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Background: Snoring, an indicator of sleep-disordered breathing (SDB), associates with all-cause and cardiovascular (CV) mortality in high-risk conditions such as chronic heart failure (HF). Because SDB and HF are exceedingly frequent in end-stage kidney disease (ESKD), we hypothesized that SDB as detected by snoring may impact upon the relationship between chronic HF and all-cause and CV mortality in these patients. Methods: We tested this hypothesis in a cohort of 827 ESKD patients, followed up for 2.3 years. Results: In this population, snoring was a strong modifier of the risk of chronic HF for all-cause and CV death. In fully adjusted Cox models, the hazard ratio (HR) associated to chronic HF for the study outcomes was highest in heavy snorers [all-cause death: HR 2.6 (95% CI 1.6-4.3, p < 0.001); CV death: HR 4.0 (95% CI 2.1-7.6, p < 0.001)], intermediate in moderate snorers [all-cause death: HR 1.6 (95% CI 1.1-2.2, p = 0.01); CV death: HR 1.8 (95% CI 1.2-2.8, p = 0.01)], and lowest and not significant in non-snorers [all-cause death: HR 0.9 (95% CI 0.6-1.6, p = NS); CV death: HR 0.8 (95% CI 0.4-1.6, p = NS)]. Conclusions: Snoring is a strong and independent effect modifier of the relationship between chronic HF and all-cause and CV mortality in ESKD. Since SDB and snoring are in part attributable to reversible pharyngeal oedema, intensified surveillance and treatment of chronic HF snorers on dialysis may translate into better clinical outcomes in this very high-risk population, an issue which remains to be tested in specifically designed clinical trials.

Objective:Hypertension is common in sleep disordered breathing (SDB) and nocturnal hypertension has a 74% prevalence in renal transplant patients. SDB is frequent in dialysis patients and reduces in the early months post-transplantation to gradually increase thereafter and BP follows the same patter

Objective:Sleep Disordered Breathing (SDB) is frequent in stage 5 CKD and in dialysis patients. Small studies in dialysis patients show that SDB ameliorates in the early months after renal transplantation (Blood Purif 2008) but the long term longitudinal evolution of SDB in renal transplant patients

Summary Background and objectives Poorphysical performanceiscommoninpatients with kidneyfailureondialysis (CKD5D). Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical performance of CKD-5D patients has not been investigated in hemodialysis patients. Design, setting, participants, & measurements This study investigated the relationship between the physical functioning scale of the Kidney Disease Quality of Life Short Form and a validated ultrasonographic measure of lung water in a multicenter survey of 270 hemodialysis patients studied between 2009 and 2010. ResultsModerate to severe lung congestion by lung ultrasonography was observed in 156 (58%) patients; among these, 60 (38%) were asymptomatic (New York Heart Association [NYHA] class I). On univariate analysis, physical functioning was inversely associated with lung water in the whole group (r=20.22; P,0.001) and in the subgroup of asymptomatic patients (r=20.40; P=0.002). Age (r=20.45; P,0.001) and past cardiovascular events (r=20.22; P=0.002) were also inversely associated with physical functioning, whereas albumin (r=0.23;P,0.001) was directly associated with the same parameter. NYHA class correlated strongly with physical functioning (r=20.52; P,0.001). In a multiple regression analysis, both NYHA class and lung water maintained an independentassociationwithphysical functioning,whereasalbuminandbackgroundcardiovascularevents failed to independently relate with the same outcome. Conclusions Symptomatic and asymptomatic lung congestion is associated with poor physical functioning in hemodialysis patients. This association is independent of NYHA, suggesting that this measurement and NYHA may have complementary value to explain the variability in physical performance in hemodialysis patients. Clin J Am Soc Nephrol 8: 1343–1348, 2013. doi: 10.2215/CJN.11111012

Pulmonary congestion is highly prevalent and often asymptomatic among patients with ESRD treated with hemodialysis, but whether its presence predicts clinical outcomes is unknown. Here, we tested the prognostic value of extravascular lung water measured by a simple, well validated ultrasound B-lines score (BL-US) in a multicenter study that enrolled 392 hemodialysis patients. We detected moderate-to-severe lung congestion in 45% and very severe congestion in 14% of the patients. Among those patients with moderate-to-severe lung congestion, 71% were asymptomatic or presented slight symptoms of heart failure. Compared with those patients having mild or no congestion, patients with very severe congestion had a 4.2-fold risk of death (HR=4.20, 95% CI=2.45–7.23) and a 3.2-fold risk of cardiac events (HR=3.20, 95% CI=1.75–5.88) adjusted for NYHA class and other risk factors. Including the degree of pulmonary congestion in the model significantly improved the risk reclassification for cardiac events by 10% (P

