Serum phosphate modifies the vascular response to vitamin D receptor activation in chronic kidney disease (CKD) patients.

BACKGROUND AND AIMS: Vitamin D receptor activation (VDRA) ameliorates endothelial dysfunction in CKD patients but also increases phosphate and FGF-23, which may attenuate the beneficial effect of VDRA on endothelial function. METHODS AND RESULTS: This is a pre-specified secondary analysis of the PENNY trial (NCT01680198) testing the effect of phosphate and FGF-23 on the flow mediated vasodilatory (FMD) response to paricalcitol (PCT, 2 µg/day) and placebo over a 12-weeks treatment period. Eighty-eight stage G3-4 CKD patients were randomized to PCT (n = 44) and Placebo (n = 44). Endothelial function was assessed by measuring endothelium dependent forearm blood flow (FBF) response to ischemia. The FMD response was by the 61% higher in PCT treated patients than in those on placebo (P = 0.01). Phosphate (+11%, P = 0.039), calcium (+3%, P = 0.01) and, particularly so, FGF23 (+164%, P < 0.001) increased in PCT treated patients. Changes in FMD by PCT associated inversely with phosphate (r = -0.37, P = 0.01) but were independent of FGF-23, calcium and PTH changes. The response to PCT was maximal in patients with no changes in phosphate (1st tertile), attenuated in those with mild-to-moderate rise in phosphate (2nd tertile) and abolished in those with the most pronounced phosphate increase (3rd tertile) (effect modification P = 0.009). No effect modification by FGF-23 and other variables was observed. CONCLUSIONS: The beneficial effect of PCT on endothelial function in CKD is maximal in patients with no or minimal changes in phosphate and it is abolished in patients with a pronounced phosphate rise. These findings generate the hypothesis that the endothelium protective effect by VDRA may be potentiated by phosphate lowering interventions.

Circulating soluble receptor for advanced glycation end product (sRAGE) and left ventricular hypertrophy in patients with chronic kidney disease (CKD).

BACKGROUND AND AIM: A decoy receptor for advanced glycation end product (soluble RAGE or sRAGE) is involved in left ventricular hypertrophy (LVH), and cardiomyopathy myocardial damage in experimental models and observational studies in patients with heart failure support the hypothesis that sRAGE attenuates the progression of heart disease and prevents death. Since sRAGE accumulates in patients with chronic kidney disease (CKD) we studied the relationship between plasma sRAGE with LVH in CKD patients. METHODS AND RESULTS: We enrolled 142 patients with an average estimated glomerular filtration rate (eGFR) of 32 ml/min/1.73 m(2) and 49 healthy control individuals matched for age and gender. Plasma sRAGE was significantly higher in CKD patients than in healthy controls. Significant inverse relationships were found between sRAGE with left ventricular mass index (LVMI) and mean wall thickness (MWT) but no such associations were found in controls. A bootstrap re-sampling validation study confirmed the estimates of the link between sRAGE and these variables. On covariance analysis, the slopes of LVMI and MWT to sRAGE were significantly steeper in CKD patients than in the controls. On logistic regression analysis 1 log unit increase in sRAGE was associated with a 82% decrease in the odds for LVH in CKD patients. CONCLUSIONS: sRAGE is an inverse marker of LVH in CKD patients. This association generates the hypothesis that the RAGE pathway could be a causal risk factor for LVH in this population and that blockade of this pathway by the endogenous decoy receptor sRAGE could attenuate LVH in the same population.

Sleep disordered breathing in renal transplant patients.

Sleep disordered breathing (SDB) is a prevalent, important nontraditional cardiovascular (CV) risk factor in end-stage renal disease patients. The prevalence of SDB in renal transplant patients is unknown. We compared polysomnographic studies in 163 transplant patients with matched samples in the general population and explored longitudinally the effect of return to dialysis after graft failure on SDB in three consecutive cases. Episodes of nocturnal hypoxemia, average and minimal O(2) saturation overnight in transplant patients did not differ from those in individuals in the general population matched for age, gender and body mass index (BMI). The prevalence of moderate-to-severe SBD in these patients did not exceed the estimated prevalence of the same disturbance in the general population. The respiratory disturbance index in transplant patients was directly associated with BMI (p < 0.001). In the longitudinal study all indicators of SDB coherently increased after transplant failure. The prevalence of SDB in transplant patients does not differ from that in well-matched individuals in the general population. The favorable effect of renal transplantation on CV risk may be at least partially explained by the lack of risk excess for SDB in this population. Longitudinal observations after transplant failure are compatible with the hypothesis that renal transplantation reverses SDB.

Circulating natriuretic peptide concentrations in patients with end-stage renal disease: role of brain natriuretic peptide as a biomarker for ventricular remodeling.

