Episodic Hyponatremia is Associated with Increased Mortality in Hemodialysis Patients

Introduction: Hyponatremia is common in many patient populations and has been linked to increased mortality. Hyponatremia in hemodialysis (HD) patients is also common, yet, only cross-sectional analyses are available. The hypothesis of the current study was that not only persistent, but also episodic hyponatremia in HD patients is associated with increased mortality. Methods: The prevalence of persistent and episodic (short duration (<3 months), high frequency (>=8 episodes) and long duration (>3 months), low (1-3 episodes) and medium (4-7 episodes) frequency) patterns of hyponatremia (plasma Na < 135 mmol/L) was investigated in 2473 patients on in-center HD, using plasma Na levels determined monthly over a median of 4.6 years. Both persistent and episodic hyponatremia are linked to mortality. Results: Normal sodium over the entire observations period was observed in 34% of patients, episodic short duration, high frequency in 9% of patients and long duration, low and medium frequency in 8% of patients. Both persistent hyponatremia and long duration, low/medium frequency were associated with decrease survival compared to patients without hyponatremia. Conclusion: Our results suggest that episodic hyponatremia may be just as an important predictor of mortality as stable hyponatremia.  This result further implies that a cross sectional analysis of hyponatremic patients undergoing hemodialysis may underestimate the risk associated with hyponatremia due to the potential for its episodic nature. *Indicates faculty mento

Estimation of GFR using β-trace protein in children

Background and objectives Sexmay affect the performance of smallmolecularweight proteins as markers of GFR because of differences in fat mass between the two sexes. The hypothesis was that the diagnostic performance of b-trace protein, a novel marker of GFR, would be significantly better in boys than in girls. Design, setting, participants, & measurements GFR, height, weight, serum creatinine, and β-trace protein were measured in 755 children and adolescents (331 girls) undergoing 99technetium diethylenetriamine penta–acetic acid renal scans from July of 1999 to July of 2006. Boys and girls were separated into formula generation cohorts (284 boys and 220 girls) and formula validation cohorts (140 boys and 111 girls). GFRestimating formulas on the basis of β-trace protein, creatinine, and height were derived using stepwise linear regression analysis of log-transformed data. The slope of the regression lines of the sex-specific eGFRswere compared. Bland–Altman analysis was used for testing agreement between 99technetium diethylenetriamine penta–acetic acid GFR and calculated GFR both with this equation in boys and girls as well as previously established Benlamri, White, and Schwartz formulas. Results In the stepwise regression analysis, β-trace protein (R2=0.73 for boys and R2=0.65 for girls) was more important than creatinine (which increased R2 to 0.81 for boys and R2 to 0.75 for girls) and height (which increased R2 to 0.88 for boys and R2 to 0.80 for girls) in the data generation groups. GFR can be calculated using the following formulas: formula present Bland–Altman analysis showed better performance in boys than in girls. The new formulas performed significantly better than the previous Benlamri, White, and Schwartz formulas with respect to bias, precision, and accuracy. Conclusions Improved and sex-specific formulas for the estimation of GFR in children on the basis of β-trace protein, serum creatinine, and height are now available

Perinatal Inhibition of NF-KappaB Has Long-Term Antihypertensive and Renoprotective Effects in Fawn-Hooded Hypertensive Rats

BACKGROUND Inhibition of transcription factor nuclear factor-kappa B (NFκB) is beneficial in various models of hypertension and renal disease. We hypothesized first that NFκB inhibition during renal development ameliorates hereditary hypertensive renal disease and next whether this was mediated via suppression of peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α). METHODS AND RESULTS Prior to the development of renal injury in fawn-hooded hypertensive (FHH) rats, a model of hypertension, glomerular hyperfiltration, and progressive renal injury, NFkB activity, measured by nuclear protein expression of NFkB subunit p65, was enhanced twofold in 2-day-old male and female FHH kidneys as compared to normotensive Wistar-Kyoto (WKY) rats (P <0.05). Treating FHH dams with pyrrolidine di thio carbamate (PDTC), an NFκB inhibitor, from 2 weeks before birth to 4 weeks after birth diminished NFkB activity in 2-day-FHH offspring to 2-day-WKY levels (P <0.01). Perinatal PDTC reduced systolic blood pressure from 20 weeks onwards by on average 25mm Hg (P <0.001) and ameliorated proteinuria (P <0.05) and glomerulosclerosis (P <0.05). In kidneys of 2-day-, 2-week-, and adult offspring of PDTC-treated FHH dams, PGC-1α was induced on average by 67% (quantitative polymerase chain reaction (qPCR)) suggesting that suppression of this factor by NFkB could be involved in renal damage. Follow-up experiments with perinatal pioglitazone (Pio), a PPARγ agonist, failed to confer persistent antihypertensive or renoprotective effects. CONCLUSIONS Perinatal inhibition of enhanced active renal NFκB in 2-day FHH had persistent antihypertensive and renoprotective effects. However, this was not the case for PPARγ stimulation. NFkB stimulation is therefore involved in renal damage in the FHH model of proteinuric renal disease by pathways other than via PPARγ.</p

