPL and EWexc (p = 0.012; 95%CI: 4.162-31.854), LBMI (p = 0.008; 95%CI: 1.720-11.219) and performing CAPD (p = 0.023; 95%CI: 4.375-54.190). In survival analysis, no relationship was found between mortality and PPL. Multivariable Cox regression showed Charlson Comorbidity Index (HR: 1.896, 95%CI: 1.235-2.913), overhydration (HR: 10.034, 95%CI: 1.426-70.587) and lower PPL (HR: 0.576, 95%CI: 0.339-0.978) were predictors for mortality. Overhydration, was a strong predictor of PPL, overpowering variables previously reported as determinants of PPL, namely clinical correlates of endothelial dysfunction or local inflammation. PPL were not associated with malnutrition or higher mortality, emphasizing the importance of volume overload control in PD patients.

Gla-Rich Protein, Magnesium and Phosphate Associate with Mitral and Aortic Valves Calcification in Diabetic Patients with Moderate CKD.

Accelerated and premature cardiovascular calcification is a hallmark of chronic kidney disease (CKD) patients. Valvular calcification (VC) is a critical indicator of cardiovascular disease and all-cause mortality in this population, lacking validated biomarkers for early diagnosis. Gla-rich protein (GRP) is a cardiovascular calcification inhibitor recently associated with vascular calcification, pulse pressure, mineral metabolism markers and kidney function. Here, we examined the association between GRP serum levels and mitral and aortic valves calcification in a cohort of 80 diabetic patients with CKD stages 2-4. Mitral and aortic valves calcification were detected in 36.2% and 34.4% of the patients and associated with lower GRP levels, even after adjustments for age and gender. In this pilot study, univariate, multivariate and Poisson regression analysis, show that low levels of GRP and magnesium (Mg), and high levels of phosphate (P) are associated with mitral and aortic valves calcification. Receiver operating characteristic (ROC) curves showed that the area under the curve (AUC) values of GRP for mitral (0.762) and aortic (0.802) valves calcification were higher than those of Mg and P. These results suggest that low levels of GRP and Mg, and high levels of P, are independent and cumulative risk factors for VC in this population; the GRP diagnostic value might be potentially useful in cardiovascular risk assessment.

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 Study.

Vascular 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.

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.

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.

Risk factors for high erythropoiesis stimulating agent resistance index in pre-dialysis chronic kidney disease patients, stages 4 and 5.

BACKGROUND/AIMS: Anemia is common in patients with chronic kidney disease (CKD). Recently, the erythropoiesis-stimulating agent/hemoglobin level (ESA/Hb) index emerged as a new factor associated with increased morbidity and mortality in this population. In this study, we evaluated the factors that influence the ESA/Hb index in a pre-dialysis CKD population. METHODS: Ninety-five patients were evaluated for clinical and laboratory parameters, nutritional status and ESA/Hb index. For comparison, we divided our population into 3 groups: G I--no ESA treatment, G II--patients with ESA/index below 50th percentile and G III--patients with ESA/Hb index above 50th percentile. We performed single and multiple regression models and logistic regression analysis. RESULTS: In a multiple regression model, age (t = -3.456, P = 0.001), SGA (t = 2.059, P = 0.047), ferritin (t = 2.386, P = 0.027), Ca × P (t = 2.066, P = 0.043), TNF-α (t = 2.673, P = 0.009) and IL-6 (t = 2.939, P = 0.004) independently influenced the ESA/Hb index. At logistic regression analysis, gender, cardiovascular disease and TNF-α were independently associated with ESA/Hb higher than 50th percentile compared to the other patients (R(2) = 0.457). CONCLUSION: In a pre-dialysis population, female gender, cardiovascular disease, malnutrition and inflammation are associated with a higher ESA/Hb index.

Statins and vitamin D: a friendly association in pre-dialysis patients.