OBJECTIVES: To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality. PATIENTS AND METHODS: One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI). RESULTS: Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002). CONCLUSIONS: Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.

Pentosidine, carotid atherosclerosis and alterations in left ventricular geometry in hemodialysis patients.

OBJECTIVE: To assess the relationship between advanced glycation end products (AGE) and cardiovascular damage in end-stage renal diseases. METHODS: Ninety-one hemodialysis patients who had been on dialysis treatment for at least six months were recruited for the study. Each patient underwent echocardiography and an echo-color Doppler study of the carotid arteries. We measured plasma pentosidine and related it to intima media thickness, atherosclerotic plaques and parameters of left ventricular geometry. RESULTS: Pentosidine was higher in patients treated by low-flux dialysis (31.0+/-16.6 pmol/mg protein) than in those treated by high-flux dialysis (25.4+/-7.6 pmol/mg protein), but this difference was of marginal statistical significance (P=0.08). On multivariate analysis, plasma IgG (beta=0.24, P=0.02) was the only independent correlate of plasma pentosidine. Intima media thickness and the number of atherosclerotic plaques were unrelated to plasma pentosidine. Mean wall thickness (beta=0.18, P<0.05), relative wall thickness (beta=0.20, P<0.05) and left ventricular end-diastolic volume (beta= -0.23, P<0.01) were independently related to plasma pentosidine. CONCLUSIONS: Pentosidine, a reliable marker of "carbonyl stress", is unrelated to intima media thickness and to the number of atherosclerotic plaques, but it is related to alterations in heart geometry. These data suggest that the effect of carbonyl stress on the cardiovascular system is complex and that the effects of AGE on the heart may be dissociated from those on the arterial system.

Gender-dependent differences in plasma leptin in essential hypertension.

Leptin, the gene product of the ob gene, is influenced by gender and insulin sensitivity. Because in human hypertension there are important endocrine-hemodynamic gender-dependent differences, we compared plasma leptin in 39 essential hypertensives (EH) and in 27 normotensive healthy subjects (HS) matched for gender, age, and fat mass. Fat mass was measured by bioelectrical impedance analysis (BIA), plasma leptin by a sensitive radioimmunoassay RIA (intraassay CV < 6%), and insulin sensitivity by the HOMA-R index. Both in essential hypertensives and in normotensive subjects plasma leptin was consistently higher in females than in males and was strictly related to fat mass. Gender differences in plasma leptin were not explained by differences in fat mass. Separate analysis of data by gender showed that leptin was significantly higher (P < .05) in hypertensive men (median, 5.4 ng/mL; interquartile range, 4.1-9.5) than in normotensive men (4.6 ng/mL, 2.6-7.4) whereas it was identical in hypertensive and normotensive women. In essential hypertensives, in a multiple regression model only fat mass, gender, and the HOMA-R index were independently linked to plasma leptin. Similarly, fat mass and gender were independent predictors of plasma leptin in normotensive subjects. In the combined group of hypertensive and normotensive men, heart rate as well as systolic and diastolic pressure were univariate predictors of leptin. However, in a multivariable model only heart rate was independently related to leptin, and neither systolic nor diastolic pressure contributed significantly to explain the variability in plasma leptin. No relationship was found between leptin and heart rate or systolic or diastolic pressure in women. These results support the notion that leptin may participate in the gender-dependent variability of human hypertension.

Metabolic response of river birch and European birch and European birch roots to hypoxia.

Flood tolerance of woody plants has been attributed to internal oxygen diffusion from shoot to root, metabolic adaptation within the root, or both. The purpose of this study was to compare several biochemical and physiological responses of birch roots to hypoxia in order to determine the nature of root metabolic adaptation to low oxygen tension. One-year-old seedlings of flood-tolerant river birch (Betula nigra L.) and flood-intolerant European birch (Betula pendula Roth) were transferred to solution culture, and the solutions were bubbled with air or nitrogen. After 18 days of hypoxia, total adenosine phosphate and ATP contents of river birch roots were 35% and 23% of controls, respectively, whereas those of European birch roots were 13% and 8%. Adenylate energy charge of river birch roots decreased between 6 and 12 days of hypoxia. In contrast, energy charge of European birch roots decreased after only 1 day of hypoxia. In vitro activity of cytochrome c oxidase and oxygen consumption capacity of excised roots from both birch species decreased under hypoxia. In vitro activity of alcohol dehydrogenase from roots of both species increased after 1 day of hypoxia. However, alcohol dehydrogenase activity from river birch roots increased 25-fold after 6 days of hypoxia, whereas that from European birch decreased back to control levels. Hypoxia decreased malate content of roots from both species. Metabolic adaptation within the root, rather than internal oxygen diffusion, appears to be responsible for the relative tolerance of river birch to hypoxia.