Background: Lung congestion is emerging as a pervasive, insidious problem in end-stage renal disease (ESRD) patients on dialysis. Summary: Chest ultrasound (US), a novel, easy-to-perform, cheap technique, which is currently applied for objective monitoring of pulmonary congestion in patients with heart failure in Europe, allows reliable quantification of lung water in clinical practice. Before hemodialysis (HD), about 60% of ESRD patients displayed moderate-severe lung congestion and this alteration is frequently asymptomatic. Lung congestion is reduced but not abolished by ultrafiltration dialysis, and about one third to one fourth of patients still have excessive lung water after dialysis. Lung congestion is also prevalent in patients on peritoneal dialysis (PD), and in apparently asymptomatic HD and PD patients this alteration is strongly associated with poor physical performance. Lung water in HD patients correlates in an inverse fashion with echocardiographic parameters of systolic and diastolic function, but it is only weakly related with hydration status measured by bioimpedance analysis. Moderate-severe lung congestion is a strong predictor of death and cardiovascular events and provides prognostic information independent of NYHA class, and traditional and nontraditional risk factors in ESRD patients on HD. Key Messages: Systematic application of chest US in ESRD patients shows that hidden or clinically manifest lung congestion is exceedingly frequent in this population. This alteration largely reflects left ventricular disorders superimposed on volume overload. The clinical usefulness of systematic application of chest US in ESRD remains to be tested in a formal clinical trial.

Background and objectives Accumulation of fluid in the lung is the most concerning sequela of volume expansion in patients with ESRD. Lung auscultation is recommended to detect and monitor pulmonary congestion, but its reliability in ESRD is unknown. Design, setting, participants, & measurements In a subproject of the ongoing Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, we compared a lung ultrasound–guided ultrafiltration prescription policy versus standard care in high-risk patients on hemodialysis. The reliability of peripheral edema was tested as well. This study was on the basis of 1106 pre– and postdialysis lung ultrasound studies (in 79 patients) simultaneous with standardized lung auscultation (crackles at the lung bases) and quantification of peripheral edema. Results Lung congestion by crackles, edema, or a combination thereof poorly reflected the severity of congestion as detected by ultrasound B lines in various analyses, including standard regression analysis weighting for repeated measures in individual patients (shared variance of 12% and 4% for crackles and edema, respectively) and κ -statistics ( κ ranging from 0.00 to 0.16). In general, auscultation had very low discriminatory power for the diagnosis of mild (area under the receiver operating curve =0.61), moderate (area under the receiver operating curve =0.65), and severe (area under the receiver operating curve =0.68) lung congestion, and the same was true for peripheral edema (receiver operating curve =0.56 or lower) and the combination of the two physical signs. Conclusions Lung crackles, either alone or combined with peripheral edema, very poorly reflect interstitial lung edema in patients with ESRD. These findings reinforce the rationale underlying the Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, a trial adopting ultrasound B lines as an instrument to guide interventions aimed at mitigating lung congestion in high-risk patients on hemodialysis.

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.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.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.

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.

Background. Chest ultrasound (US) is a non-invasive wellvalidated technique for estimating extravascular lung water (LW) in patients with heart diseases and in end-stage renal disease. We systematically applied this technique to the whole peritoneal dialysis (PD) population of five dialysis units. Methods. We studied the cross-sectional association between LW, echocardiographic parameters, clinical [pedal oedema, New York Heart Association (NYHA) class] and bioelectrical impedance analysis (BIA) markers of volume status in 88 PD patients. Results. Moderate to severe lung congestion was evident in 41 (46%) patients. Ejection fraction was the echocardiographic parameter with the strongest independent association with LW (r ¼� 0.40 P ¼ 0.002). Oedema did not associate with LW on univariate and multivariate analysis. NYHA class was slightly associated with LW (r ¼ 0.21 P ¼ 0.05). Among patients with severe lung congestion, only 27% had pedal oedema and the majority (57%) had no dyspnoea (NYHA Class I). Similarly, the prevalence of patients with BIA, evidence of volume excess was small (11%) and not significantly different (P ¼ 0.79) from that observed in patients with mild or no congestion (9%). Conclusions. In PD patients, LW by chest US reveals moderate to severe lung congestion in a significant proportion of asymptomatic patients. Intervention studies are necessary to prove the usefulness of chest US for optimizing the control of fluid excess in PD patients.

