Biagio Di Iorio

Hemofiltration and Hemodiafiltration Reduce Intradialytic Hypotension in ESRD

Symptomatic intradialytic hypotension is a common complication of hemodialysis (HD). The application of convective therapies to the outpatient setting may improve outcomes, including intradialytic hypotension. In this multicenter, open-label, randomized controlled study, we randomly assigned 146 long-term dialysis patients to HD (n = 70), online predilution hemofiltration (HF; n = 36), or online predilution hemodiafiltration (HDF; n = 40). The primary end point was the frequency of intradialytic symptomatic hypotension (ISH). Compared with the run-in period, the frequency of sessions with ISH during the evaluation period increased for HD (7.1 to 7.9%) and decreased for both HF (9.8 to 8.0%) and HDF (10.6 to 5.2%) (P < 0.001). Mean predialysis systolic BP increased by 4.2 mmHg among those who were assigned to HDF compared with decreases of 0.6 and 1.8 mmHg among those who were assigned to HD and HF, respectively (P = 0.038). Multivariate logistic regression demonstrated significant risk reductions in ISH for both HF (odds ratio 0.69; 95% confidence interval 0.51 to 0.92) and HDF (odds ratio 0.46, 95% confidence interval 0.33 to 0.63). There was a trend toward higher dropout for those who were assigned to HF (P = 0.107). In conclusion, compared with conventional HD, convective therapies (HDF and HF) reduce ISH in long-term dialysis patients.

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.

Early Changes in Bioelectrical Estimates of Body Composition in Chronic Kidney Disease

The aim of this study was to detect the potential occurrence of early abnormalities of body composition in patients with chronic kidney disease (CKD) at first referral to an outpatient nephrology clinic. Eighty-four patients with CKD (49 men and 35 women) were compared with 604 healthy control subjects (298 men and 306 women). Anthropometry and bioelectrical impedance analysis (BIA) were performed in all participants, whereas renal function, laboratory tests for nutritional status, and nutrient intake were assessed in the CKD group only. Creatinine clearance was 27.8 +/- 13.8 and 27.4 +/- 13.0 ml/min per 1.73 m(2) in male and female patients with CKD, respectively. No patient showed peripheral edema; frank malnutrition, defined by presence of serum albumin <3.5 g/dl plus body mass index <20 kg/m(2); or protein intake <0.6 g/kg per d. At the BIA, patients with CKD showed lower resistance (R) and abnormal mean impedance vectors for the bivariate normal distribution of R/height and reactance/height. Phase angle also was reduced (-22%), especially in patients with diabetes. When BIA-derived data were considered, total body water was slightly higher (+4.3% in men; +3.5% in women) and body cell mass was lower (-6.7% in men; -7.7% in women) in patients with CKD. No difference in either BIA parameters or nutritional indexes was observed among various CKD stages. Despite the absence of overt malnutrition, patients with CKD exhibit altered BIA variables from the early phases of renal disease. These alterations are related to the renal dysfunction, are more marked in the presence of diabetes, and mainly indicate the presence of overhydration in the absence of edema. Therefore, BIA represents an attractive clinical tool to detect impairment of body composition from the early stages of CKD.

Prognosis of CKD Patients Receiving Outpatient Nephrology Care in Italy

BACKGROUND AND OBJECTIVES Prognosis in nondialysis chronic kidney disease (CKD) patients under regular nephrology care is rarely investigated. Design, setting, participants, & measurements We prospectively followed from 2003 to death or June 2010 a cohort of 1248 patients with CKD stages 3 to 5 and previous nephrology care ≥1 year in 25 Italian outpatient nephrology clinics. Cumulative incidence of ESRD or death before ESRD were estimated using the competing-risk approach. RESULTS Estimated rates (per 100 patient-years) of ESRD and death 8.3 (95% confidence interval [CI], 7.4 to 9.2) and 5.9 (95% CI 5.2 to 6.6), respectively. Risk of ESRD and death increased progressively from stages 3 to 5. ESRD was more frequent than death in stage 4 and 5 CKD, whereas the opposite was true in stage 3 CKD. Younger age, lower body mass index, proteinuria, and high phosphate predicted ESRD, whereas older age, diabetes, previous cardiovascular disease, ESRD, proteinuria, high uric acid, and anemia predicted death (P < 0.05 for all). Among modifiable risk factors, proteinuria accounted for the greatest contribution to the model fit for either outcome. CONCLUSIONS In patients receiving continuity of care in Italian nephrology clinics, ESRD was a more frequent outcome than death in stage 4 and 5 CKD, but the opposite was true in stage 3. Outcomes were predicted by modifiable risk factors specific to CKD. Proteinuria used in conjunction with estimated GFR refined risk stratification. These findings provide information, specific to CKD patients under regular outpatient nephrology care, for risk stratification that complement recent observations in the general population.

