Editorial

BoTítol atorgat pel catalogador. Vincle positiu-negatiu: AFCEC_DOMENECH_X_066

Estimated glomerular filtration rate is a poor predictor of the concentration of middle molecular weight uremic solutes in chronic kidney disease

Background: Uremic solute concentration increases as Glomerular Filtration Rate (GFR) declines. Weak associations were demonstrated between estimated GFR (eGFR) and the concentrations of several small water-soluble and protein-bound uremic solutes (MW500Da). Materials and Methods: In 95 CKD-patients (CKD-stage 2-5 not on dialysis), associations between different eGFR-formulae (creatinine, CystatinC-based or both) and the natural logarithm of the concentration of several LMWP's were analyzed: i.e. parathyroid hormone (PTH), Cystatin C (CystC), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), leptin, retinol binding protein (RbP), immunoglobin light chains kappa and lambda (Ig-kappa and Ig-lambda), beta-2-microglobulin (beta M-2), myoglobin and fibroblast growth factor-23 (FGF-23)). Results: The regression coefficients (R-2) between eGFR, based on the CKD-EPI-Crea-CystC-formula as reference, and the examined LMWP's could be divided into three groups. Most of the LMWP's associated weakly (R-2 0.7). Almost identical R-2-values were found per LMWP for all eGFR-formulae, with exception of CystC and beta M-2 which showed weaker associations with creatinine-based than with CystC-based eGFR. Conclusion: The association between eGFR and the concentration of several LMWP's is inconsistent, with in general low R-2-values. Thus, the use of eGFR to evaluate kidney function does not reflect the concentration of several LMWP's with proven toxic impact in CKD

New insights on diabetes and bone metabolism

Diabetes mellitus is a common chronic metabolic disease worldwide whose prevalence has increased during the last decades. Besides its more commonly recognized complications, such as macrovascular disease, retinopathy, nephropathy and neuropathy, diabetes related bone disease has gained growing attention. Diabetic patients are more prone to fracture than the general population as well as to low turnover bone disease in the chronic kidney disease setting. In this review, we discuss the relationship between diabetes and bone as well as the pathogenesis of bone fragility in T2D

Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease

Background & objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). Design, setting, participants, & measurements In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-alpha was studied followed by an evaluation of nuclear factor (NF)-kappa B activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo. Results Monocytes incubated with SDMA showed increased IL-6 and TNF-a expression and a rise in active NF-kappa B. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 +/- 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-alpha, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-alpha at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 +/- 0.05) directly followed that of C-reactive protein (AUC: 0.82 +/- 0.04) and albumin (AUC: 0.72 +/- 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002). Conclusions The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-kappa B and resulting in enhanced expression of IL-6 and TNF-alpha, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages

In vitro anti-inflammatory effects of vitamin D supplementation may be blurred in hemodialysis patients

OBJECTIVES: This study aimed to evaluate the potential anti-inflammatory effects of vitamin D supplementation under uremic conditions, both in vivo and in vitro, and its effects on the parameters of mineral metabolism. METHODS: Thirty-two hemodialysis patients were randomly assigned to receive placebo (N=14) or cholecalciferol (N=18) for six months. Serum levels of calcium, phosphate, total alkaline phosphatase, intact parathyroid hormone (iPTH), and vitamin D were measured at baseline and after three and six months. The levels of fibroblast growth factor-23 (FGF-23), interleukin-1b (IL-1b), and high-sensitivity C-reactive protein (hs-CRP) were also measured at baseline and at six months. Human monocytes were used for in vitro experiments and treated with cholecalciferol (150 nM) and uremic serum. Cell viability, reactive oxygen species (ROS) production, and cathelicidin (CAMP) expression were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, dichlorodihydro-fluorescein diacetate assay, and real time-quantitative polymerase chain reaction, respectively. RESULTS: Both patient groups were clinically and biochemically similar at baseline. After six months, the levels of vitamin D and iPTH were higher and lower, respectively, in the cholecalciferol group than in the placebo group (po0.05). There was no significant difference between the parameters of mineral metabolism, such as IL-1b and hs-CRP levels, in both groups. Treatment with uremic serum lowered the monocyte viability (po0.0001) and increased ROS production (po0.01) and CAMP expression (po0.05); these effects were counterbalanced by cholecalciferol treatment (po0.05). CONCLUSIONS: Thus, cholecalciferol supplementation is an efficient strategy to ameliorate hypovitaminosis D in hemodialysis patients, but its beneficial effects on the control of secondary hyperparathyroidism are relatively unclear. Even though cholecalciferol exhibited anti-inflammatory effects in vitro, its short-term supplementation was not effective in improving the inflammatory profile of patients on hemodialysis, as indicated by the IL-1b and hs-CRP levels