Obesity may increase the risk for progression of CKD, but the effect of established renoprotective treatments in overweight and obese patients with CKD is unknown. In this post hoc analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, we evaluated whether being overweight or obese influences the incidence rate of renal events and affects the response to ramipril. Of the 337 trial participants with known body mass index (BMI), 105 (31.1%) were overweight and 49 (14.5%) were obese. Among placebo-treated patients, the incidence rate of ESRD was substantially higher in obese patients than overweight patients (24 versus 11 events/100 person-years) or than those with normal BMI (10 events/ 100 person-years); we observed a similar pattern for the combined endpoint of ESRD or doubling of serum creatinine. Ramipril reduced the rate of renal events in all BMI strata, but the effect was higher among the obese (incidence rate reduction of 86% for ESRD and 79% for the combined endpoint) than the overweight (incidence rate reduction of 45 and 48%, respectively) or those with normal BMI (incidence rate reduction of 42 and 45%, respectively). We confirmed this interaction between BMI and the efficacy of ramipril in analyses that adjusted for potential confounders, and we observed a similar effect modification for 24-hour protein excretion. In summary, obesity predicts a higher incidence of renal events, but treatment with ramipril can essentially abolish this risk excess. Furthermore, the reduction in risk conferred by ramipril is larger among obese than nonobese patients.

INTRODUCTION Hypertension remains a major problem in hemodialysis (HD) patients. METHODS We performed a pragmatic trial (Pragmatic Clinical Intervention on Blood Pressure Driven by Audit [CLINIDEA]) testing the effectiveness and safety of a 6-month multimodal intervention in hypertensive HD patients regarding the application of higher ultrafiltration (UF) rates or longer or more frequent dialyses in UF-intolerant patients, and an educational intervention to encourage patients to lower their salt and fluid intake. RESULTS Blood pressure (BP) in hypertensive patients (n=32) fell from 156.8 ± 13.3 / 81.1 ± 8.9 mm Hg to 147.9 ± 18.8 / 77.5 ± 11.1 mm Hg. UF intensification was well tolerated, and the BP goal was achieved without resorting to longer or more frequent dialyses. BP changes were paralleled by a consistent (p

ObjectivesThis study sought to investigate clinical and echocardiographic correlates of the lung comets score.BackgroundEarly detection of pulmonary congestion is a fundamental goal for the prevention of congestive heart failure in high-risk patients.MethodsWe undertook an inclusive survey by a validated ultrasound (US) technique in a hemodialysis center to estimate the prevalence of pulmonary congestion and its reversibility after dialysis in a population of 75 hemodialysis patients.ResultsChest US examinations were successfully completed in all patients (N = 75). Before dialysis, 47 patients (63%) exhibited moderate to severe lung congestion. This alteration was commonly observed in patients with heart failure but also in the majority of asymptomatic (32 of 56, 57%) and normohydrated (19 of 38, 50%) patients. Lung water excess was unrelated with hydration status but it was strongly associated with New York Heart Association functional class (p < 0.0001), left ventricular ejection fraction (r = –0.55, p < 0.001), early filling to early diastolic mitral annular velocity (r = 0.48, p < 0.001), left atrial volume (r = 0.39, p = 0.001), and pulmonary pressure (r = 0.36, p = 0.002). Lung water reduced after dialysis, but 23 patients (31%) still had pulmonary congestion of moderate to severe degree. Lung water after dialysis maintained a strong association with left ventricular ejection fraction (r = –0.59, p < 0.001), left atrial volume (r = 0.30, p = 0.01), and pulmonary pressure (r = 0.32, p = 0.006) denoting the critical role of cardiac performance in the control of this water compartment in end-stage renal disease. In a multiple regression model including traditional and nontraditional risk factors only left ventricular ejection fraction maintained an independent link with lung water excess (beta = –0.61, p < 0.001). Repeatability studies of the chest US technique (Bland-Altman plots) showed good interobserver and inter-US probes reproducibility.ConclusionsPulmonary congestion is highly prevalent in symptomatic (New York Heart Association functional class III to IV) and asymptomatic dialysis patients. Chest ultrasound is a reliable technique that detects pulmonary congestion at a pre-clinical stage in end-stage renal disease.

