Antonio Bellasi

Mortality in Kidney Disease Patients Treated with Phosphate Binders: A Randomized Study

BACKGROUND AND OBJECTIVES Dietary phosphorous overload and excessive calcium intake from calcium-containing phosphate binders promote coronary artery calcification (CAC) that may contribute to high mortality of dialysis patients. CAC has been found in patients in early stages of nondialysis-dependent CKD. In this population, no study has evaluated the potential role of phosphorus binders on mortality. This study aimed to evaluate all-cause mortality as the primary end point in nondialysis-dependent CKD patients randomized to different phosphate binders; secondary end points were dialysis inception and the composite end point of all-cause mortality and dialysis inception. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This is a randomized, multicenter, nonblinded pilot study. Consecutive outpatients (n=212; stage 3-4 CKD) were randomized to either sevelamer (n=107) or calcium carbonate (n=105). Phosphorus concentration was maintained between 2.7 and 4.6 mg/dl for patients with stage 3-4 CKD and between 3.5 and 5.5 mg/dl for patients with stage 5 CKD. The CAC score was assessed by computed tomography at study entry and after 6, 12, 18, and 24 months. All-cause mortality, dialysis inception, and the composite end point were recorded for up to 36 months. RESULTS In patients randomized to sevelamer, all-cause mortality and the composite end point were lower; a nonsignificant trend was noted for dialysis inception. CONCLUSIONS Sevelamer provided benefits in all-cause mortality and in the composite end point of death or dialysis inception but not advantages in dialysis inception. Larger studies are needed to confirm these results.

Sevelamer Versus Calcium Carbonate in Incident Hemodialysis Patients: Results of an Open-Label 24-Month Randomized Clinical Trial

BACKGROUND Whether the use of sevelamer rather than a calcium-containing phosphate binder improves cardiovascular (CV) survival in patients receiving dialysis remains to be elucidated. STUDY DESIGN Open-label randomized controlled trial with parallel groups. SETTINGS & PARTICIPANTS 466 incident hemodialysis patients recruited from 18 centers in Italy. INTERVENTION Study participants were randomly assigned in a 1:1 fashion to receive either sevelamer or a calcium-containing phosphate binder (although not required by the protocol, all patients in this group received calcium carbonate) for 24 months. OUTCOMES All individuals were followed up until completion of 36 months of follow-up or censoring. CV death due to cardiac arrhythmias was regarded as the primary end point. MEASUREMENTS Blind event adjudication. RESULTS At baseline, patients allocated to sevelamer had higher serum phosphorus (mean, 5.6 ± 1.7 [SD] vs 4.8 ± 1.4 mg/dL) and C-reactive protein levels (mean, 8.8 ± 13.4 vs 5.9 ± 6.8 mg/dL) and lower coronary artery calcification scores (median, 19 [IQR, 0-30] vs 30 [IQR, 7-180]). At study completion, serum phosphate levels were lower in the sevelamer arm (median dosages, 4,800 and 2,000 mg/d for sevelamer and calcium carbonate, respectively). After a mean follow-up of 28 ± 10 months, 128 deaths were recorded (29 and 88 due to cardiac arrhythmias and all-cause CV death). Sevelamer-treated patients experienced lower CV mortality due to cardiac arrhythmias compared with patients treated with calcium carbonate (HR, 0.06; 95% CI, 0.01-0.25; P < 0.001). Similar results were noted for all-cause CV mortality and all-cause mortality, but not for non-CV mortality. Adjustments for potential confounders did not affect results. LIMITATIONS Open-label design, higher baseline coronary artery calcification burden in calcium carbonate-treated patients, different mineral metabolism control in sevelamer-treated patients, overall lower than expected mortality. CONCLUSIONS These results show that sevelamer compared to a calcium-containing phosphate binder improves survival in a cohort of incident hemodialysis patients. However, the better outcomes in the sevelamer group may be due to better phosphate control rather than reduction in calcium load.