The increased mortality rate observed in patients with chronic kidney disease is related to the high prevalence of cardiovascular disease in this population. Recently, it has been shown that interventional therapy with statins and/or vitamin D could improve the outcomes of these patients. The aim of this study was to identify the risk factors for mortality in a group of patients with chronic kidney disease (stages 4 and 5--pre-dialysis) and verify whether vitamin D and statins could change the outcome. We included 95 patients (mean age--69.4) with stages 4 and 5 (pre-dialysis) of our "low-clearance" outpatient clinic, with an average eGFR of 16.9 ml/min and a mean follow-up of 24.1 months. Several biological, nutritional, laboratory and inflammatory parameters were analysed at baseline. Our population was divided into three groups: G-I, patients not medicated with either vitamin D or statins; G-II, patients medicated with either vitamin D or statins; and G-III, patients medicated with vitamin D and statins. We found (ANOVA) that the serum levels of pre-albumin (P = 0.018) and PTH (P = 0.03) were lower in G-I. Concerning the inflammatory parameters, G-I showed higher levels of hsCRP (P = 0.014) and a trend to higher IL-6 levels (P = 0.077). We found the actuarial survival at 30 months (Kaplan-Meier), to be 56.4% in G-I, 82.3% in G-II and 100% in G-III (log rank = 13.08 P = 0.0014). Using the Cox proportional hazards model, we found that the existence of coronary artery disease (P = 0.0001) and the absence of medication with vitamin D and/or statins (P = 0.005) independently influenced the mortality of our patients. In conclusion, we found, in our study, that patients under vitamin D and statins (with a synergistic effect) were less inflamed and showed a lower mortality rate.

Inflammation, homocysteine and carotid intima-media thickness.

INTRODUCTION: Cardiovascular disease is the main cause of morbidity and mortality in chronic renal patients. Carotid intima-media thickness (CIMT) is one of the most accurate markers of atherosclerosis risk. In this study, the authors set out to evaluate a population of chronic renal patients to determine which factors are associated with an increase in intima-media thickness. METHODS: We included 56 patients (F=22, M=34), with a mean age of 68.6 years, and an estimated glomerular filtration rate of 15.8 ml/min (calculated by the MDRD equation). Various laboratory and inflammatory parameters (hsCRP, IL-6 and TNF-alpha) were evaluated. All subjects underwent measurement of internal carotid artery intima-media thickness by high-resolution real-time B-mode ultrasonography using a 10 MHz linear transducer. RESULTS: Intima-media thickness was used as a dependent variable in a simple linear regression model, with the various laboratory parameters as independent variables. Only parameters showing a significant correlation with CIMT were evaluated in a multiple regression model: age (p=0.001), hemoglobin (p=00.3), logCRP (p=0.042), logIL-6 (p=0.004) and homocysteine (p=0.002). In the multiple regression model we found that age (p=0.001) and homocysteine (p=0.027) were independently correlated with CIMT. LogIL-6 did not reach statistical significance (p=0.057), probably due to the small population size. CONCLUSION: The authors conclude that age and homocysteine correlate with carotid intima-media thickness, and thus can be considered as markers/risk factors in chronic renal patients.

Anaemia correction in predialysis elderly patients: influence of the antihypertensive therapy on darbepoietin dose.

Anaemia and hypertension are common in patients with chronic renal insufficiency. The correction of anaemia with erythropoiesis stimulating agents (ESA) can improve survival and decrease the decline of renal function. Angiotensin converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (AIIRA) can also slow the progression of renal failure, but the blockade of the renin-angiotensin system can worsen anaemia. The aim of our study was to assess the impact of antihypertensive therapy (ACEI plus AIIRA) in the requirements of darbepoietin in a group of elderly predialysis patients. We included 71 patients (m = 39, f = 32), mean age of 76.3 years with a mean creatinine clearance of 17.5 ml/min. Patients were divided in two groups according to their antihypertensive therapy: G-I patients under ACEI or AIIRA therapy and G-II normotensive patients or hypertensive patients under antihypertensive drugs other than ACEI or AIIRA. The groups were compared regarding demographic, nutritional, biochemical and inflammatory parameters. We also compared the mean darbepoietin dose. In GI the mean dose of darbepoietin was higher than in GII (0.543 vs. 0.325 microg/kg/week, P = 0.032). We did not find any difference regarding other parameters analysed. We conclude that ACEI and AIIRA can increase the needs of darbepoietin in predialysis elderly patients. However, when formally indicated to treat hypertension in a specific patient, they should not be switched to another antihypertensive agent. Instead, in such cases, higher doses of ESA should be used, if necessary.