Cardiorenal syndrome type 3: pathophysiologic and epidemiologic considerations

Cardiorenal syndrome (CRS) type 3 is a subclassification of the CRS whereby an episode of acute kidney injury (AKI) precipitates and contributes to the development of acute cardiac injury. There is limited understanding of the pathophysiologic mechanisms of how AKI contributes to acute cardiac injury and/or dysfunction. An episode of AKI may have effects that depend on the severity and duration of AKI and that both directly and indirectly predispose to an acute cardiac event. Moreover, baseline susceptibility will modify the subsequent risk for cardiac events associated with AKI. Experimental data suggest cardiac injury may be directly induced by inflammatory mediators, oxidative stress, apoptosis and activation of neuroendocrine systems early after AKI. Likewise, AKI may be associated with physiologic derangements (i.e. volume overload; metabolic acidosis, retention of uremic toxins, hyperkalemia; hypocalcemia), alterations to coronary vasoreactivity, and ventricular remodeling and fibrosis that indirectly exert negative effects on cardiac function. AKI may also adversely impact cardiac function by contributing to alternations in drug pharmacokinetics and pharmacodynamics. Additional experimental and translational investigations coupled with epidemiologic surveys are needed to better explore that pathophysiologic mechanisms underpinning acute cardiac events associated with AKI and their impact on outcomes

Перспективи розвитку світової енергетики й забезпечення енергетичної безпеки України

Проблеми забезпечення енергетичної безпеки (ЕнБ) безпеки були та залишаються головними складовими забезпечення національної безпеки та загального сталого розвитку

Relation between Red Cell Distribution Width and Fibroblast Growth Factor 23 Cleaving in Patients with Chronic Kidney Disease and Heart Failure

In chronic kidney disease (CKD), both anemia and deregulated phosphate metabolism are common and predictive of adverse outcome. Previous studies suggest that iron status influences phosphate metabolism by modulating proteolytic cleavage of FGF23 into C-terminal fragments. Red cell distribution width (RDW) was recently identified as a strong prognostic determinant for cardiovascular morbidity and mortality, independently of iron status. We assessed whether RDW is associated with FGF23 cleaving in CKD patients with heart failure.The associations between RDW and either intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23, reflecting iFGF23 and C-terminal fragments together) and the iFGF23/cFGF23 ratio were analyzed in 52 patients with CKD (eGFR 34,9 ± 13.9 ml/min/1.73m2) and chronic heart failure (CHF). Associations between RDW and FGF23 forms were studied by linear regression analysis adjusted for parameters of renal function, iron metabolism, phosphate metabolism and inflammation.Median cFGF23 levels were 197.5 [110-408.5] RU/ml, median iFGF23 levels were 107.3 [65.1-162.2] pg/ml and median FGF23 ratio was 0.80 [0.37-0.86]. Mean RDW was 14.1 ± 1.2%. cFGF23 and RDW were associated (β = 1.63 x 10(-3), P < 0.001), whereas iFGF23 and RDW were not (β = -1.38 x 10(-3), P = 0.336). The iFGF23/cFGF23 ratio was inversely associated with RDW. The difference between cFGF23 and iFGF23 (cFGF23- iFGF23) was positively associated with RDW (β = 1.74 x 10(-3), P < 0.001). The association between cFGF23 and RDW persisted upon multivariable linear regression analysis, adjusted for parameters of renal function, phosphate metabolism, iron metabolism and inflammation (β = 0.97 x 10(-3), P = 0.047).RDW is associated with cFGF23 but not with iFGF23 levels in patients with CKD and CHF. This suggests a connection between RDW and FGF23 catabolism, independent of iron status and inflammation. Future studies are needed to unravel underlying mechanisms and whether these pertain to the link between RDW and outcome

Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733

Short-Term Erythropoietin Treatment Does Not Substantially Modulate Monocyte Transcriptomes of Patients with Combined Heart and Renal Failure

Combined heart and renal failure is associated with high cardiovascular morbidity and mortality. Anti-oxidant and anti-inflammatory, non-hematopoietic effects of erythropoietin (EPO) treatment have been proposed. Monocytes may act as biosensors of the systemic environment. We hypothesized that monocyte transcriptomes of patients with cardiorenal syndrome (CRS) reflect the pathophysiology of the CRS and respond to short-term EPO treatment at a recommended dose for treatment of renal anemia.Patients with CRS and anemia (n = 18) included in the EPOCARES trial were matched to healthy controls (n = 12). Patients were randomized to receive 50 IU/kg/week EPO or not. RNA from CD14(+)-monocytes was subjected to genome wide expression analysis (Illumina) at baseline and 18 days (3 EPO injections) after enrolment. Transcriptomes from patients were compared to healthy controls and effect of EPO treatment was evaluated within patients.In CRS patients, expression of 471 genes, including inflammation and oxidative stress related genes was different from healthy controls. Cluster analysis did not separate patients from healthy controls. The 6 patients with the highest hsCRP levels had more differentially expressed genes than the 6 patients with the lowest hsCRP levels. Analysis of the variation in log(2) ratios of all individual 18 patients indicated that 4 of the 18 patients were different from the controls, whereas the other 14 were quite similar. After short-term EPO treatment, every patient clustered to his or her own baseline transcriptome. Two week EPO administration only marginally affected expression profiles on average, however, individual gene responses were variable.In stable, treated CRS patients with mild anemia, monocyte transcriptomes were modestly altered, and indicated imprints of inflammation and oxidative stress. EPO treatment with a fixed dose has hematopoietic effects, had no appreciable beneficial actions on monocyte transcription profiles, however, could also not be associated with undesirable transcriptional responses