Rocco Tripepi

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.

Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

Detection of Pulmonary Congestion by Chest Ultrasound in Dialysis Patients

OBJECTIVES This study sought to investigate clinical and echocardiographic correlates of the lung comets score. BACKGROUND Early detection of pulmonary congestion is a fundamental goal for the prevention of congestive heart failure in high-risk patients. METHODS We 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. RESULTS Chest 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. CONCLUSIONS Pulmonary 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.

Pulmonary Congestion Predicts Cardiac Events and Mortality in ESRD

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<0.015). In summary, lung ultrasound can detect asymptomatic pulmonary congestion in hemodialysis patients, and the resulting BL-US score is a strong, independent predictor of death and cardiac events in this population.

ACE Inhibition Is Renoprotective among Obese Patients with Proteinuria

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.

Left atrial volume in end-stage renal disease: a prospective cohort study.

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 height2.7 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 Coxs 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 height2.7 displays prognostic value beyond and above that provided by LV mass and function.

Paricalcitol and Endothelial Function in Chronic Kidney Disease Trial

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 &mgr;g/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.

Left Atrial Volume Monitoring and Cardiovascular Risk in Patients with End-Stage Renal Disease: A Prospective Cohort Study

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.

Circulating soluble receptor of advanced glycation end product inversely correlates with atherosclerosis in patients with chronic kidney disease

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.

Chest ultrasound and hidden lung congestion in peritoneal dialysis patients

BACKGROUND Chest ultrasound (US) is a non-invasive well-validated 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 = -0.40 P = 0.002). Oedema did not associate with LW on univariate and multivariate analysis. NYHA class was slightly associated with LW (r = 0.21 P = 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 = 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.