Background. Evidence linking chronic kidney disease (CKD) with the increased risk of cardiovascular (CV) complications is firm. It is becoming clear that testing functions of the vascular endothelium in conjunction with various biomarkers may better the definition of CV risk profile in CKD patients. Methods. Using Multiplexed analysis of 16 markers reflecting pro-inflammatory, anti-inflammatory, angiogenic, metabolic and anti-fibrinolytic factors in a series of 75 patients with CKD, who underwent echo-coloured Doppler study of carotid arteries, we analysed the contribution of each parameter to the characterization of atherosclerotic burden. As control group we enrolled 33 healthy individuals. Results. On univariate analysis, intima-media thickness, number of atherosclerotic plaques and internal diameter of carotid arteries were strongly interrelated. Starting with these indicators of carotid atherosclerosis, we extracted by principal component analysis a single composite atherosclerosis severity score that accounted for 68% of the total variance of original variables. Biomarkers significantly related to severity of carotid atherosclerosis were MMP9, t-PAI-1, IL-6, NT-proBNP, IL-8 and VEGF. In multiple linear regression models adjusting for clinical variables the gain in prediction power was achieved when we added MMP9 and t-PAI-1 to the basic model. IL-6 produced the highest increase in the multiple R2 of the basic model. The combination of MMP9, t-PAI-1, IL-6, NTproBNP, IL-8 and VEGF added to the basic model achieved gain in prediction power of þ 7.5%. In this expanded model, IL-6 was the only biomarker that significantly predicted the severity of atherosclerosis. Conclusion. Multiplexed screening revealed that IL-6, MMP-9, tPAI-1 and VEGF showed a tight correlation with carotid atherosclerotic burden in patients with CKD.

BACKGROUND The clinical relevance of ambulatory blood pressure monitoring (ABPM) for risk stratification in renal transplant patients still remains poorly defined. METHODS We investigated the association between clinic and ABPM with an established biomarker of atherosclerosis (intima-media thickness [IMT] by echo-color Doppler) in a large, inclusive survey (n = 172) in renal transplant patients at a single institution. RESULTS Forty-two patients (24%) were classified as hypertensive by ABPM criteria and 29 (17%) by clinic blood pressure (BP) criteria. Average daytime and nighttime BP was 126 ± 12/78 ± 9 mm Hg and 123 ± 13/74 ± 10 mm Hg, respectively. Forty-five patients (26%) were classified as hypertensive by the daytime criterion (>135/85 mm Hg) and a much higher proportion (n = 119, 69%) by the nighttime criterion (>120/70 mm Hg). Sixty-two patients (36%) had a night-day ratio of 1 or greater, indicating clear-cut nondipping. The average nighttime systolic BP (r = 0.24, P = 0.001) and the night-day systolic BP ratio (r = 0.23, P = 0.002) were directly related to IMT, and these associations were much more robust than the 24-hour systolic BP-IMT relationship (r = 0.16, P = 0.04). Average daytime BP and clinic B were unrelated to IMT. In a multiple regression analysis adjusting for confounders, the night-day systolic BP ratio maintained an independent association with IMT (β = 0.14, P = 0.04). CONCLUSIONS In renal transplant patients, the prevalence of nocturnal hypertension by far exceeds the prevalence of hypertension as assessed by clinic, daytime, and 24-hour ABPM. Nighttime systolic BP and the night-day ratio but no other BP metrics are independently associated with IMT. Blood pressure during nighttime may provide unique information for the assessment of cardiovascular risk attributable to BP burden in renal transplant patients.