Pulse Wave Velocity Is Inversely Related to Vertebral Bone Density in Hemodialysis Patients

Abnormalities of bone mineral metabolism in patients with stage-5 chronic kidney disease may contribute to the high incidence of cardiovascular disease. Noninvasive imaging methods may help predict the simultaneous presence of vasculopathy and bone disease. Accordingly, we measured pulse wave velocity and bone mineral density (BMD), and T-scores (number of SDs below the BMD of a younger reference group) of the spine by both dual energy x-ray absorptiometry and quantitative computed tomography (QCT) in 110 maintenance hemodialysis patients. Older age, white race, diabetes mellitus, lower diastolic blood pressure, and lower albumin levels were associated with lower QCT-assessed T-scores (each P<0.05). After age and multivariable adjustment, pulse wave velocity (PWV) increased as QCT BMD decreased (the prevalence of PWV ≥9 m/s was 32.4%, 61.8%, and 76.5% for participants in the highest to the lowest tertile of QCT-assessed BMD; P<0.001). In contrast, there was no relationship between spine dual energy x-ray absorptiometry-BMD and PWV. In unadjusted models, thoracic spine QCT-assessed T-scores correlated significantly, albeit weakly, with aorta calcification (r=0.22; P=0.01) but not with coronary calcification. The odds ratio of PWV ≥9 m/s for patients taking vitamin D3 or its analogs was 0.51 (95% CI: 0.19 to 1.39). In conclusion, low spine BMD is associated with increased PWV in stage-5 chronic kidney disease, supporting the notion of a close interaction of vascular and bone disease in this patient group. QCT and not dual energy x-ray absorptiometry should be used to assess spine BMD in dialysis patients.

Investigation of Gender Heterogeneity in the Associations of Serum Phosphorus With Incident Coronary Artery Disease and All-Cause Mortality

Serum phosphorus levels in the general population have been reported to be associated with cardiovascular morbidity and mortality and increased carotid intima-media thickness. The authors examined gender heterogeneity in the association of phosphorus with all-cause mortality and incident coronary artery disease using data from the Atherosclerosis Risk in Communities Study (1987-2001). Baseline phosphorus levels were higher in women and were associated differently among men and women with traditional atherosclerosis risk factors such as age, low density lipoprotein cholesterol, diabetes mellitus, and hypertension. In a multivariable-adjusted model, men in the highest quintile of serum phosphorus level (>3.8 mg/dL) had an increased mortality rate (hazard ratio = 1.45, 95% confidence interval: 1.12, 1.88), while women did not (hazard ratio = 1.18, 95% confidence interval: 0.89, 1.57). The multivariable likelihood ratio test of effect modification by gender was significant at alpha = 0.1 (P = 0.085) for all-cause mortality. Although the associations of phosphorus with coronary artery disease also appeared to differ substantially by gender, the multivariable test for effect modification suggested that the difference was consistent with random variation (P = 0.195). These results suggest the need for further investigation into gender differences in the contribution of mineral metabolism to cardiovascular disease in the general population.

Phosphate attenuates the anti-proteinuric effect of very low-protein diet in CKD patients