Population based data on urinary excretion of calcium, magnesium, oxatate, phosphate and uric acid in children from Cimitile (southern Italy)

Population based data on 24-h urinary excretion of calcium, oxalate, magnesium, phosphate, uric acid and creatinine were collected from 220 children (aged 3–16 years) living in Cimitile, Campania, southern Italy. Mean excretion rates for 7 days were correlated with age, body weight, body mass index and height. The prevalence of hypercalciuria (>4 mg/kg body weight) and of hyperoxaluria (>60 mg/day) were 9.1% and 1.8%, respectively. The same 20 children were also identified as hypercalciuric when a calcium/creatinine ratio of greater than 0.15 was considered. No significant differences between boys and girls were found in the urinary excretion of the five constituents implicated in urolithiasis. The study data provide additional childhood reference values for urinary excretion of compounds related to stone formation.

Acute Effects of Very-Low-Protein Diet on FGF23 Levels: A Randomized Study

BACKGROUND AND OBJECTIVES High levels of fibroblast growth factor 23 are associated with mortality, CKD progression, and calcification in CKD patients. The aim of this pilot study is to assess whether a very-low-protein diet (0.3 g/kg per day) with a consequent low intake of phosphorus would reduce fibroblast growth factor 23 compared with a low-protein diet (0.6 g/kg per day) in CKD patients not yet on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A prospective, randomized, controlled crossover study was performed in which 32 patients were randomized into two groups. Group A (16 patients) received a very-low-protein diet (0.3 g/kg body wt per day) supplemented with ketoanalogues during the first week and a low-protein diet during the second week, and group B (16 patients) received a low-protein diet during the first week and a very-low-protein diet during the second week. Fibroblast growth factor 23, seric, and urinary phosphate levels were measured at baseline and the end of each study period. RESULTS After only 1 week of the very-low-protein diet, reductions in fibroblast growth factor 23 levels (33.5%), serum phosphate (12%), and urinary phosphate (34%) with the very-low-protein diet compared with the low-protein diet were observed. Serum and urinary phosphate levels and protein intake were significant determinants of fibroblast growth factor 23 (95% confidence interval=1.04-1.19, 1.12-1.37, and 1.51-2.23, respectively). CONCLUSIONS A very-low-protein diet supplemented with ketoanalogues reduced fibroblast growth factor 23 levels in CKD patients not yet on dialysis.

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.

Influence of haemodialysis on variability of pulse wave velocity in chronic haemodialysis patients

BACKGROUND The major determinants of pulse wave velocity (PWV) in haemodialysis (HD) patients are not fully known. We studied chronic HD patients to assess the effect of cyclic variations in both hydration status and blood pressure on PWV. METHODS Twenty patients were examined along three consecutive HD sessions and interdialysis periods during a week-long period. Twenty healthy subjects and 20 chronic kidney disease (CKD) patients (stage 5) were evaluated as controls. RESULTS In contrast to controls, HD patients showed cyclic changes in PWV. Specifically, PWV values in HD patients were significantly higher prior to the first HD session of the week compared with values measured prior to the other two HD sessions during the week. In addition, PWV showed significant reductions during each dialysis session (15.6 +/- 5.2 to 9.3 +/- 2.3, 13.4 +/- 4.0 to 8.7 +/- 2.4, and 12.4 +/- 2.6 to 9.2 +/- 2.2 m/sec, before and after the first, second and third weekly dialysis sessions, respectively). Nevertheless, the weighted weekly values of PWV in HD patients (10.8 +/- 5.7 m/sec) were similar to those in CKD patients (9.9 +/- 4.2 m/sec). The HD ultrafiltration rate (UF) was significantly correlated with intradialysis PWV changes (r = 0.465; P < 0.001) and with after dialysis PWV values (r = -0.654; P < 0.0001). Blood pressure changes during dialysis were weakly correlated with post-dialysis PWV (r = -0.267; P < 0.05), but not with PWV changes during dialysis. CONCLUSIONS In chronic HD patients, single PWV values varied widely during 1 week of HD sessions, whereas the weighted level showed only a slight increase. The major determinant of changes in PWV during HD appears to be the alterations in hydration status; the most representative time point for PWV measurements during HD corresponds to the interdialysis days.

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.