Background End-stage renal disease (ESRD) is a high-risk condition and left ventricular hypertrophy (LVH) is the strongest risk factor in this population. Objective and methods Since the prognostic value of left atrial (LA) size in ESRD is still unknown, we performed a prospective cohort study aimed at testing the prognostic value of LA volume in a cohort of 249 ESRD patients. Results Both un-indexed and indexed LA volume (LAV) was significantly higher in dialysis patients than in healthy subjects (P< 0.001). On multivariate analysis only left ventricular mass index (LVMI), LV ejection fraction (LVEF), ratio of early (E) to late atrial (A) mitral Doppler peak flow velocity (E/A ratio) and antihypertensive treatment maintained an independent association with LAV. During the follow-up 113 patients died. LAV added significant prognostic power to a multivariate Cox model of all-cause death and the model based on height 2,7 provided the best data fit Notably, this index maintained an independent predictive value for death (P=0.03) also when LVMI and LVEF were jointly forced into the Cox's model. Neither crude nor body surface area (BSA)-adjusted LAV had an independent association with death when tested in the Cox model including LVMI and LVEF. Conclusions In patients with ESRD, LAV indexed for height 2,7 displays prognostic value beyond and above that provided by LV mass and function.

● Background: Cardiovascular (CV) calcifications constitute a strong risk marker, and recent studies in continuous ambulatory peritoneal dialysis patients have associated valvular calcifications to inflammation, mortality, and CV events. The prognostic value of cardiac valve calcifications and their relationship with left ventricular hypertrophy and background cardiovascular risk in hemodialysis patients is still unknown. Methods: The prognostic value of heart valve calcifications (detected by echocardiography) for all-cause and CV death was tested in a cohort of 202 hemodialysis (HD) patients. Results: Forty-seven patients had 1 or more calcified valves. Background CV complications were more frequent (P 0.001) and left ventricular hypertrophy was more severe (P < 0.001) in patients with calcified valves than in those without this alteration. During the follow-up period (44 23 months), 96 patients died, 66 patients (69%) of CV causes. Valve calcifications were significantly associated with all-cause (P 0.02) and CV mortality (P < 0.001). However, in statistical models adjusting for traditional and nontraditional CV risk factors and background CV complications and left ventricular mass index (LVMI), the relationship between calcified valves and incident all-cause and CV mortality was not significant. Conclusion: In HD patients, cardiac valve calcifications predict all-cause and CV mortality in unadjusted analyses, but these associations are not evident in models adjusting for background CV complications, LVMI, and other risk factors. Cardiac valve calcifications do not provide an independent contribution in the prediction of death and CV mortality. Am J Kidney Dis 43:479-484. © 2004 by the National Kidney Foundation, Inc.

BACKGROUND Pruritus has a negative impact on quality of life (QoL) in dialysis patients. The reversibility of this symptom after renal transplantation and its impact upon QoL has scarcely been studied in these patients. METHODS Pruritus was evaluated by the Visual Analogue Scale (VAS), the Visual Rating Scale (VRS), and the Numerical Rating Scale (NRS) in 133 unselected renal transplant patients, 62 healthy subjects, and 29 hemodialysis patients. QoL was assessed by KDQOL-SF™ 1.3. The reversibility of pruritus was studied by applying retrospectively the VRS. RESULTS The prevalence of pruritus by the VRS was 62% in hemodialysis patients, 32% in renal transplant patients, and 11% in healthy subjects (P

Altered vitamin D metabolism and low levels of the active form of this vitamin, 1,25-dihydroxy-vitamin D, is a hallmark of chronic kidney disease (CKD), but there is still no randomized controlled trial testing the effect of active forms of vitamin D on vascular function in patients with CKD. Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) is a double-blinded randomized controlled trial (ClinicalTrials.gov, NCT01680198) testing the effect of an active form of vitamin D, paricalcitol (2 μg/d×12 weeks) on endothelium-dependent and endothelium-independent vasodilatation in 88 patients with stage 3 to 4 CKD and parathormone >65 pg/mL (paricalcitol, n=44; placebo, n=44). Paricalcitol treatment reduced parathormone (−75 pg/mL; 95% confidence interval, –90 to –60), whereas parathormone showed a small rise during placebo (21 pg/mL; 95% confidence interval, 5–36). Blood pressure did not change in both study arms. Baseline flow-mediated dilation was identical in patients on paricalcitol (3.6±2.9%) and placebo (3.6±2.9%) groups. After 12 weeks of treatment, flow-mediated dilation rose in the paricalcitol but not in the placebo group, and the between-group difference in flow-mediated dilation changes (the primary end point, 1.8%; 95% confidence interval, 0.3–3.1%) was significant ( P =0.016), and the mean proportional change in flow-mediated dilation was 61% higher in paricalcitol-treated patients than in placebo-treated patients. Such an effect was abolished 2 weeks after stopping the treatment. No effect of paricalcitol on endothelium-independent vasodilatation was registered. Paricalcitol improves endothelium-dependent vasodilatation in patients with stage 3 to 4 CKD. Findings in this study support the hypothesis that vitamin D may exert favorable effects on the cardiovascular system in patients with CKD.