BACKGROUND High phosphate levels attenuate nephroprotection through angiotensin-converting enzyme inhibition in patients with proteinuric chronic kidney disease (CKD). Whether this phenomenon holds true for other nephroprotective interventions like very-low-protein diet (VLPD) is unknown. METHODS We tested the hypothesis that phosphate interferes with the anti-proteinuric response to VLPD in a non-randomized, sequential study in 99 proteinuric CKD patients who sequentially underwent low-protein diet (LPD; 0.6 g/kg) and VLPD (0.3 g/kg) supplemented with keto-analogues, each for periods longer than 1 year. RESULTS Serum phosphate significantly reduced during VLPD (3.2 ± 0.6 mg/dL) when compared with LPD (3.7 ± 0.6 mg/dL, P < 0.001), an effect paralleled by a substantial decline in phosphate excretion (LPD, 649 ± 180 mg/day; VLPD, 462 ± 97 mg/day; P < 0.001). The median proteinuria during LPD was 1910 mg/24 h (interquartile range: 1445-2376 mg/24 h) and reduced to 987 mg/24 h (656-1300 mg/24 h) during VLPD (P < 0.001). No significant change in the estimated glomerular filtration rate (eGFR) was observed during the two diet periods. In linear mixed models including the diagnosis of renal disease, eGFR, 24-h urine sodium and urea and other potential confounders, there was a strong interaction between serum phosphate (P = 0.04) and phosphaturia (P < 0.001) with the anti-proteinuric response to VLPD. Accordingly, 24-h proteinuria reduced modestly in patients who maintained relatively higher serum phosphate levels or relatively higher phosphaturia to be maximal in those who achieved the lowest level of serum and urine phosphate. CONCLUSION Phosphate is an important modifier of the anti-proteinuric response to VLPD. Reducing phosphate burden may decrease proteinuria and slow the progression of renal disease in CKD patients, an issue that remains to be tested in specific clinical trials.

All-cause Mortality in Hemodialysis Patients with Heart Valve Calcification

BACKGROUND AND OBJECTIVES Calcification of the mitral and aortic valves is common in dialysis patients (CKD-5D). However, the prognostic significance of valvular calcification (VC) in CKD is not well established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 144 adult CKD-5D patients underwent bidimensional echocardiography for qualitative assessment of VC and cardiac computed tomography (CT) for quantification of coronary artery calcium (CAC) and VC. The patients were followed for a median of 5.6 years for mortality from all causes. RESULTS Overall, 38.2% of patients had mitral VC and 44.4% had aortic VC on echocardiography. Patients with VC were older and less likely to be African American; all other characteristics were similar between groups. The mortality rate of patients with calcification of either valve was higher than for patients without VC. After adjustment for age, gender, race, diabetes mellitus, and history of atherosclerotic disease, only mitral VC remained independently associated with all-cause mortality (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.03 to 2.91). Patients with calcification of both valves had a two-fold increased risk of death during follow-up compared with patients without VC (HR, 2.16; 95% CI, 1.14 to 4.08). A combined CT score of VC and CAC was strongly associated with all-cause mortality during follow-up (HR for highest versus lowest tertile, 2.21; 95% CI, 1.08 to 4.54). CONCLUSIONS VC is associated with a significantly increased risk for all-cause mortality in CKD-5D patients. These findings support the use of echocardiography for risk stratification in CKD-5D as recently suggested in the Kidney Disease Improving Global Outcomes guidelines.

Phosphate binders: New products and challenges

Optimal phosphate control in dialysis patients is extremely challenging. A growing awareness of the deleterious effect of mineral metabolism imbalances together with the lack of a satisfactory explanation for the exaggerated mortality rate in patients undergoing renal replacement therapy has led to a renewed effort to refine our approach to hyperphosphatemia. However, despite the remarkable improvements in dialysis techniques, phosphate control has not substantially improved. Achieving normo‐phosphatemia presents a multitude of practical and scientific challenges related to the optimal target level, cardiovascular health, and drug toxicities. It is the aim of the present review to summarize briefly the controversies associated with currently available phosphate binders, a cornerstone in the current management of hyperphosphatemia.

Combined Impact of Age and Estimated Glomerular Filtration Rate on In-Hospital Mortality After Percutaneous Coronary Intervention for Acute Myocardial Infarction (from the American College of Cardiology National Cardiovascular Data Registry)