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

SUMMARY: BACKGROUND & OBJECTIVES: Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-α was studied followed by an evaluation of nuclear factor (NF)–κB activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo. RESULTS: Monocytes incubated with SDMA showed increased IL-6 and TNF-α expression and a rise in active NF-κB. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 ± 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-α, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-α at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 ± 0.05) directly followed that of C-reactive protein (AUC: 0.82 ± 0.04) and albumin (AUC: 0.72 ± 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002). CONCLUSIONS: The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-κB and resulting in enhanced expression of IL-6 and TNF-α, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages

Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease

Background. Uraemic toxins are considered to be emerging mortality risk factors in chronic kidney disease (CKD) patients. p-Cresol (a prototype protein-bound uraemic retention solute) has been shown to exert toxic effects in vitro. Recently, it has been demonstrated that p-cresol is present in plasma as its sulphate conjugate, p-cresylsulphate. The present study evaluated the distribution of free and total p-cresylsulphate and sought to determine whether these parameters were associated with vascular calcification, arterial stiffness and mortality risk in a cohort of CKD patients. Methods. One hundred and thirty-nine patients (mean SD age: 67 +/- 12; males: 60%) at different stages of CKD (8% at Stage 2, 26.5% at Stage 3, 26.5% at Stage 4, 7% at Stage 5 and 32% at Stage 5D) were enrolled in this study. Results. Baseline total and free p-cresylsulphate presented an inverse relationship with renal function and were significantly associated with vascular calcification. During the study period (mean follow-up period: 779 +/- 185 days), 38 patients died [including 22 from cardiovascular (CV) causes]. In crude survival analyses, free (but not total) p-cresylsulphate was shown to be a predictor of overall and CV death. Higher free p-cresylsulphate levels (>0.051 mg/100 mL; median) were associated with mortality independently of well-known predictors of survival such as age, vascular calcification, anaemia and inflammation. Conclusions. Serum levels of free and total p-cresylsulphate (the main in vivo circulating metabolites of p-cresol) were elevated in later CKD stages. However, only free p-cresylsulphate seems to be a predictor of survival in CKD

Osteoporosis in hemodialysis patients revisited by bone histomorphometry: A new insight into an old problem

Osteoporosis in hemodialysis patients is associated with high morbidity and mortality and, although extensively studied by noninvasive methods, has never been assessed through bone biopsy. the aim of this study was to use histomorphometry to evaluate osteoporosis and identify factors related to its development in hemodialysis patients. We conducted a cross-sectional study involving 98 patients ( 35 women and 63 men; mean age: 48.4 +/- 13 years) on hemodialysis for 36.9 +/- 24.7 months. Patients were submitted to transiliac bone biopsy with double tetracycline labeling. the bone metabolism factors ionized calcium, phosphorus, bone alkaline phosphatase, deoxypyridinoline, intact parathyroid hormone, and 25( OH) vitamin D were evaluated, as were the bone remodeling cytokines osteoprotegerin (OPG), soluble receptor-activator of NF-kappa beta ligand (sRANKL) and tumor necrosis factor-alpha (TNF)alpha. Osteoporosis was defined as trabecular bone volume ( BV/ TV) greater than 1 s.d. below normal ( men < 17.4%; women < 14.7%). Forty-five patients (46%) presented osteoporosis, which was correlated with white race. We found BV/ TV to correlate with age, OPG/sRANKL ratio, TNF alpha levels, and length of amenorrhea. in multiple regression analysis adjusted for sex and age, length of amenorrhea, white race, and OPG/ sRANKL ratio were independent determinants of BV/TV. Histomorphometric analysis demonstrated that osteoporotic patients presented normal eroded surface and low bone formation rate (BFR/BS). Osteoporosis is prevalent in hemodialysis patients. Low BFR/BS could be involved in its development, even when bone resorption is normal. Cytokines may also play a role as may traditional risk factors such as advanced age, hypogonadism, and white race.Universidade Federal de São Paulo, Dept Internal Med, Div Nephrol, BR-04038002 São Paulo, BrazilUniv São Paulo, Div Nephrol, Dept Internal Med, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Internal Med, Div Nephrol, BR-04038002 São Paulo, BrazilWeb of Scienc