High estimated pulmonary artery systolic pressure (ePASP) is an established risk factor for mortality and cardiovascular (CV) events in the general population. High ePASP predicts mortality in dialysis patients but such a relationship has not been tested in patients with early CKD. Here we estimated the prevalence and the risk factors of high ePASP in 468 patients with CKD stage 2–4 and determined its prognostic power for a combined end point including cardiovascular death, acute heart failure, coronary artery disease, and cerebrovascular and peripheral artery events. High ePASP (35 mm Hg and above) was present in 108 CKD patients. In a multivariate logistic regression model adjusted for age, diabetes, hemoglobin, left atrial volume (LAV/BSA), left ventricular mass (LVM/BSA), and history of CV disease, age (OR, 1.06; 95% CI, 12 1.04–1.09) and LAV/BSA (OR, 1.05; 95% CI, 1.03–1.07) were the sole significant independent predictors of high ePASP. Elevated ePASP predicted a significantly high risk for the combined cardiovascular end point both in unadjusted analyses (HR, 2.70; 95% CI, 1.68–4.32) and in analyses adjusting for age, eGFR, hemoglobin, LAV/BSA, LVM/BSA, and the presence of diabetes and CV disease (HR, 1.75; 95% CI, 1.05–2.91). High ePASP is relatively common in patients with stage 2–4 CKD and predicts adverse CV outcomes independent of established classical and CKD-specific risk factors. Whether high ePASP is a modifiable risk factor in patients with CKD remains to be determined in randomized clinical trials.

Background Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. Study Design Cross-sectional study. Setting & Participants Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. Factor Serum uric acid level, rs734553 allele, and age. Outcome Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV). Results Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 ( P =8×10 -6 ). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (β=0.33; P =0.01), whereas no such relationship was found for internal diameter (β=−0.15; P =0.3) or PWV (β=0.10; P =0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age–internal diameter relationships in both crude and fully adjusted (β=0.40 [ P P =0.003], respectively) analyses. Limitations This is a hypothesis-generating study. Conclusions Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid–lowering interventions are needed to prove this hypothesis.

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.

Purpose Decline in physical function is commonly observed in patients with kidney failure on dialysis. Whether lung congestion, a predictable consequence of cardiomyopathy and fluid overload, may contribute to the low physical functioning of these patients has not been investigated. Methods In 51 peritoneal dialysis (PD) patients, we investigated the cross-sectional association between the physical functioning scale of the Kidney Disease Quality of Life Short Form (KDQOL-SF: Rand Corporation, Santa Monica, CA, USA) and an ultrasonographic measure of lung water recently validated in dialysis patients. The relationship between physical functioning and lung water was also analyzed taking into account the severity of dyspnea measured using the New York Heart Association (NYHA) classification currently used to grade the severity of heart failure. Results Evidence of moderate-to-severe lung congestion was evident in 20 patients, and this alteration was asymptomatic (that is, NHYHA class I) in 11 patients (55%). On univariate analysis, physical functioning was inversely associated with lung water ( r = –0.48, p < 0.001), age ( r = –0.44, p = 0.001), previous cardiovascular events ( r = –0.46, p = 0.001), and fibrinogen ( r = –0.34, p = 0.02). Physical functioning was directly associated with blood pressure, the strongest association being with diastolic blood pressure ( r = 0.38, p = 0.006). The NYHA class correlated inversely with physical functioning ( r = –0.51, p < 0.001). In multiple regression analysis, only lung water and fibrinogen remained independent correlates of physical functioning. The NYHA class failed to maintain its independent association. Conclusions This cross-sectional study supports the hypothesis that symptomatic and asymptomatic lung congestion is a relevant factor in the poor physical functioning of patients on PD.