Age and chronic kidney disease are major risk factors for poor cardiovascular outcome; however, renal function is often estimated on the basis of serum creatinine levels, and advanced renal impairment may be hidden behind near normal creatinine levels. We assessed the impact of estimated glomerular filtration rate (GFR) on in-hospital mortality in young (<65 years old), old (65 to 84 years old), and very old (> or = 85 years old) patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction. The adjusted risk of death was calculated in 169,826 patients from the American College of Cardiology National Cardiovascular Data Registry undergoing primary PCI for acute myocardial infarction. Younger patients had fewer co-morbidities, higher estimated GFR, less frequent multivessel disease, and lower unadjusted mortality rates than older patients (p <0.0001 for all comparisons). However, the adjusted risk of in-hospital mortality for patients with severe renal insufficiency (estimated GFR <30 ml/min/1.73 m(2)) compared with those with normal renal function (estimated GFR > or = 60 ml/min/1.73 m(2)) was higher in young patients (adjusted odds ratio = 7.58, 95% confidence interval 6.18 to 9.29) than old (adjusted odds ratio = 4.75, 95% confidence interval 4.14 to 5.45) and very old patients (adjusted odds ratio = 3.50, confidence interval 2.50 to 4.89). In conclusion, severe renal insufficiency is associated with a greater risk of in-hospital mortality in young than old and very old patients after primary PCI. Risk stratification for patients with acute myocardial infarction should incorporate an assessment of renal function with estimated GFR values rather than absolute serum creatinine levels as done in the currently utilized risk scoring algorithms.

Interaction of vascular and bone disease in patients with normal renal function and patients undergoing dialysis

The cardiovascular risk of patients undergoing dialysis is 20–30 times higher than that of individuals of the same age, without abnormal renal function, from the general population. Observational studies of patients with normal and abnormal renal function have shown that there is an association between bone disease, vascular calcification and cardiovascular outcome and that worsening of these conditions happens in parallel. Basic science studies are elucidating several mechanisms that could explain the interaction between bone disease, vascular calcification and cardiovascular outcome. For example, the expression of osteoprotegerin—a protein that regulates bone resorption by binding receptor activator of nuclear factor κB (RANK) ligand (RANKL), thus preventing interaction with the receptor RANK and the stimulation of osteoclast maturation—is regulated by several cytokines. Additionally, osteoprotegerin seems involved in the genesis of atherosclerosis. Imbalances of bone mineral metabolism, bone matrix secretion and vascular smooth-muscle-cell apoptosis seem involved in the ossification of the arterial wall in chronic kidney disease, and could explain some of the complex interactions between bone and vascular disease in renal failure. In this article we present a brief review of some of the basic mechanisms involved in vascular calcification and the clinical evidence of an association of vascular and bone disease.

Blood pressure variability and outcomes in chronic kidney disease

BACKGROUND We investigated the effects of visit-to-visit systolic blood pressure variability (SBPV) on both mortality and dialysis inception in a cohort of chronic kidney disease (CKD) patients not requiring dialysis therapy. Furthermore, we also explored the carry-over effect of visit-to-visit SBPV on mortality after dialysis initiation. METHODS We conducted a longitudinal retrospective, observational, multi-centre study in three tertiary care nephrology outpatient clinics. All the ambulatory CKD patients admitted to the outpatient clinics from 1 January 2004 to 31 December 2005 were screened for study eligibility. We selected all consecutive patients older than 18 years of age with a mean estimated glomerular filtration rate of <60 mL/min/m(2), free from cardiovascular disease. SBPV was defined as the ratio of the SD to the mean SBP of five values recorded during a run-in phase of 4-5 months. Data on dialysis inception and mortality were recorded through 31 December 2010. RESULTS Overall, we selected a cohort of 374 elderly (median age: 79 years) subjects. A total of 232 (62%) and 103 (29%) patients were male and had diabetes, respectively. A significant association between SBPV and the risk of death but not of CKD progression to dialysis was noted at univariate and after multivariable adjustments (hazard ratio for all-cause mortality per 1% increase in SBPV: 1.05; 95% confidence interval: 1.02-1.09; P = 0.001). Notably, no lethal event was recorded after dialysis initiation. CONCLUSIONS Current findings suggest that SBPV may be of use for risk stratification in CKD patients.