Background Pro-inflammatory cytokines play a key role in bone remodeling. Inflammation is highly prevalent in CKD-5D patients, but the relationship between pro-inflammatory cytokines and fractures in CKD-5D patients is unclear. We studied the relationship between inflammatory cytokines and incident bone fractures in a cohort of CKD-5D patients. Methods In 100 CKD-5D patients (66 on HD, 34 on CAPD; males:63, females:37; mean age: 61 ± 15; median dialysis vintage: 43 months) belonging to a single renal Unit, we measured at enrolment bone metabolic parameters (intact PTH, bone and total alkaline phosphatase, calcium, phosphate) and inflammatory cytokines (TNF-α, IL-6, CRP). Patients were followed-up until the first non traumatic fracture. Results During follow-up (median: 74 months; range 0.5 -84.0) 18 patients experienced fractures. On categorical analysis these patients compared to those without fractures had significantly higher intact PTH (median: 319 pg/ml IQ range: 95–741 vs 135 pg/ml IQ: 53–346; p = 0.04) and TNF-α levels (median: 12 pg/ml IQ: 6.4-13.4 vs 7.8 pg/ml IQ: 4.6-11; p = 0.02). Both TNF-α (HR for 5 pg/ml increase in TNF-α: 1.62 95% CI: 1.05-2.50; p = 0.03) and intact PTH (HR for 100 pg/ml increase in PTH: 1.15 95% CI: 1.04-1.27; p = 0.005) predicted bone fractures on univariate Cox’s regression analysis. In restricted (bivariate) models adjusting for previous fractures, age, sex and other risk factors both PTH and TNF-α maintained an independent association with incident fractures. Conclusions In our bivariate analyses TNF-α was significantly associated with incident fractures. Analyses in larger cohorts and with adequate number of events are needed to firmly establish the TNF α -fracture link emerged in the present study.

The soluble receptor of advanced glycation end product (sRAGE) prevents vascular damage in experimental animal models, and observational studies in the general population support the hypothesis that sRAGE may exert a protective role on the vasculature. To test this in patients with chronic kidney disease, we determined the relationship between plasma sRAGE and carotid atherosclerosis in 142 patients with an average estimated glomerular filtration rate (eGFR) of 32 ml/min per 1.73 m 2 and 49 healthy control individuals matched for age and gender. Plasma sRAGE was significantly higher in patients with chronic kidney disease than in the control cohort. In an aggregate analysis of the patients and controls, there was a significant inverse relationship between eGFR and sRAGE, with a breakpoint in the regression line at 64 ml/min per 1.73 m 2 . Significant inverse relationships were found for sRAGE to intima–media thickness and plaque number in the patients with chronic kidney disease, but no such associations were found in the controls. On covariance analysis, the slopes of intima–media thickness and plaque number to sRAGE were significantly steeper in patients with chronic kidney disease than in the controls. Furthermore, a significant interaction was found between sRAGE and smoking for predicting atherosclerotic plaques in patients with chronic kidney disease. The pathophysiological significance of this correlation will have to await more mechanistic studies.

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 O2 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.

Left atrial volume (LAV), as indexed by height(2.7), has recently emerged as an useful echocardiographic measurement to refine the estimate of cardiovascular (CV) risk in ESRD. Whether progression or regression in LAV has prognostic value in patients with ESRD is still unknown. The prognostic value for CV events of changes in LAV was tested in a cohort of 191 dialysis patients. Echocardiography was performed twice, 17 +/- 2 mo apart. Changes in LAV that occurred between the second and the first echocardiographic studies were used to predict CV events during the ensuing 27 +/- 13 mo. During the follow-up, there was a significant increase in LAV (from 10.5 +/- 5.0 to 11.6 +/- 5.6 ml/m(2.7); P < 0.001). After the second echocardiographic study, 76 patients died (52 [68%] of CV causes) and 33 had nonfatal CV events. The independent association between changes in LAV and CV events was analyzed in a multiple Cox regression model taking into account a series of potential confounders, including baseline LAV and left ventricular mass and geometry. In these models, a 1-ml/m(2.7) per yr increase in LAV was associated with a 12% increase in the relative risk for fatal and nonfatal CV events (P < 0.001). Changes in LAV predict incident CV events in dialysis patients independent of the corresponding baseline measurement and of left ventricular mass. Monitoring LA size by echocardiography is useful for monitoring CV risk in patients with ESRD.